Citations

Sarcopenia is a commonly prevalent geriatric condition mainly characterized by progressive loss of the skeletal muscle mass that results in noticeably reduced muscle strength and quality. Most of the geriatric population above 60 years of age are overweight, leading to the accumulation of fat in the muscles resulting in abated muscle function. The increased loss of muscle mass is associated with high rates of disability, poor motility, frailty and mortality. The excessive degeneration of muscles is now also being observed in middle-aged people. Therefore, geriatrics has recently started shifting towards the identification of early stages of the disability in order to expand the life span of the patient and reduce physical dependence. Recent findings have indicated that patients with increased physical activity are also affected by sarcopenia, therefore indicating the role of nutritional supplements to enhance muscle health which in turn helps to counteract sarcopenia. Various interventions with physical training have not provided substantial improvements to this disorder, thereby highlighting the crucial role of nutritional supplementation in enhancing muscle mass and strength. Nutritional supplementation has not only been shown to enhance the positive effects of physical interventions but also have a profound impact on the gut microbiome that has come forward as a key regulator of muscle mass and function. This brief review throws light upon the efficiency of nutrients and nutraceutical supplementation by highlighting their ancillary effects in physical interventions as well as improving the gut microbiome status in sarcopenic adults, thereby giving rise to a multimodal intervention for the treatment of sarcopenia.

AbstractObjectiveCareer paths leading to department chair positions are elusive. Women represent only 11% of academic emergency department (ED) chairs. It is unclear whether the pathway to chair is different for men and women; the characteristics, achievements, and qualifications among those who become ED chairs is unknown.MethodsThis study is a cross‐sectional analysis of curriculum vitae (CV) of current ED chairs in departments with Accreditation Council for Graduate Medical Education (ACGME)‐accredited residency programs. Former women chairs were included due to paucity of current women chairs. Statistics were calculated using bivariate and multivariate analysis.ResultsOf 163 eligible chairs, 88 CV (54%) were obtained, including six former women chairs. A majority (86.4%) self‐identified as White/Caucasian, 21.5% were women, 46% were chief residents, 28.4% completed additional postgraduate degrees, and 21.8% were fellowship trained. At time of chair appointment, 58% were professor rank, 53.5% held ED operations roles, and 32% served as vice chair. Women were more likely to be in educational (53% vs. 22%) versus operational (26% vs. 61%, p = 0.02) roles. Women obtained more advanced degrees (47% vs. 25%, p = 0.02), were awarded more nonfederal grants (median = 7 vs. 3, p = 0.04), and achieved more national committee leadership (median = 4 vs. 1, p = 0.02). There were no gender differences in fellowship training, awards, leadership training programs, publications, federal grants, or national/international lectures after adjusting for years in practice.ConclusionWhile the majority of chairs held prior leadership roles in ED operations, only one in five women chairs did, suggesting gender differences in the path to chair attainment. These differences in paths may contribute to persistent gender disparities in ED chairs and may be influenced by career path choices, implicit bias, and structural barriers.

TPS143 Background: Patients with KRAS and NRAS ( RAS) wild-type mCRC benefit from the epidermal growth factor receptor (EGFR) monoclonal antibodies (Abs) panitumumab and cetuximab, but nearly all patients experience resistance. Blood-based profiling of cell free DNA (cfDNA) can identify genomic alterations that drive acquired EGFR Ab resistance. After discontinuation of anti-EGFR Abs, acquired genomic alterations decay over time to undetectable levels. Some studies have suggested clinical benefit from EGFR Ab rechallenge, but there is limited evidence that EGFR Ab rechallenge improves survival compared to standard of care (SOC) therapies. We hypothesize that cfDNA profiling will identify patients appropriate for panitumumab rechallenge, and that these molecularly selected patients will have improved survival compared to current SOC therapies. Methods: This is a randomized phase II, open label study designed to compare the overall survival (OS) of panitumumab rechallenge versus SOC (investigator choice TAS-102 or regorafenib). Secondary objectives include comparisons of progression free survival, objective response rate, clinical benefit rate, and quality of life as measured by the linear analogue self-assessment (LASA) questionnaire. Eligible patients have radiographically measurable KRAS, NRAS, and BRAF codon 600 wild-type mCRC based on tumor tissue testing, and must have experienced progression or intolerance to treatment with a fluoropyrimidine, oxaliplatin, irinotecan, an anti-VEGF Ab, and an anti-PD-1 Ab if the tumor has mismatch repair deficiency or is MSI-H. Progression after at least 4 months treatment with an anti-EGFR Ab is required. All patients must be enrolled in the COLOMATE cfDNA screening protocol (NCT03765736) and meet molecular eligibility based on Guardant360 cfDNA profiling (absence of amplification of ERBB2, KRAS, NRAS, and MET; absence of mutations of BRAF, EGFR, ERBB2, KRAS, NRAS, and MET [mutant allele frequency > 0.5%]). Greater than 90 days must have elapsed between the most recent treatment with an anti-EGFR Ab and cfDNA profiling. Dosing for all study drugs is according to clinical SOC. 120 patients will be randomized 1:1 to panitumumab rechallenge or SOC. With 83 OS events, this study will have 80% power to detect an improvement in median OS from 6.5 to 10 months (HR=0.65; 1-sided α= 0.15). This study began enrollment in 6/2020. Recruitment is ongoing at 16 sites in the Academic and Community Cancer Research United (ACCRU) network (ACCRU-GI-1623). Clinical trial information: NCT03992456.

