StemCell Therapy

KEYNOTE-564 is the First Phase 3 Study to Show Positive Results for Adjuvant Immunotherapy in RCC

First-Time Disease-Free Survival Data to be Presented During Plenary Session at the 2021 ASCO Annual Meeting

Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced first-time results from the pivotal Phase 3 KEYNOTE-564 trial evaluating KEYTRUDA, Mercks anti-PD-1 therapy, for the potential adjuvant treatment of patients with renal cell carcinoma (RCC) at intermediate-high or high risk of recurrence following nephrectomy (surgical removal of a kidney) or following nephrectomy and resection of metastatic lesions. After a median follow-up of 24.1 months (14.9-41.5), KEYTRUDA demonstrated a statistically significant and clinically meaningful reduction in the risk of disease recurrence or death by 32% compared to placebo (HR=0.68 [95% CI, 0.530.87]; p=0.0010). Additionally, a favorable trend in overall survival (OS) was observed with a 46% reduction in the risk of death with KEYTRUDA as compared to placebo (HR=0.54 [95% CI, 0.300.96]; p=0.0164). As previously announced , the trial will continue to evaluate OS, a key secondary endpoint.

With the results of KEYNOTE-564, pembrolizumab is the first immunotherapy to show a clinical benefit in the adjuvant setting in kidney cancer, said Dr. Toni K. Choueiri, director of the Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School. It took several decades to achieve this milestone. We hope to build on this important research and provide new treatment options to kidney cancer patients.

As nearly half of early-stage renal cell carcinoma patients experience disease recurrence after surgery, we are particularly encouraged to see that KEYTRUDA demonstrated a statistically significant reduction in the risk of recurrence or death by 32% compared with placebo in this study, said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. These data highlight the opportunity for KEYTRUDA to become a new standard of care for patients with early-stage renal cell carcinoma and we look forward to working closely with regulatory authorities to make this treatment option available to patients.

The late-breaking results will be presented in the Plenary session of the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract #LBA5) on Sunday, June 6, 2021. As announced , data spanning more than 20 types of cancer will be presented from Mercks oncology research program at ASCO. A compendium of presentations and posters of Merck-led studies will be posted by Merck on Friday, June 4 at 9 a.m. ET. Follow Merck on Twitter via @Merck and keep up to date with ASCO news and updates by using the hashtag #ASCO21.

Merck is continuing to study KEYTRUDA, in combination or as monotherapy, as well as other investigational products across multiple settings and stages of RCC including adjuvant and advanced or metastatic disease through our broad clinical development program, which includes over 20 clinical studies and more than 4,000 patients.

KEYTRUDA is currently approved in the U.S., Europe and Japan in combination with axitinib for the first-line treatment of patients with advanced RCC.

Study Design and Additional Data from KEYNOTE-564

KEYNOTE-564 is a randomized, double-blind, Phase 3 trial ( ClinicalTrials.gov , NCT03142334 ) evaluating KEYTRUDA monotherapy versus placebo for the adjuvant treatment of patients with RCC who have undergone nephrectomy and who have intermediate-high risk, high risk, or M1 no evidence of disease (M1 NED) RCC with clear cell component. The study enrolled 994 patients who were randomized to receive either KEYTRUDA (200 mg intravenously [IV] on Day 1 of each three-week cycle for up to 17 cycles) or placebo (saline solution IV on Day 1 of each three-week cycle for up to 17 cycles). The primary endpoint is disease-free survival (DFS), and the secondary endpoints include OS and safety.

As of data cutoff (Dec. 14, 2020), the median study follow-up was 24.1 months. Findings showed KEYTRUDA demonstrated a statistically significant improvement in DFS in patients with RCC following nephrectomy or following nephrectomy and resection of metastatic lesions compared with placebo (HR=0.68 [95% CI, 0.530.87]; p=0.0010). Additionally, the two-year estimated DFS rate was 77.3% with KEYTRUDA versus 68.1% with placebo. Overall, the DFS benefit was consistent across subgroups. Median DFS was not achieved in either treatment arm based on event accrual.

Grade 3-5 treatment-related adverse events (TRAEs) occurred in 18.9% of patients in the KEYTRUDA arm and 1.2% of patients in the placebo arm. TRAEs resulting in discontinuation of any treatment occurred in 17.6% of patients in the KEYTRUDA arm and 0.6% of patients in the placebo arm. The most common TRAEs of any grade (occurring in 5% of patients) were fatigue (20.3%), pruritus (18.6%) and hypothyroidism (17.6%) in the KEYTRUDA arm and fatigue (14.3%), pruritus (11.5%) and diarrhea (10.3%) in the placebo arm. The most common immune-mediated adverse events of any grade (occurring in 3% of patients) were hypothyroidism (21.1%) and hyperthyroidism (11.9%) in the KEYTRUDA arm and hypothyroidism (3.6%) in the placebo arm. No treatment-related deaths occurred.

About Renal Cell Carcinoma (RCC)

Renal cell carcinoma (RCC) is by far the most common type of kidney cancer; about nine out of 10 kidney cancers are RCCs. Renal cell carcinoma is about twice as common in men as in women. Most cases of RCC are discovered incidentally during imaging tests for other abdominal diseases. Worldwide, it is estimated there were nearly 431,300 new cases of kidney cancer diagnosed and almost 179,400 deaths from the disease in 2020. In the U.S. alone, it is estimated there will be nearly 76,100 new cases of kidney cancer diagnosed and almost 13,800 deaths from the disease in 2021.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-PD-1 therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,400 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patients likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is stage III where patients are not candidates for surgical resection or definitive chemoradiation, or metastatic.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS) 1] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 (CPS 10), as determined by an FDA-approved test, or in patients who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status. This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR)

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the first-line treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Carcinoma

KEYTRUDA, in combination with trastuzumab, and fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

KEYTRUDA, in combination with axitinib, is indicated for the first-line treatment of patients with advanced renal cell carcinoma (RCC).

Tumor Mutational Burden-High

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test. This indication is approved under accelerated approval based on progression-free survival. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% of these patients interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen, which was at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of Cardiac/Vascular: Myocarditis, pericarditis, vasculitis; Nervous System: Meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: Uveitis, iritis and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; Hematologic/Immune: Hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic HSCT before or after antiPD-1/PD-L1 treatment. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute and chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between antiPD-1/PD-L1 treatment and allogeneic HSCT. Follow patients closely for evidence of these complications and intervene promptly. Consider the benefit vs risks of using antiPD-1/PD-L1 treatments prior to or after an allogeneic HSCT.

Increased Mortality in Patients With Multiple Myeloma

In trials in patients with multiple myeloma, the addition of KEYTRUDA to a thalidomide analogue plus dexamethasone resulted in increased mortality. Treatment of these patients with an antiPD-1/PD-L1 treatment in this combination is not recommended outside of controlled trials.

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Merck's KEYTRUDA Given After Surgery Reduced the Risk of Disease Recurrence or Death by 32% Versus Placebo as Adjuvant Therapy in Patients With Renal...

Scientists in the Perelman School of Medicine have uncovered the molecular causes of a congenital form of dilated cardiomyopathy (DCM), an often-fatal heart disorder.

This inherited form of DCMwhich affects at least several thousand people in the United States at any one time and often causes sudden death or progressive heart failureis one of multiple congenital disorders known to be caused by inherited mutations in a gene called LMNA. The LMNA gene is active in most cell types, and researchers have not understood why LMNA mutations affect particular organs such as the heart while sparing most other organs and tissues.

In a study published in Cell Stem Cell, the Penn Medicine scientists used stem cell techniques to grow human heart muscle cells containing DCM-causing mutations in LMNA. They found that these mutations severely disrupt the structural organization of DNA in the nucleus of heart muscle cellsbut not two other cell types studiedleading to the abnormal activation of non-heart muscle genes.

Were now beginning to understand why patients with LMNA mutations have tissue-restricted disorders such as DCM even though the gene is expressed in most cell types, says study co-senior author Rajan Jain, an assistant professor of cardiovascular medicine and cell and developmental biology at the Perelman School of Medicine.

This story is by Sophie Kluthe. Read more at Penn Medicine News.

Read the rest here:
Stem cell study illuminates the cause of an inherited heart disorder | Penn Today - Penn Today

Misfolded proteins (orange) in the endoplasmic reticulum may play a role in Wolfram syndromes many symptoms.

By Mitch LeslieFeb. 11, 2021 , 2:00 PM

Maureen Marshall-Doss says the first sign that her vision was deteriorating came when she misidentified the color of a dress. At a backyard get-together about 20 years ago, the Indianapolis resident pointed out an attractive yellow dress another woman was wearing. You see that as yellow? Shes wearing a pink dress, Marshall-Doss recalls her husband responding.

Today, Marshall-Doss is virtually blind. With help from custom made eyeglasses that magnify objects 500 times, I can see shapes, she says. But she can no longer drive and had to quit the job she loved as a school librarian. Along with her dimming vision, she has type 1 diabetes and has lost her sense of taste and smell.

Marshall-Doss is one of 15,000 to 30,000 people around the world with Wolfram syndrome, a genetic disease. For decades, the condition remained enigmatic, untreatable, and fatal. But in the past few years, insights into its mechanism have begun to pay off, leading to the first clinical trials of drugs that might slow the illness and sparking hopes that gene therapy and the CRISPR DNA-editing tool might rectify the underlying genetic flaws. Here is a rare disease that the basic science is telling us how to treat, says physiologist Barbara Ehrlich of the Yale School of Medicine.

The research could also aid more than the relatively few patients with Wolfram syndrome. Driving the diseases many symptoms is a malfunction of the endoplasmic reticulum (ER), the multichambered organelle that serves as a finishing school for many cellular proteins. Known as ER stress, the same problem helps propel far more common illnesses, including type 2 diabetes, amyotrophic lateral sclerosis (ALS), Parkinsons disease, and Alzheimers disease. Wolfram syndrome is the prototype of an endoplasmic reticulum disorder, says medical geneticist Fumihiko Fumi Urano of Washington University School of Medicine in St. Louis. Because Wolfram syndrome is simpler, says Scott Oakes, a cell biologist and pathologist at the University of Chicago, researchers think it could illuminate the mechanisms of other ER-disrupting diseases, which affect hundreds of millions of people worldwide.

In the late 1930s,four children with diabetes were going blind, and doctors were stumped. Like many other people in the United States struggling through the Great Depression, the siblings ate a paltry diet, subsisting on potatoes, bread, oatmeal, and a little milk. But after examining three of the children, Donald Wolfram, a physician at the Mayo Clinic in Rochester, Minnesota, and an ophthalmologist colleague ruled out malnutrition as the cause of their puzzling condition. Lead poisoning and syphilisthough common enoughwerent to blame, either. When Wolfram and his partner wrote up the cases in 1938, they concluded that the symptoms could be manifestations of an hereditary or acquired cerebral lesion.

The physicians were right that the syndrome eventually named for Wolfram is hereditary. Recessive mutations in the gene for a protein called wolframin are responsible for most cases, with glitches in a second gene causing most of the rest. However, the pair was wrong to think the defect lies only in the brain. Instead, the symptoms stem from widespread cell death. Its definitely a disease that affects the whole body, Marshall-Doss says.

The first sign of the illness, appearing when patients are children, is usually diabetes mellitus, or faulty sugar metabolism, sparked by the demise of insulin-secreting beta cells in the pancreas. Most patients also develop the unrelated condition diabetes insipidus, in which the pituitary gland doesnt dole out enough of a hormone that helps control the bodys fluid balance, causing the kidneys to produce huge amounts of urine.

Mutations in the gene for wolframin disrupt the endoplasmic reticulum and lead to cell death throughout the body, causing a range of symptoms.

V. Altounian/Science

Ellie White, 19, of Centennial, Colorado, who was diagnosed with Wolfram syndrome 12 years ago, says she hasnt had a full night of sleep since she was 3 years old. She gets up again and again to use the bathroom and monitor her blood sugar.

Yet she and other patients say that as disruptive as those problems are, they are not the diseases most dismaying consequence. The biggest symptom of Wolfram syndrome that affects me the most is my vision, White says. Because neurons in the optic nerve perish, patients usually go blind within 10 years of their first visual symptoms.

Other neurons die as well. As the disease progresses, brain cells expire, and walking, breathing, and swallowing become difficult. Most people with Wolfram syndrome die before age 40, often because they can no longer breathe. At 57, Marshall-Doss is one of the oldest patients; one of her mutated genes may yield a partly functional version of wolframin, triggering a milder form of the disease, Urano says.

Two advanceshave made it possible to begin to tackle those symptoms. The first was Uranos discovery nearly 20 years ago that linked Wolfram syndrome to ER stress. The ER is where about one-third of a cells newly made proteins fold into the correct shapes and undergo fine-tuning. Cells can develop ER stress whenever they are under duress, such as when they dont have enough oxygen or when misfolded proteins begin to pile up inside the organelle.

In test tube experiments, Urano and his colleagues were measuring the activity of genes to pinpoint which ones help alleviate ER stress. One gene that popped up encodes wolframin, which scientists had shown in 1998 was mutated in patients with Wolfram syndrome. Following up on that finding, Urano and his team determined that wolframin takes part in whats known as the unfolded protein response, which is a mechanism for coping with ER stress in which cells take steps including dialing back protein production.

Scientists think wolframin plays a key role in the unfolded protein response, though they havent nailed down exactly how. When wolframin is impaired, cells become vulnerable to ER stress. And if they cant relieve that stress, they often self-destruct, which could explain why so many neurons and beta cells die in the disease.

Defective wolframin may harm cells in other ways. The ER tends the cells supply of calcium, continually releasing and absorbing the ion to control the amount in the cytoplasm. Changes in calcium levels promote certain cellular activities, including the contraction of heart muscle cells and the release of neurotransmitters by neurons. And wolframin affects calcium regulation.

Beta cells genetically engineered to lack functional wolframin brim with calcium, Ehrlich and colleagues reported in July 2020 in theProceedings of the National Academy of Sciences. When exposed to lots of sugar, the altered cells release less insulin and are more likely to die than healthy beta cells, the team found. The cells share that vulnerability with beta cells from patients with Wolfram syndrome. We think that excess calcium is leading to excess cell death, Ehrlich says.

ER malfunctions could hamstring other organelles as well. The ER donates calcium to the mitochondria, the cells power plants, helping them generate energy. In 2018, a team led by molecular biologist Ccile Delettre and molecular and cellular biologist Benjamin Delprat, both of the French biomedical research agency INSERM, discovered that in cells from patients with Wolfram syndrome, mitochondria receive less calcium from the ER and produce less energy. Those underpowered mitochondria could spur the death of optic nerve cells, the researchers speculate.

Fumihiko Urano holds dantrolene, a muscle relaxant drug he helped test as a treatment for Wolfram syndrome.

The link between ER stress and Wolfram syndrome has been crucial for identifying potential treatments because otherwise we would have nothing to target, Urano says. But a second development was also key, he says: the advocacy and support of patient organizations, such as the Snow Foundation and the Ellie White Foundation, headed by its namesakes mother. The foundations have stepped up with money for lab research and clinical trials when other sources, including government agencies, didnt come through.

Scientists, patients, and their advocates say Urano also deserves much of the credit. Besides treating patients, he heads the international registry of cases and has taken the lead in organizing clinical trials, screening compounds for possible use as treatments, and devising potential therapies. Fumi is clearly the driving force, says Stephanie Snow Gebel, co-founder of the Snow Foundation, who about 10 years ago helped persuade him to forgo a plum job as department chair at a Japanese university and take over the Wolfram program at Washington University.

Patients could soonstart to reap the benefits. In 2016, Urano and colleagues started the worlds first clinical trial for the disease: a phase 1/2 study of dantrolene, an approved muscle relaxant. The molecule was a top performer when they screened 73 potential treatments for their ability to save cells with terminal ER stress. Dantrolene didnt improve vision in the 22 participants, including White, the scientists reported in an October 2020 preprint. But in some patients, beta cells appeared to be working better and releasing more insulin. The drug is safe, but Urano says it will need to be chemically tweaked to target its effects before future trials are warranted.

Researchers are pursuing other possible treatments targeting ER stress or calcium levels. In 2018, U.K. scientists launched a trial that will include 70 patients to evaluate sodium valproate, a therapy for bipolar disorder and epilepsy that, in the lab, prevents cells with faulty wolframin from dying. Last year, another compound that emerged from Uranos screens, the diabetes drug liraglutide, entered a clinical trial. Also last year, an experimental drug developed by Amylyx Pharmaceuticals for Alzheimers disease and ALS received orphan drug designation from the U.S. Food and Drug Administration for Wolfram syndrome because it curbs ER stress. That designation offers tax breaks and other incentives, and it will get trials started sooner, Urano says.

Ehrlich and her team have a candidate of their own that they have begun to test in rodents: the drug ibudilast, which is approved in Japan to treat asthma. The researchers found it reduces calcium levels in beta cells lacking wolframin and boosts their survival and insulin output. New screening projects may reveal still more candidates.

But Urano knows that even if a treatment receives approval, it would be only a Band-Aid for Wolfram syndrome. Hoping to develop a genetic cure, he and colleagues are introducing replacement genes into cells from patients and from mice engineered to replicate the disease. The researchers are endowing the cells with healthy copies of the gene for wolframin or the gene for a protein that reduces ER stress to determine whether they restore cellular function and reduce cell death. At INSERM, Delettre and colleagues are also evaluating whether directing a working gene into optic nerve cells can curtail vision loss in mice with faulty wolframin. The scientists are still gathering data, but early results suggest the treatment can halt the deterioration.

Urano and his collaborators have also turned to the genome editor CRISPR, deploying it to correct the gene defect in patients stem cells and then growing them into beta cells. When the researchers transplanted the revamped cells into mice with diabetes, the animals blood sugar returned to healthy levels, the team reported in April 2020 inScience Translational Medicine.

Stem cell biologist Catherine Verfaillie of KU Leuven is collaborating on the CRISPR research. But she notes that because the faulty wolframin gene affects so many tissues, researchers will have to figure out how to deliver the CRISPR components to most cells in large organs such as the brain and livera prospect she calls pretty daunting. Urano agrees, predicting that CRISPR-based Wolfram therapies might take 10 to 20 years to develop. The alternative approach, gene therapy, could reach clinical trials more quickly, in 3 to 10 years, he says, because researchers have more experience with gene therapy and have created several treatments that have already been approved for other illnesses.

Because it stems from a single genetic glitch, Wolfram syndrome could also help scientists tease out the role of the ER in more complex diseases, including neurological conditions, type 2 diabetes, and cancer. The ER also falters in those diseases, causing cells to die, but the mechanism is harder to discern because they stem from myriad genetic and environmental factors. In Alzheimers disease, for instance, neurons develop ER stress as misfolded proteins accumulate inside and outside the cells.

Besides deepening researchers understanding of other conditions, the research on Wolfram syndrome might even deliver candidate treatments. Everyone would be very excited if we can make advances in targeting ER stress in Wolfram syndrome, Oakes says. It would open up the whole field to doing this in other degenerative diseases.

See the rest here:
The race to treat a rare, fatal syndrome may help others with common disorders like diabetes - Science Magazine

REDWOOD CITY, Calif.--(BUSINESS WIRE)--Jasper Therapeutics, Inc., a biotechnology company focused on hematopoietic cell transplant therapies, today announced positive preliminary findings from its ongoing multicenter Phase 1 clinical trial of JSP191, a first-in-class anti-CD117 (stem cell factor receptor) monoclonal antibody, as a conditioning agent in older patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) undergoing hematopoietic (blood) cell transplantation.

