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The clinical course of follicular lymphoma (FL) is thought to be influenced by the infiltrating immune cells in the tumor microenvironment. Focusing on the distribution patterns of T cells may be a promising approach to estimate the prognosis of FL, especially histological transformation. This study was a retrospectively cohort study in the relationship between the pathological distribution pattern of T cells in the tumor microenvironment and clinical course of FL. One hundred twenty-eight patients with FL initially diagnosed at the University of Tokyo Hospital from January 2008 to January 2017 were evaluated. We classified each patient's specimen at initial diagnosis by the distribution pattern of tumor infiltrating CD3-positive cells, intra-follicle focal (IFF), intra-follicle diffuse (IFD), extra-follicle marginal (EFM), and extra-follicle diffuse (EFD). We analyzed the distribution pattern's correlation with other prognostic factors including overall survival (OS), progression free survival (PFS), and transformation. Among 128 cases, 81 had evaluable pathological specimen. Based on our criteria, in the intra-follicle,17 cases (21%) were classified as IFF. Sixty-four cases (79%) were classified as IFD. In the extra follicle, 25 cases (31%) were classified as EFM. Fifty-six cases (69%) were classified as EFD. There was significant difference in risk of transformation between the EFM and EFD around extra-follicle area in the adjusted model (p 0.05). Also, cases with IFF and EFM had significantly higher risk of transformation compared to cases with other T cell distribution patterns (p 0.01). We proposed a new classification of CD3-positive T cell distribution patterns around the follicle lesions in FL and demonstrated its clinical significance.

Background: Our objective was to characterize cancer immunity marker expression in gynecologic cancers and compare immune landscapes between gynecologic tumor subtypes and with non-gynecologic solid tumors. Methods: RNA expression levels of 51 cancer-immunity markers were analyzed in patients with gynecologic cancers vs. non-gynecologic cancers, and normalized to a reference population of 735 control cancers, ranked from 0-100, and categorized as low (0-24), moderate (25-74), or high (75-100) percentile rank. Results: Of the 72 patients studied, 43 (60%) had ovarian, 24 (33%) uterine, and 5 (7%) cervical cancer. No two immune profiles were identical according to expression rank (0-100) or rank level (low, moderate, or high). Patients with cervical cancer had significantly higher expression level ranks of immune activating, pro-inflammatory, tumor infiltrating lymphocyte markers and checkpoints than patients with uterine or ovarian cancer (p1% versus 0% had significantly higher expression levels of pro-inflammatory markers (58 vs. 49%, p=0.0004). Compared to patients with non-gynecologic cancers, more patients with gynecologic cancers express high levels of IDO-1 (44 vs. 13%, pConclusions: Patients with gynecologic cancers have complex and heterogeneous immune landscapes that are distinct from patient to patient and from other solid tumors. High levels of IDO1 and LAG3 suggest that clinical trials with IDO1 inhibitors or LAG3 inhibitors, respectively, may be warranted in gynecologic cancers.

Tyrosine kinase inhibitors (TKI) or immune checkpoint blockade (ICB), either alone or in combination, confers a significant overall survival (OS) benefit for metastatic RCC in the first-line setting. However, guidance for optimal treatment selection in elderly patients remains limited.A database search was performed to identify eligible randomized controlled trials (RCTs) evaluating first-line regimens for patients with advanced RCC older than 65 years old. The primary outcomes were progression-free survival (PFS) and OS. Indirect comparisons of available regimens were estimated using a random-effects network meta-analysis.A total of 14 and five RCTs were eligible for PFS and OS analyses. Compared with sunitinib, pembrolizumab plus axitinib (HR 0.68, 95% CI 0.48-0.97) and pembrolizumab plus lenvatinib (HR 0.61, 95% CI 0.4-0.94) were associated with improved OS. Pembrolizumab plus lenvatinib, nivolumab plus cabozantinib, pembrolizumab plus axitinib, and cabozantinib alone each showed improved PFS over sunitinib. Among these, pembrolizumab plus lenvatinib showed better PFS than pembrolizumab plus axitinib (HR 0.58, 95% CI 0.37-0.91), but no PFS difference compared to nivolumab plus cabozantinib (HR 0.63, 95% CI 0.39-1.03) and cabozantinib alone (HR 0.84, 95% CI 0.40-1.77). Network ranking showed pembrolizumab plus lenvatinib provided the favored OS and PFS benefit for elderly patients.The combination of ICB with TKI such as pembrolizumab plus lenvatinib needs to be considered over monotherapy in the elderly population, but further validation using real-world data or prospective trials is necessary to confirm the efficacy and safety of first-line regimens for the geriatric population with advanced RCC.

