Stem Cell Clinic

FDA Approves Merck’s KEYTRUDA (pembrolizumab) as Adjuvant Therapy for Certain Patients With Renal Cell Carcinoma (RCC) Following Surgery – Business…

By Stem Cell Treatment

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA, Mercks anti-PD-1 therapy, for the adjuvant treatment of patients with renal cell carcinoma (RCC) at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. The approval is based on data from the pivotal Phase 3 KEYNOTE-564 trial, in which KEYTRUDA demonstrated a statistically significant improvement in disease-free survival (DFS), reducing the risk of disease recurrence or death by 32% (HR=0.68 [95% CI, 0.53-0.87]; p=0.0010) compared to placebo. Median DFS has not been reached for either group.

Despite decades of research, limited adjuvant treatment options have been available for earlier-stage renal cell carcinoma patients who are often at risk for recurrence. In KEYNOTE-564, pembrolizumab reduced the risk of disease recurrence or death by 32%, providing a promising new treatment option for certain patients at intermediate-high or high risk of recurrence, said Dr. Toni K. Choueiri, director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, and professor of medicine, Harvard Medical School. With this FDA approval, pembrolizumab may address a critical unmet treatment need and has the potential to become a new standard of care in the adjuvant setting for appropriately selected patients.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of KEYTRUDA. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or permanently discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. For more information, see Selected Important Safety Information below.

KEYTRUDA is foundational for the treatment of patients with certain advanced cancers, and this approval marks the fourth indication for KEYTRUDA in earlier stages of cancer, said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. KEYTRUDA is now the first immunotherapy approved for the adjuvant treatment of certain patients with renal cell carcinoma. This milestone is a testament to our commitment to help more people living with cancer.

In RCC, Merck has a broad clinical development program exploring KEYTRUDA, as monotherapy or in combination, as well as other investigational products across multiple settings and stages of RCC, including adjuvant and advanced or metastatic disease.

Data Supporting the Approval

KEYTRUDA demonstrated a statistically significant improvement in DFS in patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions compared with placebo (HR=0.68 [95% CI, 0.53-0.87]; p=0.0010). The trial will continue to assess overall survival (OS) as a secondary outcome measure.

In KEYNOTE-564, the median duration of exposure to KEYTRUDA was 11.1 months (range, 1 day to 14.3 months). Serious adverse reactions occurred in 20% of these patients receiving KEYTRUDA. Serious adverse reactions (1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% of those treated with KEYTRUDA, including one case of pneumonia. Adverse reactions leading to discontinuation occurred in 21% of patients receiving KEYTRUDA; the most common (1%) were increased alanine aminotransferase (1.6%), colitis and adrenal insufficiency (1% each). The most common adverse reactions (all grades 20%) in the KEYTRUDA arm were musculoskeletal pain (41%), fatigue (40%), rash (30%), diarrhea (27%), pruritus (23%) and hypothyroidism (21%).

About KEYNOTE-564

KEYNOTE-564 (ClinicalTrials.gov, NCT03142334) is a multicenter, randomized, double-blind, placebo-controlled Phase 3 trial evaluating KEYTRUDA as adjuvant therapy for RCC in 994 patients with intermediate-high or high risk of recurrence of RCC or M1 no evidence of disease (NED). Patients must have undergone a partial nephroprotective or radical complete nephrectomy (and complete resection of solid, isolated, soft tissue metastatic lesion[s] in M1 NED participants) with negative surgical margins for at least four weeks prior to the time of screening. Patients were excluded from the trial if they had received prior systemic therapy for advanced RCC. Patients with active autoimmune disease or a medical condition that required immunosuppression were also ineligible. The major efficacy outcome measure was investigator-assessed DFS, defined as time to recurrence, metastasis or death. An additional outcome measure was OS. Patients were randomized (1:1) to receive KEYTRUDA 200 mg administered intravenously every three weeks or placebo for up to one year until disease recurrence or unacceptable toxicity.

About Renal Cell Carcinoma (RCC)

Renal cell carcinoma is by far the most common type of kidney cancer; about nine out of 10 kidney cancer diagnoses are RCCs. Renal cell carcinoma is about twice as common in men than in women. Most cases of RCC are discovered incidentally during imaging tests for other abdominal diseases. Worldwide, it is estimated there were more than 431,000 new cases of kidney cancer diagnosed and more than 179,000 deaths from the disease in 2020. In the U.S., it is estimated there will be more than 76,000 new cases of kidney cancer diagnosed and almost 14,000 deaths from the disease in 2021.

About Mercks Early-Stage Cancer Clinical Program

Finding cancer at an earlier stage may give patients a greater chance of long-term survival. Many cancers are considered most treatable and potentially curable in their earliest stage of disease. Building on the strong understanding of the role of KEYTRUDA in later-stage cancers, Merck is studying KEYTRUDA in earlier disease states, with approximately 20 ongoing registrational studies across multiple types of cancer.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (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 1,600 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 patient's 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:

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):

Non-muscle Invasive Bladder Cancer

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ 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) solid tumors 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 MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

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

Gastric Cancer

KEYTRUDA, in combination with trastuzumab, 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.

Esophageal Cancer

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

Cervical Cancer

KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (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 cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

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 adult patients with advanced renal cell carcinoma (RCC).

KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.

Tumor Mutational Burden-High Cancer

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) or locally advanced cSCC that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test.

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 PD-1 or the 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. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. 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% 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 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

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 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

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 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 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

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 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

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 <0.1% (1) of patients.

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 <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

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 <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

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 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

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 <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. 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)

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FDA Approves Merck's KEYTRUDA (pembrolizumab) as Adjuvant Therapy for Certain Patients With Renal Cell Carcinoma (RCC) Following Surgery - Business...

Mum with brain fog and pins and needles in hands devastated by ‘ticking time bomb’ MS – Mirror.co.uk

By Stem Cell Treatment

The 36-year-old often suffers from "brain fog" forgetting the names of objects and getting confused during conversations along with several physical symptoms

Image: Tracey Harland)

A mum with a young daughter has opened up about living in constant anxiety with her multiple sclerosis (MS) as she aims to raise 45,000 to go towards her treatment.

Mum-of-one Tracey Harland from Houghton-le-Spring, near Sunderland, was diagnosed with MS in January 2019 after living with strange symptoms like pins and needles in her hands for years.

The 36-year-old would also often suffer from "brain fog" forgetting the names of objects and getting confused during conversations along with several physical symptoms, reports Chronicle Live.

Tracey, who described her MS as a "ticking time bomb", has since opened up on living with the fear one day she will wake up and not be able to walk.

The mum wants to be able to treat her MS to secure a better future for herself, partner Reece, 43, and four-year-old daughter Esme.

She explained: "I could start to lose the function of my hands, lose my sight, end up in a wheelchair.

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"When you have MS, you're constantly thinking about waking up and wondering if you'll be able to walk that day.

"There is no warning sign, you can't prepare for it. One day I will just be walking and my vision will go a bit wobbly, it's really scary.

"I have symptoms I deal with on a daily basis but I have this constant anxiety.

"I don't want to be a burden to my daughter."

Tracey lived with her symptoms for so long she believed "everyone suffered from them" and believed they were down to a problem with her back.

But as her symptoms got more worrying, Tracey believed she had MS and this was confirmed in January 2019 when she got an MRI scan.

The mum explained: "I used to get a stabbing pain in my foot and pins and needles in my hands and arms. I have got cognitive issues and I used to get tingling down my spine.

"I would get brain fog so I'd forget the names of things and if we were talking I'd forget what you said at the beginning and get confused about where the conversation was going.

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"When my daughter was born, about nine months later I got numbness on the right side of my face and it went down my neck and down my arm.

"I would go to my osteopath and in a couple of weeks, it would go away. I thought it was all down to issues with my back.

"I went to my GP who said: 'I think this is stress, you've just had a baby, you've returned to work' and they were really pushing anti-depressants.

"I said it doesn't feel quite right, I don't feel like this is what you think it is."

After her diagnosis, Tracey realised her symptoms made sense adding: "That's when I realised a lot of my symptoms I had been dealing with all these years, that I thought were normal were down to my MS.

"When my symptoms flared up I thought I overdid it with my back. All these years, I thought it was normal and everybody had these."

Tracey said MS is a progressive, silent disease that is still progressing in the background.

It is likely she will progress to secondary progressive MS which is when the bigger issues begin like losing speech and mobility.

Tracey is now hoping to raise enough money to get stem cell treatment (HSCT) at a clinic in Clinica Ruiz in Mexico, Monterrey which is 85% effective at halting the disease and could possibly reverse previous damage.

The HSCT treatment is available in the UK but Tracey said the NHS criteria is extremely strict and she is not eligible for it currently.

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The mum will stay at the clinic for 28 days where she will receive chemotherapy to kill her rouge immune system.

Although MS medication to slow down the progress is available on the NHS, Tracey believes the HSCT treatment is the best option.

She said: "I'm 36-year-old I have a four-year-old daughter I don't want to be slowing down the progression I want it to go away.

"This should be the first line of treatment, why take all these drugs to slow down the progression and wait to see how much worse it gets when you can potentially stop it."

Tracey's best friend Kirsty Spence set up a Go Fund Me page in a bid to raise the 45,000 needed.

She said: "The thought of not being able to push her child on a swing, chase her around the garden or just do a simple thing or go for a walk with her daughter and soon-to-be husband is a constant worry for Tracey.

"As MS is just a ticking time bomb with no cure, she has described it as living with a shadow over her life, constantly living with the fear that one relapse could change her whole world forever.

"Tracey is a beautiful soul, who never asks for anything from anyone. She is selfless, loving, and the strongest woman I know.

"She is a wonderful partner, daughter, sister, granddaughter, niece, and friend and a truly amazing mother to her daughter.

"To give her this chance of a healthy life would be the greatest gift anyone could offer."

If you would like to donate, you can do so here.

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Mum with brain fog and pins and needles in hands devastated by 'ticking time bomb' MS - Mirror.co.uk

What Are New Medical Solutions That Can Help Treat Patients? – iLounge

By Stem Cell Doctors

The biomedical field is constantly working to make new medical solutions that can help treat patients with various illnesses and conditions. Today, there are numerous medical solutions used today to help ease medical treatment for patients. These solutions include new medical devices, implants, software used to run medical equipment, and information technology systems.