Data from the first six patients who received a single dose of JSP191 prior to transplantation showed successful engraftment in all six patients. Complete donor myeloid chimerism (equal or greater than 95%) was observed in five of six evaluable patients at 28 days, and all three evaluable patients had total donor chimerism equal or greater than 95% observed at day 90. In addition, at 28 days, three of five evaluable patients showed complete eradication of measurable residual disease (MRD) as measured by next-generation sequencing. Two of the five evaluable patients showed substantial reductions in MRD. No treatment-related serious adverse events were reported.

The findings were presented by lead investigator Lori Muffly, M.D., M.S., Assistant Professor of Medicine (Blood and Bone Marrow Transplantation) at Stanford Medicine, as a late-breaking abstract at the 2021 Transplantation & Cellular Therapy (TCT) Meetings of the American Society for Transplantation and Cellular Therapy (ASTCT) and the Center for International Blood & Marrow Transplant Research (CIBMTR).

These early clinical results are the first to demonstrate that JSP191 administered in combination with a standard non-myeloablative regimen of low-dose radiation and fludarabine is well tolerated and can clear measurable residual disease in older adults with MDS or AML undergoing hematopoietic cell transplantation a patient population with historically few options, said Kevin N. Heller, M.D., Executive Vice President, Research and Development, of Jasper Therapeutics. These patients could be cured by hematopoietic cell transplantation, but the standard-of-care myeloablative conditioning regimens used today are highly toxic and associated with high rates of morbidity and mortality particularly in older adults. Traditional lower intensity transplant conditioning regimens are better tolerated in older adults, but are associated with higher rates of relapse in MDS/AML patients with measurable residual disease. JSP191, a well-tolerated biologic conditioning agent that targets and depletes both normal hematopoietic stem cells and those that initiate MDS and AML, has the potential to be a curative option for these patients.

The open-label, multicenter Phase 1 study (JSP-CP-003) is evaluating the safety, tolerability and efficacy of adding JSP191 to the standard conditioning regimen of low-dose radiation and fludarabine among patients age 65 to 74 years with MDS or AML undergoing hematopoietic cell transplantation. Patients were ineligible for full myeloablative conditioning. The primary outcome measure of the study is the safety and tolerability of JSP191 as a conditioning regimen up to one year following a donor cell transplant.

We designed JSP191 to be given as outpatient conditioning and to have both the efficacy and safety profile required for use in newborn patients and older patients for successful outcomes, said Wendy Pang, M.D., Ph.D. Executive Director, Research and Translational Medicine, of Jasper Therapeutics. We are enthusiastic about the reduction of measurable residual disease seen in these patients, especially given that it is associated with improved relapse-free survival. We are excited to continue our research in MDS/AML, with plans for an expanded study. We are evaluating JSP191, the only antibody of its kind, in two ongoing clinical studies and are encouraged by the positive clinical data seen to date.

About MDS and AML

Myelodysplastic syndromes (MDS) are a group of disorders in which immature blood-forming cells in the bone marrow become abnormal and do not make new blood cells or make defective blood cells, leading to low numbers of normal blood cells, especially red blood cells.1 In about one in three patients, MDS can progress to acute myeloid leukemia (AML), a rapidly progressing cancer of the bone marrow cells.1 Both are diseases of the elderly with high mortality. Each year, about 5,000 patients with MDS and 8,000 people with AML in the G7 countries receive hematopoietic cell transplants. These transplants are curative but are underused due to the toxicity of the current high-intensity conditioning regimen, which includes the chemotherapy agents busulfan and fludarabine.

About JSP191

JSP191 (formerly AMG 191) is a first-in-class humanized monoclonal antibody in clinical development as a conditioning agent that clears hematopoietic stem cells from bone marrow. JSP191 binds to human CD117, a receptor for stem cell factor (SCF) that is expressed on the surface of hematopoietic stem and progenitor cells. The interaction of SCF and CD117 is required for stem cells to survive. JSP191 blocks SCF from binding to CD117 and disrupts critical survival signals, causing the stem cells to undergo cell death and creating an empty space in the bone marrow for donor or gene-corrected transplanted stem cells to engraft.

Preclinical studies have shown that JSP191 as a single agent safely depletes normal and diseased hematopoietic stem cells, including in animal models of SCID, myelodysplastic syndromes (MDS) and sickle cell disease (SCD). Treatment with JSP191 creates the space needed for transplanted normal donor or gene-corrected hematopoietic stem cells to successfully engraft in the host bone marrow. To date, JSP191 has been evaluated in more than 90 healthy volunteers and patients.

JSP191 is currently being evaluated in two separate clinical studies in hematopoietic cell transplantation. A Phase 1/2 dose-escalation and expansion trial is evaluating JSP191 as a sole conditioning agent to achieve donor stem cell engraftment in patients undergoing hematopoietic cell transplantation for severe combined immunodeficiency (SCID), which is potentially curable only by this type of treatment. Data presented at the 62nd American Society of Hematology (ASH) Annual Meeting showed that a single dose of JSP191 administered prior to stem cell transplantation in a 6-month-old infant was effective in establishing sustained donor chimerism followed by development of B, T and NK immune cells. No treatment-related adverse events were reported. A Phase 1 clinical study is evaluating JSP191 in combination with another low-intensity conditioning regimen in patients with MDS or AML undergoing hematopoietic cell transplantation. For more information about the design of these two ongoing clinical trials, visit http://www.clinicaltrials.gov (NCT02963064 and NCT04429191).

Additional studies are planned to advance JSP191 as a conditioning agent for patients with other rare and ultra-rare monogenic disorders and autoimmune diseases.

About Jasper Therapeutics

Jasper Therapeutics is a biotechnology company focused on the development of novel curative therapies based on the biology of the hematopoietic stem cell. The companys lead compound, JSP191, is in clinical development as a conditioning antibody that clears hematopoietic stem cells from bone marrow in patients undergoing a hematopoietic cell transplant. This first-in-class conditioning antibody is designed to enable safer and more effective curative hematopoietic cell transplants and gene therapies. For more information, please visit us at jaspertherapeutics.com.

1 https://www.cancer.org/cancer/myelodysplastic-syndrome/about/what-is-mds.html

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Jasper Therapeutics Announces Positive Data from Phase 1 Clinical Trial of JSP191 as Targeted Stem Cell Conditioning Agent in Patients with...

Even as a hollow ball of embryonic cells, developing fish and mammals are not entirely defenceless.

The very first tissue, formed on the surface of a vertebrate blastula, has been shown to possess an innate immune response.

Incredible new research has shown that long before the development of organs or specialized immune cells, this simple protective layer, known as the epithelium, can reach out with its arm-like protrusions and detect, ingest, and destroy defective cells - helping to increase the embryo's chance of survival.

This 'surprisingly' efficient process, which was filmed in zebrafish and later confirmed in mice, is the earliest sign of an immune response in vertebrates.

Better understanding how it works could help researchers figure out why some embryos fail to form in those earliest states, potentially leading to new approaches for treating infertility or early miscarriages.

"Here we propose a new evolutionarily conserved function for epithelia as efficient scavengers of dying cells in the earliest stages of vertebrate embryogenesis," says cell biologist Verena Ruprecht from the Centre for Genomic Regulation.

"Our work may have important clinical applications by one day leading to improved screening methods and embryo quality assessment standards used in fertility clinics."

In developing animals, it's not uncommon for embryos to produce cellular errors during rapid cell division, and these can cause the whole embryo to fail if not taken care of. In fact, such mistakes are thought to be a leading reason for why embryos do not survive to reach implantation.

Scientists have long suspected there is an innate immune response at play, keeping fragile young embryos from threats such as sporadic cell death, inflammation, and infectious agents.

Recent research has revealed such innate immune responses in both mouse and human embryonic stem cells. But up until now, no one had ever seen it in action at the earliest stages.

This newest study is the first to explain how 'garbage collectors' like apoptotic cells are cleared out of the blastula without a specialised immune system. As you can see in the footage below, it looks a little like PAC-MAN.

So how does it work?

The blastula is a hollow ball, one cell thick, and the first stage of embryogenesis. The next stage includes further division into three germ layers, known as the gastrula.

In both these preliminary stages, researchers found evidence for the clearance of apoptotic cells, which initiate cell death.

Using four dimensional in vivo imaging of mice and zebrafish embryos, the authors show two types of epithelial 'arms' that seem to gobble up and destroy these apoptotic cells.

The first protrusion is called a phagocytic cup, and it helps scoop up and swallow the apoptotic target, a process known as phagocytosis. This structure is not unlike what we see in adult organisms, where epithelial phagocytosis keep organs and tissues healthy from infection and inflammation.

The second protrusion is a previously undescribed structure that is fast and can mechanically push apoptotic targets around, herding them into manageable positions.

"The cells cooperate mechanically," explains developmental biologist Esteban Hoijman, "like people distributing food around the dining table before tucking into their meal, we found that epithelial cells push defective cells towards other epithelial cells, speeding up the removal of dying cells."

Three dimensional tracking of these defective cells show they actually accumulate inside the epithelium, which suggests this protective layer is singling out certain cells specifically and gulping them up.

Even in conditions with abundant apoptosis, or cell death, occurring, zebrafish embryos were able to survive, which suggests this immune response is a highly efficient one.

Within two hours, in fact, the authors found the embryonic epithelium could remove 68 apoptotic particles.

Even when programmed cell death was triggered in the blastula using only two photons of illumination, the embryo showed epithelial clearance, indicating an impressive level of sensitivity.

"Together, these observations establish epithelial clearance as an error-correction mechanism that is present at the blastula stages of embryonic development," the authors conclude.

Zebrafish are model organisms for studying embryonic development, but to see whether this 'epithelial scavenging' also stood in mammals, the authors investigated what cell death looks like in mouse blastocysts.

Through time lapse imaging, the results reveal several apoptotic events, whereby cells are forced out of the blastocyst cavity and later ingested by the trophoblast. This is a tissue on the outside of the mammalian embryo that later forms a large part of the placenta. It also shows some level of innate immune response.

When mouse blastocysts were transplanted with apoptotic embryonic stem cells, the authors observed trophoblast cells eating up the targets.

Similar functions have also been documented in the human trophectoderm, which suggests the phagocytic epithelium has also been conserved in mammals and doesn't just appear in fish.

Knowing how mammal embryos survive from blastocyst to implantation could not only allow scientists to develop better fertility treatments, it could also teach us something about the early immune system - a power we could possibly try to replicate in adult tissues.

"Here we show that during early vertebrate development, epithelial cells specialize to perform phagocytic immune functions in the complete absence of immune cells," the authors write.

"At later developmental stages, professional phagocytes differentiate and can share their phagocytic tasks with mesenchymal or epithelial cells."

Future research will determine if the same innate immune process is also observed in invertebrates.

The study was published in Nature.

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The Very First Signs of an Immune Response Have Been Filmed in a Developing Embryo - ScienceAlert

Gorgeous little Arlo McArthur looks the picture of health and happiness.

Loved and adored by his family this little lively three-year-old from Milngavie is spoiled rotten by his three big sisters and his ultimate day out is playing golf with his daddy.

But behind the cheeky grin lies a devastating truth - he's a "ticking-timebomb" and needs a stem cell transplant to save his life.

So today, we've joined with Arlo's mum Nicole, dad Ian and his three doting sisters Carys, Brooke and Holly in asking Glasgow Live readers to step up and help this brave little boy.

They need young men, between 16 and 30 to volunteer to be tested to see if they are a match for the toddler. There's not much to it, a simple swab test carried out at home is enough for the experts to determine if you're a match.

The more people who register to be tested the better chance there is of finding the ideal candidate willing to donate the bone marrow little Arlo desperately needs.

For this family your help could mean the difference between life and death.

They've lived with the knowledge since he was 10 weeks old that a rare genetic condition could rob their precious little boy of his future.

Diagnosed with Wiskott-Aldrich Syndrome, it means Arlo's immune system doesn't function properly and it's difficult for his bone marrow to produce platelets, making him prone to bleeding.

Its estimated there are between 1 and 10 cases per million males worldwide. Arlo was only the third case at Queen Elizabeth University Hospital.

Doctors say they cant take the risk with an older donor as he was lucky to survive a previous transplant which failed when he was a baby.

His back-up is his dad Ian, 31, but he's only a half-match.

Sadly little Arlo's story isn't unique, across the country 2,300 people a year need a stem cell transplant and charity Anthony Nolan coordinates the search and raises money to support their vital work.

Nicole, 37, dreams of seeing her little boy attend his first day at school next August and believes someone out there can help that dream come true.

She pleaded: "Were asking as many people as possible to register and help give Arlo the life he deserves.

"We want to love and enjoy having our little boy around for a long time. He should be able to live out his life of dreams.

"Put yourself in the shoes of a parent whose child is ill, or someone else who is about to lose a loved one. Youve just been told in a room that they wont make it without stem cells. How does it feel?

"Its not just our Arlo, there are plenty of Arlos out there who need your help."

"People don't realise how easy it is to do. It's not this big operation, just a few injections and a day at an out-patient clinic to save someone's life. I wish it was opt-out, like organ donation.

"We dont have much time but I know in my heart the right match is out there."

To find out how you can can join the register and help the fight to save little Arlo and others just like visit Anthony Nolan's website here.

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Arlo's Army needs stem cell donor as mum begs for help to save three-year-old's life - Glasgow Live

TOKYO and BOTHELL, Wash., Feb. 12, 2021 /PRNewswire/ -- Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") and Seagen Inc. (Nasdaq: SGEN) today announced primary results from the phase 3 EV-301 trial comparing PADCEV (enfortumab vedotin-ejfv) to chemotherapy in adult patients with locally advanced or metastatic urothelial cancer who were previously treated with platinum-based chemotherapy and a PD-1/L1 inhibitor. At the time of pre-specified interim analysis, patients who received PADCEV in the trial lived a median of 3.9 months longer than those who received chemotherapy. Median overall survival was 12.9 vs. 9.0 months, respectively (HR=0.70 [95 percent Confidence Interval (CI): 0.56-0.89], p=0.001). For patients in the PADCEV arm of the trial, maculopapular rash, fatigue and decreased neutrophil count were the most frequent Grade 3 or greater treatment-related adverse events (TRAEs) occurring in more than 5 percent of patients.

Urothelial cancer is the most common type of bladder cancer and can also be found in the renal pelvis, ureter and urethra.1

Thefindings were published in the New England Journal of Medicine and presented during the virtual scientific program of the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU) (Abstract 393).

"Improving survival is especially meaningful in patients who have had their cancer progress following chemotherapy or other treatment," said Daniel P. Petrylak, M.D., Professor of Medicine and of Urology, Yale Cancer Center, and corresponding author of the published study.

"Enfortumab vedotin is the first medicine to reduce the risk of death compared to chemotherapy in patients with locally advanced or metastatic urothelial cancer who have received a platinum-containing chemotherapy and an immunotherapy," said Professor Thomas Powles, M.D., Director, Barts Cancer Centre, Queen Mary University of London, who presented results at ASCO GU.

Patients who received PADCEV in the trial also showed improvement in the following secondary endpoints:

Other safety findings included:

"Patients who received PADCEV lived longer than those who received chemotherapy an important finding, especially in light of the high unmet need faced by people with advanced urothelial cancer," said Andrew Krivoshik, M.D., Ph.D., Senior Vice President and Oncology Therapeutic Area Head, Astellas.

"Since its accelerated approval by the FDA in late 2019, physicians have adopted PADCEV into their practice, and these confirmatory results provide additional evidence of its benefit for people living with advanced bladder cancer," said Roger Dansey, M.D., Chief Medical Officer, Seagen.

Results of EV-301 are expected to be submitted to the U.S. Food and Drug Administration by the end of March as the confirmatory trial following the drug's accelerated approval in 2019. The results of EV-301 will also be included in submissions to global health authorities.

About Urothelial Cancer Urothelial cancer is the most common type of bladder cancer (90 percent of cases) and can also be found in the renal pelvis (where urine collects inside the kidney), ureter (tube that connects the kidneys to the bladder) and urethra.1 Globally, approximately 549,000 new cases of bladder cancer and 200,000 deaths are reported annually.2

About the EV-301 Trial The EV-301 trial (NCT03474107) is a global, multicenter, open-label, randomized phase 3 trial designed to evaluate enfortumab vedotin versus physician's choice of chemotherapy (docetaxel, paclitaxel or vinflunine) in approximately 600 patients with locally advanced or metastatic urothelial cancer who were previously treated with a PD-1/L1 inhibitor and platinum-based therapies. The primary endpoint is overall survival and secondary endpoints include progression-free survival, overall response rate, duration of response and disease control rate, as well as assessment of safety/tolerability and quality-of-life parameters.

About PADCEV (enfortumab vedotin-ejfv) PADCEV was approved by the U.S. Food and Drug Administration (FDA) in December 2019 and is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery or in a locally advanced or metastatic setting. PADCEV was approved under the FDA's Accelerated Approval Program based on tumor response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.3

PADCEV is a first-in-class antibody-drug conjugate (ADC) that is directed against Nectin-4, a protein located on the surface of cells and highly expressed in bladder cancer.3,4 Nonclinical data suggest the anticancer activity of PADCEV is due to its binding to Nectin-4 expressing cells followed by the internalization and release of the anti-tumor agent monomethyl auristatin E (MMAE) into the cell, which result in the cell not reproducing (cell cycle arrest) and in programmed cell death (apoptosis).4 PADCEV is co-developed by Astellas and Seagen.

PADCEV Important Safety Information

Warnings and Precautions

Adverse Reactions Serious adverse reactions occurred in 46% of patients treated with PADCEV. The most common serious adverse reactions (3%) were urinary tract infection (6%), cellulitis (5%), febrile neutropenia (4%), diarrhea (4%), sepsis (3%), acute kidney injury (3%), dyspnea (3%), and rash (3%). Fatal adverse reactions occurred in 3.2% of patients, including acute respiratory failure, aspiration pneumonia, cardiac disorder, and sepsis (each 0.8%).

Adverse reactions leading to discontinuation occurred in 16% of patients; the most common adverse reaction leading to discontinuation was peripheral neuropathy (6%). Adverse reactions leading to dose interruption occurred in 64% of patients; the most common adverse reactions leading to dose interruption were peripheral neuropathy (18%), rash (9%) and fatigue (6%). Adverse reactions leading to dose reduction occurred in 34% of patients; the most common adverse reactions leading to dose reduction were peripheral neuropathy (12%), rash (6%) and fatigue (4%).

The most common adverse reactions (20%) were fatigue (56%), peripheral neuropathy (56%), decreased appetite (52%), rash (52%), alopecia (50%), nausea (45%), dysgeusia (42%), diarrhea (42%), dry eye (40%), pruritus (26%) and dry skin (26%). The most common Grade 3 adverse reactions (5%) were rash (13%), diarrhea (6%) and fatigue (6%).

Lab Abnormalities In one clinical trial, Grade 3-4 laboratory abnormalities reported in 5% were: lymphocytes decreased (10%), hemoglobin decreased (10%), phosphate decreased (10%), lipase increased (9%), sodium decreased (8%), glucose increased (8%), urate increased (7%), neutrophils decreased (5%).

Drug Interactions

Specific Populations

For more information, please see the full Prescribing Information for PADCEV here.

About Astellas Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+ healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into value for patients. For more information, please visit our website at https://www.astellas.com/en.

About Seagen Seagen Inc. is a global biotechnology company that discovers, develops and commercializes transformative cancer medicines to make a meaningful difference in people's lives. Seagen is headquartered in the Seattle, Washington area, and has locations in California, Canada, Switzerland and the European Union. For more information on our marketed products and robust pipeline, visit http://www.seagen.com and follow @SeagenGlobal on Twitter.