Skeletal-related events (SREs) are related to morbidity and mortality in patients with bone metastatic prostate cancer, and preventive strategies based on patient risk assessment are recommended. However, potentiating factors for SREs in patients with bone metastatic prostate cancer are not well elucidated. We analyzed the clinical data from a controlled arm of a clinical trial comparing denosumab with zoledronate in patients with bone metastatic, castration resistant prostate cancer (ClinicalTrial.gov ID: NCT00321620) available at Project Data Sphere, a broad-access research platform. The primary endpoint was the first SRE after the inclusion to the trial, and the time to the first SRE was analyzed using Cox proportional hazards model based on patients’ baseline characteristics including age, race, ECOG performance status (PS), Gleason score, TNM stage at diagnosis, metastasis pattern, and urine and serum laboratory data. Seven hundred ten patients without documented history of osteopenia or osteoporosis whose data was available in the zoledronate arm of the trial were analyzed. The median age of the patients was 71 years old, the median follow-up was 225 days, and 295 patients (42%) had at least one SRE during this period. The univariate analysis showed that history of SREs, Gleason score ≥ 7, elevated serum alkaline phosphatase (ALP), and high urine N-telopeptide cross-links/creatinine ratio (NTx/Cre) are significant baseline risk factors for SREs. Patients with the characteristics of history of SREs, Gleason score ≥ 7 and elevated serum ALP also showed a significantly higher hazard ratio of SREs in multivariate analysis. The incidence of SREs in patients with bone metastatic prostate cancer may be higher in those with history of SREs, Gleason ≥ 7, and elevated serum ALP.

