Cancer cells can escape T-cell-mediated cellular cytotoxicity by exploiting the inhibitory programmed cell-death protein 1 (PD-1)/programmed cell death 1 ligand 1 (PD-L1) immune checkpoint. Indeed, therapeutic antibodies that block the PD-1-PD-L1 axis induce durable clinical responses against a growing list of solid tumours. B-cell lymphomas also leverage this checkpoint to escape immune recognition, although the outcomes of PD-1-PD-L1 blockade, and the correlations between PD-L1 expression and treatment responses, are less-well elucidated in these diseases than in solid cancers. Nevertheless, in patients with Hodgkin lymphoma, amplification of the gene encoding PD-L1 is commonly associated with increased expression of this protein on Reed-Sternberg cells. Correspondingly, PD-1 blockade with nivolumab has been demonstrated to result in response rates as high as 87% in unselected patients with relapsed and/or refractory Hodgkin lymphoma, leading to the FDA approval of nivolumab for this indication in May 2016. The PD-1/PD-L1 axis is probably also important for immune evasion of B-cell lymphomas with a viral aetiology, including those associated with human immunodeficiency virus (HIV) and Epstein-Barr virus (EBV). This Review is focused on the role of PD-1-PD-L1 blockade in unleashing host antitumour immune responses against various B-cell lymphomas, and summarizes the clinical studies of this approach performed to date.

PD-1-PD-L1 immune-checkpoint blockade in B-cell lymphomas

Parkinson Disease P arkinson disease involves the nervous system, specifically, movement and control of muscles. Parkinson disease affects more than 1 million individuals in the United States. Because it is more common in older persons, the incidence (number of new cases) of Parkinson disease is increasing as the population grows older. Parkinson disease was first described in 1817 and was originally called " shaking palsy. " Medical researchers later discovered that parkinsonian symptoms were due to degeneration of nerve cells in an area of the brain called the substantia nigra. These cells supply dopamine, a chemical that modulates movement, to other areas of the brain called the basal ganglia. Parkinson disease is progressive and leads to severe limitations in activity and quality of life if the disorder is not treated. Neurologists (doctors who specialize in treating diseases of the nervous system) and neurosurgeons (doctors who specialize in surgery of the nervous system) individualize each person' s treatment to manage the symptoms and slow the progress of Parkinson disease. The January 21, 2004, issue of JAMA includes an article about treatment of Parkinson disease. The JAMA Patient Page is a public service of JAMA. The information and recommendations appearing on this page are appropriate in most instances, but they are not a substitute for medical diagnosis. For specific information concerning your personal medical condition, JAMA suggests that you consult your physician. This page may be photocopied noncommercially by physicians and other health care professionals to share with patients. Any other print or online reproduction is subject to AMA approval. To purchase bulk reprints, call 718/946-7424. • Levodopa (a synthetic medication) replaces dopamine for patients with Parkinson disease, improving symptoms of tremor and rigidity. • Carbidopa helps reduce adverse effects of levodopa and increases the amount of dopamine in the brain (and not in the rest of the body). • Several other medications are available to decrease symptoms or slow the progression of Parkinson disease. • Antidepressants may be prescribed if depression occurs. • Pallidotomy—a probe delivering electrical current is used to create a permanent lesion (scar) in a specific area of the brain (the globus pallidus) to lessen rigidity, tremor, and abnormal movements (dyskinesias). • Thalamotomy—electrical current creates a small, permanent lesion in the area of the brain called the thalamus. This helps reduce tremor and rigidity. • Deep brain stimulation—an electrode is placed into a specific deep brain structure. Electrical …

Journal of the American Medical Association

1 Integrative Functional Gastroenterology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran. 2 Food Security Research Center And Department of Community Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran. 3 Psychosomatic Research Center, Isfahan University of Medical Sciences, Isfahan, Iran. 4 Behavioral Sciences Research Center, Isfahan University of Medical Sciences, Isfahan, Iran. 5 Integrative Functional Gastroenterology Research Center And Psychosomatic Research Center, Isfahan University of Medical Sciences, Isfahan, Iran. 6 University of Adelaide, Discipline of Medicine, Adelaide, Australia. 7 Discipline of Psychiatry, University of Sydney And Department of Psychiatry, Westmead Hospital, Sydney, New South Wales, Australia. 8 Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States And Faculty of Health, University of Newcastle, Callaghan, NSW 2308, Australia.