About the Astellas and Seagen Collaboration Astellas and Seagen are co-developing enfortumab vedotin under a collaboration that was entered into in 2007 and expanded in 2009.

Astellas Cautionary Notes In this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties.

Information about pharmaceutical products (including products currently in development), which is included in this press release is not intended to constitute an advertisement or medical advice.

Seagen Forward Looking Statements Certain statements made in this press release are forward looking, such as those, among others, relating to the submission of data from the EV-301 trial for presentation at an upcoming scientific congress; intended regulatory actions, including plans to submit the results of the EV-301 trial to the FDA as the confirmatory trial following the drug's accelerated approval in the U.S. and plans to seek global registrations; and the therapeutic potential of PADCEV, including its efficacy, safety and therapeutic uses. Actual results or developments may differ materially from those projected or implied in these forward-looking statements. Factors that may cause such a difference include the possibilities that we may experience delays in the submission of results to the FDA; that the results from the EV-301 trial may not be sufficient to convert PADCEV's accelerated approval in the U.S. to regular approval or to support any other global registrations; that, even if PADCEV receives regular approval in the U.S. or any other global registrations, the product labeling may not be as broad or desirable as anticipated; that ongoing and subsequent clinical trials may fail to establish sufficient efficacy; that adverse events or safety signals may occur; and that adverse regulatory actions may occur. More information about the risks and uncertainties faced by Seagen is contained under the caption "Risk Factors" included in the company's Annual Report on Form 10-K for the year ended December 31, 2020filed with the Securities and Exchange Commission. Seagen disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as required by law.

References

1American Society of Clinical Oncology. Bladder cancer: introduction (5-2019). https://www.cancer.net/cancer-types/bladder-cancer/introduction. Accessed January 27, 2021. 2Cancer today: data visualization tools for exploring the global cancer burden in 2020. https://gco.iarc.fr/today/home. Accessed January 27, 2021. 3PADCEV [package insert] Northbrook, IL: Astellas Pharma Inc. 4Challita-Eid P, Satpayev D, Yang P, et al. Enfortumab vedotin antibody-drug conjugate targeting nectin-4 is a highly potent therapeutic agent in multiple preclinical cancer models. Cancer Res 2016;76(10):3003-13.

SOURCE Astellas Pharma Inc.

http://www.us.astellas.com

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Astellas and Seagen Announce Phase 3 Trial Results Demonstrating Survival Advantage of PADCEV (enfortumab vedotin-ejfv) in Patients with Previously...

Introduction

Head and neck squamous cell carcinoma (HNSCC) is one of the major causes of cancer-associated illness and death, with more than 600,000 newly diagnosed cases worldwide each year1 and a continuously increasing incidence rate.2 HNSCC includes cancers of the oral cavity, pharynx, and larynx. The anatomical structures of the head and neck can be damaged by the tumor itself or treatments such as surgical resection and chemoradiotherapy, which sometimes cause speech, swallowing, and breathing impairments.3,4 Patients with HNSCC have been shown to bear greater psychological distress than those with other types of cancer.5

Despite the currently available therapies, patients with advanced HNSCC still experience poor outcomes.68 For example >50% of patients with locoregionally advanced HNSCC experience recurrence or metastases development within 3 years of treatment.911 Treatment options for patients with the recurrent and metastatic disease following progression after a platinum-based regimen are limited, and the median overall survival of such patients is less than 7 months.1215

The recurrence and metastasis of HNSCC are facilitated by immune evasion;16 therefore, as one of the methods to inhibit immune evasion, the use of programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway inhibitors is considered effective in the treatment of recurrent HNSCC.1719 Nivolumab, a fully human IgG4 antiPD-1 monoclonal antibody, has shown remarkable antitumor efficacy and safety when administered to patients with recurrent HNSCC whose disease had progressed within 6 months of platinum-based chemotherapy;19 Furthermore, nivolumab treatment has been shown to improve the quality of life of these patients.20 However, PD-1 inhibitors can upregulate T cells in vivo, which may lead to the development of graft-versus-host disease (GVHD) in patients after allogeneic hematopoietic stem cell transplantation (allo-HSCT).2123 To the best of the authors knowledge, no studies have investigated the safety and efficacy of nivolumab in patients with HNSCC after allo-HSCT. Here, we report the case of a patient who experienced excellent control of left buccal squamous cell carcinoma with nivolumab after the failure of platinum-based chemotherapy despite receiving allogeneic bone marrow transplantation.

Without any family history of tumor, a 33-year-old man was diagnosed with Philadelphia chromosome-positive T cell acute lymphoblastic leukemia on March 19, 2014. He received one course of vincristine and prednisone therapy and four courses of vincristine, daunorubicin, cyclophosphamide, and prednisone therapy. He was in complete remission at the end of therapy. Subsequently, allogeneic bone marrow transplantation was performed; the donor was his human leukocyte antigen (HLA)-haploidentical sibling (sister). He experienced chronic GVHD (c GVHD) of the oral cavity and skin 3 months after transplantation, for which he was treated with steroid hormone- and cyclosporine-based therapies. Skin rejection lasted for more than 3 years. Imatinib mesylate was administered for 2 years after transplantation, and his leukemia was well controlled.

In August 2018, the patient developed an ulcer of approximately 0.5 0.5 cm size in the left buccal mucosa; the ulcer was slightly painful and covered with white moss. In September 2018, the patient was admitted to Peking University Stomatological Hospital, where a biopsy of the buccal mucosa was performed. The pathology results showed the presence of squamous cell carcinoma in the left cheek. Unfortunately, this patient was not a right candidate for HNSCC in terms of exposure to risk factors, such as long terms of smoking and drinking. On October 10, 2018, 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (CT) showed that the mass in the left cheek was metabolically active, which is consistent with the activity of a malignant tumor. One course of an adjuvant therapy regimen (nimotuzumab [200 mg d0] + docetaxel [60 mg d1, 8]+ nedaplatin [60 mg d2, 3]) was administered on October 26, 2018. Following this, the patient developed degree II thrombocytopenia and redness, swelling, and ulceration of the cheek, which had discharge with a peculiar smell. On November 29, 2018, a head and neck CT scan showed a left buccal malignant tumor with the destruction of the neighboring mandibular bone and lymph node enlargement in the left submaxillary region and right carotid sheath. The CT examination revealed disease progression. Following a multidisciplinary consultation in our hospital, surgery was not recommended; instead, a chemotherapy-based comprehensive treatment was recommended as a better option for the patient. The patient received chemotherapy with albumin paclitaxel (200 mg d1, 8)+ bleomycin (15,000 units d2, 9) from November 30, 2018 to January 9, 2019. On another CT scan, the curative effect was evaluated as partial remission (showed in Video 1, Figure 1A); subsequently, two courses of a chemotherapy regimen comprising nivolumab (140 mg d1) + albumin paclitaxel (200 mg d1, d8) were administered. A CT examination showed stable disease (SD) on March 12, 2019, following which the patient was administered 120 mg of nivolumab once every 2 weeks from March 15 to May 23, 2019. Another CT examination was performed on May 28, 2019 (showed in Video 2, Figure 1B). During the therapy course, the related tumor markers showed an overall downward trend, the new metastases did not appear, the patients status became better than before. Subsequently, another CT examination performed in August 02, 2019 showed the extent of the tumor was obvious reduction than before (showed in video 3, Figure 1C). And the corresponding CT report in August 02, 2019 was described as follows Compared with the CT on 28 May, 2019, the extent of the tumor in the left cheek became obviously smaller, the tubercle in the left submandibular and the lymph nodes in the left neck also became smaller. There were no other significant changes in this image. Most importantly, the patient did not develop any form of GVHD following nivolumab administration.

Figure 1 Head and neck CT images showing tumor before (A) and after treatment with nivolumab (B, C, respectively).

Abbreviation: CT, computed tomography.

Note: The arrows indicate the maximum length diameter of tumor or tumor site.

Reliable data on the clinical safety and efficacy of nivolumab in the treatment of recurrent or metastatic HNSCC have been obtained in a Phase III randomized clinical trial (CheckMate 141).19 In this trial, 361 patients with recurrent HNSCC for whom disease had progressed within 6 months after platinum-based chemotherapy were enrolled between May 29, 2014, and July 31, 2015. The median follow-up duration for overall survival (OS) was 5.1 months (range, 016.8 months). OS was significantly greater in patients randomized to receive nivolumab than in those who received standard second-line, single-agent systemic therapy with either methotrexate, docetaxel, or cetuximab (hazard ratio, 0.70; 97.73% confidence interval (CI), 0.510.96; P = 0.01). The median OS was 7.5 months (95% CI, 5.59.1) in the nivolumab group versus 5.1 months (95% CI, 4.06.0) in the standard therapy group. The one-year survival was also greater in patients who received nivolumab than in those who received standard therapy (36.0%vs. 16.6%). Furthermore, the response rate was higher in those who received nivolumab than in those who received standard therapy (13.3% vs 5.8%); however, the median progression-free survival was not significantly different between the groups (2.0 vs 2.3 months; P=0.32). In this study, patients who were treated with nivolumab had a longer OS than those treated with standard therapy, regardless of tumor PD-L1 expression or p16 status. Grade 3 or 4 treatment-related adverse events occurred in 13.1% of patients who received nivolumab and 35.1% of those who received standard therapy. Physical function, role functioning, and social functioning were stable in the nivolumab group, whereas they were substantially worse in the standard therapy group.20 Moreover, among Asian patients, the survival benefits were consistent with the global group.24

It was unclear whether nivolumab could be used in patients with recurrent HNSCC after allo-HSCT, though Khaddour et al proved the efficacy and safety of Pembrolizumab in patients who underwent allo-HSCT after relapsed and refractory Szary Syndrome and cutaneous squamous cell carcinoma.25 However, some case reports (Table 1) and clinical trials (Table 2) have reported the efficacy and safety of nivolumab when administrated to patients with recurrent hematological malignancies (mostly Hodgkins lymphoma) after allo-HSCT.

Table 1 Case Reports of Nivolumab Use After Allo-HSCT

Table 2 Studies on Nivolumab Use After Allo-HSCT

In Herbaux et al, nivolumab (3 mg/kg, once every 2 weeks) was administered to 20 patients with Hodgkins lymphoma who experienced relapse after allo-HSCT. The overall response rate was 95%, the 1-year progression-free survival rate was 58.2%, and the 1-year OS rate was 78.8%.26 Compared with other treatment options, nivolumab was more effective in these patients.2730 Haverkos et al reported results after a median follow-up duration was 428 days (range, 133833 days). After treatment with PD-1 inhibitors [nivolumab 3 mg/kg, once every 2 weeks (n = 28) and pembrolizumab (n =3)], the overall response rate of 31 patients with relapsed lymphoma after allo-HSCT was 77%, the median progression-free survival was 591 days (range,400644 days), and 68% of the patients survived to the end of the study.23 These two studies showed that nivolumab is effective when administered to patients with recurrent blood cancers after allo-HSCT, which is consistent with the results of several other case reports3134 and case series.35,36 The PD-1/PD-L1 pathway plays a key role in the regulation of the balance among T cell activation, T-cell tolerance, and immune-mediated tissue damage. This pathway protects healthy cells from excessive inflammatory or autoimmune responses.37,38 Some studies have shown that the activation of the PD-1/PD-L1 pathway can reduce acute and chronic GVHD, whereas its blockade can accelerate the graft-versus-host response and increase the associated mortality.21,22,39 It is unclear whether the PD-1 inhibitor nivolumab increases the risk of GVHD and the associated mortality in patients after allo-HSCT.23,26 Some clinical studies and case reports have shown that nivolumab treatment-related GVHD and consequent death in patients after allo-HSCT might be affected by the following factors. First, GVHD after antiPD-1 treatment has been observed most frequently in matched sibling donor transplants; for which Haverkos et al reported an incidence of 75%.23 In a Phase I pilot study, without GVHD or G3/G4 immune toxicity after receiving multiple doses of nivolumab was only among one patient whose donor source was Haploidentical+cord blood Fludarabine.40 Second, a history of GVHD, especially for the acute GVHD, may lead to an increased risk of nivolumab treatment-related GVHD after allo-HSCT. In a French cohort, all patients who presented with acute GVHD after nivolumab treatment had a prior history of acute GVHD, among which three patients presented with steroid-refractory nivolumab-induced GVHD, and GVHD was not observed among patients without a history of GVHD.26 This phenomenon was also observed in Steinerovs medical report.41 In the study by Haverkos et al, 63% of patients with a history of GVHD prior to antiPD-1 treatment developed treatment-emergent GVHD after receiving antiPD-1.23 Third, the shorter the interval between transplantation and nivolumab use, the greater the risk of GVHD. In the study by Herbaux et al, the median intervals between transplantation and nivolumab use in cases with the presence and absence of GVHD were 8.5 months and 28.5 months, respectively.26 In another study by Wang et al, the reported four patients all experienced immune-related adverse events following nivolumab treatment and the median time from transplantation to nivolumab use was 7.8 months.40 Fourth, dose is a risk factor for nivolumab treatment-related GVHD. In a case report, chronic skin GVHD was observed when the dose of nivolumab was adjusted from 0.5 mg/kg to 2 mg/kg.33 Other factors, such as immunosuppressive therapy at the time of nivolumab administration, may also influence nivolumab treatment-related GVHD. Recently, a comprehensive literature review was launched by Awais et al to assess the safety and efficacy of the use of checkpoint inhibitors (ipilimumab, nivolumab and pembrolizumab) in blood cancers before and after allo-HSCT. Collective data showed that checkpoint inhibitors use after allo-HSCT for post-transplant relapse had higher efficacy but the risk of GVHD was significant. Moreover, the investigation indicated that higher drug doses, shorter intervals between checkpoint inhibitors exposure and allo-HSCT and prior history of GVHD had a positive correlation with the risk of GVHD.42

In the present case, HNSCC was effectively controlled without any nivolumab treatment-related acute or chronic GVHD after nivolumab administration, while the weight loss being the only adverse event. After comprehensive analysis, we found that many factors may impede the development of nivolumab treatment-related GVHD in our patient. On one hand, the appropriate donor, no use of checkpoint inhibitors prior to allo-HSCT, the long interval between nivolumab administration and allo-HSCT (36 months) and the standard dose use of nivolumab were the negative factors for GVHD development. On the other hand, the chronic GVHD of the oral cavity and skin before nivolumab use might lead to the development of GVHD. However, it remained unknown what role the immunosuppressant therapy played in the occurrence of GVHD, though we definitely known that immunosuppressant was administered more than 2 years after allo-HSCT and discontinued for 2 years before treatment with nivolumab in our patient. Finally, whether the two primary cancers in our case affected the efficacy and safety of nivolumab by some unknown pathways were unclear, which needed further exploration.

Nivolumab has been shown to be effective in patients with HNSCC for whom platinum-based therapy has failed. However, little is known about the efficacy and safety of nivolumab in patients with HNSCC who have undergone allo-HSCT. Our case report shows that nivolumab could be used effectively and safely in such patients, however, more clinical trials are required to confirm these results.

This study was approved by the Medical Ethics Committee of Tianjin Medical University Cancer Institute and Hospital. The authors state that they have obtained verbal and written informed consent from the patient for the inclusion of their medical and treatment history within this case report.

This work was supported by the Tianjin Science and Technology Commission (18ZXXYSY00070), Key Task Project of Tianjin Health and Family Planning Commission (16KG128), Anticancer Key Technologies R&D Program of Tianjin (12ZCDZSY16200), and Natural Science Foundation of Tianjin (18JCYBJC91600).

The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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16. Ferris RL. Immunology and Immunotherapy of head and neck cancer. J Clin Oncol. 2015;33(29):32933304. doi:10.1200/JCO.2015.61.1509

17. Chow LQM, Haddad R, Gupta S, et al. Antitumor activity of pembrolizumab in biomarker-unselected patients with recurrent and/or metastatic head and neck squamous cell carcinoma: results from the phase Ib KEYNOTE-012 expansion cohort. J Clin Oncol. 2016;34(32):38383845. doi:10.1200/JCO.2016.68.1478

18. Seiwert TY, Burtness B, Mehra R, et al. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 2016;17(7):956965. doi:10.1016/S1470-2045(16)30066-3

19. Ferris RL, Blumenschein G Jr, Fayette J, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med. 2016;375(19):18561867. doi:10.1056/NEJMoa1602252

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21. Blazar BR, Carreno BM, Panoskaltsis-Mortari A, et al. Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-gamma-dependent mechanism. J Immunol. 2003;171:12721277. doi:10.4049/jimmunol.171.3.1272

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27. Peggs KS, Kayani I, Edwards N, et al. Donor lymphocyte infusions modulate relapse risk in mixed chimeras and induce durable salvage in relapsed patients after T-cell-depleted allogeneic transplantation for hodgkins lymphoma. J Clin Oncol. 2011;29:971978. doi:10.1200/JCO.2010.32.1711

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[Full text] Successful Use of Nivolumab in a Patient with Head and Neck Cancer Aft | OTT - Dove Medical Press

There is also hope that influenza antivirals such as favipiravir and molnupiravir could be repurposed in the fight against coronavirus, with small trials showing they improve lung function. Large trials are under way, with results expected in the spring.

One clever antiviral treatment in the pipeline is called Recombinant ACE-2. To infect the body, coronavirus uses grippy rods called spike proteins to latch on to the human ACE-2 protein on the outside of cells. In laboratory studies, scientists have shown they can deploy artificial ACE-2 proteins as decoys, thereby luring the virus away from real cells. However, it has yet to be proven in animals or humans.

Drugs that boost the immune system also look promising. Scientists are currently testing whether the blood plasma of recovered patients could improve survival rates. Using the blood of patientsurvivors of an illness dates back to the 1918 Spanish Flu pandemic, before vaccines or antivirals were available. It relies on the fact that the blood of recovered patients contains powerful antibodies already trained to fight the virus.

Last week, a large trial by Oxford showedthat blood plasma does not prevent death in seriously ill patients, but the team is still awaiting a full breakdown of results to see if it benefited certain sub-groups. International trials are also currently testing whether plasma works if used earlier.

Similar to blood plasma, synthetic antibodies are also giving hope. Scientists look for people who have mounted a strong response to coronavirus then artificially replicate their immune proteins.

Eli Lilly's monoclonal antibody bamlanivimab has been shown to reduce people's risk of being hospitalised by 72 per cent compared to a placebo. It is currently under review by the Medicines and Healthcare Products Regulatory Agency (MHRA). Likewise, Regeneron's antibody cocktail reduced visits to hospital by 57 per cent.

Giving monoclonal antibodies as a prophylactic also appears to be beneficial, with bamlanivimab found to reduce the risk of developing coronavirus by 80 per cent for care home residents and staff.

Stephen Evans, professor of pharmacoepidemiology at the London School of Hygiene and Tropical Medicine (LSHTM), said: "They are the first anti-viral drugs that demonstrably work in the first phase of the disease just after the virus has infected someone but before it has had time to cause a lot of damage."

Another way of boosting immunity is to give patients synthetic interferons. When the body is under attack, it produces molecules called interferons which boost the immune system while also keeping it in check.

Last summer, the British pharma company Synarigen published results showing its inhaled form of interferon "SNG001" lowered the risk of severe Covid-19 in infected patients. Larger studies are ongoing.

For many seriously ill coronavirus patients, the immune system does not need any help, but requires dampening down.The steroid dexamethasone has been shown to cut deaths of severely ill patients by one-third and is now given to severely ill NHS patients as standard.