Introduction: Targeted therapies and immunotherapies have changed the treatment strategy for advanced colorectal cancer. Characterizing associations of actionable gene mutations with microsatellite instability (MSI) and tumor mutational burden (TMB) could suggest mechanistically intriguing combinations of targeted and immunotherapies. Methods: Publicly available genetic and overall survival (OS) data of patients with colorectal cancer were analyzed. (N=3,548, MSK-MET through cBioPortal for cancer genomics) We investigated the correlations among actionable gene mutations (BRAF V600E, KRAS G12C, HER2 amplification, NTRK fusion, and RET fusion), MSI and TMB (>20/Mb). The association of actionable mutations, MSI and TMB patterns with OS was analyzed. Results: BRAF V600E, KRAS G12C, HER2 amplification, NTRK fusion, RET fusion, MSI and TMB >20 was observed in 6.9, 3.1, 2.8, 0.3, 0.2, 9.2 and 9.9%, respectively. BRAF V600E showed mutual exclusivity toward KRAS G12C and HER2 amplification. MSI and TMB > 20 were associated with the presence of BRAF V600E, NTRK fusion, and RET fusion and the absence of KRAS G12C and HER2 amplification. MSI and TMB > 20 were highly correlated. (Table) Among patients with MSI (N=316), BRAF V600E was associated with shorter OS. (Hazard ratio (HR) 2.22, 95% confidence interval (CI); 1.12 - 4.41) In the patients without MSI, TMB >20 showed significantly longer OS, compared with TMB ≤20. (HR 0.26, 95% CI; 0.085 - 0.82) Association of NTRK or RET fusion with survival could not be reliably assessed due to small sample size (n < 10 for both). Conclusion: There is significant correlation among targetable genetic mutations, MSI and TMB in colorectal cancer, and biomarker profiles are associated with differences in OS. Future studies should evaluate whether combinations of targeted therapies and immunotherapy have better efficacy than monotherapy approaches in selected patients. Correlation among actionable gene mutations and immunomic signatures (OR and 95 % CI) KRAS G12C HER2 amp NTRK fusion RET fusion MSI TMB >20 BRAF V600E 0 (0 - 0.44) * 0 (0 - 0.49) * 0 (0 - 6.79) 0 (0 - 9.31) 10.0 (7.39 - 13.5) * 8.76 (6.52 - 11.7) * KRAS G12C 0.31 (0.01 - 1.78) 0 (0 - 16.0) 0 (0 - 21.9) 0.18 (0.02 - 0.67) * 0.16 (0.02 - 0.61) * HER2 amp 0 (0 - 17.5) 0 (0 - 23.9) 0.10 (0.00 - 0.57) * 0.09 (0.00 - 0.51) * NTRK fusion 0 (0 - 315) 20.0 (4.25 - 124) * 18.4 (3.91 - 115) * RET fusion 24.9 (4.06 - 261) * 23.0 (3.74 - 241) * MSI 1.52 x 104 (4.20 x 103 - 4.50 x 1015) * Citation Format: Hirotaka Miyashita, Gabriel Brooks, Razelle Kurzrock, Shumei Kato. Correlation among actionable gene mutations, microsatellite instability and tumor mutational burden in advanced colorectal cancer and association with survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 928.

Aim Deterioration of patients from COVID-19 is associated with cytokine release syndrome attributed to an elevation in pro-inflammatory cytokines. Vitamin D reduces proinflammatory cytokines, and has the possibility of reducing complications from respiratory tract illnesses. Method This was a retrospective, observational, cohort study of patients with COVID-19 disease within a New York City Health System. Adult patients were included if they tested positive for SARS-CoV-2, and had a serum 25-hydroxy vitamin D level (25(OH)D) within the three previous months prior to their detected SARS-CoV-2 test. Patients were compared and evaluated based upon their 25(OH)D levels. The primary endpoints were hospitalization, need for oxygen support, and 90-day mortality. Results 437 COVID-19 patients were included [67 (IQR: 56–79) years] within this cohort. Deficient plasma 25(OH)D levels (

Highlights • Fever was associated with poor outcomes in patients with COVID-19. • Leukocytosis was associated with severe disease. • Leukopenia was associated with a better prognosis. • CRP was associated with poor prognosis. • Leuocytosis and CRP on arrival may predict severe COVID-19., Background Since December 2019, coronavirus 2019 (COVID-19) has spread worldwide. Identifying poor prognostic factors is helpful for risk stratification. In this meta-analysis, we investigated the association between severe COVID-19 and a change in white blood cell (WBC) count, an elevation of C-reactive protein (CRP), and fever. Moreover, we aimed to evaluate the diagnostic accuracy of leukocytosis and an elevation of CRP. Methods We performed a systematic search of PubMed, EMBASE, Scopus, and the Cochrane Library through April 20th, 2020. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. A sensitivity analysis was conducted according to the study size (>200 or 55 or