The following are some of the most popular medical technologies that are used today:

Information technologies are another type of technology used today in medicine. For example, imaging systems let doctors examine patients like never before by allowing them to see inside a persons body without performing surgery first. One famous example of this type of medical solution is 3-D imaging software that uses pictures taken with an X-ray machine to give doctors a model to track health changes over time. Another example includes using information technology systems to control medical equipment or devices through smartphone computer programming or apps.

This type of technology allows doctors to use medical equipment with greater accuracy and helps make their work easier. For example, different types of imaging software help provide more transparent images for radiologists when they read X-rays and MRIs. This helps with making a diagnosis quicker. Thats why most hospitals would prefer to work with Wound Care, a web-based EHR tool. Such tools help record patient vitals and wound assessments to track each patients progress and provide better treatment.

These products can be used as medical solutions for people who want to check their health but dont want to visit a doctors office. Wearable health technologies include everything from smartwatches that measure heart rate and blood pressure functions to fitness trackers that help wearers monitor daily activity levels. Even Google has made its smart contact lenses that can track glucose levels for people with diabetes. However, these devices are designed specifically for individuals suffering from chronic diseases such as arthritis or Parkinsons disease in many cases.

Synthetic biology and genetic engineering tools are a technology used to treat illnesses or conditions that affect organs in the body. For example, if a patient has heart disease, they may need a new heart valve. In this case, doctors can use synthetic biology and genetic engineering tools to create a different kind of heart valve from those typically made from cow tissue. These valves have been tested on animals, and now researchers are testing them on humans as well.

Laboratory-grown organs are another medical solution used to help treat patients who need transplants for certain diseases or conditions that may have caused organ failure. A typical example is how stem cells taken from bone marrow can be turned into blood cells and then used to help treat patients with leukemia. Other types of laboratory-grown organs being tested in clinical trials today include partially functional livers and lungs grown from stem cells.

Medical equipment is another technology doctors can use when treating patients. For example, medical imaging devices like CT scanners and MRI machines help provide images of the bodys internal structures for diagnosis so doctors can see problems most other methods cannot detect. Another type of medical equipment includes surgical robots that can be moved by a computer program to perform surgery on a patient. This reduces the need for an incision since some procedures only require small openings or ones that heal very well without stitches or staples closing them up afterward.

Stem cells and stem cell therapies are a type of medical solution used to treat patients who have conditions that can be life-threatening or cause other severe complications. For example, patients with leukemia may need transplanted blood cells from healthy donors. In this case, doctors can use stem cells to develop those types of blood cells that will provide the best chance of curing the patients cancer without harming their body.

Other examples include using cord blood stem cells from newborns to make different kinds of healthy blood and immune system cells for older children and adults with certain diseases or using skin or other non-embryonic stem cells to make insulin-producing pancreatic beta cells for people diagnosed with diabetes Type 1.

Overall, biomedical technologies have been beneficial in making it easier for doctors to diagnose and treat their patients. Thanks to these technologies, many patients can live long, healthy lives with their illnesses or conditions under control. As technology continues advancing over time, even more, advanced solutions will come out, which should further help improve patient care. However, the use of new medical solutions must be approved by a doctor before being used on a patient.

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What Are New Medical Solutions That Can Help Treat Patients? - iLounge

Slidell mom with months to live, couldn’t afford to fight ‘very treatable’ cancer – WWLTV.com

By Stem Cell Doctors

They told me if I was going to have cancer, this is the one to have because it's very treatable. That gave me a lot of hope then, it wasn't going to be this bad.

SLIDELL, La. A Slidell mother in her late 40's, was hoping for a chance to try an experimental treatment to save her life, but she kept facing obstacles that now may have taken away her chances for survival.

It's a battle that many others in her situation face. They don't have access to the latest medical treatments.

Now the system continues to fail a cancer patient who is running out of time.

It's a moment in time most people might take for granted.Aparent sitting at the dining table helping a child with homework.But not for a single mom of three, NicoleHarris.

That is the hardest part. It's very hard. It breaks my heart. I feel like I'm failing them, Nicolle Harris, 49, said crying about her illness taking her away from her children.

It all started with back pain two years ago.Nicole was told it was arthritis.Several months went by.She started going down.

At that time I couldn't walk. I couldn't bathe myself. I couldn't do anything.

Then from blood work and a bone marrow biopsy,the long-awaited diagnosis.

I was terrified because it's cancer, said Harris.

Multiple Myeloma is a cancer of white blood cells called plasma cells. That's what fights infections by making antibodies.

They told me if I was going to have cancer, this is the one to have because it's very treatable. That gave me a lot of hope then, it wasn't going to be this bad, she remembers.

There was radiation, chemo, and a stem cell transplant. That failed immediately. Then more chemo, and more chemo, eight treatments in all. Then new hope, a clinical trial at MD Anderson in Houston. But soon those hopes vanished.

There's no way I could come up with that kind of money. I mean I'm sitting here with a treatment that could give me years right in my grasp, and I couldn't have it, Harris said through tears.

You see, Nicole is on Medicaid. Being this sick, she could no longer work cleaning houses with her friend. The initial assessment in Houston was nearly $40,000. Medicaid would not pay because it was out of state.

Through a chain of E-mails forwarded several times over, Medical Watch learned of Nicole's desperation. We reached out to the LSU Health Cancer Clinical Trials program.

The state of Louisiana has poorer outcomes than the rest of the country with respect to a variety of cancers, and much of this is due to access of care, explained Dr. John Stewart, Director of the LSU, LCMC Cancer Center.

Dr. Stewart has just come back to Louisiana for this position. His goal is to create a system that gets rid of health disparities in cancer care.

I think that it is unacceptable that a patient has to leave the state to get care for complex malignancies, and so one of the drivers for our cancer center is to offer state-of-the-art multidisciplinary care for cancer at home, said Dr. Stewart.

The Louisiana Cancer Research Center is already home to many national cancer clinical trials with the latest investigational treatments. Dr. Stewart wants to grow that program. And that's where hope was reborn for Nicole. LSU Health doctors lined her up with that same clinical trial in Houston, opening here in New Orleans.

That means the world to me. It gives me hope, like I have a chance to be with my kids for a little bit longer. Instead of three months, I could have three years, she said.

But just days ago, again shattered hopes. In the months-long delay, Nicole's plasma cell numbers have plummeted. Even though the clinical trial is now in her own backyard, she no longer qualifies for that new, investigational treatment. She is running out of time, and is already out of money.

I've been trying for a year and a half just to get disability. I haven't even been able to get that yet. I was approved medically, but not financially because all the stimulus payments were in my account, and so I had to start all over again and they said it could be five months or more, Harris lamented.

But if the doctors are right, she doesn't have five months. Multiple bones are breaking. There's excruciating pain. Nicole's mother has moved in to her Slidell home to care for her.

When asked what's getting her through this ordeal, she replied crying, My kids. Yeah, I don't want to leave them.

Her daughter says she gets sad sometimes and copes with alone time.

I will just I guess sit in my room and I guess hug a pillow, said fifth-grader, Alaina Harris.

It's driving her oldest, a senior in high school,and really the man of the house,to focus on grades and get into LSU,then to veterinary school.

When asked where does his resilience comes from, Damien Harris replied with a chuckle, My mom, and my Maw Maw. They're both hard workers.

And while she can watch her three children with tremendous pride,Nicole now waits for the last chance at hope.Doctors want to change her chemo medicine. It has a 10 percent chance of helping.

But for nearly two weeks, doctors have been waiting for Medicaid insurance approval. Two weeks: that's an eternity in Nicole's life.

Nicole now has lymphedema in her hip and leg. That is a build-up of fluid when the lymph system is blocked. The earliest a doctor from her original physicians office can see her, is two weeks from now.

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Cell and Gene Therapy Market to reach US$ 47,095.2 Mn by end of 2028, Says Coherent Market Insights – PRNewswire

By Stem Cell Doctors

SEATTLE, Nov. 18, 2021 /PRNewswire/ -- According to Latest Report, The global cell and gene therapy marketis estimated to account for 47,095.2 Mn in terms of value by the end of 2028.

Genetic mutations can lead to a wide range of serious malfunctions at the cellular level, including diseases such as cancer. These treatments use "living drugs" to repair damaged tissues and replace diseased organs, and they have the potential to cure a wide variety of ailments. In addition to regenerating damaged organs, cell and gene therapy can cure cancer, and the treatment process is fast-paced, with significant progress made in recent years. For the cell and gene therapy industry to reach its full potential, early interaction with payers and regulators is crucial. This will facilitate a fast-tracked clinical trial. While embracing new platform technologies is challenging, early collaboration with other industries will ensure a faster path to market for the new therapies. In addition to this, a play-to-win attitude is critical to success in this field. The success of gene and cell therapies will depend on achieving clinical and research goals.

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Market Drivers

1. Increasing incidence of cancer and other target diseases is expected to drive growth of the global cell and gene therapy market during the forecast period

With growing incidence of cancer and target diseases such as measles and tuberculosis, the adoption of gene and cell therapy has increased. According to the World Health Organization (WHO), in 2019, around 1.4 million people died from tuberculosis worldwide with around 10 million people being diagnosed with the same. According to the same source, in 2018, around 9.6 million died due to cancer with over 300,000 new cases of cancer being diagnosed each year among children aged 0-19 years across the globe. Gene therapy uses genes to treat or prevent disease, where it allows doctors to insert a gene into a patient's cells instead of using drugs or surgery. Therefore, it has the potential to completely treat genetic disorders.

2. Growing investments in pharmaceutical R&D activities are expected to propel the global cell andgene therapy market growth over the forecast period

Key pharmaceutical companies in the market are focused on research and development activities pertaining to gene therapy. Currently, gene therapy is being widely researched for various diseases including cancer, cystic fibrosis, hemophilia, AIDS, and diabetes. For instance, in November 2021, Sio Gene Therapies reported positive interim data for gene therapy trial of Phase I/II of AXO-AAV-GM1 for the treatment of GM1 gangliosidosis, a genetic disorder that progressively destroys nerve cells in the brain and spinal cord.