The rest is here:
The drug treatments offering the best hope of a way out of the Covid crisis - Telegraph.co.uk

Fortunately, many viruses produce an enzyme called an RNA-dependent RNA polymerase. Nearly a decade ago, the pharmaceutical company Gilead began work on a drug called Remdesivir to target the enzyme. It was the first drug rolled out to NHS patients last May, and clinical trials have shown it helps patients get out of hospital four days earlier.

There is also hope that influenza antivirals such as favipiravir and molnupiravir could be repurposed in the fight against coronavirus, with small trials showing they improve lung function. Large trials are under way.

One clever antiviral treatment in the pipeline is called Recombinant ACE-2. Scientists have shown they can deploy artificial ACE-2 proteins as decoys, thereby luring the virus away from real cells. However, it has yet to be proven in animals or humans.

Drugs which boost the immune system also look promising. Scientists are testing whether the blood plasma of recovered patients could improve survival rates. Last week, a large trial by Oxford shows that blood plasma does not prevent death in seriously ill patients, but the team is waiting to see if it benefited certain sub-groups.

Synthetic antibodies are also giving hope. Scientists look for people who have mounted a strong response to coronavirus then artificially replicate their immune proteins.

Eli Lilly's monoclonal antibody bamlanivimab has been shown to reduce people's risk of being hospitalised by 72 per cent and is under review by the Medicines and Healthcare Products Regulatory Agency. Regeneron's antibody cocktail reduced trips to the hospital by 57 per cent. Stephen Evans, professor of pharmacoepidemiology at the London School of Hygiene and Tropical Medicine, said: "They are the first anti-viral drugs that demonstrably work in the first phase of the disease, just after the virus has infected someone but before it has had time to cause a lot of damage."

Another way of boosting immunity is to give synthetic interferons, which boost the immune system while also keeping it in check. Last year, British pharma company Synairgen published results showing interferon "SNG001" lowered the risk of severe Covid-19.

See the original post here:
In the war against Covid, an arsenal of drugs is on the way - Telegraph.co.uk

Shelby County Judge William Bostick III on Monday ordered 47-year-old Jeff West to serve 16 years in prison for the death of his wife, Kat West.

In November, Jeff West was convicted of reckless manslaughter in the death of 42-year-old Kat West, a Calera mother and online exhibitionist.

Kat West died from a blow to the head from a Lucid Absinthe bottle wielded by her husband, a jury deemed. He has maintained his innocence for more than three years, contending she died as the result of a drunken, accident fall.

Jeff West addressed the court before sentencing. He talked of all hes missed while jailed over the past three years. He never mentioned his wife by name or her death, only saying I lost my best friend.

Bostick said he took into consideration Kat Wests familys pleas of leniency. He said he gave less weight to the testimony of Nancy Martins request, however. Martin, Kat Wests mother, has supported her son-in-law throughout the entire criminal process. The judge said, In my opinion, shes ignored the evidence in this case.

He said he also considered Jeff Wests military history, his lack of criminal record and his strong ties to the community.

We dont drag people into courts of law and try them for who they are. We drag people into courts of law and try them for what they did,' Bostick said. Our laws designed to punish people not for who they are but for what they do. In this case the the jury found you to be responsible for your wifes death. They imposed that responsibility on you. You were afforded the opportunity to accept responsibility for causing your wifes death. You have, for your own reasons, taken the position that you dont intend to do that. So the jury had to do that for you.

I know there were some versions of the evidence that may say Kat was responsible for her own death, or her drinking. She contributed to her demise, but I dont consider that mitigating at all in this case,' the judge said. Domestic violence always follows according to a pattern. Kats death was foreseeable I dont believe you woke up the morning that this offense occurred and decided todays the day Im going to kill her. I dont believe the happened. But I do believe this could have been avoided, I do believe it was foreseeable and I do believe with the jury that it is your reckless acts that caused her death.

West will receive credit for the nearly three years hes already served. He will appeal.

The case was prosecuted by assistant district attorneys Daniel McBrayer and Ben Fuller. Joined by District Attorney Jill Lee, they spoke following Mondays sentencing. Obviously we would have preferred a 20-year sentence just as we would have preferred a murder verdict,' McBrayer said. We respect the judges sentence and the jurys verdict. We are glad he will see the inside of a prison for this killing. We think thats important.

Prior to the start of last years trial, Jeff West was offered a plea deal that would have allowed him to be released immediately for time served. He turned down that deal. That is our standard practice. Here in this case we did make an offer that was within the voluntary guidelines but that was premised on the defendant accepting responsibility for this crime and he didnt,' McBrayer said. So thats why you see a difference in what we offered in the case and the ultimate sentence we asked for.

McBrayer was asked for his reaction to Jeff Wests statement in which he only barely mentioned his wife. It struck me that he mentioned very little other than himself,' he said.

McBrayer described Jeff West as calculating. I think he was very thoughtful and deliberative about every action and every word that he said in this case,' he said. The jury found this was a reckless act but it was backed up by intentional actions, whether it was moving the body , what he said to police, and when he said it.

Fuller said Jeff West has refused to accept any responsibility. Its been consistent throughout the trial. That was our point he bears responsibility from start to finish and he just refuses to accept that,' he said.

Jeff Wests attorney, John Robbins, said he was expecting a 20-year sentence. I appreciate we didnt get the full maximum sentence. My position has been that even though he was convicted of manslaughter,' he said, I think this was a case that probation would have been appropriate, especially after serving almost three years on this so far.

He said he asked Jeff West if he was sorry he did not take the plea deal. He still satisfied with that position that hes taken since Day 1,' Robbins said. Im not at liberty to tell you exactly what he said, but you can read between the lines.

Im sorry the prosecution wants him to come out and say I did this. Since Day 1 he has denied it and thats his position. It wasnt going to change,' he said. He had an opportunity to take that position and go home. He refused to admit to something that he didnt do. You have to respect the person for that.

Robbins talked about how much weight is given to a victims family and their wishes in criminal cases. Usually, the victims family does not take the side of the defendant which is what happened in this case.

Still, Robbins said, the same amount of equity should be given to the wishes of Kat Wests family. You cant take into consideration only when its convenient for you,' Robbins said. Thats what the prosecution did. Its convenient when the family wants to jump up and down and want vengeance. On the other hand, when the family wants leniency and mercy, we want to ignore that.

Here is full coverage of the death of Kat West

Kat West was killed Friday, Jan. 12, 2018.

Her body was found about 5 a.m. the following day by a 19-year-old neighbor who was on her way to work at a fast-food restaurant. The victim was wearing only a sports bra. A cell phone was nearby with a green bottle on top of it, which witnesses said appeared staged.

Kat West touted herself on social media as a stay-at-home mom but also had a subscription-only website, where she went by the name Kitty Kat West. Her Twitter and Instagram accounts, also under the name of Kitty Kat West, featured revealing photos of West, and directed viewers to her paid adult website, which cost $15.99 per subscription.

Jeff West, a former Birmingham Southern College campus security officer and U.S. Army veteran, has been held in the Shelby County Jail since his arrest three years ago. The couple had a daughter, Logan, who also goes by Lola, who is a teen.

During Mondays sentencing hearing, the couples 15-year-old daughter, a student at Calera High School, testified on behalf of her father, asking a judge to release him. She said she grew up in a loving home. Her father, she said, never spanked her nor was he ever loud or abusive. Instead, she described him as always calm.

He has always been my shield against the world,' Logan told the judge. Please give me my father back as soon as possible.

During a recess, Logan hugged her father for nearly two minutes.

Both Jeff Wests mother, Sue West, and mother-in-law, Nancy Martin, also testified on his behalf. The two families have presented a united front since the 2018 death and Jeff Wests arrest.

Martin, the only witnesses for the defense at last years trial, said she was shocked that he was convicted in the death of her daughter. He has always been a kind and caring person,' Martin said. He is a good man.

The Martins have custody of Logan but share the responsibility with Jeff Wests parents. We are a family,' she said.

Sue West, speaking for herself and her husband, Jerry West, broke down while talking about her son. He has always been empathetic and kind,' she said. He tries to see the good in everyone and every situation. He is the most forgiving person I know.

I need my child back,' Sue West said. Logan needs her dad back. This has been an absolute nightmare.

Jeff West (Shelby County Jail)

Also in Mondays sentencing hearing, McBrayer and Fuller again presented a photo of Kat West as she was found that Saturday morning, face down, bloodied and wearing only a pink bra.

They also played audio of a portion of his interview with police during which Jeff West was asked if the couple had arguments. He said it was nothing out of the ordinary but that they argued over her drinking. I dont like her drinking,' he told them.

Asked why they bought liquor that night, he said, I love her and she said she could control it.

In closing arguments, McBrayer said that Jeff West is a trained crime scene investigator who clearly knew what he was doing that night. He said even as recently as last week, Jeff West refused to take responsibility for the crime. He is what he always was, calculating,' McBrayer said.

He said Jeff West is a trained crime scene investigator who knew what he was doing when he staged the Lucid Absinthe bottle on top of the cell phone. Those two things, her drinking and her social media use, were what drove Jeff West to kill her, he said. He said evidence also showed that Jeff West moved his wifes body after he killed her to make it look like she had been hit by a vehicle.

The killing, and the consequences, merit a tougher sentence than the minimum guidelines call for. McBrayer asked that Jeff West get 20 years in prison.

Robbins, in his sentencing closing statements, said its been a difficult case on everyone involved. Not every person is the same, not every crime is the same and he said the judge should consider that when imposing Jeff Wests sentence, especially his 21 years of service in the U.S. Army during which he saw combat. He has no criminal record, and strong family times to the community.

He was not convicted of an intentional act,' Robbins said.

Robbins asked for no more than time served plus one additional year. He asked that the judge consider the familys feelings. Theyre pleading for mercy,' Robbin said.

The week-long trial took place in November 2020 at which time prosecutors said they believed Jeff West was motivated to kill his wife over her excessive drinking and frequent use of social media to promote her adult website.

In the hours leading up to the killing, the couple had shared a date night dinner and drinks out and a stop at a liquor store after where they bought Jameson whiskey and the bottle of Absinthe.

They both drank a lot and then Jeff West took two photos of his wife, who posed in a pink bra, pink multi-colored panties and pink stiletto shoes.

At some point, prosecutor Daniel McBrayer said, an argument erupted. He is tired and fed up with this Instagram stuff, McBrayer said. He grabs her phone and chunks it out the front door where it lands in the street. Prior testimony showed that Kat Wests phone was cracked.

Kat West went outside to retrieve her phone. She was wearing only the pink bra no pants or panties or shoes. McBrayer has said he believes Jeff West grabbed the liquor bottle, followed her outside and, holding the bottle in an inverted position, delivered the fatal blow to her head.

This marriage was not in a good place, McBrayer said during last years trial. This (was) a relationship on the rocks.

Jeff West carefully placed the Absinthe bottle on top of her cell phone and went back inside, leaving the front door open, McBrayer said. Jeff West then waited for somebody to find his wifes dead body in the street.

Shes dead. He doesnt know what to do because hes got a body outside of his (home) McBrayer said.

Crime scene photos and autopsy photos shown to the jury throughout the trial showed her head and upper body lying in the gutter and asphalt while her legs were in a neighbors grass. A couple of feet from her body was a large pool of blood and a blood trail flowing downhill.

A crime analyst testified that Jeff Wests left thumb and left ring finger fingerprints were found on the Lucid Absinthe bottle in an inverted position. In other words, the prints indicated the bottle was held upside down and by the bottles throat rather than its base.

Jeff Wests attorney, however, said he didnt believe Kat West was killed. She fell and hit her head, Robbins said. Theres no murder here.

A state medical examiner called by the prosecution testified that the wound to Kat Wests skull was so significant that it was not likely to have been caused by a fall.

Alabama Department of Forensic Sciences pathologist Dr. Stephen Boudreau said the laceration to Kat Wests skull was two inches long with the skin split open and contusions surrounding the wound.

The force of the blow and subsequent brain bleed, Boudreau said, pushed the brain down to the stem with deadly results.

It was a considerable amount of force to cause an injury like that, the doctor said. Kat West would likely have lost consciousness immediately, he said. Scalp wounds bleed like mad...its (the brain) a very vascular structure.

Asked if it was possibly to get that type of injury from a fall, Boudreau said it wasnt likely, especially at her height of 5-feet, 2-inches. The doctor said Kat West died from blunt force trauma. Whatever it was had an edge, but it wasnt sharp, he said of the object he believes caused her death.

Boudreau also testified that Kat Wests blood alcohol content was .23, nearly three times the legal limit to drive, and said urine and eye fluid toxicology testing indicated that at some point that night her alcohol levels would have been significantly higher.

Kat West had some bruises on her right leg in varying stages of healing that werent likely due to whatever incident caused her death, Boudreau testified. She also had a fresh injury to her toe that probably happened in the same time frame of the fatal head injury.

Home of Jeff and Kat West on Greenwood Circle in Calera.

Robbins said while the couple had arguments, like most married couples do, there was no discord or threat of violence in the marriage -- especially not that night.

Both sides discussed frequent text messages between the two. While the prosecution pointed out frequent arguments via text mostly one-sided with Kat West being the verbal aggressor Jeff Wests attorney also tried to use them to his advantage.

In December, about three weeks before Kat Wests death, she accused her husband via text of throwing away 14 years of marriage. Another text read, Im never doing this holiday again with you.

But text messages exchanged between the two on the day of the killing showed them making plans for that night and using terms of endearment with one another. The couple had matching tattoos on their wrists that read 4Life and often ended their texts with 12345 meaning I love you for life or 123, meaning I love you.

Jurors also heard testimony about forensics found on Kat Wests phone, which included the phones Health App, showing the number of steps she took, or where her phone was, the night authorities believe she was killed. The last time her phone moved, according to the data, was at 1054 p.m. and recorded 87 steps.

Data from the ADT alarm system showed the front door to the West home opened at 10:53:01 p.m. on Jan 12, 2018 and closed at 10:53:11 p.m. It opened again at 1:51:46 a.m. and remained open until 5:12:45 a.m., at which time it closed.

Jeff West had told investigators he fell asleep about 10:30 p.m. and didnt wake up again until 5:15 a.m. when he was awakened by his dogs barking at the fleet of police vehicles outside of his home. Though he said he went to bed at 10:30 p.m., testimony from his Health App phone data showed he took 18 steps from 11:03 p.m. until 11:10 p.m.

Robbins pointed out that that no blood or DNA was found on Jeff Wests clothes or his hands. And, Robbins said, no hair or scalp or brain tissue was found on the Lucid Absinthe bottle. Theres no suggestion of a struggle or fight in the house, Robbins said.

Jeff West, the attorney said, cooperated with police throughout the entire interrogation, voluntarily giving them permission to search the couples phones. He addressed the observation that Jeff West showed little to no emotion in the lengthy videotaped interview with police.

People deal with stressful situations, trauma, in different ways,' Robbins said. Not everybody stands there and cries. Hes a trained soldier. Soldiers are trained to keep their emotions in check.

Jeff West initially was expected to take the stand in his defense. However, he later spoke with his family and told the judge he would instead stay silent.

Go here to read the rest:
Kat Wests husband, Jeff West, sentenced to 16 years in wifes death - AL.com

Excitement took wing in the scientific community in the early 1990s, when the first gene therapy trial showed significant success, only to crash at the end of the decade with a patients tragic death.

Twenty years later, the excitement is back and greater than before. Although safety remains a concern, investigators are breaking ground in cell and gene therapy, and many believe that ultimately, a string of cured cancers will follow.

In 2017, the excitement over these therapies returned in spades when the FDA signed off on a cell-therapy drug for the first time, approving the chimeric antigen receptor (CAR) T-cell treatment tisagenlecleucel (Kymriah; Novartis) for patients with B-cell precursor acute lymphoblastic leukemia. At last, scientists had devised a way to reprogram a persons own T cells to attack tumor cells.

Were entering a new frontier, said Scott Gottlieb, MD, then-FDA commissioner, in announcing the groundbreaking approval.

Gottlieb was not exaggerating. The growth in CAR T-cell research is exploding. Although only a handful of cell and gene therapies are on the market, the FDA predicted in 2019 that it will receive more than 200 investigational new drug applications per year for cell and gene therapies, and that by 2025, it expects to have accelerated to 10 to 20 cell and gene therapy approvals per year.

We can absolutely cut the number of cancer deaths down so that one day in our lifetimes it can be a rare thing for people to die of cancer, said Patrick Hwu, MD, president and CEO of Moffitt Cancer Center in Florida and among gene therapys pioneers. It still may happen here and there, but itll be kind of like people dying of pneumonia. Its like, He died of pneumonia? Thats kind of weird. I think cancer can be the same way.

Essentially, you can kill any cancer cell that has an antigen that is recognized by the immune cell, Hwu said. The key to curing every single cancer, which is our goal, is to have receptors that can recognize the tumor but dont recognize the normal cells.

Community oncologists will need to be increasingly familiar about the various products, including their immediate and longer-term risks, Bo Wang, MD, and Deepu Madduri, MD, recently wrote in OncologyLive.1 It is key to understand the optimal time for referring these patients to an academic institution, as well as how to manage the requisite post CAR T-cell therapy in the community setting. Madduri is an assistant professor of medicine, hematology and medical oncology, as well as associate director of cellular therapy service, and director of clinical operations with the Center of Excellence for Multiple Myeloma at The Tisch Cancer Institute and the Icahn School of Medicine at Mount Sinai in New York, New York. Wang is a third-year clinical fellow in hematology/oncology at Mount Sinai.

Early referral to academic centers and hospitals equipped to deliver therapies is crucial for patients eligible for therapy. However, as advances continue in the field, community practices may be called upon to administer therapies in their clinic.

The Community Oncology Alliance (COA) envisions a broader role for the settings in which CAR T-cell therapies can be administered. When the Centers for Medicare & Medicaid Services (CMS) was considering coverage for CAR T-cell therapies in 2019, COA officials argued against limiting approvals to hospitals.

It is important to understand that there are state-of-the-art community oncology practices that have significant experience and capabilities in administering highly complex treatments, COA officials wrote in a letter to CMS. For example, stem cell transplants, which are similar in complexity to CAR T therapy, are performed successfully in the community oncology practice setting.2

Broader use of gene therapies depends on several factors, including navigating the logistics of gene therapies, addressing the high costs, and managing toxicities.3

Autologous CAR T-cell therapies involve a manufacturing process that requires coordination between the treating facility and the processing facility. Following leukapheresis, patients may require maintenance therapy to control disease progression during the manufacturing time, which can take 3 to 5 weeks.

In terms of cost, gene and cell therapies can cost from $375,000 to $475,000 per dose and they may face coverage restrictions from payers. Approvals could take weeks to obtain.3,4

Because of cytokine release syndrome and neurotoxicities associated with CAR T-cell therapy, the FDA mandates risk evaluation and mitigation strategy training for centers.

Further, providers may find that real-world experiences with gene therapies are different from those seen in the clinical trial setting, according to Ankit J. Kansagra, MD.

In a presentation at the 2020 American Society of Clinical Oncology Virtual Education Program, Kansagra, an assistant professor of medicine and Eugene P. Frenkel, MD, Scholar in Clinical Medicine at Harold C. Simmons Comprehensive Cancer Center in Dallas, Texas, said that in practice patients may be older and have more aggressive disease, with double- and triple-hit lymphomas.4

Specifically, Kansagra noted that medications such as steroids and/or tocilizumab (Actemra) to prevent or treat cytokine release syndrome or other toxicities were more frequently used in the real-world setting than what had been seen in clinical trials.