Colitis is a major immune-related adverse event associated with programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors, but the risk of colitis with PD-1 versus PD-L1 inhibitors is not well characterized. We performed a meta-analysis for the incidence of all grade and grade 3-4 colitis with PD-1 inhibitor (nivolumab, pembrolizumab, and cemiplimab) or PD-L1 inhibitor (atezolizumab, avelumab, and durvalumab) monotherapy using a fixed effects model. We also conducted subgroup meta-analyses of non-small cell lung cancer (NSCLC) or urothelial carcinoma (UC) trials, and a network meta-analysis of randomized trials comparing PD-1 or PD-L1 inhibitors with docetaxel for NSCLC. We also analyzed the Food and Drug Administration Adverse Event Reporting System database to estimate the reporting odds ratio of each medication. PD-1 inhibitors were associated with a higher incidence of all grade and grade 3-4 colitis compared with PD-L1 inhibitors in the analysis of all cancer types [1.49% vs. 0.83%, relative risk; 1.80, 95% confidence interval (CI); 1.22-2.67 for all grade colitis, and 0.85% vs. 0.34%, relative risk; 2.52, 95% CI; 1.46-4.37 for grade 3-4 colitis]. The meta-analyses of NSCLC and UC trials, and the network meta-analysis of NSCLC trials were also suggestive of a higher risk of colitis with PD-1 versus PD-L1 inhibitors. The reporting odds ratio of colitis with PD-1 versus PD-L1 inhibitors was 1.80 (95% CI; 1.53-2.14). In this meta-analysis of clinical trials exploring PD-1 and PD-L1 inhibitors in solid tumors, PD-1 inhibitors were associated with a higher risk of colitis.

Background The best regimen of neo-adjuvant therapy for triple-negative breast cancer (TNBC) is unknown. Recent studies have shown promising data that adding carboplatin or pembrolizumab improves the rate of pathologic complete response (pCR) in TNBC. Therefore, we performed a network meta-analysis to define the overall, most effective, neo-adjuvant systemic therapy for TNBC. Methods We searched for studies comparing different neo-adjuvant regimens in patients with TNBC. We performed a network meta-analysis comparing the regimens using the random-effects model. We focused on anthracycline, bevacizumab, pembrolizumab, and platinum salts (Pl). All study regimens contained a taxane. We analyzed the rate of pCR (ypT0/is, N0), and the incidence of febrile neutropenia, grade 3-grade 4 thrombocytopenia, nausea/vomiting, and diarrhea. Results We identified a total of 13 randomized control trials for this analysis. We compared ten different classes of regimens. We found that regimens containing Pl were significantly superior to non-PI-containing regimens for the rate of pCR. Similarly, pembrolizumab-containing regimens were associated with significantly higher pCR rates. Regimens containing bevacizumab significantly increased the rate of pCR as well. However, it was equivocal as to whether the addition of Pl to pembrolizumab-containing regimen increases pCR rates. Adding anthracycline into the regimen did not show an improved rate of pCR. In the safety analysis, regimens containing Pl were associated with a significantly higher incidence of febrile neutropenia and grade 3-grade 4 thrombocytopenia. The regimen containing anthracycline plus bevacizumab plus Pl was associated with a higher risk of gastrointestinal adverse events. Conclusions For TNBC, regimens containing bevacizumab, pembrolizumab, or Pl are most effective in terms of pCR rates, though it is unclear whether combining all these medications has the greatest efficacy. Additionally, the benefit of using anthracycline in the neo-adjuvant therapy regimen for TNBC is not apparent, which may warrant a further head-to-head comparison.

Purpose Sleep apnea syndrome (SAS) is a relatively common disorder, but many patients with SAS are still undiagnosed. Using Japanese annual health check and medical claims data, we analyzed the association between hemoglobin upswing, defined as an increase in hemoglobin level within the reference range, and the incidence of SAS. Methods In this study, we used the Japan Medical Database Center (JMDC) annual health check and medical claims data of 351,930 male individuals aged 40−59 who had their hemoglobin concentration checked in 2014. We initially identified the reference range of hemoglobin level based on the mean and the standard deviation of hemoglobin concentration in this population. We examined the effect of hemoglobin upswing on the incidence of SAS using Cox proportional hazards models. Results The hemoglobin upswing was defined as a change greater than 1.19 g/dL in the reference range of 13.1 to 17.2 g/dL. During a mean follow-up period of approximately 1285 days, 1.9% of the individuals with hemoglobin upswing were diagnosed with SAS, while 1.6% of those without hemoglobin upswing were diagnosed with SAS. The hazard ratio of hemoglobin upswing to the incidence of SAS was 1.21 (95% CI; 1.01–1.44, p = 0.04). Conclusion We herein revealed the association between hemoglobin upswing and the incidence of SAS in a middle-aged male population. A statistically significant increase in hemoglobin concentration even in the reference range should be paid attention to as it may indicate the presence of SAS.