Market Opportunity

1. Increasing demand for cell and gene therapies can present lucrative growth opportunities

The demand for cell and gene therapies is increasing with growing cases of genetic disorders, chronic diseases, etc. According to the Cystic Fibrosis Foundation (CFF), in the U.S., over 1,000 new cases of cystic fibrosis are diagnosed each year. Moreover, According to the WHO, the number of people with diabetes has increased from 108 million in 1980 to 422 million in 2014. According to the same source, in 2016, around 1.6 million deaths were directly caused due to diabetes. Cell and gene therapies have the potential to treat the aforementioned diseases.

2. Growing regulatory approval can provide major business opportunities

Key companies are focused on research and development activities, in order to gain regulatory approval and enhance market presence. For instance, in March 2021, Celgene Corporation, a subsidiary of Bristol Myers Squibb, received the U.S. Food and Drug Administration (FDA) approval for the first cell-based gene therapy Abecma indicated for the treatment of multiple myeloma.

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Market Trends

1. Stem cell therapy

In the recent past, stem cell therapies have gained significant importance across the healthcare sector. Stem cell therapy has the potential to treat tissue damage and have low immunogenicity. Furthermore, it can enhance the growth of new healthy skin tissues, improve collagen production, stimulate hair development after loss, and can be used in the treatment of various diseases including Parkinson's disease, Alzheimer's disease, cancer, spinal cord injury, etc.

2. North America Trends

Among regions, North America is expected to witness significant growth in the global cell and gene therapy market during the forecast period. This is owing to ongoing clinical trials combined with key companies focusing on R&D activities pertaining to cell and gene therapy. Moreover, the presence of key market players such as Thermo Fisher Scientific, Takara Bio Inc., Catalent Inc., and more are expected to boost the regional market growth in the near future.

Competitive Section

Major companies operating in the global cell and gene therapy market are Thermo Fisher Scientific, Merck KGaA, Lonza, Takara Bio Inc., Catalent Inc., F. Hoffmann-La Roche Ltd, Samsung Biologics, Wuxi Advanced Therapies, Boehringer Ingelheim, Novartis AG, and Miltenyi Biotec.

For instance, in July 2021, Minova Therapeutics Inc. entered into a collaboration and license agreement with Astellas Pharma Inc. for the research, development, and commercialization of novel cell therapy programs for diseases caused by mitochondrial dysfunction.

Global cell and gene therapy Market, By Region:

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Coherent Market Insightsis a global market intelligence and consulting organization focused on assisting our plethora of clients achieve transformational growth by helping them make critical business decisions. We are headquartered in India, having sales office at global financial capital in the U.S. and sales consultants in United Kingdom and Japan. Our client base includes players from across various business verticals in over 57 countries worldwide.

Contact Us:Mr. Shah Senior Client Partner Business Development Coherent Market Insights Phone: US: +1-206-701-6702 UK: +44-020-8133-4027 Japan: +81-050-5539-1737 India: +91-848-285-0837 Email: [emailprotected] Website: https://www.coherentmarketinsights.com Follow Us:LinkedIn |Twitter

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Cell and Gene Therapy Market to reach US$ 47,095.2 Mn by end of 2028, Says Coherent Market Insights - PRNewswire

FMQs: Senior Glasgow doctor warns claims doctors act in secret or conceal information could damage public confidence as Andrew Slorance widow claims…

By Stem Cell Doctors

Dr Scott Davidson, deputy medical director at NHS Greater Glasgow and Clyde, refuted claims made in Holyrood on Thursday around the death of Andrew Slorance and warned the allegations could damage the publics confidence in medical care.

The comments came after First Minister Nicola Sturgeon said the Scottish Government would not tolerate cover-ups or secrecy, after Louise Slorance said she had only found out her husband, who was being treated for cancer at Queen Elizabeth University Hospital (QEUH), had picked up a deadly fungal infection after trawling through his medical records.

A separate statement from NHS Greater Glasgow and Clyde said the health board did not recognise the claims being made in relation to Mr Slorances death.

Dr Davidson said: My heart goes out to Mr Slorances wife and loved ones as they continue to mourn his loss. We are reaching out to the family and very much hope they will take up our offer to discuss their concerns.

On some of the wider claims being made, there should be no doubt that as clinicians, our primary aim is to provide professional care and treatment for our patients and support their loved ones.

"We dont act in bad faith or attempt to conceal information and that applies equally across the organisation to all of our staff, both clinical and non-clinical, and to suggest otherwise is not acceptable and has caused considerable upset to all of our hard-working and committed staff.

He added: It is also of concern to us, as clinicians, that this could damage the publics confidence in the quality of care we provide. I hope that by meeting with the family, we can explain in detail the care provided to Mr Slorance, answer any questions they may have and provide some comfort going forward.

Speaking earlier at First Ministers Questions, Ms Sturgeon described Mr Slorance as someone she knew very well and a greatly valued member of the Scottish Government team.

She said the chief operating officer of NHS Scotland had raised the claims with NHS Great Glasgow and Clyde.

Mr Slorance, who was head of the Scottish Governments response and communication unit, went into hospital to be treated for cancer in October last year.

Scottish Labour leader Anas Sarwar described the failings at the hospital as the worst scandal of the devolution era.

Ms Sturgeon said: First of all, I can assure the chamber that I have read Louise's words very closely.

"Firstly, because I will always do that, when relatives of those who have died or received substandard care in our National Health Service, because that's part of my duty. But in this case obviously I have done that because Andrew was someone I knew very well.

"He is deeply missed by everyone who had the privilege of working with him and that certainly includes me.

"I think I first met Andrew on the very first day I served in government back in 2007. He made an exceptional contribution to the Scottish Government and my thoughts are often with his loved ones, in particular his wife and his children.

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"My officials have engaged already this morning with Greater Glasgow and Clyde health board, so that the concerns that have been raised are properly investigated.

"We will do everything possible to ensure his family get the answers that they are seeking and also consider very carefully whether the concerns that have been raised by Louise Slorance have raised wider issues that require to be addressed.

Ms Sturgeon added: The chief operating officer of NHS Scotland has contacted Greater Glasgow and Clyde this morning to start to establish the facts and I've asked for information to be available later today and then we will assess what further steps required to be taken.

"I will not this government will not tolerate cover-ups or secrecy on the part of any health board. Where there are concerns about that we will address those concerns.

During his time in hospital, Mr Slorance tested positive for Covid-19 and another life-threatening infection, both of which his widow believes he contracted while at QEUH.

The 49-year-old had been fighting a rare and incurable cancer mantle cell lymphoma for the previous five years.

Mrs Slorance only discovered the fact her husband had been infected with the common fungus, aspergillus, which can be dangerous if it infects those with a weaker immune system, when she requested a copy of his medical records.

A public inquiry is underway to investigate the construction of the QEUH campus in Glasgow and the Royal Hospital for Children and Young People and Department of Clinical Neurosciences in Edinburgh.

The inquiry was ordered after patients at the Glasgow hospital died from infections linked to pigeon droppings and the water supply, and the opening of the Edinburgh site was delayed due to concerns over the ventilation system.

Mr Sarwar said there was a culture of cover-up, denial, and families being failed in the Queen Elizabeth hospital.

He said: From start to finish, the Queen Elizabeth University Hospital scandal has happened under Nicola Sturgeons watch. She was health secretary when the hospital was commissioned and built.

And she was First Minister when it was opened. So she must answer why, despite everything that has happened, do we still have a culture of cover-up, secrecy and denial with families being forced to take on the system to get the truth?

The Glasgow health board leadership has lost the confidence of clinicians, patients, parents and the public. Given everything that has already happened, and everything that has already been uncovered, why is the leadership still in place?

Mr Sarwar added: Not a single person has been held accountable for the catastrophic errors at this hospital. In any other country in the world, there would be resignations and sackings. But under this government its denial and cover-up.

How many more families have to lose loved ones before anyone is held to account?

A statement from NHS Greater Glasgow and Clyde said: Our thoughts and deepest sympathies remain with the family of Mr Slorance.

"At all times we have been open and honest with the family about the treatment provided and we are reaching out to them to further discuss the issues they have raised. After an initial clinical review, we are confident that the care and treatment provided was appropriate and we do not recognise the claims being made.

Infection control procedures at the QEUH are rigorous and of the highest standard. The hospitals public inquiry is currently underway and we have been providing every support to the inquiry team and will continue to do so.

"We are also providing support to both patients and staff throughout the process.

Mr Slorance, a former journalist, was the first head of media relations for the Scottish Parliament after its creation in 1999 and was Alex Salmonds official spokesman between 2007 and 2010.

In 2012, he joined the governments resilience division as head of the response and communications unit responsible for responding to and planning for major emergencies.

Mr Slorance was first diagnosed with mantle cell lymphoma in 2015, but the disease had recently returned. He had been due to undergo a stem cell transplant, but the procedure was postponed due to the coronavirus pandemic.

He wrote a popular blog about his battle with the disease and raised a significant amount of money for cancer charities most recently a 300-mile cycle challenge, which he undertook just months before his death.

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FMQs: Senior Glasgow doctor warns claims doctors act in secret or conceal information could damage public confidence as Andrew Slorance widow claims...

Former Tranmere player Gary Stevens’ son dies after battle with leukaemia – The Chester Standard

By Stem Cell Doctors

FORMER Tranmere and England star Gary Stevens' son Jack has died following a courageous battle with leukaemia.

Gary, who also played for Everton and Rangers, had revealed last year that four-year-old Jack, was diagnosed with Juvenile myelomonocytic leukaemia (JMML), a rare form of blood cancer that affects young children.

Jack had been responding well to treatment but he was forced to restart chemotherapy with doctors indicating he desperately needed a stem cell donor.

In September, Gary, 58, spoke to Everton's website about Jack's prognosis.

As you can imagine, this is the worst possible news for all of us, said Gary, who lived in Bromborough for many years until he moved to Australia in 2011.

He was doing so well, and the search is back on for a suitable stem cell donor."

The Goodison Park club had appealed for donors to come forward in an effort to help their former player who played over 200 times for the Toffees.

