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Simple Summary: Food and Drug Administration (FDA) drug approvals from July 2007 to June 2019 were reviewed to identify oncology approvals, and trials with age details were reviewed for the study. We hypothesized that the clinical trials that do not report race are likely to suffer from a higher degree of age disparity. The study demonstrated that a significant number of clinical trials leading to cancer drug approvals suffer from racial and age disparity when compared to real-world populations and that the two factors may be interrelated. Age discrepancy between the clinical trial population and the real-world population was higher for studies that did not report race (mean difference −8.8 years (95% CI −12.6 to −5.0 years)) vs. studies that did report it. We recommend continued efforts to recruit diverse populations in clinical trials and make concerted efforts to implement national strategies in order to realize healthcare equity. In the meantime, detailed reporting of patient demographic characteristics in publications should be considered standard. Background: Concern exists that the clinical trial populations differ from respective cancer populations in terms of their age distribution affecting the generalizability of the results, especially in underrepresented minorities. We hypothesized that the clinical trials that do not report race are likely to suffer from a higher degree of age disparity. Methods: Food and Drug Administration (FDA) drug approvals from July 2007 to June 2019 were reviewed to identify oncology approvals, and trials with age details were selected. The outcomes studied were the weighted mean difference in age between the clinical trial population and real-world population for various cancers, the prevalence of race reporting and association of age and race reporting with each other. Results: Of the 261 trials, race was reported in 223 (85.4%) of the trials, while 38 trials (14.6%) had no mention of race. Race reporting improved minimally over time: 29 (85.3%) in 2007–2010 vs. 49 (80.3%) in 2011–2014 vs. 145 (85.4%) during the period 2015–2019 (p-value = 0.41). Age discrepancy between the clinical trial population and the real-world population was higher for studies that did not report race (mean difference −8.8 years (95% CI −12.6 to −5.0 years)) vs. studies that did report it (mean difference −5.1 years, (95% CI −6.4 to −3.7 years), p-value = 0.04). Conclusion: The study demonstrates that a significant number of clinical trials leading to cancer drug approvals suffer from racial and age disparity when compared to real-world populations, and that the two factors may be interrelated. We recommend continued efforts to recruit diverse populations. [ABSTRACT FROM AUTHOR]