Cancer-associated thrombosis (CAT) is a common complication in patients with malignancy. Although direct oral anticoagulants (DOACs) have emerged as a treatment option for CAT, there have not been head-to-head comparisons of these agents. We searched MEDLINE and EMBASE from inception to April 2020 for studies comparing the effect of different long-term anticoagulation strategies for venous thromboembolism (VTE) in patients with cancer. We performed a network meta-analysis comparing the antithrombotic strategies in the selected studies using random-effects model. We identified a total of 20 studies [9 randomized control trials (RCTs) and 11 subgroup analyses from other unique RCTs] with total of 6699 patients for inclusion in our analysis. There was no significant difference in recurrent VTE, all-cause death, major bleeding and clinically relevant non-major bleeding among DOACs. When DOACs were combined, recurrent VTE was significantly decreased in DOACs compared to low-molecular weight heparin (LMWH) and Vitamin K antagonist (VKA) [RR (95% CI) 0.75 (0.59-0.94); RR (95% CI) 0.51 (0.39-0.66), respectively] without significant increase in major bleeding or clinically relevant non-major bleeding. In patients with CAT, there was no significant difference in recurrent thrombotic event among different DOACs. Bleeding risk was comparable among all anticoagulation strategies. When DOACs were combined, DOACs were associated with a significant decrease in recurrent VTE with comparable bleeding risk to LMWH and VKA.

Background Monoclonal gammopathy of undetermined significance (MGUS) is an indolent, premalignant plasma cell disorder with the potential of transforming into symptomatic multiple myeloma (MM). There are multiple risk factors that contribute to transformation. Agent Orange (AO) has been linked with multiple malignant and nonmalignant conditions. Patients and Methods We conducted a retrospective chart review of patients with monoclonal gammopathy who were seen at John D. Dingell Veterans Affairs Medical Center (Detroit, Michigan) between 2005 and 2015 with MGUS, smoldering multiple myeloma, and MM. We explored baseline patient characteristics and explored AO exposure. Dates of diagnosis, dates of progression, and expiration dates were recorded to time to progression and overall survival (OS). Results We identified 211 patients with monoclonal gammopathy; 96% were male and 122 were African American. Eleven patients had reported AO exposure. Cumulative risk of progression in the overall population was 1.4% at 1 year. Risk of transformation in the population exposed to AO was significantly higher with a hazard ratio (HR) of 11.19 (95% confidence interval [CI], 2.10-59.47; P = .005). OS was numerically shorter in AO-exposed patients with a median OS of 7 years compared with 11.1 years in those not exposed. However, AO exposure was not associated with OS in multivariable analysis (HR, 0.50; 95% CI, 0.07-3.83; P = .508). Conclusion Monoclonal gammopathy is a premalignant condition with the risk of progressing to MM. Exposure to AO has been implicated in multiple conditions including MM. Our study demonstrates an increased risk of progression in exposed patients.