PURPOSE: As oxaliplatin results in cumulative neurotoxicity, reducing treatment duration without loss of efficacy would benefit patients and healthcare providers. PATIENTS AND METHODS: Four of the six studies in the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) collaboration included patients with high-risk stage II colon and rectal cancers. Patients were treated (clinician and/or patient choice) with either fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPOX) and randomly assigned to receive 3- or 6-month treatment. The primary end point is disease-free survival (DFS), and noninferiority of 3-month treatment was defined as a hazard ratio (HR) of < 1.2- v 6-month arm. To detect this with 80% power at a one-sided type one error rate of 0.10, a total of 542 DFS events were required. RESULTS: 3,273 eligible patients were randomly assigned to either 3- or 6-month treatment with 62% receiving CAPOX and 38% FOLFOX. There were 553 DFS events. Five-year DFS was 80.7% and 83.9% for 3-month and 6-month treatment, respectively (HR, 1.17; 80% CI, 1.05 to 1.31; P [for noninferiority] .39). This crossed the noninferiority limit of 1.2. As in the IDEA stage III analysis, the duration effect appeared dependent on the chemotherapy regimen although a test of interaction was negative. HR for CAPOX was 1.02 (80% CI, 0.88 to 1.17), and HR for FOLFOX was 1.41 (80% CI, 1.18 to 1.68). CONCLUSION: Although noninferiority has not been demonstrated in the overall population, the convenience, reduced toxicity, and cost of 3-month adjuvant CAPOX suggest it as a potential option for high-risk stage II colon cancer if oxaliplatin-based chemotherapy is suitable. The relative contribution of the factors used to define high-risk stage II disease needs better understanding.

Abstract Immunosuppression of unknown etiology is a hallmark feature of glioblastoma (GBM) and is characterized by decreased CD4 T cell counts and down regulation of MHC class II expression on peripheral blood monocytes in patients. This immunosuppression is a critical barrier to the successful development of immunotherapies for GBM. We recapitulated the immunosuppression observed in GBM patients in the C57BL/6 mouse and investigated the etiology of low CD4 T cell counts. We determined that thymic involution was a hallmark feature of immunosuppression in three distinct models of CNS cancer, including mice harboring GL261 glioma, B16 melanoma, and in a spontaneous model of Diffuse Intrinsic Pontine Glioma (DIPG). In addition to thymic involution, we determined that tumor growth in the brain induced significant splenic involution, reductions in peripheral T cells, reduced MHC class II expression on hematopoietic cells, and a modest increase in bone marrow resident CD4 T cells with a naïve phenotype. Using parabiosis we report that thymic involution, declines in peripheral T cell counts, and reduced MHC class II expression levels were mediated through circulating blood-derived factors. Conversely, T cell sequestration in the bone marrow was not governed through circulating factors. Serum isolated from glioma-bearing mice potently inhibited proliferation and functions of T cells both in vitro and in vivo. Interestingly, the factor responsible for immunosuppression in serum is nonsteroidal and of high molecular weight. Through further analysis of neurological disease models, we determined that the aforementioned immunosuppression was not unique to cancer itself, but rather occurs in response to CNS injury. Noncancerous acute neurological insults also induced significant thymic involution and rendered serum immunosuppressive. Both thymic involution and serum-derived immunosuppression were reversible upon clearance of brain insults. These findings demonstrate that CNS cancers cause multifaceted immunosuppression and pinpoint circulating factors as a target of intervention to restore immunity.