/pdf/the-study-on-the-epidemiology-of-psychological-alimentary-dv9sd2h1qy.pdf

The study on the epidemiology of psychological, alimentary health and nutrition (SEPAHAN): Overview of methodology

The tumor microenvironment is a complex ecosystem comprised of many different cell types, abnormal vasculature and immunosuppressive cytokines. The irregular growth kinetics with which tumors grow leads to increased oxygen consumption and, in turn, hypoxic conditions. Hypoxia has been associated with poor clinical outcome, increased tumor heterogeneity, emergence of resistant clones and evasion of immune detection. Additionally, hypoxia-driven cell death pathways have traditionally been thought of as tolerogenic processes. However, as researchers working in the field of immunotherapy continue to investigate and unveil new types of immunogenic cell death (ICD), it has become clear that, in some instances, hypoxia may actually induce ICD within a tumor. In this review, we will discuss hypoxia-driven immune escape that drives poor prognostic outcomes, the ability of hypoxia to induce ICD and potential therapeutic targets amongst hypoxia pathways.

Hypoxia-Driven Immune Escape in the Tumor Microenvironment.

Objective Real-life studies on patients with primary CNS lymphoma (PCNSL) are scarce. Our objective was to analyze, in a nationwide population-based study, the current medical practice in the management of PCNSL. Methods The French oculo-cerebral lymphoma network (LOC) database prospectively records all newly diagnosed PCNSL cases from 32 French centers. Data of patients diagnosed between 2011 and 2016 were retrospectively analyzed. Results We identified 1,002 immunocompetent patients (43% aged >70 years, median Karnofsky Performance Status [KPS] 60). First-line treatment was high-dose methotrexate-based chemotherapy in 92% of cases, with an increasing use of rituximab over time (66%). Patients 60 years of age, WBRT and HCT-ASCT consolidation were administered in only 9% and 2%, respectively. The complete response rate to initial chemotherapy was 50%. Median progression-free survival was 10.5 months. For relapse, second-line chemotherapy, HCT-ASCT, WBRT, and palliative care were offered to 55%, 17%, 10%, and 18% of patients, respectively. The median, 2-year, and 5-year overall survival was 25.3 months, 51%, and 38%, respectively ( 60 years: 15.4 months, 44%, and 28%). Age, KPS, sex, and response to induction CT were independent prognostic factors in multivariate analysis. Conclusions Our study confirms the increasing proportion of elderly within the PCNSL population and shows comparable outcome in this population-based study with those reported by clinical trials, reflecting a notable application of recent PCNSL advances in treatment.

/pdf/management-and-outcome-of-primary-cns-lymphoma-in-the-modern-gipa8wtxl3.pdf

Management and outcome of primary CNS lymphoma in the modern era: An LOC network study

In this review, the importance of the hypoxia inducible factor (HIF) pathway in tumorigenesis and cancer treatment outcomes will be discussed. The outcomes of phase II and III clinical trials of direct HIF inhibitors in the treatment of cancer will be reviewed. The HIF signaling pathway is activated by tumor-induced hypoxia or by inactivating mutations of the VHL gene. HIF is a transcription factor which regulates the expression of genes involved in adjusting mechanisms to hypoxia such as angiogenesis or apoptosis as well as tumor growth, invasion, and metastasis. The HIF pathway has a key role in development of resistance to different treatment modalities and higher expression of the HIF molecule is associated with poor prognosis. Clinical studies of the HIF inhibitors in patients with advanced/refractory cancers suggest benefit and warrant further studies of the HIF inhibitors either as a single agent or in combination with other therapeutic agents.

HIF Inhibitors: Status of Current Clinical Development

BACKGROUND Antiviral therapy has altered the prognosis of patients with human immunodeficiency virus (HIV)-associated non-Hodgkin lymphoma (NHL), but patterns of lymphoma-directed therapy in the community are unknown. METHODS The authors analyzed the National Cancer Data Base records of 10,769 patients who were diagnosed with HIV-associated lymphoma from 2004 through 2012. Changes in clinical characteristics and chemotherapy delivery over time were evaluated. Factors that were associated with not receiving chemotherapy were studied using multivariable logistic regression, reporting odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS The proportion of black or Hispanic patients with HIV-associated NHL increased from 41% in 2004 to 55% in 2012 (P < .0001). Chemotherapy was received by 81% of patients with diffuse large B-cell lymphoma, 90% of those with Burkitt lymphoma, 61% of those with primary effusion lymphoma (PEL), and 35% of those with primary central nervous system lymphomas (PCNSL). Between 2004 and 2012, this proportion increased only for patients with PCNSL (P < .00001). Chemotherapy was less likely to be received by patients who were older, black, or without private insurance. It was delivered more frequently in hospitals designated as academic (OR for nonreceipt, 0.68; 95% CI, 0.51-0.92) or in hospitals that had ≥3 HIV-positive cases per year (OR, 0.71; 95% CI, 0.58-0.86). Survival improved in patients with diffuse large B-cell lymphoma (P = .007), Burkitt lymphoma (P = .0002), and PCNSL (P = .019), but not in those with PEL (P = .94). Receipt of chemotherapy in patients with PEL was not associated with better survival. CONCLUSIONS Disparities in chemotherapy delivery need attention, because a majority of HIV-positive patients with NHL in the United States are now black or Hispanic. Higher volume centers were associated with an increased likelihood of chemotherapy administration. Survival gains in patients with PCNSL parallel an increase in chemotherapy use, supporting its role in therapy. [See Editorial on pages 000-000, this issue.] Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2689-2697. © 2016 American Cancer Society.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.30112