The data of head-to-head comparisons of the anti-fracture efficacy of bone modifying agents (BMAs) in patients with hormone receptor-positive breast cancer receiving aromatase inhibitor (AI) are not available. Therefore, we conducted a network meta-analysis to compare the efficacy of different BMAs in patients with breast cancer receiving adjuvant AI. We performed a network meta-analysis to compare the change of bone mineral densities (BMDs) and the risk of fracture in the selected studies using a random effect model. The primary outcomes are the change of BMD of lumbar spine (LS) and total hip (TH) from the baseline (ΔBMD, %) at 1 and 2 years and the risk of fracture. We identified and included a total of 16 randomized controlled trials for this analysis. All BMAs included (risedronate, zoledronate, and denosumab) were associated with a significant increase in BMD of LS and TH at 1 and 2 years compared with no upfront treatment group. Among BMAs, zoledronate and denosumab use resulted in significantly higher BMD of LS and TH at 1 and 2 years compared with risedronate. The risk of fracture was significantly lower in the patients who received denosumab or risedronate compared with the patients without upfront treatment (Relative risk (RR) [95% CI] 0.51 [0.38–0.67] and 0.54 [0.35–0.83], respectively). Among the bisphosphonates, zoledronate increased BMD the most, but risedronate, not zoledronate, use was associated with lower risk of fracture. Denosumab increased BMD not only of LS but also of the cortical-bone-rich hip, and showed a significant reduction of fracture risk.

Hepatotoxicity is a major immune-related adverse event that may become life-threatening. The impact of adding immune checkpoint blockade (ICB) to systemic therapy on the incidence of hepatotoxicity remains unknown. We performed a systematic review and meta-analysis to compare the incidence of hepatotoxicity among patients with cancer who received therapy with and without addition of ICB. PubMed, Embase, Web of Science, and Cochrane Library were searched to select phase 3 randomized controlled trials (RCTs) evaluating the effect of adding ICB to systemic therapy, placebo, or supportive care. The odds ratio (OR) of any grade and grade 3-5 hepatitis, elevations in aspartate aminotransferase (AST), and alanine aminotransferase (ALT) was pooled for meta-analysis. 43 RCTs with 28,905 participants were analyzed. Addition of ICB increased the incidence of hepatitis (any grade: OR, 2.13, 95% confidence interval [CI] 1.52-2.97, grade 3-5: OR, 2.66, 95% CI 1.72-4.11), elevated AST (any grade: OR, 2.16, 95% CI 1.73-2.70, grade 3-5: OR, 2.72, 95% CI 1.86-3.99), and elevated ALT (any grade: OR, 2.01, 95% CI 1.59-2.54, grade 3-5: OR, 2.40, 95% CI 1.62-3.55). Subgroup analysis based on the ICB mechanism revealed no significant heterogeneity among each mechanism for hepatitis (any Grade: I