As it stands now, only a fraction of eligible patients are receiving CAR T-cell therapies, Kansagra said. Potentially, 9750 patients a year may be eligible for CAR T-cell therapies in approved and upcoming hematologic indications. From 2016 to 2019, a total of 2058 patients received CAR T-cell infusion.4

Next steps for transplanting these novel therapies to clinical practice will require changes in key areas, Kansagra said, such as supply chain management, patient support, and financial systems (Figure).4

Figure. Next Steps for Effective Delivery of Gene and Cell Therapies4

Meanwhile, multiple myeloma experts advise providers to be ready for change. As commercially available myeloma CAR T-cell therapies are approved, it will be even more important for community oncologists to better understand these therapies so they can offer them to their patients, Wang and Madduri wrote.1

Cell therapy involves cultivating or modifying immune cells outside the body before injecting them into the patient. Cells may be autologous (self-provided) or allogeneic (donor-provided); they include hematopoietic stem cells and adult and embryonic stem cells. Gene therapy modifies or manipulates cell expression. There is considerable overlap between the 2 disciplines.

Juliette Hordeaux, PhD, senior director of translational research for the University of Pennsylvanias gene therapy program, is cautious about the FDAs predictions, saying shed be thrilled with 5 cell and/or gene therapy approvals annually.

For monogenic diseases, there are only a certain number of mutations, and then well plateau until we reach a stage where we can go after more common diseases, Hordeaux said.

Safety has been the main brake around adeno-associated virus vector [AAV] gene therapy, added Hordeaux, whose hospitals program has the institutional memory of both Jesse Gelsingers tragic death during a 1999 gene therapy trial as well as breakthroughs by 2015 Giants of Cancer Care winner in immuno-oncology Carl H. June, MD, and others in CAR T-cell therapy. Sometimes there are unexpected toxicity [events] in trials.I think figuring out ways to make gene therapy safer is going to be the next goal for the field before we can even envision many more drugs approved.

In total, 3 CAR T-cell therapies are now on the market, all targeting the CD19 antigen. Tisagenlecleucel was the first. Gilead Sciences received approval in October 2017 for axicabtagene ciloleucel (axi-cel; Yescarta), a CAR T-cell therapy for adults with large B-cell non-Hodgkin lymphoma. Kite Pharma, a subsidiary of Gilead, received an accelerated approval in July 2020 for brexucabtagene autoleucel (Tecartus) for adults with relapsed/ refractory mantle cell lymphoma.

Another CD19-directed therapy under FDA review for relapsed/refractory large B-cell lymphoma, is lisocabtagene maraleucel (liso-cel; JCAR017; Bristol Myers Squibb). Idecabtagene vicleucel (ide-cel; bb2121; Bristol Myers Squibb) is under priority FDA review, with a decision expected by March 31, 2021. The biologics license application for ide-cel seeks approval for the B-cell maturation antigendirected CAR therapy to treat adult patients with multiple myeloma who have received at least 3 prior therapies.5

The number of clinical trials evaluating CAR T-cell therapies has risen sharply since 2015, when investigators counted a total of 78 studies registered on the ClinicalTrials. gov website. In June 2020, the site listed 671 trials, including 357 registered in China, 256 in the United States, and 58 in other countries.6 Natural killer (NK) cells are the research focus of Dean A. Lee, MD, PhD, a physician in the Division of Hematology and Oncology at Nationwide Childrens Hospital in Columbus, Ohio. He developed a method for consistent, robust expansion of highly active clinical-grade NK cells that enables repeated delivery of large cell doses for improved efficacy. This finding led to several first-in-human clinical trials evaluating adoptive immunotherapy with expanded NK cells under an FDA investigational new drug application. Lee is developing both genetic and nongenetic methods to improve tumor targeting and tissue homing of NK cells. His efforts are geared toward pediatric sarcomas.

The biggest emphasis over the past 20 to 25 years has been cell therapy for cancer, talking about trying to transfer a specific part of the immune system for cells, said Lee, who is also director of the Cellular Therapy and Cancer Immunology Program at Nationwide Childrens Hospital, at The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital, and at the Richard J. Solove Research Institute.

However, Lee said, NKs have wider potential. This is kind of a natural swing back. Now that we know we can grow them, we can reengineer them against infectious disease targets and use them in that [space], he said.

Lee is part of a coronavirus disease 2019 (COVID-19) clinical trial, partnering with Kiadis, for off-the-shelf K-NK cells using Kiadis proprietary platforms. Such treatment would be a postexposure preemptive therapy for treating COVID-19. Lee said the pivot toward treating COVID19 with cell therapy was because some of the very early reports on immune responses to coronavirus, both original [SARS-CoV-2] and the new [mutation], seem to implicate that those who did poorly [overall] had poorly functioning NK cells.

The revolutionary gene editing tool CRISPR is making its initial impact in clinical trials outside the cancer area. Its developers, Jennifer Doudna, PhD, and Emmanuelle Charpentier, PhD, won the Nobel Prize in Chemistry 2020.

For patients with sickle cell disease (SCD), CRISPR was used to reengineer bone marrow cells to produce fetal hemoglobin, with the hope that the protein would turn deformed red blood cells into healthy ones. National Public Radio (NPR) did a story on one patient who, so far, thanks to CRISPR, has been liberated from the attacks of SCD that typically have sent her to the hospital, as well from the need for blood transfusions.7

Its a miracle, you know? the patient, Victoria Gray of Forest, Mississippi, told NPR.

She was among 10 patients with SCD or transfusion-dependent beta-thalassemia treated with promising results, as reported by the New England Journal of Medicine.8

Stephen Gottschalk, MD, chair of the department of bone marrow transplantation and cellular therapy at St Jude Childrens Research Hospital, said, Theres a lot of activity to really explore these therapies with diseases that are much more common than cancer.

Animal models use T cells to reverse cardiac fibrosis, for instance, Gottschalk said. Using T cells to reverse pathologies associated with senescence, such as conditions associated with inflammatory clots, are also being studied.

CAR T, I think, will become part of the standard of care, Gottschalk said. The question is how to best get that accomplished. To address the tribulations of some autologous products, a lot of groups are working with off-the-shelf products to get around some of the manufacturing bottlenecks. I believe those issues will be solved in the long run.

See the article here:
Harnessing the Potential of Cell and Gene Therapy - OncLive

Ibram X. Kendi: What I learned from cancer

This is where I find myself, at the threshold between an old familiar state and an unknown future. Cancer no longer lives in my blood, but it lives on in other ways, dominating my identity, my relationships, my work, and my thoughts. Im done with chemo but I still have my port, which my doctors are waiting to remove until Im further out of the woods. Im left with the question of how to repatriate myself to the kingdom of the well, and whether I ever fully can. No treatment protocols or discharge instructions can guide this part of my trajectory. The way forward is going to have to be my own.

My first foray into this new selfhood is learning how to drive. As I get more comfortable behind the wheel, a hazy idea begins to crystallize into a grand plan. I need to leave the familiar, to trust that I can navigate the world alone. I need to become my own caregiver. It took me a while to say I was a cancer patient. Its time for me to figure out who I am now. By the time I finally pass my drivers test, the next step is obvious: Im going to embark on a solo cross-country road trip.

Over the next few weeks, I pack all of my belongings into boxes, put the boxes into storage, and sublet my apartment. I cant afford to buy my own car but my friend Gideon generously offers the use of his old Subaru. Between the extra income from renting out my apartment and the $4,000 in my savings account, I should be able to make do. I plan to camp and crash on couches as often as possible, staying in only the occasional motel room. I scour Craigslist for secondhand camping gear and buy a portable propane gas stove, a subzero sleeping bag, a foam bedroll, and a tent. I pack all this, along with a crate of books, a first-aid kit, a camera, and a sack of kibble for my scruffy terrier mutt, Oscar, into the car. Before leaving, I go in for a last checkup with my oncologist.

My road trip will take me 15,000 miles across 33 states. It will last 100 days, the maximum amount of time my medical team has agreed to until my next follow-up appointment. As I turn the keys in the ignition and drive away from New York City, I realize that this is a rite of passage that I hope will bridge the distance between no longer and not yet.

Either my GPS is a liar or I am an erratic driver, but I always seem to take nearly twice as long as it predicts to get to where Im going. Take a right turn inrecalculating its robotic voice says condescendingly when I miss yet another exit. My next destination, Columbus, Ohio, will entail my longest drive yet. The GPS predicts that, if I follow its barrage of orders exactly as told, I will arrive in nine hours and 21 minutes. Unlikely.

Since hitting the road, Im on no ones clock but my own.

Two weeks earlier, when I first left home, I was so tense that I regularly had to remind myself to breathe. Each minute behind the wheel presented new and overwhelming scenarios: Do I have the right of way? What does a blinking red light mean? Was that an Egyptian hieroglyph on the traffic sign? Lane changes and merging onto the freeway had proved especially stressfulan existential guessing game of will I live or will I not. But with each day, I am feeling more confident, and it has been at least 72 hours since another driver has honked at me in anger or bewilderment.

Originally posted here:
I Survived Cancer, and Then I Needed to Remember How to Live - The Atlantic

Introduction

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by a reciprocal chromosomal translocation which forms the abnormal BCR-ABL1 fusion gene because of an acquired reciprocal t (9; 22) (q34; q11) translocation. The disease is traditionally described as manifesting in one of the three distinct clinical phases: chronic phase (CP), accelerated phase (AP), and blast crisis (BC).1 The introduction of tyrosine kinase inhibitors (TKIs) dramatically improved the outcomes of patients with CML. At present, patients with chronic phase CML (CML-CP) can attain long-term survival.2,3 The Sokal, Hasford, and European Treatment and Outcome Study (EUTOS) scores are used to determine the prognosis of CML patients. However, there are still some patients in which the treatment failed and their CML-CP transformed to CML-AP or CML-BC.46 Hoffmann VS et als team reported that 3.114% of CML patients had progressive clinical features at diagnosis or during long-term follow-up.7 In previous studies, clinical workers usually focused on the effect of treating CML-CP patients with TKIs.8,9 Although the prognosis of patients with CML-CP is accurate, the characteristics and markers for determining the prognosis of the advanced phase of CML are still not clear. The BCR-ABL1 transcript and somatic variants in epigenetic modifiers were confirmed, and these can be used to predict the response to imatinib.10,11 Lauseker M et als study determined that blast counts, age, chromosomal aberrations, and hemoglobin are the prognostic factors for patients with advanced phase.12 In another study, the results showed that many factors such as myeloid immunophenotype, treatment with TKIs before transformation to CML-BC, patients' age, and platelet counts <102109/L could predict poor survival rates in CML-BC patients.13 Studies have discovered various prognostic factors that are related to chronic or advanced phase of CML. However, for patients diagnosed with CML the factors that can be used to determine their prognosis and survival outcomes are still not clear.

During follow-up periods, a complete Blood Count (CBC) is used to assess the effect of treating CML patients with TKIs.14 The red blood cell distribution width (RDW) is a simple parameter that is part of the standard full blood count and measures of the heterogeneity in the size of a circulating patients erythrocytes. The RDW is provided by automated hematology analyzers and it reflects the distribution of the red blood cell (RBC) volume.15 There is increasing evidence that an elevated RDW is associated with a poor prognosis for people in the general population,16,17 as well as in patients with coronary artery disease,1820 metabolic syndrome,21 and heart failure.22,23 Traditionally, RDW has been used in the investigation of the etiology of anemia.24 The previous study only used the upper limit of the normal RDW range (RDW value 15.0%) to predict the prognosis and the response of CML-CP patients to treatment.25 However, it may not be suitable for determining the prognosis of CML patients when they are diagnosed at their first admission. Yuta Baba et als team identified a new RDW cutoff using different clinical outcomes of patients with myelodysplastic syndrome.26 Therefore, the hypothesis that different RDW values indicate the occurrence and the different phases of CML is proposed. In addition, it is suggested that assessing patients RDW is more favorable for assessing their treatment and for their follow-up evaluations.

The present study found that RDW was temporarily elevated when the CML-CP of patients transformed to the advance phase. The present study used X-tile software and data from a training and validation cohort established the most suitable RDW cutoff value based on the different phases of CML. In addition, univariate and multivariate analyses were used to determine which factors are associated with the advanced phase of CML in all patients. Based on the records of the patients, the role of RDW as a predictor of the prognosis and survival outcomes of the patients was also confirmed in the present study.

Our study retrospectively reviewed 153 CML patients from January 2009 to December 2019 at the Second Affiliated Hospital & Yuying Childrens Hospital of Wenzhou Medical University. The patients were all over 18 years of age and were treated with TKIs and their outcome was followed up for at least 12 months. CML-CP and CML-AP/BC were diagnosed according to the European Leukemia Net (ELN2013) criteria.27

The criteria for excluding patients from the present study were: patients age <18 years (n = 19); patients data were not completed (n = 11); patients without follow-up data (n = 7); patients initially treated with interferon- (n = 8); patients treated with any chemotherapeutic agent prior to or in combination with TKI treatment (n = 6); patients that received a blood transfusion prior to TKI treatment (n = 9); patients that received a hematopoietic stem cell transplant during follow-up (n = 8); and patients who had an NYHA grade of III/IV (n = 3). The framework and criteria used to select patients for inclusion in the present study are described in Figure 1.

Figure 1 Flow chart of the criteria used to select the patients for inclusion in the present study.

The clinical characteristics of the patients that were recorded included their age, gender, history of smoking, Splenomegaly, history of cardiovascular system diseases, and with what they were initially treated. We defined a patient as a nonsmoker if they had never smoked or had smoked less than 100 cigarettes in their lifetime. All others were classified as smokers. The detailed clinical information of the patients is summarized in Table 1. The definitions of a partial cytogenetic response (PCyR), a major molecular response (MMR), and a complete cytogenetic response (CCyR) were in accordance with the recommendations of the ELN 2013. The categories of response to treatment with TKIs included optimal, warning, and failure responses, and were defined according to the ELN 2013 recommendations.27

Table 1 Clinical Characteristics of the CML Patients

The overall survival (OS) of a patient was defined as the length of time from diagnosis to death or the last follow-up. Event-free survival (EFS) was defined as the time period from the date of diagnosis to the date of the first event or the last follow-up. Events were defined as either two consecutive confirmations of a loss of CCyR, the transformation of CML-CP to CML-AP/BC, or any cause of death. Transformation-free survival (TFS) was defined as the period from the date of the diagnosis when the patients CML-CP transformed to CML-AP/BC or the last follow-up. All of the patients consented to participate in the present study by signing an informed consent form. The present study was approved by the Research Ethics Board of The Second Affiliated Hospital & Yuying Childrens Hospital of Wenzhou Medical University (Number: LCKY2020-430) and it was conducted in accordance with the Declaration of Helsinki.

In our study, the CBC was obtained from patients peripheral venous blood using a Sysmex XI5000, Japan. The RDW values at diagnosis were obtained prior to treatment. Accordingly, the range 11.6~15.0% was considered normal.

To avoid overfitting and to analyze the interobserver reproducibility of the RDW values, the CML patients were randomly assigned to training cohort (n = 106; 70%) and validation cohort (n = 47; 30%) using R software version 3.0.1 (http://www.R-project.org). The distribution of the p value of the RDW cutoff value was determined using X-tile software, version 3.6.1 (Yale University School of Medicine, New Haven, Conn) and also confirmed using the training cohort, which included patients with advanced phase.

The statistical analyses were performed using the software SPSS V. 26.0 (SPSS; Chicago, IL, USA). Categorical data were compared between groups using Fishers exact test or the chi-square test. Continuous data were compared using the t-test. The relationship between the clinical features and the advanced phase of CML were analyzed using univariate and multivariate analyses. The KaplanMeier method was used to analyze OS, EFS, TFS, and the CML-associated deaths. The Log rank test was used to compare OS, EFS, TFS, and CML-associated deaths between groups of patients with low and high RDW values. A p value less than 0.05 was considered statistically significant.

The 153 CML patients included in the present study consisted of 137 and 16 newly diagnosed CML-CP and CML-AP/BC patients, respectively. During follow-up examinations, the CML-CP of 11 patients was determined to have transformed to CML-AP/BC. One-hundred and eighteen of the 137 patients with CML-CP had RDW values higher (86.13%; range 13.3~22.9%) than the normal range. The 16 patients diagnosed with CML-AP/BC when diagnosed all had RDW values (100%; range 15.2~19.9%) that were higher than the normal range.

The patients in the high RDW group had higher WBC counts (p < 0.001), lower hemoglobin levels (p < 0.001), lower RBC counts (p < 0.001), higher RDW when diagnosed (p < 0.001), a higher probability of splenomegaly, and higher probabilities of blast and eosinophils in the peripheral blood (p < 0.05) compared to patients in the low RDW group and in the training cohort, whereas, when comparing patients in the high and low RDW groups, no differences were observed in their ages, gender, platelet count, history of smoking, or diseases of their cardiovascular systems (Table 1). Furthermore, based on patients in the validation cohort, differences in the WBC count, hemoglobin level, RBC count, and RDW when diagnosed were also found for patients in the low and high RDW groups in the validation cohort (p < 0.05). No statistical differences were observed in any of the other clinical features (Table 1). Our study also additionally analyzed the differences in patients with CP between low and high RDW groups in patients with CP (Supplement Table 1).

There were 137 newly diagnosed CML-CP patients, 16 newly diagnosed CML-AP/BC patients, and 11 patients developed to CML-AP/BC during the followed period. Besides, our study also collected 168 healthy peoples RDW value, who did not have tumors and other diseases (age; range 18~68 years). There were significant differences in RDW value among Normal and CML-CP groups (p < 0.001; Figure 1A), Normal and CML-AP/BC groups (p < 0.0001; Figure 2A), CML-CP and CML-AP/BC groups (p = 0.0003; Figure 2A).

Figure 2 (A) Differences in the RDW values between healthy people (normal, n = 168) and patients with CML-CP (n = 137) and CML-AP/BC (n = 27). (B) The distribution of the p values of the different RDW cutoff values of the patients (n = 106) in the training cohort (***p<0.001).

Application of the X-tile software to the training cohort (n = 106, 90%) determined that an RDW value of 16.8% distinguished between patients with CML-CP and CML-AP/BC (p = 0.0069, Figure 2B). Application of the KaplanMeier method to the training (p = 0.0028, Figure 3A) and validation cohort (p = 0.0221, Figure 3B) showed that patients in both cohorts with higher RDW values have significantly shorter OS than patients with low RDW values. Furthermore, the distribution of patients in the training (Figure 3C) and validation (Figure 3C) cohorts with advanced phase CML in the high and low RDW groups are also shown.

Figure 3 The overall survival of patients in the training (A) and validation (B) cohorts. The distribution of patients in the training (C) and validation (D) cohorts with advanced phase CML and in the high and low RDW groups which were based on the RDW cutoff value.

To further prove the practicality of using this RDW cutoff value to predict the CML phase, Spearmans rank correlation coefficient was used to determine if there is a correlation between RDW values and blast cells in the bone marrow when diagnosed. The result showed that the RDW value is a better factor for predicting patients with the advanced phase (p = 0.011; r = 0.543) than patients with CML-CP.

Our study investigated the extent to which the RDW value could predict CML patients response to treatment as measured using the recommendations of the ELN 2013. Compared to the CML patients in the low RDW group, the CML patients in the high RDW group were associated with a significantly poorer response to treatment after 3, 6, and 12 months after the commencement of treatment (Table 2).

Table 2 Associations Between RDW and the Responses Treatment with TKIs

The OS (p = 0.0008; Figure 4A) and EFS (p = 0.0221; Figure 4B) of patients in the high RDW group were significantly less than that of the patients in the low RWS group, respectively. Furthermore, the CML-associated deaths were significantly higher in patients with advanced CML (83.3%) compared to patients with CML-CP and with high (14.5%) and low (2.4%) RDW values (p < 0.001; Figure 4D). The RDW values could not be used to predict TFS (p = 0.0821; Figure 4C).