Everton announced the news of Jack's death on their Twitter page with a picture of Gary and Jack.

The club wrote: "Everyone at Everton is deeply saddened to learn that Gary Stevens four-year-old son, Jack, has passed away following his courageous battle with leukaemia.

"Our thoughts are with Gary and his family at this incredibly sad time."

Tranmere also joined the tributes on Twitter.

They wrote: "The thoughts of everyone at Tranmere Rovers are with Gary Stevens and his family at this sad time."

Gary signed for Rovers inn September 1994 for a fee of 350,000. He featured regularly at right back for the Prenton Park club over the next four seasons, making 127 league appearances and helping them qualify for the Championship playoffs before managing three successive mid table finishes. He retired from playing at the end of the 199798 season.

He also played for England winning a total of 46 appearances, and playing at the World Cup in both 1986 and 1990.

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Former Tranmere player Gary Stevens' son dies after battle with leukaemia - The Chester Standard

Braeden Lichti – Investing in Precision Medicine to Yield New Treatments for Neurodegenerative Diseases – PRNewswire

By Stem Cell Doctors

VANCOUVER, BC, Nov. 18, 2021 /PRNewswire/ --Advances in the collective genetic understanding of diseases, and the ability to identify disease biomarkers, is ushering in a new era of personalized medicine. Technologies such as CRISPR/Cas9 are also paving the way for improved, more tailored treatments targeted to a specific genetic marker of a disease. As our understanding of the molecular underpinnings of disease continue to improve, so, too, will the technologies at our disposal to treat them.

We've already seen the benefits of this type of personalized medicine in the cancer realm. Using a person's (or disease's) genes to drive cancer therapy is known as precision medicine. Precision medicine can help doctors identify high-risk cancer patients, choose treatment options, and evaluate treatment effectiveness. Precision medicine can also be used to prevent certain types of cancer, diagnose certain types of cancers early (leading to earlier treatment and better outcomes), and diagnose specific types of cancer more correctly.

As targeted therapies continue to advance, we will continue to see their impacts flow beyond that of the cancer realm. One area in which interest is ramping up is neurodegenerative diseases, which are chronic, progressive diseases affecting the brain and its constituent cells. Neurologic disease can be genetic, or caused by a stroke or brain tumor. Examples of neurodegenerative disease include Alzheimer's Disease, Parkinson's Disease, and Huntington's Disease. These diseases have a genetic component, with specific genes playing a role in the development and progression of disease, especially in rare forms. Neurodegenerative conditions, like cancer, are devastating and costly. Collectively, neurodegenerative conditions cost people in the United States $655 billion in 2020.

Can we apply concepts from targeted therapies developed for cancer to create better outcomes for patients suffering from neurodegenerative diseases? What's more, can precision medicine be used to treat other large unmet needs in the field of neurology, such as neuropsychiatry, pain, epilepsy, sleep disorders, and stroke?

Precision medicine in neuroscience and neurology is where many companies have dedicated their time and efforts. Three companies trading on the NASDAQ in this space that investors should research are Alnylam, Ionis Pharmaceuticals, and Regeneron.

Neuroscience research companies are clamoring to make use of the plethora of cellular and molecular biology data that is emerging about drugs and the patients who use them. There is much more information to be gleaned from diseases and patients than the genetics, which may not reveal information about the ways that genes are formally transcribed and expressed. Emerging technologies, therefore, also look at the RNA profiles of a drug response, patient, or disease state, called transcriptomics; and the set of proteins expressed by a cell, tissue, or organism, called proteomics. While a challenge with gene therapy is reimbursement by insurance providers, research is underway that can make gene therapies more common, and pave the way for more established insurance structures.

RNA targeting is an active area of research for neurodegenerative disease, with companies such as Skyhawk Therapeutics, Regeneron Pharmaceuticals, Alnylam Pharmaceuticals, and Takeda involved. By modifying genetic transcription via RNA technologies, these companies hope to develop novel treatments for disorders of the central nervous system. The study of RNA profiles in a given cell, tissue, or organism is known as transcriptomics, and this area will likely heat up as these researchers work to develop pioneering RNA technologies to target neurodegenerative disease.

Proteomics, or the study of the proteins expressed by a cell, tissue, or organism, will also play a role in precision medicine for neurological disorders. In June 2021, the United States Food and Drug Adminstration approved the first therapy addressing the underlying biology of Alzheimer's disease. The drug, Biogen's Aducanumab, is a monoclonal antibody therapy that works by clearing a substance known as beta-amyloid, a protein that scientists believe causes Alzheimer's, from the brain. The drug, which was found to exhibit a unique proteomic profile upon treatment in mice, was the first approved for Alzheimer's in 20 years, and while it is thought to be effective in a limited number of Alzheimer's disease cases (namely, people in the early stages of Alzheimer's), it represents a step forward in neurodegenerative disease research.

The FDA's approval of Aduhelm, which was under an accelerated timeframe, has created more interest in the area of Alzheimer's and Parkinson's disease treatments. Scientists believe that a protein called tau is more closely associated with dementia than beta-amyloid, so they are also seeking to develop drugs targeting tau protein. In the realm of Parkinson's disease, research is underway to target a compound called alpha-synuclein, which, like amyloid beta and tau protein in Alzheimer's, is associated with cognitive decline in Parkinson's disease. There are a number of approaches in development to target tau. Investors can expect many more biotech companies and venture firms moving into this space to develop innovative and alternative treatments.

This work is not without significant challenges. One obstacle in neurodegenerative research is creating drugs that can bypass the brain's blood-brain-barrier, which keeps the brain safe from toxic substances or pathogens that would otherwise make their way into the brain. Another challenge is the fact that neurodegeneration affects a subset of neurons, which may have different levels of vulnerability to such disease. It is not yet fully clear which factors predispose certain neurons to develop pathology over others.

Yet as drug discovery continues to leverage the latest techniques in genomics, transcriptomics, and proteomics, and combinations of these technologies, this will unlock new potential for companies to create novel, increasingly personalized, therapies. For example, advances in genomics may provide insight into how neurodegeneration occurs in the brain.

Drug discovery in neurodegeneration also overlaps with that of other diseases, due to common disease pathways. For example, phosphatidylinositol 3-Kinase (PI3K) inhibitors are implicated not only in COVID-19 and breast cancer, but also Parkinson's Disease. Stem cell therapies, which could benefit patients suffering from many conditions, can also have significant applications in the neurodegenerative realm. Stem cells could potentially be used to restore lost brain tissue, or to release compounds such as anti-inflammatory factors and growth factors supporting repair of the nervous system. Stem cell therapies, which are already in use for conditions such as cancer, could thereby restore function to neurodegenerative patients. Therefore, advances made in the treatment of other disease states could potentially innovate the field of neurodegeneration as well.

PRLog ID: http://www.prlog.org/12894142

SOURCE Braeden Lichti

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Braeden Lichti - Investing in Precision Medicine to Yield New Treatments for Neurodegenerative Diseases - PRNewswire

Global Cancer Therapy Market Expected to Reach $268 Billion In 2026, With A CAGR Of 9.15% – PRNewswire

By Stem Cell Doctors

PALM BEACH, Fla., Nov. 16, 2021 /PRNewswire/ -- FinancialNewsMedia.com News Commentary - The COVID-19 pandemic has affected the healthcare systems globally and also has a significant impact on the cancer therapy market. As per the article published in Cancer Connect 2020, doctors from Dana Farber Cancer Institute determined that during the COVID-19 pandemic, there was a 46% decrease in the diagnoses of the six most common cancer types - breast, colorectal, lung, pancreatic, gastric, and esophageal cancers. Also, the Centers for Disease Control and Prevention (CDC) and many medical professional organizations recommended that cancer screening and other health prevention services, along with elective surgeries, to be postponed unless the risks outweighed the benefits and to secure the hospital infrastructure for the treatment of COVID-19 patients. Thus, the COVID-19 pandemic has impacted the cancer therapy market. However, the situation is expected to gradually improve. According to a reportfrom Mordor Intelligence the global cancer therapy market was valued at approximately USD 158 billion in 2020, and it is expected to witness a revenue of USD 268 billion in 2026, with a CAGR of 9.15% over the forecast period. Active companies in the markets today include: Hoth Therapeutics, Inc. (NASDAQ:HOTH), Cassava Sciences, Inc. (NASDAQ: SAVA), Biogen Inc. (NASDAQ: BIIB), Camber Energy, Inc.(NYSE: CEI), Intercept Pharmaceuticals, Inc. (NASDAQ: ICPT).

The report continued: "The factors that are driving the market growth include increasing patient assistance programs (PAPs), increasing government initiatives for cancer awareness, rising prevalence of cancer worldwide, and strong R&D initiatives from key players, along with the increasing demand for personalized medicine The increasing incidence of cancer cases is expected to drive the need for advanced cancer therapies for the effective treatment of patients. Thus, given the aforementioned factors, the cancer therapy market is expected to witness tremendous growth over the forecast period. Targeted therapy is a rapidly growing field of cancer research, and researchers are studying many new targets Thus, in view of the increasing product approvals and high research activities related to targeted therapies against cancers, the studied segment is expected to grow over the forecast period."

Hoth Therapeutics, Inc. (NASDAQ:HOTH) BREAKING NEWS: Hoth Therapeutics Announces a Sponsored Research Agreement to Further Develop Novel mRNA Cancer Therapeutic HT-KIT Hoth Therapeutics, Inc., a patient-focusedbiopharmaceutical company,today announced that it has signed a Sponsored Research Agreement with North Carolina State University ("NC State") to support the continued research and development of HT-KIT, a novel therapeutic for the treatment mast cell cancers.

The research will be led by Dr. Glenn Cruse, Assistant Professor, and will focus on characterizing the HT-KIT dose and dosing frequency for treatment of aggressive mastocytosis and mast cell neoplasms using humanized tumor mouse models. In addition, the research will expand therapeutic potential of HT-KIT for the treatment of other cancers where aberrant cKIT signaling contributes to the cancer progression, such as gastrointestinal stromal tumors (GIST) and acute myeloid leukemia (AML).