Dear Editor,Since December 2019, coronavirus 2019 (COVID-19) has spread worldwide.1 Some data have suggested that the prevalence and mortality of COVID-19 are different among races. 2However, this analysis did not account for potential confounding factors.Since chronic kidney disease (CKD) is common, the number of COVID-19 patients with CKD will increase. However, there are scarce data about outcomes in CKD patients. We herein investigated the outcomes from COVID-19 in AAs compared to those in whites.We analyzed Mount Sinai Health System (MSHS) medical records up to April 5, 2020, using Epic SlicerDicer software. We extracted data from patients who had positive for the COVID-19 reverse-transcription polymerase chain reaction (RT-PCR) test. Sex, age, race, and comorbidities (hypertension, diabetes mellitus, ischemic heart disease, heart failure, and atrial fibrillation) were extracted using the 10th revision of the International Statistical Classification of Diseases code. Mortality and intensive care unit (ICU) admission were tracked through April 12, 2020. Relative risks (RR) and 95 % confidence interval (CI) in each race stratified by age groups and comorbidities were calculated using a Fisher’s exact test. MSHS waived Institutional Review Board approval since this research used only deidentified, aggregate-level data.During the study period, 1,269 AAs COVID-19 patients with 105 CKD patients and 1,450 whites COVID-19 patients with 80 CKD patients were detected. AAs were younger (median 66, IQR 55-76) than whites (median 75, IQR 65-83) (p< 0.001). There was no significant difference in mortality between AAs and whites (0.65 [0.36-1.15]). This tendency was observed after stratification by age and medical conditions. Similarly, AAs did not have an increased risk of ICU admission (0.84 [0.6-1.18])) even after stratification by age and comorbidities (Table).To the best of our knowledge, this is the first study that compared the risk of severe outcomes among races in CKD patients. Although it has been suggested that there might be racial disparity in COVID-19, our study did not show any significant differences in outcomes, even after stratifying patients by age and comorbidities. Our data suggested that we do not need to stratify these patients by race.The racial and ethnic diversity in NYC enabled us to investigate differences in outcomes among races in the same cohort. However, our study has several limitations. First, the number of patients was relatively small. Second, we did not access individual data, which prevented us from performing multivariate analyses. The fact that AAs were younger might mask differences among races.In conclusion, AAs with CKD did not have a higher risk of mortality or ICU admission than whites with CKD. This trend was consistent after stratification by age, sex, or comorbidities.Acknowledgements: noneConflict of Interest Disclosures: TY reports no conflict of interest. TM reports no conflict of interest. NC reports no conflict of interest. HM reports no conflict of interest. SC repots no conflict of interest. SM reports no conflict of interest.Reference1. Team CC-R. Preliminary Estimates of the Prevalence of Selected Underlying Health Conditions Among Patients with Coronavirus Disease 2019 - United States, February 12-March 28, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(13):382-386.2. Health N. Age adjusted rate of fatal lab confirmed COVID-19 cases per 100,000 by race/ethnicity group as of April 6, 2020 (Accessed Aprio 12, 2020). 2020.

Bacterial peritonitis, an infection of the ascitic fluid, can be classified etiologically as spontaneous or secondary bacterial peritonitis. The former is mainly caused by portal hypertension and its subsequent effects, whereas the latter is caused by the direct dissemination of bacteria into the peritoneal cavity. Previous reports have described some distinguishing features of these two entities. Here, we report the first known case of bacterial peritonitis with Aeromonas hydrophilia and Escherichia coli in a patient with malignant ascites associated with pancreatic carcinoma who exhibited features of both spontaneous and secondary peritonitis. Our report suggests that clinicians should also consider bacterial peritonitis in patients with malignant ascites who present with ostensibly cancer-related symptoms.

The data of head-to-head comparisons of the effect of bone-modifying agents (BMAs) in patients with androgen deprivation therapy (ADT) for prostate cancer without skeletal metastasis is limited. Thus, we conducted a network meta-analysis to compare each BMA for the efficacy of bone mineral densities (BMDs) and the risk of fracture. We performed a network meta-analysis to compare the change of BMDs and the risk of vertebral fracture in the studies included using a random-effect model. The primary outcomes are the change of BMD of the lumbar spine (LS) and the total hip (TH) from the baseline at 1 year from the initiation of the BMA and the risk of vertebral fracture. We identified and included 15 studies in this analysis. All BMAs except risedronate showed a significant increase of BMD of the LS compared with groups without BMA, among which zoledronate showed the most BMD gain. At TH, bisphosphonates (alendronate, pamidronate, and zoledronate) and denosumab showed significant elevation compared with the no-BMA group. Denosumab was associated with the most BMD gain at the TH. Only denosumab reduced the risk of vertebral fracture (relative risk [95% confidence interval]: 0.40 [0.20–0.81]). Although zoledronate showed the highest BMD gain at the LS, it did not reduce the risk of vertebral fracture in this analysis. Most bisphosphonates and denosumab significantly increased BMD at the LS and the TH in patients receiving ADT for prostate cancer without skeletal metastasis. In particular, zoledronate and denosumab were the most potent BMAs in terms of BMD increment at the LS and the TH, respectively. However, denosumab, not zoledronate, was the only BMA that showed a significant risk reduction of vertebral fracture. We need further studies to examine the change of bone quality and the effect on the risk of non-vertebral and hip fractures.