Figure 4 The relationship between CML-CP patients with low and high RDW values and their (A) OS, (B) EFS, and (C) TFS. (D) The death rates of patients with CML-CP in the low and high RDW groups, and those with advanced phase CML, respectively.

To evaluate the correlation between the RDW values and the therapeutic effect of TKIs, the dynamic changes in the RDW values of CML patients following treatment over time with TKIs were analyzed. The RDW value was initially elevated at 1 month (median 16.6% when diagnosed and 17.6% after 1 month of treatment; p = 0.001, Figure 5A) but declined significantly after 3 months (median 15.7% at 3 months; p = 0.001 Figure 4A) of treatment with TKIs. Furthermore, compared with the RDW values of the CML patients at diagnosis, the RDW values were significantly lower after 6 months of treatment with TKIs treatment (median14.5%; p < 0.001, Figure 5A).

Figure 5 (A) Changes in the RDW value of patients with CML that were treated over time with TKIs. (B) Changes in the RDW values in the different groups of CML patients that were treated over time with TKIs. (**p<0.01; ***p<0.001).

To compare the longitudinal changes of the RDW values between patients in the low and high RDW groups, the patients with CML-CP were compared with patients with CML-CP and advanced CML, ie, all-CML. The RDW values of the patients in all CML and low RDW groups at diagnosis returned to the normal range after 6 months of treatment with TKIs (Figure 5B).It took 2 years for the patients in, while the high RDW group patients tend to return to the normal range in 2 years (Figure 5B).

The univariate analysis showed that ages (OR, 1.063; 95% CI, 1.029~91.098; p < 0.001), WBC counts (OR, 0.214; p < 0.001), RBC count (OR, 0.594; 95% CI, 0.356~0.992; p < 0.001), hemoglobin level (OR, 0.970; 95% CI, 0.952~0.989; p = 0.047), RDW value when diagnosed (OR, 1.264; 95% CI, 1.024~1.559; p = 0.029), platelet count (OR, 0.997; 95% CI, 0.996~0.999; p = 0.006), eosinophil in PB (OR, 0.214; p < 0.001), basophil in PB (OR, <0.001; 95% CI, 1.029~91.098; p < 0.001), history of cardiovascular system disease (OR, 1.648; 95% CI, 1.103~2.463; p = 0.001) were all significantly associated with advanced phase (Table 3). However, gender, history of smoking, and splenomegaly were not associated with the advanced phase (Table 3).

Table 3 Univariate and Multivariate Analyses of Factors for the Advanced Phase in All Patients

The multivariate analysis showed that age (OR,1.081; 95CI% 1.039~1.125; p < 0.001), being a female (OR,0.332; 95CI% 0.119~0.926; p = 0.035), platelet count (OR,0.997; 95CI% 0.994~0.999; p=0.001), RDW value when diagnosed (OR,1.469; 95CI% 1.121~1.925; p=0.005) were correlated with advanced phase, but while not any of the other variables (Table 3).

CML is a neoplastic disease, and its genetic and cytogenetic changes play important roles in the prognosis and treatment process of patients. Our study demonstrated that higher RDW values are an adverse prognostic and survival outcomes biomarker for CML-CP patients. The multivariate analysis demonstrated that age, platelet count, and RDW at diagnosis were related to the advanced phase. Consequently, the dynamic changes of the RDW values of CML patients could help clinical workers manage the follow-up treatment of the patients. In agreement with the significance of responses to early treatment, the RDW value at diagnosis also predicted the outcomes, because it reflected an early response at 3 months, to treatment.28 The vast majority of CML patients are diagnosed with CML-CP. However, some patients present with features of advanced phase at diagnosis. Most studies analyzing prognostic factors and survival outcomes for CML-AP/BC refer to patients that developed this advanced phase of CML from an initial diagnosis of CML-CP.29,30 The results of these studies indicate that despite the availability of TKIs, the treatment options and the outcome for these patients are still poor. After transformation from CML-CP to CML-BC, the median survival time in a German CML-study IV was 7.9 months.13 Therefore, there is still a need for more markers to predict the advanced phase and for the prognosing patients with CML-CP. Detection of the BCR-ABL1 transcript level is the gold standard method for monitoring CML minimal residual disease and the optimal management of CML patients.31 Although there are many emerging technologies, such as digital PCR, to detect the transcription level of BCR-ABL1,3234 RDW detection is a widely available and inexpensive test that is performed as part of the complete blood count. It is important to point out that the average lifespan of RBCs is 120 days; thus, RDW could be used as an indicator during the long-term follow-up of patients with CML.

Our study showed that RDW plays an important role in determining the prognosis and the effect of treatment with TKIs. What follows is a description of the reasons why RDW plays a key prognostic role in CML. It is well established that the RDW value is elevated when the destruction of RBCs increases or there is an increase in the production of infective defective RBCs.15 CML is a specific disease in which the CML stem cells have to differentiate towards the erythroid cell lineage, resulting in the involvement of malignant clone-derived erythropoiesis.35 Some studies have recently revealed that patients harboring IDH1/2 and ASXL1 mutations had significantly higher RDW values than those without these mutations.36,37 Furthermore, these mutations are often present in CML cells and are associated with the status of the disease in CML patients.37 Although baseline prognostic factors for the efficacy of treatment with second TKIs have not yet been determined, the multiple predictors for the efficacy of treatment with imatinib have already been reported. A recent study showed that the Sokal low and medium/high groups responded equally to dasatinib treatment.38 Another study proved that Treatment-Free Remission after second-line nilotinib treatment in patients with CML-CP was greatly improved and none had CML progression to AP or BC.39 However, in our study, only 14 patients chose to be treated with the second TKIs treatment. We did not make a distinction between patients treated with first and second TKIs in our study, we analyzed the change in RDW values of patients treated with TKIs as a whole.

We were aware of some limitations in our study. Our study split the 153 patients into a training and validation cohort for the internal validation. However, the sample size of the CML patients that enrolled in the study was not large and the results of single-center retrospective cohort studies are not generalizable to other populations.

The stratification of CML patients according to their RDW value can be used to determine their prognosis, survival outcomes, and advanced phase. This stratification is beneficial to subsequent treatment. To avoid CML-CP transforming to advanced phase, patients whose RDW 16.8% when diagnosed need more time for follow-up. In the future, we will validate these findings in a larger population, which may provide new insights into CML therapy and follow-up treatment.

This work was supported by the Natural Science Foundation of Zhejiang Province, China [No. LY18H200006], Science and Technology Planning Project of Wenzhou, Zhejiang, China (No. Y20180108), Basic Public Welfare Technology Research Project of Zhejiang Province [LGF20H200005], and the Lin Hes New Medicine and Clinical Translation Academician Workstation Research Fund [18331203].

The authors report no conflicts of interest in this work.

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[Full text] Higher Red Blood Cell Distribution Width is a Poor Prognostic Factor f | CMAR - Dove Medical Press

An emotional programme is set to air about West Belfast woman Eimear Gooderham who passed away in 2019.

She sadly died after undergoing a stem cell transplant as part of her cancer treatment.

UTV presenter Sarah Clarke first met Eimear back in 2018 when, with she and her family made a desperate appeal for more people to join the stem cell register.

This was Eimear's only hope, after the return of her cancer and her family members not being a match.

Sarah kept in touch with the family and, when a match was found, Eimear recorded video diaries charting her treatment in Dublin to be incorporated into a UTV programme about her journey.

Whilst the transplant itself was successful, Eimear sadly suffered complications from the treatment and passed away.

Eimear's Wish tells her story, much of it in her own words from extracts from her video diary.

Her Dad Sen and sister Seinn, share memories of Eimear, give their perspectives on what happened, talking about the positive ways they have been dealing with their grief since she passed away.

A consultant haematologist also gives an insight into the impact of stem cell transplants, and of the hope that this type of surgery can offer, with Sean reiterating that Eimear's Wish is to have more people sign up to the donor register.

Sen said: We hope the programme will highlight the need for more people in Northern Ireland to join the stem cell donor register, especially young men aged between 16 and 30.

"They produce more and stronger stem cells than any other group, and crucially they dont get pregnant, as women cant donate stem cells during pregnancy and for 12 months afterwards. There is also a lack of age-appropriate care for teenagers and young adults with life threatening illnesses such as blood cancer.

"The current facilities and the environment in which our teenagers and young adults receive their treatment and care is very poor. There also needs to be better facilities for the childrens carers.

Sarah added: It was Eimears dying wish to raise awareness of stem cell donation and to help further research into the treatment to help others. And although this programme is an entirely different one from the one we set out to make, I hope that it will in some way help to do that.

Are you a lover of Style, Beauty or Interiors? Maybe you want the latest tips on keeping fit, eating right, organising your home and staying well, not to mention all the latest showbiz goss and the craic around town? If that sounds right up your street then follow Belfast Live's brand new lifestyle page Be.

You can find us on Facebook ,Twitter and Instagram.

We at UTV are very grateful that Eimear herself, before her death, and Sen and Seinn, despite their grief, shared so much in the making of the programme creating a positive and lasting legacy in this remarkable young woman's memory."

Watch Up Close Eimears Wish on UTV on Thursday 28th January at 10.45pm and on catch up HERE.

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West Belfast woman to be remembered in special TV documentary - Belfast Live

EIMEAR Gooderham (ne Smyth) was just 25 when she died peacefully in hospital with her family at her bedside.

It was just a week after she had married Phillip Gooderham in hospital and she was buried in the wedding dress she never got to wear.

Almost two years on, her family hope a television documentary about Eimear - a make-up artist from the Coolnasilla area of west Belfast - will help create a positive and lasting legacy in her memory.

The programme, due to be broadcast on UTV and presented by journalist Sarah Clarke, features Eimear's own video diaries, which she had hoped would raise awareness of a campaign for stem cell donors that she launched before her death.

Ms Clarke said the documentary had aimed to "follow Eimear's journey, treatment and her recovery".

"She was very open about her battle and while a lot of the programme is distressing, it shows how courageous Eimear was," she said.

Eimear was diagnosed with stage two Hodgkins Lymphoma, a type of blood cancer, in September 2016.

She underwent 12 cycles of intensive chemotherapy and was given the all-clear in spring 2017.

But the disease returned and in December that year, Eimear was treated with an autologous stem cell transplant, intensive chemotherapy and her own stem cells returned afterwards to rescue her bone marrow from the effect of the treatment.

Months later she was given the good news she was in remission, but the Hodgkins Lymphoma returned again and doctors said her best chance of survival was another stem cell transplant - this time from a donor.

With neither of her siblings a match, she desperately needed to find a stem cell donor.

Eimear and her father Sean launched an appeal to raise awareness of the stem cell register, which allows donors of the correct tissue types to be matched with patients.

Their campaign saw the number of people joining the register in Northern Ireland soar.

Determined to use her own experience to help others, Eimear began filming videos on her phone for the UTV documentary.

Her desire to show her cancer battle as well as her upbeat outlook on life are reflected in the diaries, with many filmed as she underwent treatment.

Speaking ahead of the broadcast tonight, Ms Clarke said her own family's cancer battle had also inspired her to tell Eimear's story.

"In 2017, my nephew Jack was diagnosed with leukaemia, aged just 15," she said.

"I remember my brother Simon, who is a doctor, saying they may have to pursue a stem cell transplant. He knew how difficult it would be to find a match and to endure.

"Fortunately Jack didn't need it, but he had to undergo a year of intensive chemo and four years of maintenance chemo.

"It was rough and a very difficult period and thankfully he's now in remission, but it made me relate to Eimear and San's appeal."

On October 31 2018 - a year before Eimear and Phillip had planned to marry - she received her stem cell transplant.

A video extract of the days after the operation shows Eimear describe how "it's been really rough", as the donor's cells began attacking her cells - a condition known as graft versus host disease.

Despite being discharged from hospital, months later she became ill again with complications associated with the transplant - she was losing her brave battle.

Phillip tells the programme: "I wanted to tell her it was going to be ok, but I didn't want to lie to her. I wanted it to be over so she wasn't in pain".

In June 2019, the couple tied the knot and Eimear got "her final wish".

"We had had it planned, we had to cancel our wedding so it was, in the most horrific circumstances, the nicest way to end her life, by her getting her final wish," said Phillip.

Eimear died on June 27 2019.

Since then her family have continued to campaign to raise awareness of stem cell donation.

Her father Sean said they hope the programme will "highlight the need for more people in Northern Ireland to join the stem cell donor register, especially young men aged between 16 and 30".

Sarah also said while the documentary is "not exactly the one we set out to make, its still one of hope and courage".

"It was Eimears dying wish to raise awareness of stem cell donation and to help further research into the treatment to help others," she said.

"She was adamant she wanted people to sign the register and raise awareness. Her family feel the onus is now on them to continue this.

"The programme pays tribute to a courageous young woman and her family's desire to create a positive and lasting legacy in her memory."

Up Close: Eimears Wish is on UTV at 10.45pm.

Link:
UTV documentary tells of young Belfast woman's lasting legacy to promote stem cell donation - The Irish News

During a Targeted Oncology Case Based Peer Perspectives Roundtable event, Loretta J. Nastoupil, MD, associate professor, director, Lymphoma Outcomes Database, section chief, New Drug Development, in the Department of Lymphoma/Myeloma, Division Cancer Medicine, at The University of Texas MD Anderson Cancer Center, discussed the case of a 74-year-old patients with diffuse large B-cell lymphoma.

Targeted OncologyTM: What are the potential second- and third-line therapy options for this patient at this point in their treatment?

NASTOUPIL: The current NCCN [National Comprehensive Cancer Network] guidelines...look like a laundry list of a number of different therapeutic options and [do] not necessarily provide an algorithm for what might be the preferred choice based [on] certain patient characteristics.1 It just signifies that there may be several different chemoimmuno-therapy approaches and then even some potential targeted therapy approaches.

Then in the third line, CAR [chimeric antigen receptor] T-cell therapy becomes an option for patients.

Why is the tafasitamab and lenalidomide regimen listed in this poll? What is the rationale for combining these agents?

For those who may not be familiar, tafasitamab is a naked CD19 antibody, not a CAR T therapy. Its not an antibody-drug conjugate but a naked antibody engineered for enhanced ADCC [anti- body-dependent cellular cytotoxicity].

Tafasitamab and lenalidomide were approved in July 2020 for the treatment of DLBCL.2 Its an interesting label in that it is approved for patients who are not transplant candidates, and so that raises the question of how you define a nontransplant candidate. Its approved in combination withlenalidomide, 25 mg dosed 1 through 21 of a 28-day cycle; the lenalidomide is continued for a maximum of 12 cycles, but the tafasitamab is continued as monotherapy until disease progression or intolerance.

Tafasitamab was engineered for enhanced ADCC and direct cell death. Investigators saw encouraging activity in a phase 1 trial as a single agent. Then the rationale for combination with lenalidomide is because of the enhanced ADCC and because of activity seen with rituximab [Rituxan] and lenalidomide across a number of B-cell lymphoma subtypes. It was felt that this might be an interesting synergistic combination, and then [investigators] set out to explore it further in this phase 2 study in relapsed/refractory DLBCL.

Which trial looked at this combination, and what was the design?

The L-MIND study [NCT02399085] was an open-label, multi-center study.3 [Investigators] evaluated patients with relapsed/ refractory DLBCL. Now some important eligibility criteria are worth noting. They restricted eligibility to patients who had had 1 to 3 prior lines of therapy, so this is not a heavily pretreated patient population.

Patients who were ineligible for high-dose chemotherapy or autologous stem cell transplant were evaluated. There are not agreed-upon criteria for whos not a transplant candidate, other than failing to have chemotherapy-sensitive disease. But because this [trial] would enroll patients whod only had 1 prior line of therapy, that opens the discussion to how you would define a nontransplant candidate. This was done in a number of European sites where age alone is a factor, so generally patients over the age of 70 are deemed not appropriate candidates for stem cell transplant; its one of the more common criteria that were applied for defining this patient population.

The study schema outlined the dosing of lenalidomide at 25 mg [daily], which is standard in multiple myeloma studies. Its a bit higher than the standard dosing done in most Hodgkin or non-Hodgkin lymphoma studies and speaks to the evolution of treatment over time, particularly when weve combined [lenalidomide] with other agents. Most of the time were starting at 20 mg, but for the purposes of this study, in the schema it was 25 mg of lenalidomide.

Its also important to note that there was an induction phase with the combination, and particularly during cycle 1, tafasitamab was dosed weekly with an additional loading dose on day 4 of cycle 1 and then continued weekly up to all 3 cycles so 12 weeks of treatment. Beyond cycle 3, it was dosed every other week or every 2 weeks until disease progression or intolerance. The primary end point of the study was objective response rate [ORR] as assessed by independent central review, and then key secondary end points included progression-free survival [PFS], duration of response [DOR], and overall survival [OS], in addition to safety.

There were 81 patients enrolled on the single-arm phase 2 study, and that speaks to the fact that lymphoma is a rare tumor type. The median age was 72, again [considering] that age over 70 was one of the most common criteria utilized to define a nontransplant candidate. About 51% of the patient population had an IPI risk score of 3 or higher, 75% had advanced-stage disease, median number of prior lines of therapy was 2, and primary refractory [disease] comprised only about 19% of the patient population. These patients generally were not primary refractory, though [the trial] did include some. Prior stem cell transplant patients might be a poor transplant candidate because theyve already had transplant; [these patients comprised] about 11% of the patient population.

What were the efficacy data seen in the L-MIND study?

The ORR determined by the independent central review was quite notable. The ORR in patients with relapsed/refractory DLBCL was 60%, and the complete response rate was 43%. Probably even more important is that it appeared to be durable. The median DOR was 21.7 months. It was not reached among those patients who achieved a complete response, which was almost half the study population....DOR for patients who had a partial response [was markedly lower at] only 4.4 months, and 72% of [all] patients had an ongoing response beyond 12 months.

Importantly, there was a PFS in this patient population of 12.1 months, and median OS had not been reached. At 18 months, 64% of the patient population was still alive. I think this is important because if you put this into context, prior to the introduction of CAR T, if we look at the SCHOLAR-1 datawhich were of a retrospective analysis of patients treated at MD Anderson Cancer Center, at Mayo Clinic, and in the Lysa group, which is a large French group the median OS...was 6 months for patients with relapsed/ refractory DLBCL in second line or later.4 Again, this is a marked improvement over that.

The median PFS is also quite notable at 12 months [at 50%] because the median PFS for the CAR T population was only about 6 months. Now this probably reflects a specific patient population in that most of these patients were not as heavily pretreated as the CAR T population. A small percent- age were primary refractory.

Are other studies in the DLBCL setting looking at this regimen?

There were data reported at the 2020 American Society of Clinical Oncology Annual Meeting [from] the RE-MIND study [NCT04150328]....They essentially compared [the L-MIND] results with a synthetic control where they captured retrospective data of single-use lenalidomide in relapsed/refractory DLBCL and then tried to match that in terms of baseline characteristics.5

It looks like [the combination] was at least a significant improvement over lenalidomide monotherapy. Then the question is really: Is it better than the other options currently available in the relapsed DLBCL space? And that hasnt been answered. Its moving into front line. The phase 1b data were reported. Theres a randomized study that is launching, so that will then raise the question of how we sequence treatment in DLBCL.

What was the toxicity profile of tafasitamab and lenalidomide for these patients?