"We are pleased to announce the continuation of our development of HT-KIT after our earlier announcement of beginning API and drug product manufacturing," said Stefanie Johns, Chief Scientific Officer of Hoth Therapeutics, Inc. "We remain focused on pushing this important cancer therapeutic through to the clinic. The research conducted by Dr. Cruse and NC State will help direct the continued development and clinical planning of this potentially life-saving therapy."

About HT-KIT - HT-KIT is a new molecular entity (NME) under development for treatment of mast cell derived cancers and anaphylaxis. HT-KIT was developed Dr. Glenn Cruse, Assistant Professor at North Carolina State University. The HT-KIT drug is designed to more specifically target the receptor tyrosine kinase KIT in mast cells, which is required for the proliferation, survival and differentiation of bone marrow-derived hematopoietic stem cells. Mutations in the KIT pathway have been associated with several human cancers, such as gastrointestinal stromal tumors and mast cell-derived cancers (mast cell leukemia and mast cell sarcoma). Based on the initial proof-of-concept success, Hoth intends to initially target mast cell neoplasms for development of HT-KIT, which is a rare, aggressive cancer with poor prognosis. The same target, KIT, also plays a key role in mast cell-mediated anaphylaxis, a serious allergic reaction that is rapid in onset and may cause death. Anaphylaxis typically occurs after exposure to an external allergen that results in an immediate and severe immune response. CONTINUED Read the Hoth Therapeutics full press release by going to: https://ir.hoththerapeutics.com/news-releases

In other news and developments of note in the markets this week:

Cassava Sciences, Inc. (NASDAQ: SAVA), a clinical-stage biotechnology company focused on Alzheimer's disease, recently announced financial results for the third quarter ended September 30, 2021. Net loss for the third quarter ended September 30, 2021, was $9.6 million, or $0.24 per share, compared to a net loss of $1.4 million, or $0.06 per share, for the same period in 2020. Net cash used in operations was $22.2 million during the first nine months of 2021. Net cash use for operations for full-year 2021 is expected to be approximately $25 to $30 million, up from previous guidance of $20 to $25 million due to a significant prepayment made to a contract research organization for our Phase 3 clinical program with simufilam. An additional $22.0 million was used during the third quarter of 2021 for an all-cash purchase of an office complex in Austin, Texas, which will serve as the Company's future corporate headquarters. Cash and cash equivalents were $241.5 million as of September 30, 2021, with no debt.

Camber Energy, Inc.(NYSE American: CEI) recently announced its majority-owned subsidiary, Viking Energy Group, Inc., entered into an Exclusive Intellectual Property License Agreement with ESG Clean Energy, LLC ("ESG") regarding ESG's patent rights and know-how related to stationary electric power generation, including methods to utilize heat and capture carbon dioxide. The license is exclusive for all of Canada (unlimited number of systems), and non-exclusive for up to twenty-five locations in the United States.

Biogen Inc. (NASDAQ: BIIB) and Eisai Co., Ltd. (Tokyo, Japan) recently announced that data from approximately 7,000 plasma samples from more than 1,800 patients in the ADUHELM (aducanumab-avwa) Phase 3 clinical trials showed a statistically significant correlation between plasma p-tau reduction and less cognitive and functional decline in Alzheimer's disease. Reductions in plasma p-tau181 were also correlated with a lowering of amyloid beta plaque. The pre-specified analysis of plasma samples was conducted by an independent lab, drawing from the two pivotal ADUHELM Phase 3 EMERGE and ENGAGE trials. The findings were presented today at the Clinical Trials on Alzheimer's Disease conference (CTAD), held November 9-12 virtually and in Boston, Massachusetts.

The analysis highlighted that ADUHELM significantly reduced tau pathology, a defining feature of Alzheimer's disease, as measured by plasma p-tau181, when compared to placebo. The effect was greater with higher doses and longer duration of ADUHELM treatment. Greater reduction in plasma p-tau181 also had a statistically significant correlation with less decline in cognition and function in ADUHELM-treated patients. Furthermore, the analysis demonstrated a statistically significant correlation between change in plasma p-tau181 and lowering of amyloid beta plaque, showing the effect of ADUHELM on the two core pathological features of Alzheimer's disease.

Intercept Pharmaceuticals, Inc. (NASDAQ: ICPT), a biopharmaceutical company focused on the development and commercialization of novel therapeutics to treat progressive non-viral liver diseases, recently announced results from a new analysis examining obeticholic acid's (OCA) potential to improve transplant-free survival in patients with PBC. The data will be featured in a late-breaking podium presentation at The Liver Meeting, the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), which is being held virtually from Friday, November 12 to Monday, November 15, 2021. The analysis was also selected as a "Best of The Liver Meeting" abstract in the Cholestatic and Autoimmune Liver Diseases category.

"This collaborative study used an innovative approach to contribute new understandings about how treatment of patients with PBC with OCA may impact clinical outcomes: we compared patients with PBC who were treated with OCA in the open-label long-term safety extension of the Phase 3 POISE trial, with external controls from two large representative academic-led patient registries. When compared to real-world patient outcome data, the results provide insights into OCA's potential to improve transplant-free survival in patients with PBC treated in a trial setting," said Professor Gideon Hirschfield, FRCP, Ph.D., Lily and Terry Horner Chair in Autoimmune Liver Disease at the University of Toronto. "Data describing the effect of OCA on mortality and need for liver transplant in patients with PBC is eagerly awaited, but such data is inevitably challenging to generate. Notably, when doing this comparison, we found consistent results across the two databases. We hope this analysis can soon be extended to include more patients treated with OCA, and approaches such as this can help the field overcome obstacles to generating meaningful clinical outcome data."

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Global Cancer Therapy Market Expected to Reach $268 Billion In 2026, With A CAGR Of 9.15% - PRNewswire

The Architecture of the Human Fovea Webvision

By Stell Cell Research

By Helga Kolb, Ralph Nelson, Peter Ahnelt, Isabel Ortuo-Lizarn and Nicolas Cuenca

Abstract

We summarize the development, structure, different neural types and neural circuitry in the human fovea. The foveal pit is devoid of rod photoreceptors and of secondary and tertiary neurons, allowing light to directly stimulate cones and give us maximal visual acuity. The circuitry underlying the transmission to the brain occurs at the rim of the fovea. The predominant circuitry is concerned with the private cone to midget bipolar cell and midget ganglion cell pathways. Every cone drives two midget bipolar cells and two midget ganglion cells so that the message from a single cone is provided to the brain as a contrast between lighter signals (ON pathways) or darker signals (OFF pathways). The sharpening of this contrast message is provided by horizontal-cell feedback circuits and, in some pathways by amacrine circuitry. These midget pathways carry a concentric color and spatially opponent message from red and green cones.

Blue cones are sparse, even largely missing in the foveal center while occurring at somewhat higher density than elsewhere in the cone mosaic of the foveal slope. Signals from blue cones have different pathways to ganglion cells. The best understood is through an ON-type blue-cone-selecting bipolar cell to a non-midget, small bistratified ganglion cell. An OFF-center blue midget bipolar is known to be present in the fovea and connects to a blue OFF midget ganglion cell. Another OFF blue message is sent to a giant melanopsin ganglion cell that is present in the foveal rim area, but the circuitry driving that is less certain and possibly involves an intermediate amacrine cell. The H2 horizontal cells are thought to be feedback neurons primarily of the blue cone system.

Amacrine cells of the fovea are mostly small-field and glycinergic. The larger field GABAergic amacrines are present but more typically surround the fovea in a ring of processes, with little or no penetration into the foveal center. Thus, the small field glycinergic amacrines are important in some sort of interplay with the midget bipolarmidget ganglion cell channels. We have anatomical descriptions of their synaptology but only a few have been recorded from physiologically. Both OFF pathway and ON pathway amacrines are present in the fovea.

The central point of the visual field ahead of us is the image falling on the fovea in the human retina. This is the area of our visually sensitive retina where the cone photoreceptors are tightly packed, where rod photoreceptors are excluded and where all intervening layers of the retina are pushed aside concentrically to allow light to reach the densely packed sensory cones with minimum scatter from overlying tissues. The fovea is where focusing on fine detail in the image is perfected, allowing us to read, discriminate colors well and sense three-dimensional depth.

General features of the fovea

Figure 1. The normal human retina fundus photo shows the optic nerve (right), blood vessels and the position of the fovea (center).

Looking at the retina lining the back of the eyeball in a human, we can see the clear landmark of the optic nerve head (papilla) and radiating blood vessels (Figure 1). Temporal to the optic nerve head at a distance approximately 2.5 optic nerve (disk) diameters at roughly 3.4 mm distance lies a dark brown-yellowish area (Figure 1), in the center of which is the tiny circular fovea. The position of the fovea can be seen clearly in the retina illustrated in Figure 2A. This eye was treated with RNA-later for preservation, allowing for a clear view of a yellow macula lutea area and including the brown central point, (foveal pit) (Figure 2A).

Figure 2A.An isolated human retina shows the optic nerve (right), blood vessels and the fovea (center) with surrounding macula lutea (yellow). Cuenca et al, prepublication.

The area called the macula by ophthalmologists is a circular area around the foveal center of approximately 5.5 mm diameter (Figure 2B) The macula lutea with the yellow pigmentation extends across the fovea into the parafoveal region and a little beyond. This area is about 2.5 mm in diameter (Figure 2B). The actual fovea is about 1.5 mm in diameter and the central fovea consists of a foveal pit (umbo) that is a mere 0.15 mm across (Figure 2B). This foveal pit is almost devoid of all layers of the retina beneath the cone photoreceptors. On the edges of the foveal pit the foveal slope is still mainly devoid of other layers but some cell bodies of retinal interneurons, bipolar and horizontal cells and even some amacrine cell processes are becoming evident. By the 0.35 mm diameter circular area the first ganglion cell bodies, the retinal neurons sending signals to the brain, are beginning to appear. All the central fovea that measures 0.5 mm across is avascular (FAZ).

Figure 2B.A map of the whole macular area to show the dimensions of the foveal pit, foveal avascular zone, parafovea, perifovea, and the limits of the macula. Inset shows the dimensions of the foveal avascular zone, which is the fovea we are discussing here.