Background Richter syndrome (RS) represents an aggressive disease resulting from transformation of chronic lymphocytic leukemia (CLL) to diffuse large B-cell or Hodgkin lymphoma. In 80% of cases, RS is clonally related to CLL. New therapies like ibrutinib have limited efficacy in RS with anticipated median overall survival (OS) of 3.5 months from the time of CLL transformation. Adriamycin-based regimens combined with rituximab represent the standard induction treatment for RS; and those who demonstrate responsive disease are generally offered an allogeneic hematopoietic cell transplant (allo-HCT) despite the lack of randomized controlled studies. Outcomes following allo-HCT in RS are limited to single-institution case series or registry data. We performed a systematic review of the medical literature to assess the totality of evidence pertaining to the efficacy (or lack thereof) of allo-HCT in RS. Material and methods We performed a comprehensive search of the medical literature using PubMed/Medline and EMBASE on September 28, 2018. We extracted data on clinical outcomes pertaining to the benefits (complete remission [CR], OS and progression-free survival [PFS]) and harms (relapse and non-relapse mortality [NRM]), independently by two authors. Our search identified a total of 240 references. Four studies (n= 72 patients) were eligible for inclusion in this systematic review/meta-analysis (Figure 1). Three single-institution studies were from the United States and one data registry study from the European Society for Blood and Marrow Transplantation. Results Reduced intensity conditioning (RIC) regimens were more commonly prescribed (n=50, 69.4%) and the cell source was predominantly peripheral blood stem cells (n=54, 75%). Post-allograft pooled CR rate (3 studies, n=47 patients) was 33% (95%CI=4-71%) with high heterogeneity among studies (I2 =84.2%). Pooled OS rate (3 studies, n=52 patients) was 54% (95%CI=28-79%) with high heterogeneity among studies (I2 =69.8%) (Figure 2) ; and these 3 studies reported OS at 4-years, 3-years and 2-years, respectively. Pooled PFS (3 studies, n=52 patients) was 30% (95%CI=18-44%) with no heterogeneity among studies (I2 =0). Pooled relapse rates (3 studies, n=52 patients) was 28% (95%CI=9-52%) with high heterogeneity (I2 =62.7%). Pooled NRM associated with allo-HCT was 24% (95%CI=29.4%) with low heterogeneity (I2 =29.4%). Conclusion Allo-HCT is an effective treatment for RS with a resulting pooled OS rate (between 2-4 years) of 54%. One study identified age (< 60 years), chemosensitive disease and use of RIC regimens to be associated with better relapse-free survival. Feasibility and efficacy of combining novel therapies +/- donor lymphocyte infusion(s) should be studied to help reduce the risk of post-transplant relapse. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint blockade has shown remarkable efficacy across various cancers but has failed to improve outcomes in patients with relapsed medulloblastoma (MB). While it is thought that the cold, immunosuppressive tumor microenvironment of MB accounts for this poor efficacy, the precise mechanisms contributing to immune suppression in this context remain unclear. In this study, we explore the immune landscape of MB using a previously unexplored syngeneic mouse model. Our study demonstrates that this model faithfully recapitulates the cold, immunosuppressive tumor microenvironment observed in human disease. Importantly, our research uncovers mechanisms employed by myeloid cells and tumor cells to evade immune detection while highlighting the therapeutic potential of targeting V-domain Ig Suppressor of T-cell Activation (VISTA), a novel inhibitory immune checkpoint, to enhance anti-tumor immunity. Background: Relapsed medulloblastoma (MB) poses a significant therapeutic challenge due to its highly immunosuppressive tumor microenvironment. Immune checkpoint inhibitors (ICIs) have struggled to mitigate this challenge, largely due to low T-cell infiltration and minimal PD-L1 expression. Identifying the mechanisms driving low T-cell infiltration is crucial for developing more effective immunotherapies. Methods: We utilize a syngeneic mouse model to investigate the tumor immune microenvironment of MB and compare our findings to transcriptomic and proteomic data from human MB. Results: Flow cytometry reveals a notable presence of CD45hi/CD11bhi macrophage-like and CD45int/CD11bint microglia-like tumor-associated macrophages (TAMs), alongside regulatory T-cells (Tregs), expressing high levels of the inhibitory checkpoint molecule VISTA. Compared to sham control mice, the CD45hi/CD11bhi compartment significantly expands in tumor-bearing mice and exhibits a myeloid-specific signature composed of VISTA, CD80, PD-L1, CTLA-4, MHCII, CD40, and CD68. These findings are corroborated by proteomic and transcriptomic analyses of human MB samples. Immunohistochemistry highlights an abundance of VISTA-expressing myeloid cells clustering at the tumor–cerebellar border, while T-cells are scarce and express FOXP3. Additionally, tumor cells exhibit immunosuppressive properties, inhibiting CD4 T-cell proliferation in vitro. Identification of VISTA's binding partner, VSIG8, on tumor cells, and its correlation with increased VISTA expression in human transcriptomic analyses suggests a potential therapeutic target. Conclusions: This study underscores the multifaceted mechanisms of immune evasion in MB and highlights the therapeutic potential of targeting the VISTA–VSIG axis to enhance anti-tumor responses. [ABSTRACT FROM AUTHOR]

Prolonged survival and durable responses in several late-stage cancers such as melanoma and lung cancer have been made possible with the use of immune checkpoint inhibitors targeting the programmed cell-death protein 1 (PD-1) or its ligand PD-L1. While it is prudent to focus on the unprecedented and durable clinical responses, there are subsets of cancer patients that do not respond to immunotherapies or respond early and then relapse later. Many pathways of resistance have been characterized, and more continue to be uncovered. To overcome the development of resistance, an in-depth investigation is necessary to identify alternative immune receptors and signals with the overarching goal of expanding treatment options for those with demonstrated resistance to PD1 checkpoint immunotherapy. In this mini-review, we will discuss the mechanisms by which tumors exhibit resistance to anti-PD-1/PD-L1 immunotherapy and explore strategies to overcome such resistances. [ABSTRACT FROM AUTHOR]

Even for seasoned neurosurgeons who have mastered the microvascular decompression (MVD) techniques, trigeminal neuralgia (TGN) secondary to vertebrobasilar dolichoectatic vessels remains a challenge. Often, patient is either medically infirm or unwilling for invasive surgical interventions. Alternative treatment options including Gamma Knife radiosurgery (GKRS) are considered in such a situation with variable success. This study aimed to evaluate the role of GKRS in patients with trigeminal neuralgia with dolichoectatic vessels and severe cross compression. We prospectively managed three male patients of intractable TGN secondary to dolichoectatic vascular compression with single-session GKRS. The cisternal component of the trigeminal nerve was targeted with 90 Gy radiation at 100% isodose with a single 4-mm collimator. The patients were regularly evaluated on clinical parameters for pain relief (Barrow Neurological Institute (BNI) score), sensory complaints, and outcome. All patients had satisfactory pain control (BNI I–IIIa) at 3 months of interval only to get recurrent pain (BNI IV–V) after 6 months. The treatment was eventually considered a failure after 6-month duration and one patient needed MVD for pain control. Post-GKRS pain control remains inferior in patients with dolichoectasia compared with typical TGN. GKRS should be offered only as a salvage or rescue procedure and should not be used as an alternative treatment of MVD in patient population with dolichoectatic vessels. [ABSTRACT FROM AUTHOR]