Human immunodeficiency virus-associated lymphomas in the antiretroviral therapy era: Analysis of the National Cancer Data Base

Therapy and outcomes of primary central nervous system lymphoma in the United States: analysis of the National Cancer Database

Irritable bowel syndrome (IBS) is a common chronic functional gastrointestinal disorder1 which negatively affects health related quality of life (HRQoL) among the patients.2,3 Previous studies showed that psychological factors and extra-intestinal symptoms affect HRQoL in patients with IBS more than bowel symptoms themselves do.1,4 Psychological factors such as personality factors have been shown to play a role in IBS.5 In addition, personality traits have been shown to be associated with poor HRQoL.6

Personality is an important mediator of chronic stress.7 Recently, a new personality construct, type D or ‘distressed’ personality, has been proposed.6,8 This construct is a result of an investigation on coping styles in men with coronary heart disease.7–9

The taxonomy of type D personality is based on two global and stable personality traits, namely negative affectivity (NA) and social inhibition (SI).10 NA refers to the tendency to experience negative emotions across time or situations.7,8 High-NA individuals experience more feelings of dysphoria, anxiety, and irritability. They also have a negative view of self and scan the world for signs of impending trouble. SI refers to the tendency to inhibit the expression of emotions or behaviors in social interactions to avoid disapproval by others. High-SI individuals tend to feel inhibited, tense, and insecure when with others.8 People with type D personality experience more stress in their lives and are more vulnerable to psychological distress.8,10

Type D patients are at increased risk for a wide range of adverse health outcomes.6,10 Finally, Type D patients are at risk for clustering of psychological risk factors, including depression, anxiety, and irritability, and low levels of self-esteem, well-being, and positive affect.11 The evidence showed that type D personality decreases HRQoL in patients with cardiovasular disorders.6 However, not much data is available about the effect of type D personality on quality of life in patients with non-cardiac disorders. For example, only in a recent study Hansel et al. found that type D personality is associated with decreased perceived HRQoL in patients with functional gastrointestinal disorders.12 However, there is no study about the association between type D personality and HRQoL in patients with IBS. Identifying and modifying determinants of HRQoL in IBS patients can help policy makers to make proper decisions.

Therefore, the aim of this study was to determine the association between type D personality and HRQoL in IBS patients.

Type D personality and quality of life in patients with irritable bowel syndrome.

On August 13, 2021, the FDA approved belzutifan (WELIREG, Merck), a first-in-class hypoxia-inducible factor (HIF) inhibitor for adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery. The FDA granted approval based on the clinically meaningful effects on overall response rate (ORR) observed in patients enrolled in Study MK-6482-004. All 61 patients had VHL-associated RCC; some also had CNS hemangioblastomas and/or pNET. For VHL disease-associated RCC, ORR was 49% [95% confidence interval (CI), 36-62], median duration of response (DoR) was not reached, 56% of responders had DoR ≥12 months, and median time to response was 8 months. Twenty-four patients had measurable CNS hemangioblastomas with an ORR of 63% (95% CI, 41-81), and 12 patients had measurable pNET with an ORR of 83% (95% CI, 52-98). For these tumors, median DoR was not reached, with 73% and 50% of patients having response durations ≥12 months for CNS hemangioblastomas and pNET, respectively. The most common adverse reactions, including laboratory abnormalities, reported in ≥20% were anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. Belzutifan can render some hormonal contraceptives ineffective and can cause embryo-fetal harm during pregnancy. This article summarizes the data and the FDA thought process supporting traditional approval of belzutifan for this indication. 

Jaleh Fallah

Papers

HIF Inhibitors: Status of Current Clinical Development

Human immunodeficiency virus-associated lymphomas in the antiretroviral therapy era: Analysis of the National Cancer Data Base

Therapy and outcomes of primary central nervous system lymphoma in the United States: analysis of the National Cancer Database

Type D personality and quality of life in patients with irritable bowel syndrome.

FDA Approval Summary: Belzutifan for von Hippel-Lindau Disease–Associated Tumors