The avascular nature of the central fovea is depicted in Figure 3. A human retina wholemount has the blood vessels immunostained with antibodies against Collagen IV and is photographed by stacked images in a confocal microscope. It is absolutely clear that the smallest capillaries even, do not intrude into the foveal center (Figure 3, f) of 500 m diameter, thereby known as the avascular zone.

Figure 3.Wholemount of human retina with blood vessels immunostained with Collagen IV. The confocal microscopy of stacked images clearly shows the optic nerve head (ON) and all the blood vessels to the smallest capillaries. The capillaries surround the fovea (f), but do not enter it, thereby making the fovea avascular.

In vertical section of the human retina from the optic nerve head through the foveal pit and beyond (Figure 4), it is clear where the fovea is located relative to the nerve head (on). Figure 4 (a) is a confocal image after immunostaining with antibodies that are specific for cone photoreceptors [arrestin antibodies for cones, green; cytochrome C antibodies for mitochondria, blue; and for Mller glial cells and RPE, antibodies against cytoplasmic retinaldehyde binding protein (CRALBP), red]. In comparison is seen an optical coherence tomography (OCT) picture in Figure 4 (b) of exactly the same area of human retina. In both images it is clear that the second and third order neurons of the inner nuclear and ganglion cell layers respectively are not present in the foveal pit.

Figure 4.(a) An immunostained human retina section covering the optic nerve (ON) and the foveal pit. Cones, anti-arrestin (green); pigment epithelial and Mller cells, anti CRALPB (red) (109); mitochondria, anti-cytochrome C (blue). (b) An OCT image of the same retinal area in a normal human subject. The second and third order neurons of the retinal inner nuclear and ganglion cell layers respectively are not present in the foveal pit. Adapted from Cuenca, Ortuo-Lizarn and Pinilla 2018 (110).

In the foveal pit the only neurons are cone photoreceptors, all with slim inner segments, packed cell bodies, up to 6 layers deep reaching to the floor of the foveal pit (Figure 5, green cells). However, there are many expanded-looking Mller glia surrounding these cones (Figure 5, red profiles). A central bouquet of cones has their synaptic pedicles ending at the foveal pit floor (Figure 5, green spots, arrows), whereas the cones surrounding them stretch their axons (known as Henle fibers) and presynaptic pedicles away from the center of the foveal pit to the foveal slope area (Figure 5, green spots form a continuous line, arrows). The lack of blood vessels in the central pit can be seen by the absence of the blue circular profiles there (Figure 5, bv).

Figure 5.Vertical section of the human fovea immunostained with antibodies to cone arrestin (green), CRALBP (red) and Collagen IV (blue).

OBrien and colleagues (1) very elegantly illustrated the cone axons radiating out from the foveal pit forming the Henle fiber layer and terminating in distant pedicles in a whole mount monkey retina (Figure 6). The picture would be very similar in a human retina. The Henle fiber layer is a combination of outward radially directed axons of the cones, and where rods begin to appear, also rod axons, and Mller cell processes. It is interesting to note in Figure 5 that the pedicles of the very central bouquet of cones are widely spaced ending on the foveal pit floor. We know from Figure 5 that these central bouquet cone pedicles are separated by voluminous Mller cell elements.

Figure 6.A wholemount monkey fovea immunostained with cone arrestin. The axons of the cones radiate out to a ring of cone pedicles. Central bouquet cone axons stay in the foveal pit. From OBrien et al., 2012 (1).

Understanding how the primate fovea develops from fetal to adult stage of the retina has been a very difficult task in vision research. This has, of course been due to the difficulty of obtaining retinas from human pre-birth and baby eyes. Even fetal monkey material has been scarce to obtain. Dr. Anita Hendrickson (Figure 7) at the University of Washington, Seattle, spent most of her career pursuing this subject of retinal research, and has contributed almost all we know.

Figure 7.A young Anita Hendrickson at her microscope. From her obituary in 2017 (111).

The earliest fetal retinas examined (2) were from a week-22 eye. The fovea is not recognizable at this stage, because the central region of the retina, where the fovea will develop, consists primarily of several layers of ganglion cell bodies and inner nuclear layer cells (INL), presumably amacrine and bipolar cells (Figure 8, a). A single layer of developing cones stretches from outer plexiform layer (OPL) to pigment epithelium and choroid (Figure 8, a, right inset). A hint of a developing cone pedicle is seen (Figure 8, right red arrow) but there is no sign of outer segments of cones (Figure 8, right, apposing red arrowheads). By fetal week 28, an indentation of the retina at the thickest ganglion cell layer appears and can be considered the earliest sign of the foveal pit (Figure 8, b, P). The inner nuclear layer has become thinner and appears pushed out of the pit (P) but a kind of split is occurring in the middle of the INL known as the transient layer of Chievitz (TC, Figure 8, c) (3). By fetal week 37 (Figure 8, c) a pronounced foveal pit is evident (P), the ganglion cells are thinned to 2 or 3 deep and the TC area in the INL appears like a sheared, radially projecting area of probable Mller cell fibers. Through the latter two fetal stages, where the foveal pit is becoming obvious, the cones are still immature, arranged in a single layer and have no visible outer segments (Figure 8, b and c). However, there is the first suggestion of the cone axons being tilted away from their cell bodies to form the early Henle fiber layer.

Figure 8.Foetal human retina at (a) foetal week (Fwk) 22, (b) Fwk 28, and (c) Fwk 37. The foveal position is not noticed at week 22 but in later weeks becomes dimpled as ganglion cells become displaced out radially from the developing foveal pit. In the beginning the retina is thick, multilayered and cones are undeveloped with no outer segments or visual pigment (a: right enlarged photo, red arrow heads point to a cone nucleus, a stubby inner segment, and a developing cone pedicle). From Hendrickson et al., 2012 (26).

It is interesting to closely examine the cone photoreceptors in the fetal 35-to-37-week retinas as illustrated by Hendrickson and coauthors (2). Figure 9 shows how immature the cones of the foveal pit are compared with those of the cones at some distance from the fovea (Figure 9. 2 mm from fovea). At the foveal pit area, the cones are just stubby cells with a synaptic pedicle, little to no lengthened inner segment and zero outer segments (Figure 9, fovea). By 800 m to 2 mm from the developing foveal pit, the cones become elongated vertically and have definite cone pedicles. Most cell bodies descend away from the external limiting membrane and have elongating axons that are angled away from the foveal pit, forming the early Henle fiber layer. Inner segments are long, but the outer segments are still not formed. (Figure 9, 800 m and 2 mm).

Figure 9.Sections of the retina of a human foetus at 25 weeks gestation. The cones of the fovea are still undeveloped with no outer segments, and a synaptic area with no axon. From 800 m to 2 mm from the foveal center there are clear elongated inner segments but still no outer segments. The slanting of the cone axons out radially is beginning to be evidence of a developing Henle fiber layer. From Hendrickson et al., 2012 (26).

At birth of the human baby the retina in the eye is looking recognizably foveate (Figure 10, a). The foveal pit now contains a very thin, only one layer thick, ganglion cell layer, a thin inner plexiform layer (IPL) but a prominent inner nuclear layer (INL) (Figure 10, a). The cones are now evident as straight vertical cones with synaptic pedicles, cell bodies and inner segments. There are probably developing cone outer segments too (not easy to see at this magnification). But the pit is still several cell layers thick with only the cones on the foveal slope beginning to angle away from the pit. Further out on the foveal slope the cone Henle fiber layer is obvious now (Figure 10, a). By 15 months after birth, the baby retina has a definite fovea and even the central cones are angling out to the foveal slope. Inner and outer segments are well developed in the pit and no other layers of the retina are here anymore (Figure 10, b and c). By 13 years the fovea is completely developed (Figure 10, d) (2).

Figure 10.The foveal retina sections of a human from (a) postnatal 8 days (P8d), through (b) 15 months, to fully formed (d) 13 years. (c) At 15 months the cones are thin, have outer segments and squash together and, except for the central bouquet, send axons radially outwards as the Henle fiber layer. Second order neurons and ganglion cells are pushed along the foveal slope to form a pile of ganglion cell bodies at the foveal rim. From Hendrickson et al., 2012 (26).

What forces could cause this remarkable transformation of an evenly thick multi-cell, layered retina to become concavely dimpled, buckled up and stretched outwards to form a single layered pit at the fovea and a high sided sloping tissue with the highest concentration of cell layers at the foveal rim. The developmental effort is to ensure that a central area of the retina is concentrated with the slimmest packed cones with no obstruction of incoming light by secondary and tertiary cell layers.

The most recent investigations on this developmental phenomenon in the human (primate) retina provide evidence that the radial retinal glia the Mller cells and possibly the astrocytes of the ganglion cell layer are instrumental in this process (4). The Mller cells of the foveal pit are closely associated with the cone fibers and together they make up the Henle fibers layer (Figure 11A, red profiles). Bringmann and colleagues suggest that the Mller cells exert tractional forces onto cone axons fibers by a vertical contraction of the central most Mller cells and cones so they become elongated and very thin (Figure 11, B, blue arrows). After widening of the foveal pit by elimination of astrocytes in the pit and ganglion cell layers, the Henle fibers are forced, by horizontal contraction of their surrounding Mller cell processes in the outer plexiform layer, to pull the cone and then rod photoreceptor centrifugally away from the pit (Figure 11, B, orange arrows).

Figure 11.(A) A human fovea drawing to show that the Henle fiber layer consists of cone photoreceptor axons as well as envelopingMller cells and fibers (red). B) Drawing to show the central foveal cone bouquet of thin and closely packed cones in the foveal pit. The cone axons on the foveal slope move radially out with the Mller cells to form the Henle fiber layer and end in pedicles that make connection with bipolar cells at some distance from the foveal pit. Blue arrows show the vertical squeezing and packing of the cones in the foveal pit and orange arrows show the displacement horizontally of the foveal cone axons, during development of the adult fovea.

The term foveal cone mosaic generally refers to the strikingly regular patterns of condensed cone inner and outer segments with largely triangular crystalline organization, which nevertheless includes non-randomly distributed discontinuities (5, 6). The less familiar and less understood part of foveal cones is the further course towards their synaptic terminals. It includes a two-step transition. From a two-dimensional mosaic for image reception it is rearranged into to a three-dimensional somata tiling, which then again spreads out to establish the concentric monolayered pedicle meshwork (7-9).