Abstract OBJECTIVES Neuroendocrine thymic tumours (NETTs) are a distinct subgroup of rare malignancies. An international, multicentre retrospective analysis was used to study the clinicopathological features, current pattern of diagnosis, treatment and outcomes of patients with NETT. METHODS One hundred and forty-six NETT treated from 1989 to 2016 at 21 centres in China, Europe and North America were retrospectively collected and reclassified according to the World Health Organization histological type and International Thymic Malignancy Interest Group (ITMIG)/International Association for Studies in Lung Cancer (IASLC)/Union for International Cancer Control (UICC) staging. Clinicopathological features, diagnostic and therapeutic approaches and outcomes were investigated. Results in the earlier and latter halves of the study period were also compared. RESULTS The pretreatment work-up relied exclusively on computed tomography in 85.6% (125/146) of cases. Most patients had advanced disease, with 32.2% (47/146) having lymph node involvement. Higher-grade histological type was associated with more advanced disease (P &lt; 0.05). Induction therapies and surgical procedures were used more often in the latter half of the study. However, the complete resection rate remained unchanged, being 71.5% (98/137) in the whole group. Complete resection was associated with significantly longer 5-year overall survival (77.2% vs 51.2%; P &lt; 0.001) than incomplete or no resection. Significant survival differences were seen with the T, N and M categories of ITMIG/IASLC/UICC staging. Poorly differentiated carcinoma, ITMIG/IASLC/UICC stage IIIa or above and incomplete or no resection were independent risk factors for worse survival. No survival difference was noted between the earlier and the latter halves of the study (58.2% vs 71.9%; P = 0.299). CONCLUSIONS Current management similar to that for thymomas is unsatisfactory in providing disease control or long-term survival for patients with NETT. Specific diagnostic tools and novel therapeutic agents are needed to improve management outcomes of this disease.

Abstract Diffuse large B-cell lymphoma (DLBCL) is the major type of aggressive B-cell lymphoma. High-grade B-cell lymphoma (HGBCL) with MYC/BCL2 double-hit (DH) represents a distinct entity with dismal prognosis after standard immunochemotherapy in the current WHO lymphoma classification. However, whether TP53 mutation synergizes with MYC abnormalities (MYC rearrangement and/or Myc protein overexpression) contributing to HGBCL-like biology and prognosis is not well investigated. In this study, patients with DLBCL with MYC/TP53 abnormalities demonstrated poor clinical outcome, high-grade morphology, and distinct gene expression signatures. To identify more effective therapies for this distinctive DLBCL subset, novel MYC/TP53/BCL-2–targeted agents were investigated in DLBCL cells with MYC/TP53 dual alterations or HGBCL-MYC/BCL2-DH. A BET inhibitor INCB057643 effectively inhibited cell viability and induced apoptosis in DLBCL/HGBCL cells regardless of MYC/BCL2/TP53 status. Combining INCB057643 with a MDM2-p53 inhibitor DS3032b significantly enhanced the cytotoxic effects in HGBCL-DH without TP53 mutation, while combining with the BCL-2 inhibitor venetoclax displayed potent therapeutic synergy in DLBCL/HGBCL cells with and without concurrent TP53 mutation. Reverse-phase protein arrays revealed the synergistic molecular actions by INCB057643, DS3032b and venetoclax to induce cell-cycle arrest and apoptosis and to inhibit AKT/MEK/ERK/mTOR pathways, as well as potential drug resistance mechanisms mediated by upregulation of Mcl-1 and RAS/RAF/MEK/ERK pathways. In summary, these findings support subclassification of DLBCL/HGBCL with dual MYC/TP53 alterations, which demonstrates distinct pathobiologic features and dismal survival with standard therapy, therefore requiring additional targeted therapies. Implications: The clinical and pharmacologic studies suggest recognizing DLBCL with concomitant TP53 mutation and MYC abnormalities as a distinctive entity necessary for precision oncology practice. Visual Overview: http://mcr.aacrjournals.org/content/molcanres/19/2/249/F1.large.jpg.