Plasma cell disorders including plasmacytomas and multiple myeloma (MM) are exquisitely radiosensitive, and thus, radiation therapy (XRT) is used effectively in their management. The role of XRT in the setting of novel MM therapeutics has not been explored. The 2016 National Cancer Database (NCDB) for MM with patients diagnosed between 2004 and 2013 was studied. Association between utilization of XRT as part of initial therapy and patient, disease, or treating facility characteristics was studied. A total of 111,281 cases with 91.6% MM, 7% osseous plasmacytoma (PLA-O), and 1.4% extramedullary plasmacytoma (PLA-E) were identified. XRT was utilized as part of initial therapy in 25.4% cases, including 69.3% of PLA-O, 60% of PLA-E, and 21.5% of MM patients. Patients with PLA-E and MM were significantly less likely to receive XRT as compared to PLA-O (p < 0.001). A significantly decreased use of XRT was noted over time (p < 0.001), and for advancing patient age (p < 0.001), women (p < 0.001), and blacks (p < 0.001), and with increasing income (p = 0.015). Patients with Medicare were less likely to receive XRT (OR 0.86, 95% CI 0.78, 0.94) as compared to uninsured as were those with initial treatment at academic or high-volume facilities and facilities performing stem cell transplant. There was overall decreased utilization of XRT in recent years, possibly due to advent of efficacious systemic agents for MM therapy, with a higher XRT utilization for plasmacytomas. Patterns of XRT use need to be explored prospectively, so that uniform standards of healthcare delivery can be maintained and treatment heterogeneity can be minimized. [ABSTRACT FROM AUTHOR]

Wherever possible, we should postpone surgery for COVID-19 positive patients until they become COVID-19 negative. For a COVID-19 patient, the COVID status needs to be addressed first followed by neurosurgical ailment [Figure 1]. Neurol India 2020;68:246-54. 7 Nahshon C, Bitterman A, Haddad R, Hazzan D, Lavie O. Hazardous postoperative outcomes of unexpected COVID-19 infected patients: A call for global consideration of sampling all asymptomatic patients before surgical treatment. [Extracted from the article]

Summary: CD38 is expressed on Waldenström macroglobulinaemia (WM) cells, but its role as a therapeutic target remains undefined. With recent approval of the anti‐CD38 monoclonal antibody, daratumumab (Dara), we hypothesized that blocking CD38 would be lethal to WM cells. In vitro Dara treatment of WM cells (including ibrutinib‐resistant lines) elicited antibody‐dependent cellular cytotoxicity (ADCC), complement‐dependent cytotoxicity (CDC), antibody‐dependent cell phagocytosis (ADCP) and direct apoptosis. In vivo, Dara treatment was well tolerated and delayed tumour growth in RPCI‐WM1‐xenografted mice. CD38 is reported to augment B‐cell receptor (BCR) signalling; we noted that Dara significantly attenuated phosphorylated SYK, LYN, BTK, PLCγ2, ERK1/2, AKT, mTOR, and S6 levels, and this effect was augmented by cotreatment with ibrutinib. Indeed, WM cells, including ibrutinib‐resistant WM cell lines treated with the ibrutinib + Dara combination, showed significantly more cell death through ADCC, CDC, ADCP and apoptosis relative to single‐agent Dara or ibrutinib. In summary, we are the first to report the in vitro and in vivo anti‐WM activity of Dara. Furthermore, we show a close connection between BCR and CD38 signalling, which can be co‐targeted with ibrutinib + Dara to induce marked WM cell death, irrespective of acquired resistance to ibrutinib. [ABSTRACT FROM AUTHOR]

The article presents a case of an 86-year-old male who has minimally persistent urticarial papules and plaques for several years to determine the effectiveness of ibrutinib as treatment for schnitzler syndrome, a rare dermatologic disorder. Topics discussed include some disease symptoms like intermittent fever, arthralgia, and lymphadenopathy, as well as the other treatment used like the humanized IL-1 receptor antagonist anakinra.