The mature human fovea consists of 3 spectral types of cone: red or long wavelength sensitive cones, L-cones; green or medium wavelength cones, or M-cones; and blue or short wavelength cones, S-cones. These three types of cone are tightly packed and at their most concentrated (up to 200,000/mm2 in the fovea (8, 10) (see Webvision Facts and Figures). Rods are not present in the foveal pit, appearing first halfway into the foveal slope, beyond the 300 m diameter area (see Figure 2B).

It is extremely difficult to get a horizontal section through the central fovea particularly including the central bouquet of cones because of the concave nature of the fovea. Figure 12.1 manages to get such a view of a horizontal slice through the inner segments of the cones of a human fovea (7). The tiniest central cones in the center of the photograph (Figure 12.1) are very slim at 2.5-3 m in diameter and become progressively larger as they move along a radial gradient from the central bouquet. It is noticeable that the cones are not uniformly distributed in a hexagonal mosaic. Small patches of cones are hexagonal and then the patch is interrupted and shifts the surrounding patches slightly (Figure 12.1). Ahnelt and coauthors (11) noticed that these shifts in the mosaic usually were associated with the position of a slightly larger diameter cone. They proposed that these larger cones were the short wavelength cones, the S-cones, and described their morphological differences from the surrounding, more common L- and M-cones (11).

Figure 12.1.A horizontally sectioned and stained human retina at the foveal pit and rod free area. From Ahnelt et al, 1987 (11).

S-cones are relatively rare in the retina compared with the much more dominant L- and M- cones. The S-cones are, however, ubiquitous in all vertebrate retinas, with the exception of cetaceans (12). As far as other mammals are concerned S-cones are commonly paired with L-cones to give them a dichromatic color sense. These L-cones vary in spectral peak, and the more mid-spectral types are called M-cones. In old world monkeys and apes, and in man an L-opsin gene duplication and further mutation produced an extra mid-spectral L-cone opsin subtype, M-cone opsin. The combination of L-cones, M-cones and S-cones provides trichromacy. This trichromacy allows discrimination of green, yellow and blue/purple hues.

There are differences in the genetic structure and locus of the S-cone visual pigment compared with the M- and L-cone pigments (13), yet the S-cones always form a consistent 8-10% of the mammalian cone photoreceptor population (14, 15). In primates and humans of course, the S-cones are rather scarce in the foveal pit. Some authors suggest that there is a so-called blue cone blind spot (16). However, S-cones peak in number on the foveal slope of the human retina and here form about 12% of the population. Figure 12.2, (a) shows the peak S-cone distribution on the foveal slope in a human retina as identified by the larger size and arrangement in the mosaic breaking up the regular hexagonal pattern distribution of the other cone types. In Figure 12.2, (b) the S-cones have been colored in for clarity.

Figure 12.2.A whole-mount photograph of the foveal slope of a human retina. P (upper right corner) is the foveal pit. Larger cone profiles break up the mosaic of cones into disjointed groups of closely packed smaller profile cones [arrows in (a, b) and colored in as S-blue cones in (b)]. From Ahnelt et al., 1987 (11).

Since these earlier identifications of foveal S-cones on morphological criteria (11), antibodies against the S-cone pigments in the cone outer segments have been developed and are able to positively identify the S-cones in the overall population by immunocytochemical methods. In figure 13, the human foveal pit (FP) and foveal slope are immunostained with an S-cone antibody and illustrate the S-cones as black spots and angled black cone outer segments. In the foveal pit only a few S-cones appear interspersed in the mosaic of highest density (Figure 13). However, their proportion increases in surrounding areas and are at their highest density on the foveal slope (Figure 13 brown spots, top and right-hand side).

Figure 13.The foveal pit (FP) and part of the foveal slope are immunostained with an S-cone opsin in a human retina.

Figure 14 illustrates immunostaining in vertical section and the scarcity of S-cones in the foveal pit compared to the increase in number of this population of cones on the foveal slope, of a human retina. A map of the S- cone distribution in another human fovea is shown in Figure 15. The lighter to darker blue shading indicates less dense to denser S- cone presence. Note in both images (Figs. 14 and 15) there are very small numbers of S-cones in the foveal pit.

Figure 14.Vertical section of a human foveal pit immunostained with antibodies against cone arrestin for all cones (red), and JH455, which labels S-cones (green). Few S-cones are found in the foveal pit.

Figure 15.Every S-cone is labelled with S-cone opsin antibody in a human fovea. The more intense blue shading indicates greater densities of S-cones in the foveal slope where they reach 12% of the cone population.

It has been rather easy to identify S-cones in the human fovea and the rest of the retina by these immunocytochemical techniques where S- cones can be visualized and distinguished from the surrounding L- or M-cones. Figure 16 shows a spectacular confocal image of the cones in near peripheral human retina by immunolabeling with cone arrestin, and by the HJ455 antibody to S-cones, that shows up the S-cone opsin both in the outer and inner segments.

Figure 16.Near peripheral retinal human cones stained with HJ455 antibody that identifies the S-cones (green) amongst the arrestin (red) labeled cones.

Sadly, the L-cones and M-cones are not distinguishable on immunostaining techniques because their visual pigments are so close in structure. There is presently no antibody developed to separately mark them into L- or M- cone types. So, to identify L- and M-cones in the human fovea we must go to other more sophisticated techniques. Psychophysical measurements have suggested that L- cones usually outnumber M-cones by 2:1 in the human fovea (17). Microspectrophotometry of all cones in small patches of cones in the fovea of monkeys, has revealed that L- and M-cones occur in about equal proportion (18).

Newer techniques, introduced by Roorda and Williams (19), use adaptive optics to make direct measurements of spectral sensitivity of foveal cones in the living human eye (Figure 17). They found that humans varied greatly in the proportions of L-cones to M-cones: some individuals have almost equal proportions while others have a higher proportion of L-cones, even to the extreme of 16 L-cones to every M-cone (Figure17, BS). While the sparser S-cones are spaced regularly, the L- and M-cones lie randomly in the mosaic meaning that clusters of cones of the same spectral type will occur together as suggested from Mollon and Bowmakers paper (18). Roorda and coauthors (20) concluded that L- and M-cones are in a random distribution in the foveal center (21). Nevertheless, the human subjects HS and BS in Figure 17 would seem intuitively to have a different perception of color. But both subjects were reported to have normal color vision (19). A single cone is achromatic, and its stimulation doesnt result in color vision unless there is comparison to stimulation of a neighbouring cone with different opsin (22). This comparison is done by retinal and brain neural circuitry (see later section on horizontal cell roles in spectral antagonism). Some elegant recent human adaptive optics studies and psychophysical reporting found that 79% of targeted cones in the foveal center, tested for color perception, correctly identified the color (hue) (22). Interestingly, others, using similar techniques of adaptive optics and human reports of hue for single cone stimulation with colored light in the fovea, found a considerable proportion of cones produced only white sensations (21).

Figure 17.Method of adaptive optics shows mosaics of L (red), M (green) and S (blue) cones in four human subjects with normal color vision. The ratio of S to L and M cones is constant, but that of L to M cones varies from 2.7:1 (L:M) to 16.5:1 (L:M). Adapted from Roorda and Williams, 1999 (19).

The process of centrifugal displacement by the Henle layer affects cone pedicles in different ways, depending on their eccentricity (Figure 18).

Figure 18.Foveal pit in blue and the foveal slope to the foveal edge in grey. Cone pedicles lack telodendria in the foveal pit. Pedicles with increasing eccentricity along the slope have tadpole-like shape. More peripherally cone pedicles are round in shape and have telodendrial interconnections. The transition coincides with the appearance of capillaries (red) and microglia (green spots). The thin blue line denotes the elliptical course of the external limiting membrane sectioned at the foveal slope at 1 degree (300 m eccentricity).

In the central bouquet of cones in the foveal pit, the pedicles appear to stay in place (Figure 18). In serial semithin (Figure 19, a) and electron microscopic (Figure 19, b) sections, a few roundish pedicles can be found at the foveal floor (Figure 19, a-c, circles). They are isolated from each other, thus lacking any connections to other cones via telodendria. Still they are contacted by dendritic processes running horizontally from a few interneurons (presumably bipolar and horizontal cells) from the foveal slope or even those neurons lying embedded in voluminous Mller cell processes (Figure 19 b-c, red circles around pedicles).

Figure 19.LM and EM appearances of cone pedicles. (a), (b) and (c) are isolated pedicles of the foveal pit (red circles). There are large Mller-cell processes and neural processes running to the cone pedicles. (d) and (e) show tadpole-like cone pedicles on the foveal slope. (f) Pedicles at the first capillary zone are arranged in curved, bead-like series. (g) Higher magnification shows the telodendrial network between most cone pedicles in (f). (a) is from Ahnelt, 1998 (112), ganglion cell (gc), Mller cell (Mc), cone axon (ax), scale bar 50 m. (g) is from Ahnelt and Pflug 1986 (113).

From the outer central cones, Henle fibers of short length terminate in peculiar tadpole-like pedicles (Figure 18, Figure 19, d-e). They too are largely isolated from neighboring terminals and are characteristic of the cone pedicles until about 1 or 288 m out (23). Beyond this zone still almost entirely established by cone terminals only the pedicles make up a patchy mosaic (Figure 19, f-g). These terminals elaborate telodendrial networks that end on neighboring cone pedicles at gap junction connections (1, 24). This pedicle mosaic tends to establish radial arrays yet is locally influenced by interspersed glia (Figure 19, g).

The cones of the foveal pit project vertically downwards (Figure 20, a). As the concentrated central cones have to extend their axons radially out of the pit they, together with Mller cells, become the Henle fibers. The cone axons become longer and longer as they project onto the foveal slope and into the parafovea (Figure 20, b, 200-400 m long). From then on, further out into the perifovea, the axons begin to shorten and by 3 mm eccentricity from the foveal pit axons are essentially no length at all (Figure 20, c-d, 4000 m periphery). The Henle fiber layer is over as is the macula lutea (Figure 2A, Figure 2B).