The most common adverse events [AEs] were neutropenia, anemia, and thrombocytopenianot surprising to me because again this is an antibody in combination with lenalidomide.3 Grade 3 or higher neutropenia occurred in 48% of patients and grade 3 or higher thrombocytopenia in 17% of patients. Fortunately, febrile neutropenia was not high. There was 10% with grade 3 and 2% with grade 4. Growth factor use was at the discretion of the treating physician. It was not built into the protocol in terms of prophylactic use.

For the most common AEs that were nonhematologic, [what was noticeable was] the vast majority were grade 1/2, though about 9% of patients had a grade 3 rash, which is not unusual for lenalidomide in lymphoma. One percent had grade 3 diarrhea, and about 5% had hypokalemia. Some of that might be related to diarrhea and some nausea. Cough was about 1% at grade 3 or higher, and bronchitis was 1% at grade 4. Fatigue was another common AE, with 15% at grade 1 or 2.

Serious AEs occurred in 51% of the study population, although 19% were attributed to the study drug; 12% discontinued therapy as a result of toxicity, and then 9% had an AE of special interest. The AEs of special interest included tumor flare in 3 patients, and 1 patient with grade 2 basal cell carcinoma. Grade 3 [allergic dermatitis] occurred in 3 patients. There were 13% who had a treatment-emergent AE that led to death; however, according to the [investigators], none [of the deaths] were thought to be related to study treatment. The severity and incidence of the toxicities after lenalidomide was discontinued decreased, suggesting that a lot of the toxicity was due to the combination and not the CD19 monotherapy.

Read this article:
L-MIND Trial Results Show CD19 Antibody Is Reasonable in R/R DLBCL - Targeted Oncology

Judith Graham

This story also ran on CNN. It can be republished for free.

As public demand grows for limited supplies of covid-19 vaccines, questions remain about the vaccines appropriateness for older adults with various illnesses. Among them are cancer patients receiving active treatment, dementia patients near the end of their lives and people with autoimmune conditions.

Recently, a number of readers have asked me whether older relatives with these conditions should be immunized. This is a matter for medical experts, and I solicited advice from several. All strongly suggested that people with questions contact their doctors and discuss their individual medical circumstances.

Experts advice may be helpful since states are beginning to offer vaccines to adults over age 65, 70 or 75, including those with serious underlying medical conditions. Twenty-eight states are doing so, according to the latest survey by The New York Times.

Q: My 80-year-old mother has chronic lymphocytic leukemia. For weeks, her oncologist would not tell her yes or no about the vaccine. After much pressure, he finally responded: It wont work for you, your immune system is too compromised to make antibodies. She asked if she can take the vaccine anyway, just in case it might offer a little protection, and he told her he was done discussing it with her.

First, some basics. Older adults, in general, responded extremely well to the two covid-19 vaccines that have received special authorization from the Food and Drug Administration. In large clinical trials sponsored by drugmakers Pfizer and Moderna, the vaccines achieved substantial protection against significant illness, with efficacy for older adults ranging from 87% to 94%.

But people 65 and older undergoing cancer treatment were not included in these studies. As a result, its not known what degree of protection they might derive.

Dr. Tobias Hohl, chief of the infectious diseases service at Memorial Sloan Kettering Cancer Center in New York City, suggested that three factors should influence patients decisions: Are vaccines safe, will they be effective, and what is my risk of becoming severely ill from covid-19? Regarding risk, he noted that older adults are the people most likely to become severely ill and perish from covid, accounting for about 80% of deaths to date a compelling argument for vaccination.

Regarding safety, there is no evidence at this time that cancer patients are more likely to experience side effects from the Pfizer-BioNTech and Moderna vaccines than other people. Generally, we are confident that these vaccines are safe for [cancer] patients, including older patients, said Dr. Armin Shahrokni, a Memorial Sloan Kettering geriatrician and oncologist.

The exception, which applies to everyone, not just cancer patients: people who are allergic to covid-19 vaccine components or who experience severe allergic responses after getting a first shot shouldnt get covid-19 vaccines.

Efficacy is a consideration for patients whose underlying cancer or treatment suppresses their immune systems. Notably, patients with blood and lymph node cancers may experience a blunted response to vaccines, along with patients undergoing chemotherapy or radiation therapy.

Even in this case, we have every reason to believe that if their immune system is functioning at all, they will respond to the vaccine to some extent, and thats likely to be beneficial, said Dr. William Dale, chair of supportive care medicine and director of the Center for Cancer Aging Research at City of Hope, a comprehensive cancer center in Los Angeles County.

Balancing the timing of cancer treatment and immunization may be a consideration in some cases. For those with serious disease who need therapy as quickly as possible, we should not delay [cancer] treatment because we want to preserve immune function and vaccinate them against covid, said Hohl of Memorial Sloan Kettering.

One approach might be trying to time covid vaccination in between cycles of chemotherapy, if possible, said Dr. Catherine Liu, a professor in the vaccine and infectious disease division at Fred Hutchinson Cancer Research Center in Seattle.

In new guidelines published late last week, the National Comprehensive Cancer Network, an alliance of cancer centers, urged that patients undergoing active treatment be prioritized for vaccines as soon as possible. A notable exception: Patients whove received stem cell transplants or bone marrow transplants should wait at least three months before getting vaccines, the group recommended.

The American Cancer Societys chief medical and scientific officer, Dr. William Cance, said his organization is strongly in favor of cancer patients and cancer survivors getting vaccinated, particularly older adults. Given vaccine shortages, he also recommended that cancer patients who contract covid-19 get antibody therapies as soon as possible, if their oncologists believe theyre good candidates. These infusion therapies, from Eli Lilly and Co. and Regeneron Pharmaceuticals, rely on synthetic immune cells to help fight infections.

Q: Should my 97-year-old mom, in a nursing home with dementia, even get the covid vaccine?

The federal government and all 50 states recommend covid vaccines for long-term care residents, most of whom have Alzheimers disease or other types of cognitive impairment. This is an effort to stem the tide of covid-related illness and death that has swept through nursing homes and assisted living facilities 37% of all covid deaths as of mid-January.

The Alzheimers Association also strongly encourages immunization against covid-19, both for people [with dementia] living in long-term care and those living in the community, said Beth Kallmyer, vice president of care and support.

What I think this question is trying to ask is Will my loved one live long enough to see the benefit of being vaccinated? said Dr. Joshua Uy, medical director at a Philadelphia nursing home and geriatric fellowship director at the University of Pennsylvanias Perelman School of Medicine.

Potential benefits include not becoming ill or dying from covid-19, having visits from family or friends, engaging with other residents and taking part in activities, Uy suggested. (This is a partial list.) Since these benefits could start accruing a few weeks after residents in a facility are fully immunized, I would recommend the vaccine for a 97-year-old with significant dementia, Uy said.

Minimizing suffering is a key consideration, said Dr. Michael Rafii, associate professor of clinical neurology at the University of Southern Californias Keck School of Medicine. Even if a person has end-stage dementia, you want to do anything you can to reduce the risk of suffering. And this vaccine provides individuals with a good deal of protection from suffering severe covid, he said.

My advice is that everyone should get vaccinated, regardless of what stage of dementia theyre in, Rafii said. That includes dementia patients at the end of their lives in hospice care, he noted.

If possible, a loved one should be at hand for reassurance since being approached by someone wearing a mask and carrying a needle can evoke anxiety in dementia patients. Have the person administering the vaccine explain who they are, what theyre doing and why theyre wearing a mask in clear, simple language, Rafii suggested.

Q: Im 80 and I have Type 2 diabetes and an autoimmune disease. Should I get the vaccine?

There are two parts to this question. The first has to do with comorbidities having more than one medical condition. Should older adults with comorbidities get covid vaccines?

Absolutely, because theyre at higher risk of becoming seriously ill from covid, said Dr. Abinash Virk, an infectious diseases specialist and co-chair of the Mayo Clinics covid-19 vaccine rollout.

Pfizers and Modernas studies specifically looked at people who were older and had comorbidities, and they showed that vaccine response was similar to [that of] people who were younger, she noted.

The second part has to do with autoimmune illnesses such as lupus or rheumatoid arthritis, which also put people at higher risk. The concern here is that a vaccine might trigger inflammatory responses that could exacerbate these conditions.

Philippa Marrack, chair of the department of immunology and genomic medicine at National Jewish Health in Denver, said theres no scientifically rigorous data on how patients with autoimmune conditions respond to the Pfizer and Moderna vaccines.

So far, reasons for concern havent surfaced. More than 100,000 people have gotten these vaccines now, including some who probably had autoimmune disease, and theres been no systematic reporting of problems, Marrack said. If patients with autoimmune disorders are really worried, they should talk with their physicians about delaying immunization until other covid vaccines with different formulations become available, she suggested.

Last week, the National Multiple Sclerosis Society recommended that most patients with multiple sclerosis another serious autoimmune condition get the Pfizer or Moderna covid vaccines.

The vaccines are not likely to trigger an MS relapse or to worsen your chronic MS symptoms. The risk of getting COVID-19 far outweighs any risk of having an MS relapse from the vaccine, it said in a statement.

Were eager to hear from readers about questions youd like answered, problems youve been having with your care and advice you need in dealing with the health care system. Visitkhn.org/columniststo submit your requests or tips.

Kaiser Health News (KHN) is a national health policy news service. It is an editorially independent program of the Henry J. Kaiser Family Foundation which is not affiliated with Kaiser Permanente.

This story can be republished for free (details).

Read more here:
If I Have Cancer, Dementia or MS, Should I Get the Covid Vaccine? - Kaiser Health News

BOSTON--(BUSINESS WIRE)--Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced that the U.S. Food and Drug Administration (FDA) has cleared the IND, enabling the company to proceed with initiating a clinical trial for VX-880, an investigational stem cell-derived, fully differentiated pancreatic islet cell therapy to treat T1D. Vertex plans to initiate a Phase 1/2 clinical trial in the first half of 2021 in patients who have T1D with impaired hypoglycemic awareness and severe hypoglycemia.

As we celebrate the 100th anniversary of the discovery of insulin this year, we are excited to bring a first-in-class cell therapy to the clinic with the potential to meaningfully impact people living with T1D, said Bastiano Sanna, Ph.D., Executive Vice President and Chief of Cell and Genetic Therapies at Vertex. We look forward to getting our clinical program underway and testing our unique approach of replacing pancreatic islet cells, which are destroyed in people with type 1 diabetes, with our stem cell-derived fully differentiated insulin-producing pancreatic islet cells.

About VX-880VX-880, formerly known as STx-02, is an investigational allogeneic human stem cell-derived islet cell therapy that is being evaluated for patients who have T1D with impaired hypoglycemic awareness and severe hypoglycemia. VX-880 has the potential to restore the bodys ability to regulate glucose levels by restoring pancreatic islet cell function, including insulin production.

The VX-880 clinical trial will involve an infusion of fully differentiated, functional islet cells, as well as the chronic administration of concomitant immunosuppressive therapy, to protect the islet cells from immune rejection.

About the Phase 1/2 Clinical TrialThe clinical trial is a Phase 1/2, single-arm, open-label study in subjects who have T1D with impaired hypoglycemic awareness and severe hypoglycemia. This will be a sequential, multi-part clinical trial to evaluate the safety and efficacy of different doses of VX-880. Approximately 17 patients will be enrolled in the clinical trial.

About Type 1 DiabetesT1D results from the autoimmune destruction of insulin-producing islet cells in the pancreas, leading to loss of insulin production and impairment of blood glucose control. The absence of insulin leads to abnormalities in how the body processes nutrients, leading to high blood glucose levels. High blood glucose can lead to diabetic ketoacidosis and over time, to complications such as kidney disease/failure, eye disease (including vision loss), heart disease, stroke, nerve damage and even death. Due to the limitations and complexities of insulin delivery systems, it can be difficult to achieve and maintain balance in glucose control in patients with T1D. Hypoglycemia remains a critical limiting factor in glycemic management, and severe hypoglycemia can cause loss of consciousness, coma, seizures, injury, and can be fatal.

There are currently limited treatment options beyond insulin for the management of T1D.

About VertexVertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases. The company has multiple approved medicines that treat the underlying cause of cystic fibrosis (CF) a rare, life-threatening genetic disease and has several ongoing clinical and research programs in CF. Beyond CF, Vertex has a robust pipeline of investigational small molecule medicines in other serious diseases where it has deep insight into causal human biology, including pain, alpha-1 antitrypsin deficiency and APOL1-mediated kidney diseases. In addition, Vertex has a rapidly expanding pipeline of cell and genetic therapies for diseases such as sickle cell disease, beta thalassemia, Duchenne muscular dystrophy and type 1 diabetes mellitus.

Founded in 1989 in Cambridge, Mass., Vertex's global headquarters is now located in Boston's Innovation District and its international headquarters is in London. Additionally, the company has research and development sites and commercial offices in North America, Europe, Australia and Latin America. Vertex is consistently recognized as one of the industry's top places to work, including 11 consecutive years on Science magazine's Top Employers list and a best place to work for LGBTQ equality by the Human Rights Campaign. For company updates and to learn more about Vertex's history of innovation, visit http://www.vrtx.com or follow us on Facebook, Twitter, LinkedIn, YouTube and Instagram.

Special Note Regarding Forward-Looking StatementsThis press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including, without limitation, statements made by Bastiano Sanna, Ph.D., in this press release, statements regarding the development, plans and expectations for our T1D pipeline program, including our plans to initiate a Phase 1/2 clinical trial in people with T1D and expected timeline of our clinical trials, statements regarding patient enrollment and dosing, statements regarding potential clinical trial results and anticipated benefits of VX-880, and our plans to provide further updates on our T1D pipeline program. While Vertex believes the forward-looking statements contained in this press release are accurate, these forward-looking statements represent the company's beliefs only as of the date of this press release and there are a number of risks and uncertainties that could cause actual events or results to differ materially from those expressed or implied by such forward-looking statements. Those risks and uncertainties include, among other things, that the FDA may not approve our IND, that data from a limited number of patients may not be indicative of final clinical trial results, that data from the company's development programs may not support registration or further development due to safety, efficacy or other reasons, that the COVID-19 pandemic may impact the status or progress of our clinical trials, and other risks listed under the heading Risk Factors in Vertex's most recent annual report and subsequent quarterly reports filed with the Securities and Exchange Commission at http://www.sec.gov and available through the company's website at http://www.vrtx.com. You should not place undue reliance on these statements. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.

(VRTX-GEN)

Link:
Vertex Announces FDA Clearance of Investigational New Drug (IND) Application for VX-880, a Novel Cell Therapy for the Treatment of Type 1 Diabetes...

Abstract

The timing of origin of eukaryotes and the sequence of eukaryogenesis are poorly constrained because their fossil record is difficult to interpret. Claims of fossilized organelles have been discounted on the unsubstantiated perception that they decay too quickly for fossilization. We experimentally characterized the pattern and time scale of decay of nuclei, chloroplasts, and pyrenoids in red and green algae, demonstrating that they persist for many weeks postmortem as physical substrates available for preservation, a time scale consistent with known mechanisms of fossilization. Chloroplasts exhibit greater decay resistance than nuclei; pyrenoids are unlikely to be preserved, but their presence could be inferred from spaces within fossil chloroplasts. Our results are compatible with differential organelle preservation in seed plants. Claims of fossilized organelles in Proterozoic fossils can no longer be dismissed on grounds of plausibility, prompting reinterpretation of the early eukaryotic fossil record and the prospect of a fossil record of eukaryogenesis.

The origin of eukaryotes is among the most formative of events in Earth history, facilitating the emergence of complex multicellular life. However, almost every aspect of eukaryogenesis has proven controversial, not least the sequence of acquisition of eukaryotic characters and the timing of origin of crown eukaryotes (1). The last eukaryote common ancestor (LECA) would have had all fundamental eukaryotic characteristics, including a complex cytoskeleton, nucleus, mitochondria, and other membrane-bound organelles, but when and in what order these traits were acquired before LECA is uncertain. The fossil record has been effectively silent on these issues, in part because of the challenge of identifying early fossil eukaryotes, which have conventionally been discriminated on the basis of size, cyst wall complexity, and circumstantial evidence of a cytoskeleton (2). Unfortunately, none of these criteria are definitive, since the size distinction from prokaryotes is probabilistic, not deterministic, and an actin cytoskeleton is an ancestral feature of archaea, not a eukaryotic innovation (3). Thus, the challenge of discriminating stem from crown eukaryotes, as well as eukaryotes from prokaryotes, appears insurmountable (4). Fossilized organelles would provide a more definitive criterion for identifying eukaryote-grade fossils, as well as informing on the evolutionary assembly of eukaryotes and the timing of emergence of the fundamental clades of photosynthetic eukaryotes. While there are many claims of fossilized nuclei and other organelles through the Proterozoic and Phanerozoic [e.g., (514)], their identification is often contentious and many are instead interpreted as collapsed cytoplasmic remains. This null interpretation stems largely from classical experiments in which the cytoplasm of decaying bacteria collapsed into small dense structures that resemble nuclei (15, 16), and it is now commonly held that organelles cannot fossilize because they decay too quickly (13). However, there is no experimental evidence to support this view, and there are unequivocal records of intracellular organelles from the recent geologic past (510). Taphonomy experiments characterize patterns of decay, providing an interpretative model for the fossil record. These experiments have previously aided interpretation of Ediacaran Wengan embryo-like fossils, demonstrating the feasibility of fossilizing embryos and precluding the interpretation of these fossils as giant sulfur bacteria (17, 18). Here, we undertake taphonomy experiments on eukaryotic organelles to complement classical experiments on bacterial-grade cells, to test the general view that organelles decay too rapidly to be fossilized.

We performed taphonomy experiments on four species of algae: the unicellular green alga Chlorella sp., the colonial green algae Volvox aureus and Pandorina morum, and the multicellular red alga Rhodochorton sp. These species reflect different ecologies and evolutionary grades: freshwater (green algae) versus marine (red alga), unicellularity (Chlorella) versus multicellularity, large colony size (V. aureus) versus small colony size (P. morum), and pyrenoids (green algae) versus none (red alga). Sampling across Rhodophyta and Viridiplantae facilitates a test of consistency among the results. The algae were euthanized in -mercaptoethanol (BME) to prevent autolysis (18) and allowed to decay for 6 weeks in either fresh water (the green algae) or artificial seawater (Rhodochorton), reflecting their natural ecology. We performed parallel experiments under oxic and anoxic conditions to control for the effects of aerobic microbial activity; there was no difference in the patterns of decay between the two groups, but anoxic conditions exhibited slower rates in agreement with previous taphonomy experiments (19, 20). Periodic sampling allowed the identification of sequences of decay in the organelles (Fig. 1). The time span of the experiments was chosen to exceed that required for exceptional fossil preservation through phosphate or silica mineral replication, two mineral systems that facilitate fossilization with subcellular fidelity [e.g., (21)].

Acquisition of different features as decay progresses in oxic and anoxic groups. Samples were taken while the algae were alive (L), immediately after death (FK), and every 2 to 3 days for 6 weeks. The development of holes in Rhodochorton was particularly noticeable, and so this was measured separate from the collapse of the chloroplast edges. In P. morum, the cells themselves collapsed after death.

Cells of V. aureus are broadly the same as those of the closely related P. morum, but colonies contain anywhere from 500 to 10,000 cells held in place by a complex network of cytoplasmic bridges and extracellular matrix (Fig. 2A) (22). After death, the colonies maintained their general shape for several weeks, although the cells gradually became less evenly spaced and the colonies deformed (Fig. 2B). Some colonies ruptured, while others formed large, misshapen conglomerates (Fig. 2B). Within the cells, the chloroplasts and nuclei remained after 6 weeks, although nuclei usually disappeared before chloroplasts (Figs. 1 and 2, C and E). Pyrenoids were the least decay resistant, although their surrounding starch grain ring persisted (Fig. 2, D and E). Chloroplasts deformed as they decayed, thinning and perforating before fragmenting and disappearing (Fig. 2F), but nuclei were more consistent in appearance (Fig. 2, C and E).