Figure 20.Cone morphology in the foveal pit (a), foveal slope (b) and peripheral retina (c). Cones and ON bipolar cells are immunostained with GNB3 (green). Drawing (d) shows the cone morphologies in the different areas. An S-cone (blue-green) is shown in comparison with the M/L-cone types.

S-cones and M/L-cones differ in the time course of mitotic differentiation and expression of opsins. According to Xiao and Hendickson (25), S-opsin and various synaptic proteins are detectable at fetal week 11, while various synaptic and transduction proteins appear in M/L cone subclasses before their opsin visual pigments are detected at fetal week 13 (26). It is clear that S-cones develop in a different mosaic than M/L-cones. Ahnelt and coworkers (7) have noted that cones likely to be short wavelength sensitive tend to occur in irregular positions in both, foveal and peripheral areas. Figure 21A shows an opsin labeled S-cone (asterisk) positioned between seemingly linear series of unlabeled M/L-cone inner segments. Thus in the foveal all-cone mosaic, S-cones appear to interrupt the linear beads of L/M cone-cell inner segments and clearly do not belong to the mosaic of M- and L-cones (6).

Figure 21A.Human cone inner segment mosaic on the foveal slope. Note the first rod (r), and the bead-like arrangement (colored lines) of the M- and L-cones circumventing an S-cone labeled by an S-opsin antibody (asterisk).

The S-cones form a random mosaic like the M/L cones except at the foveal slope area where they are at highest concentration. Here they approach a non-random distribution (25).

Figure 21B shows a schematic summary (7) of cone arrangement in the mosaic of the foveal slope area where the S-cones develop first and reach the non-random mosaic arrangement (25, 27). Three L/M cone patches are exemplified with false colors (yellow, dark blue green and light green). These have migrated downward from an initial position near the external limiting membrane (ELM) to form bead-like arrangements of M/L cone cell bodies in the depths of the outer nuclear layer (ONL). Their axons (Henle fibers) emerge from the cone nuclear layer and radiate centrifugally towards their pedicles. At the intersection of the L/M patches sits an S-cone always with its cell body, unmigrated, up at the outer limiting membrane. Figure 21B left top, indicates the original position (transparent ovals) of M/L cell bodies before mosaic condensation and their presumed path (tapered rays) to their adult positions.

Figure 21B.The transformation of the foveal cone mosaic groups (yellow, dark green, light green) by condensation of their inner/outer segments to vertical sequences of beaded cell bodies and descending, radiating axons in the Henle fiber layer. At left, the original position of the yellow groups cell bodies (line of ovals) before mosaic condensation is indicated, as well as their eventual path (curved lines) to their adult positions. Apparently, S-cones (blue) do not participate in this process, as their cell bodies stay close to the ELM (external limiting membrane, large arrow). Adapted from Ahnelt et al, 2004 (7).

As we have illustrated in Figure 2B, the whole fovea is roughly 1.5 mm across and so any cell found within 750 m of the foveal center is considered a foveal associated cell. It has been hard to get good staining of horizontal cells (HC) of the fovea but some Golgi impregnated human retinas in our possession did allow us to see a few within the 750 m of eccentricity around the central foveal pit (Figure 22) (28).

Figure 22.The shape and size of horizontal cells in the human fovea (Golgi staining). The smallest HCs are in the avascular zone edge of the foveal slope (350 m). The closest HCs stained on the inner foveal slope (200 m) are stretched out, with dendrites following the circular foveal pit circumference and reaching into the central bouquet of cones. From Kolb et al., 1994 (28).

The closest to the foveal center, which is of course cell free except for cone photoreceptors and some dendrites running up to synapse with the central cones, would be the HC at 200 m from the foveal center (Figure 22, top cell). These horizontal cells are elongated and arranged concentrically in a circle around the foveal center and on the far edge of the foveal pit. The area could still be in the avascular zone. Note the dendrites are reaching quite far to contact central cones. The cells are axon bearing, but morphologically it is difficult to judge of which type. The cells at 350 m (Figure 22) are much smaller than the foveal edge HC but now recognizable as H1, H2 and H3 cell types (28). The smallest are the H1 cells that appear to contact about 4-5 cones, judging by their dendritic clusters. H2 cells are wirier and more irregular than H1 and H3 cells but have quite closely packed and profuse dendrites (Figure 22). These H2 cells would be reaching into the foveal slope area, where we know there is the highest density of S-cones, to contact the latter cone type. H3 cells may also be reaching into the foveal slope but we know from previous data they do not receive synapses from S-cones (29, 30). There are no evident axons on these Golgi stained horizontal cells (Figure 22, 350 m), which probably reflects understaining.

The three horizontal cells at 500 m from the foveal center (Figure 22) would also be foveal HCs but in an area where blood vessels occur and the first rod photoreceptors are present. As can be seen they are a little larger in dendritic field size (Figure 22). The H1 cell contacts 6 cones and the H3 about 8-9 cones (Figure 22). H1 and H2 types here have axons (small arrows in Figure 22), which will expand into axon terminals in contact with rods in the case of H1, and with S-cones in the case of H2 cells (31).

By confocal microscopy the central human fovea can be seen to contain parvalbumin immunoreactive horizontal cells (Figure 23, a-b; green cells under the cone pedicles). Parvalbumin identifies H1/H3 horizontal cell types and it is likely that the Golgi staining at the 200 m distance from the central foveal pit is therefore of these types. They are elongated and not closely packed. Their dendrites would be reaching to contact central foveal bouquet cones (Figure 23, b). In contrast, the H1s of the foveal slope are closely packed with vertically squashed cell bodies and small bushy dendrites reaching to the closely packed cone pedicles at the ends of the Henle-fiber-layer cone axons (Figure 23, c). These HCs are clearly the same as those in the Golgi preparations at 300-500 m (Figure 22).

Figure 23.Vertical section of the human fovea cut along the edge of the foveal pit. H1 horizontal cells are immunostained with anti-parvalbumin (green) and cone photoreceptors with recoverin (red). H1 cells are very crowded together in the foveal slope.

The H2 cells of the human retina are known to be particularly associated with the S-cone (blue) photoreceptors (see Webvision chapter on S-cone pathways). We know that H2 cells stain with antibodies to calbindin in the human retina as compared to parvalbumen staining for H1/H3 cells. Figure 24 (white arrows) shows a few calbindin positive HCs (red cells, arrows) on the foveal slope in human retina. In addition to the H2 cells with cell bodies close to the OPL, there are diffuse cone bipolar cells contacting several cones, and amacrine cells stained with calbindin. These red, diffuse bipolar cells have cell bodies lower in the inner nuclear layer and long slanted single apical dendrites as compared to the red H2 cells. Note in this section of human fovea the first rods are present on the foveal slope and the first rod bipolar cells are staining for the antibody to PKC (Figure 24, green cells).

Figure 24.Human foveal slope area immunolabeled with antibodies against calbindin (red) that marks H2 horizontal cells, some bipolar and some amacrine cell types. H2 cells are marked with arrows. The first rod bipolar cells on the foveal slope are labeled with PKC-alpha antibodies (green).

Horizontal cells of the vertebrate retina are known to have important roles in sharpening and scaling of responses from photoreceptors through the subsequent retinal pathways to influence the ganglion cell output (32). At the first level of the outer plexiform layer, horizontal cells are involved in feedback of signal from surrounding cones to each individual cones receptive field. This surround input is expanded well beyond the horizontal cells dendritic connectivity field by virtue of gap junctions that join the dendrites of many horizontal cells of the same type together. i.e. in human retina the H1-H1 cells would be joined in gap junctions and the H2 cells would likewise be joined to other H2 cells (See the Webvision chapter Myriad roles for gap junctions in retinal circuits). This large feedback effect provokes an expanded region of antagonistic signal compared with the central cone signal. In the case of M- or L-cones the antagonistic surround is a mixed M- and L-cone signal. In other words, individual M- and L-cones do not show classic spectral opponency just mixed M- / L-cone surround antagonism (33). The feedback in the case of an S-cone would come from H2 cells, whose contacts include surrounding M- and L-cones. Indeed S-cones have been recorded from in monkey retina and found to have blueyellow spectral opponency as well as center-surround organization (34, 35). Presumably spatial opponency would be transmitted from the M- and L-cones to their respective bipolar cell connections, and in the case of the S-cone, a true spectral opponency has been proven to be transmitted as well (34). No recordings have been made in foveal cones to really see if an M- or L-cone has a spectrally opponent surround like that of (albeit peripheral) S-cones (35).

A long time ago the great Spanish anatomist, Santiago Ramn y Cajal described the neurons of the different vertebrate retinas as seen by sectioned Golgi-stained material. He noted many different types of bipolar cells in the various species and that there were particularly tiny dendritic spreads for some bipolar cells in the bird retina (36). He suggested that these bipolar cells contacted single cones.

In 1941, Stephen Polyak (Figure 25) published books on the neural cell types revealed by Golgi and other silver methods in monkey and human retinas and brain. In central monkey and human retinas Polyak observed and illustrated several types of bipolar cells, but he was very concentrated on the remarkably small dendritic tops of some types that he construed as contacting single cones. He named these bipolar cells, midget bipolar cells (mbc).

Figure 25.Steven Polyak circa 1940.

Figure 26 shows Polyaks original drawing of these midget bipolar cells and larger dendritic field size bipolar cells that would appear to contact several cones (Figure 26, imb, fmb and dfb). Polyak also drew and commented briefly that the midget bipolar cells appeared to be of two varieties, one that had a long axon to the inner plexiform layer, and the other a much shorter axon ending higher in the inner plexiform layer. At the same time, there were midget ganglion cells that had small dendritic trees that came in the two varieties possibly reaching to the axon terminals of the two types of midget bipolar cells (Figure 26, mgcs).

Figure 26.Original drawings of Polyak (90). Bipolar cells and ganglion cells of the central retina. We now know that the invaginating midget bipolar cells (imb) and flat midget bipolar cells (fmb) are physiologically different. Polyak described midget ganglion cells (mgc) as of two types, which we now know are OFF mgc and ON mgc. These connect to fmbs and imbs respectively. Large field bipolar cells (dfb) and parasol ganglion cells were also described by Polyak. The cone spectral types have been colored in by the present authors.

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