(A to F) V. aureus and (G to L) P. morum. Living colonies of V. aureus (A) show clear cell boundaries and structure, but after death, the colonies display some disaggregation (B). As decay progresses, chloroplasts become less regular in shape (C and E) and develop holes and thin patches (F). Pyrenoids disappear from within the chloroplast, leaving holes ringed by starch grains with no pyrenoid visible (D and E). Some nuclei were still visible weeks after death with no evidence of deformation (C and E). Living colonies of P. morum are closely arranged (G), but this collapses after cell death, resulting in the loss of Y-shaped junctions (H). One chloroplast was observed leaving the cell in a cloud (I), but usually, chloroplasts developed holes and thin patches as they decayed (J and K). In late stages of decay, small amounts of green chloroplast were left surrounding the remnants of the starch grain ring (L). Nuclei could still be observed well into decay (K and L). Pyrenoids decayed quickly to leave empty starch grain rings, but this varied within colonies, with some cells still with visible pyrenoids (J and L). n, nucleus; c, chloroplast; s, starch grain ring; p, pyrenoid; y, Y-shaped junction; t/h, thinning/holes within the chloroplast. The number of days postmortem is indicated in the top right corner. Scale bars, 50 m (A), 91.4 m (B), 9.1 m (C), 9.0 m (D), 9.0 m (E), 9.1 m (F), 7.8 m (G), 6.3 m (H), 9.1 m (I), 9.1 m (J), 9.1 m (K), and 9.0 m (L).

Colonies of P. morum are composed of between 4 and 32 cells with Y-shaped junctions (Fig. 2G) (22). Each has a single cup-shaped chloroplast occupying most of the volume, one to several pyrenoids, several vacuoles, and a nucleus in the gap left by the shape of the chloroplast (22). The colonies started to collapse immediately after death; cells decreased in volume and separated, leading to loss of the Y-shaped junctions (Fig. 2H). Nuclei were still visible and undeformed 6 weeks postmortem, although their abundance decreased (Figs. 1 and 2, K and L). Chloroplasts were the most decay resistant of the organelles analyzed, present in many cells after 6 weeks, but showed evidence of deformation: irregular edges, holes, and thinned areas developed before the chloroplast ultimately fragmented and became indiscernible (Fig. 2, J to L). Pyrenoids were the least decay resistant, decaying within 3 weeks and leaving a hole in the chloroplast. No pyrenoids were observed without the chloroplast, but the starch grain ring that surrounds the pyrenoid was very decay resistant, often observed as an isolated ring after the rest of the cell contents decayed away (Fig. 2, J and L).

Unicellular Chlorella is similar to component cells of colonial Pandorina and Volvox: A large cup-shaped chloroplast with a single pyrenoid occupies most of the cell, with a nucleus and vacuoles in the gap (Fig. 3A) (22). Immediately after death, cells showed little or no evidence of change (Fig. 3B). Nuclei were visible throughout the 6 weeks and showed no evidence of degradation (Fig. 3, C, F and G). Pyrenoids were the least decay resistant, while chloroplasts were the most decay resistant (Fig. 1). Chloroplasts occasionally escaped the cell during decay if the cell ruptured early (Fig. 3F). Otherwise, chloroplasts collapsed, producing irregular edges before developing holes, thinning, fragmenting, and disaggregating (Fig. 3, C to F).

(A to G) Chlorella sp. and (H to N) Rhodochorton sp. Living cells of Chlorella (A) show little difference from those immediately after death (B). As decay progresses, chloroplasts collapse, becoming less regular in shape (C and D). Pyrenoids disappear quickly, leaving empty starch grain rings (E), while chloroplasts thin and develop holes (D to F). Nuclei could still be observed in some cells (C, F, and G). In some cases, the chloroplast can escape the cell (F). Living Rhodochorton cells (H) also show little difference from those immediately after death, although chloroplasts collapse and deform quickly (I). Holes develop within the chloroplasts (J and K) and in later stages of decay can occasionally conglomerate along the cell walls along with the cytoplasmic contents (L) or pull away from the cell wall (M). Nuclei can still be observed in some cells, even when much of the cytoplasm is gone (K and N). The number of days postmortem is indicated in the top right corner. Scale bars, 10 m (A), 18.7 m (B), 15 m (C), 18.5 m (D), 18.4 m (E), 15.8 m (F), 18.7 m (G), 12.6 m (H), 11.8 m (I), 14.9 m (J), 15.4 m (K), 14.1 m (L), 10.4 m (M), and 14.8 m (N).

The filamentous red alga Rhodochorton has cells with a central nucleus and two to three discoid chloroplasts that do not have pyrenoids (Fig. 3H) (23). The color and texture of the cytoplasm often obscure view of the nucleus, but nuclei could still be observed in some cells 6 weeks postmortem (Fig. 3, K and N). However, chloroplasts collapsed quickly, as evidenced by the irregular edges and discoid shapes, before forming holes and fragmenting (Fig. 3, I to K). These deformed chloroplasts remained in the cells for the full 6 weeks. The holes that developed were often in the center of the chloroplast, resulting in ring-shaped remains, but could also form along the edges (Fig. 3, J and K). As decay progressed, the cytoplasmic contents sometimes condensed along the edges of the cell, with fragments of chloroplast within (Fig. 3, L and M).

Claims of ancient fossilized intracellular organelles have generally been rejected, despite similarity in size, shape, and locus to organelles in living eukaryotes, on the basis of the following: (i) The composition of nuclei and other organelles (water, proteins, and nucleic acids) indicates that they will degrade rapidly after death, and (ii) if one organelle is preserved, then others should also (13). Our taphonomy experiments were designed not to simulate fossilization but, rather, to determine whether eukaryotic organelles persist postmortem as physical structures on a time scale compatible with permineralization, mineral replication, or stabilization as organic remains. Fossilization can progress rapidly: Phosphatization and silicification can occur within weeks of death (21).

Our experimental results demonstrate that organelles undergo broadly the same patterns of decay over similar time scales in all four algal species. Nuclei were resistant to notable deformation during decay, whereas chloroplasts underwent extensive changes: Irregular edges, holes, thin patches, and fragmentation occurred before full disintegration. However, chloroplasts, in particular, and nuclei, to a lesser extent, could still be observed in cells 6 weeks after death. The decrease in frequency of nuclei over decay time may be due to chloroplast collapse in the green algae, obscuring or engulfing nuclei, and the rough texture of the cytoplasm in Rhodochorton, which obscures identification of nuclei even in living cells. Pyrenoids disappeared quickly, but evidence of their presence remained in the form of the hole within the starch grain ring, often the last remaining structure in a decaying cell. These results agree with previous studies using Allium cepa (onion), which showed that nuclei can persist as physical structures on time scales compatible with their mineral replication (21, 24), although we observed no deformation of nuclei. Given that our experimental models include marine and freshwater species, unicellular and multicellular species, as well as representatives of two of the fundamental scions of Archaeplastida (Rhodophyta and Viridiplantae), it is reasonable to conclude that these observations can be generalized. The available experimental evidence indicates that claims of fossil eukaryotic organelles should be taken seriously.

There are numerous compelling claims of fossil nuclei, chloroplasts, and even mitochondria in Cenozoic plant remains that preserve histological detail of organelle structure (610, 25), and some of which even remain biochemically reactive to specific histological stains (6, 9, 10). In mummified Eocene Metasequoia leaves, the least degraded chloroplasts had clear thylakoid membranes and grana stacks, while the more degraded specimens showed evidence of chloroplast fragmentation, as seen in our experiments (9). Similarly, amber has yielded exquisitely preserved chloroplasts that are almost indistinguishable from living chloroplasts, with no loss of shape or structure (6, 25). Miocene angiosperm leaves (Fig. 4A) from the Clarkia beds of Idaho (USA) are among the best studied, revealing that chloroplasts and cell walls are more decay resistant than nuclei since they are present in the fossils more frequently (26, 27). However, nuclei have been described from the stem of a Jurassic fern (Fig. 4B) (5) and within Carboniferous gymnosperm pollen (28), demonstrating that they can be preserved. These empirical observations are consistent with our experimental results: Chloroplasts are the most decay resistant of organelles, but nuclei persist for a considerable length of time postmortem. Mode of preservation has also played a role in preserving these organelles; the Clarkia beds were preserved by volcanic ash, leading to desiccation before preservation as organic fossils (29), while the Jurassic fern was permineralized rapidly by hydrothermal vents (5). The less well-preserved Carboniferous gymnosperm nuclei were from coal balls that would not have fossilized as rapidly as the fern or the Miocene gymnosperms and angiosperms (28).

(A) Fossil of a Zelkova leaf from the Miocene Succor Creek Formation showing a chloroplast adpressed to the cell wall, with grana stacks visible and a densely stained starch grain. Transmission electron micrograph after a carbohydrate cytochemical analysis; image from (29) courtesy of Karl Niklas, Cornell University. (B) Segment of the stem of a royal fern from Jurassic deposits with clear nuclei in each cell. Light micrograph; image courtesy of Benjamin Bomfleur, University of Mnster. (C) Tomographic virtual section through Megasphaera, a fossil from the Wengan Biota that is suggested to have nuclei. Data courtesy of (35). (D) Intracellular structures in the holotype of R. chitrakootensis have previously been interpreted as pyrenoids but are unlikely to be so. Tomographic reconstruction; data from (41) courtesy of Stefan Bengtson, Swedish Museum of Natural History. (E) Bangiomorpha pubescens, currently considered the oldest crown eukaryote. Light micrograph; image courtesy of Nicholas Butterfield, University of Cambridge. (F) Caryosphaeroides and (G) Glenobotrydion from the Bitter Springs Biota have been suggested to be early eukaryotes with putative nuclei or chloroplasts. Light micrographs; images from (38) courtesy of SEPM. (H) Shuiyousphaeridium and (I) Dictyosphaera from the Ruyang Group, putative early eukaryotes with intracellular structures suggested to be nuclei or collapsed cellular contents. Light micrographs; images courtesy of Shuhai Xiao, Virginia Tech. (J) Leptoteichos from the Gunflint Iron Formation with a putative nucleus. Light micrograph; image from (45) courtesy of SEPM (Society for Sedimentary Geology) (SEPM). Scale bars, 1.4 m (A), 25.6 m (B), 250 m (C), 38.2 m (D), 25 m (E), 3.3 m (F), 13.8 m (G), 14.3 m (H), 25.3 m (I), and 3.5 m (J).

Wengan embryoids: Bacteria, holozoans, or algae?. Intracellular structures in Wengan phosphatic embryo-like fossils (Fig. 4C) have been central to debate over their affinity. The interpretation of intracellular structures as nuclei precludes a bacterial interpretation (30), favoring affinity with metazoans (31) or nonmetazoan holozoans (32). Claims that the intracellular structures are too large to be nuclei and that they are preserved in late mineralization phases, after the decay of original biological structures (33, 34), have already been refuted (12, 35). However, the nucleus interpretation has been rejected principally on the basis of plausibility and the expectation that other organelles should also be preserved (36). The algal taphonomy experiments demonstrate that nuclei persist postmortem on a time scale compatible with phosphatization (21), and the absence of chloroplasts is further evidence against an algal interpretation.

Bitter Springs: Organelles or shrunken cytoplasm?. The assumption that nuclei (and by extension other organelles) cannot be preserved in fossils rests in bacterium taphonomy experiments conducted to test claims of eukaryotes in the ~830million year (Ma) Bitter Springs Formation, Australia (15, 37). Intracellular structures in Caryosphaeroides, composed of a pale outer ring surrounding a darker inner spheroid (Fig. 4F), were interpreted as a nucleus (38); diffuse structures around a dark, angular central structure in Glenobotrydion were interpreted as chloroplasts surrounding a pyrenoid (39) or nuclear residues (Fig. 4G) (40). Taphonomy experiments demonstrated that bacterial cells can produce cytoplasmic collapse structures that resemble nuclei, leading to the null interpretation of the Bitter Springs intracellular structures as taphonomic artifacts of bacterial cells (15). However, our complementary experiments using algae show that the organelle interpretations cannot be rejected so easily; the structures in Caryosphaeroides and Glenobotrydion could be nuclei or chloroplasts but are unlikely to be pyrenoids on the basis of the relative decay resistance of these organelles. The intracellular structures in Glenobotrydion resemble decayed remains of a chloroplast surrounding the remnants of a pyrenoid, while more data are needed on the consistency of size, number, shape, and locus of the intracellular structures in Caryosphaeroides to aid their interpretation.

Rafatazmia: The earliest red alga?. Rafatazmia chitrakootensis, from the ~1600-Ma Tirohan Dolomite of India, has been interpreted as a rhodophyte and therefore the oldest crown eukaryote (41). Suspended within comparatively large eukaryote-scale cells, there is sometimes a single large, central, rhomboidal structure or several smaller structures located near the septa between cells, interpreted as pyrenoids and pit plugs, respectively (Fig. 4D) (41). Our experiments indicate that pyrenoids would not be present ordinarily without the surrounding chloroplast. Preservation probability does not always correlate with decay resistance (42). However, the structures in the holotype wholly fill the cell and are not readily rationalizable with a chloroplast, nucleus, or their degraded remains. Furthermore, many of these purported intracellular structures are irregular in shape and size and appear to be mineralized in the same phase as void-filling cement, with the exception of the holotype. There is not sufficient evidence to identify pit plugs within the cells; without pit plugs, there is little support for a rhodophyte affinity, and the oldest definitive crown-group eukaryote is therefore Bangiomorpha, a silicified filamentous fossil from the ~1047-Ma Hunting Formation of Canada (Fig. 4E) (43, 44). Despite being well preserved, placement of Bangiomorpha within Bangiaceae is not due to any subcellular detail but its general simplicity and the arrangement of wedge-shaped cells in multiseriate filaments (43); this is insufficient to justify a Bangiaceae or crown-rhodophyte affinity. There are no organelles obviously preserved in the fossils, reflecting considerable decay leaving only recalcitrant cell walls.

The oldest eukaryotes: Nucleated or not?. Unicellular Dictyosphaera and Shuiyousphaeridium (~1700-Ma Ruyang Group of China) are the oldest widely accepted eukaryotic fossils, often preserved associated with intracellular structures that have been compared to nuclei (Fig. 4, H and I) (13). However, despite their consistency of size, locus, number, and shape, the nucleus interpretation has been rejected on the basis of plausibility and the absence of other organelles; they are instead interpreted as contracted cytoplasmic contents (13). Our experimental results demonstrate that the nucleus interpretation cannot be rejected, as it has been, on taphonomic grounds and that the absence of chloroplasts may simply reflect the fact that Dictyosphaera and Shuiyousphaeridium were not photosynthetic eukaryotes. The miniscule size, low abundance, and need for staining in living cells for observation suggest that mitochondria are unlikely to be identifiable in fossil material that is not amenable to transmission electron microscopy analysis or staining. Leptoteichos golubicii [1880-Ma Gunflint Iron Formation, Canada (45)] is an even older candidate eukaryote with intracellular structures originally interpreted as collapsed cytoplasmic contents (Fig. 4J); the authors were reluctant to accept a nucleus and eukaryote interpretation because of its great geologic age. These structures strongly resemble the putative nuclei in Caryosphaeroides but, similarly, they require detailed characterization of size, locus, number, and shape consistency before a definitive conclusion can be reached.

Growing evidence supports the two-domain tree of life, with Eukarya unusually having two stem lineages that arise from their -proteobacterial and archaeal relatives (46). Although there can be little hope of palaeontological insight into the former before its coalescence with the archaeal lineage, our experiments demonstrate that there is promise that aspects of the process of eukaryogenesis relating to the origin of organelles may be preserved in the fossil record. However, while it may be possible to distinguish eukaryote-grade fossils, for instance with a preserved nucleus, it will remain challenging to rationalize whether these represent stem or crown eukaryotes. Hence, evidence of preserved nuclei in Dictyosphaera and Shuiyousphaeridium provides definitive evidence of their eukaryote-grade organization, supplementing circumstantial evidence of an actin skeleton. They provide the oldest definitive evidence of total-group eukaryotes, but definitive evidence of the divergence of crown eukaryotes must rest with the preservation of secondary organelles, specifically chloroplasts and pyrenoids, that is before evidence for the emergence of fungi and metazoans. At present, this record rests with ~1047-Ma Bangiomorpha (44). However, our experiments provide a basis for pushing back the record of both total group and crown eukaryotes based on the preservation of nuclei, chloroplasts, and pyrenoids, illuminating the time scale and pattern of eukaryogenesis and diversification.

The algae were obtained from Sciento.co.uk and immediately sampled to confirm species identification and provide baseline images of the living algae. The algae were then euthanized in 300 mM BME for a minimum of 24 hours, providing time for the cells to settle to the bottom of the tubes. Excess BME was removed with a pipette, and the algae were rinsed in tap water for the freshwater species and artificial seawater for Rhodochorton. Samples were taken immediately after euthanization. Each species was then divided into 32 1-ml tubes and separated into two experimental groups: the oxic group, with the lid of the tube removed and water topped up to prevent desiccation, and the anoxic group, where the lid remained sealed until sampling. The addition of water to the oxic group may have affected the chemical gradients surrounding the algae, and mechanical damage may have occurred while the water was being added. However, since there was little difference between the rates of decay between the oxic and anoxic groups and no difference in the patterns of decay, these appear to have had negligible effects on the decay of the algae. The tubes were then placed in a dark Scientific Laboratory Supplies Ltd. (SLS) incubator at room temperature (17.5C) to control for effects of different temperatures on the speed of decay and sampled every 2 to 4 days for 6 weeks.

To take samples, a small volume of the algae that had settled to the bottom of the tube was removed using a 1-ml Pasteur pipette and transferred to a microscope slide. Tubes were only sampled once, providing 16 samples across the 6 weeks of the experiment. The tip of a pipette was then dipped in 1% methylene blue and mixed into the algae to enhance the contrast, although this was not necessary for Rhodochorton because of its natural coloring. The samples were examined under an Axioskop 40 light microscope with a Leica DFC295 camera. Images were taken of colonies and individual cells using 10, 20, 40, and 100 lenses and the Leica Application Suite version 4.2.0. Conventional adjustments of color levels, contrast, and brightness were performed on the images using Adobe Photoshop CC 2014 version 2.2.

For each sample, a proportion of random cells (around 100 to 160 cells for Chlorella and V. aureus and around 40 cells for Rhodochorton and P. morum) were scored on the basis of whether the nucleus was visible; whether the chloroplast had holes and/or had collapsed; and, in the species with pyrenoids, whether the pyrenoid was visible within the starch grain ring. The numbers of cells counted were based on the abundance of the cells in the images taken during sampling; because of the large size of the colonies of V. aureus and the small size and abundance of cells of Chlorella, more cells were visible in each photograph. Rhodochorton cells are much larger and were therefore less abundant in the photographs, and P. morum colonies are both limited in cell number and overlapping, resulting in fewer visible cells. The data on decay characteristics were analyzed using Microsoft Excel.

E. Javaux, Early eukaryotes in Precambrian oceans, in Origins and Evolution of Life: An Astrobiological Perspective, P. Lpez-Garca, H. Martin, Eds. (Cambridge Astrobiology, Cambridge Univ. Press, 2011), pp. 414449.

R. E. Lee, Phycology (Cambridge Univ. Press, 2008).

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