4532 Background: Multiple regimens incorporating tyrosine kinase inhibitors (TKI) or immune checkpoint inhibitors (ICI), either alone or in combination, confer a significant OS benefit in 1L metastatic clear cell RCC. However, guidance for optimal treatment selection in elderly patients remains limited. A network meta-analysis (NMA) was performed to compare the efficacy of 1L treatments for elderly patients with aRCC. Methods: Database search was performed through Pubmed, Embase, Web of Science, and Scopus. Eligible studies were randomized controlled trials (RCTs) evaluating first-line regimens for patients with aRCC older than 65 years old. The primary outcomes were progression-free survival (PFS) and overall survival (OS). Indirect comparisons of available regimens were estimated using a random-effects NMA. Results: 14 RCTs with more than 2,100 patients and 5 RCTs with 1,529 patients were eligible for PFS and OS analyses, respectively. Compared with sunitinib (Sun), the pembrolizumab (Pem) + axitinib (Axi) (HR 0.68, 95% CI 0.48-0.97) and Pem + lenvatinib (Len) (HR 0.61, 95% CI 0.4-0.94) regimens were associated with significantly improved OS. In comparing the TKI-ICI combinations with dual ICI nivolumab (Niv) + ipilimumab (Ipi), no significant OS differences were observed (Pem + Len: HR 0.71, 95% CI 0.40-1.27; Pem + Axi: HR 0.79, 95% CI 0.47-1.34; Avelumab (Ave) + Axi: HR 1.03, 95% CI 0.58-1.85; Niv + cabozantinib [Cab]: HR 1.03, 95% CI 0.57-1.93, using Niv + Ipi as a reference). Pem + Len, Niv + Cab, Pem + Axi, and Cab alone each showed improved PFS over Sun (Table). Among these, Pem + Len showed a PFS advantage compared to Pem + Axi (HR 0.58, 95% CI 0.37-0.91), but no PFS difference compared with the other regimens (vs Niv + Cab: HR 0.63, 95% CI 0.39-1.03; vs Cab alone: HR 0.84, 95% CI 0.40-1.77). Conclusions: Pem + Len and Pem + Axi provided the largest OS benefit in elderly patients for 1L aRCC. Pem + Len showed improved PFS compared with Pem + Axi, but no difference compared with Niv + Cab or Cab alone. Further validation using real-world data is needed to confirm the efficacy and safety of first-line regimens for the geriatric population with aRCC.[Table: see text]

2555 Background: Although immune checkpoint blockade (ICB) has revolutionized cancer treatment, not all patients with cancer benefit from ICB. One possible explanation for poor responders/resistance is the variable expression level of the target molecules (e.g., PD-1 and PD-L1) in the tumor microenvironment. There are recent or ongoing trials targeting variable pathways for immune evasion (e.g., LAG3 or IDO1). It is therefore of interest to know the expression levels related to variable immune checkpoints so that clinical trials can focus on the patients who can benefit from the cognate treatment. Methods: Overall, 514 patients with various solid tumors seen at the University of San Diego, Moores Center for Personalized Cancer Therapy were analyzed. The expression levels of checkpoint markers (ADORA2A, BTLA, CD276, CTLA4, IDO1, IDO2, LAG3, NOS2, PD-1, PD-L1, PD-L2, PVR, TIGIT, TIM3, VISTA, and VTCN) in the tumor samples were measured through RNA sequencing and normalized to internal housekeeping gene profiles, and ranked from 0 to 100 percentile based on a reference population. The expressions of each checkpoint marker were correlated with cancer types, microsatellite instability (MSI), tumor mutational burden (TMB), and programmed death-ligand 1 (PD-L1) status on immunohistochemistry. Results: In this cohort, 60% were female, median age of 60, and included 30 different tumor types, with colorectal cancer being the most common (27%). The rank values of all checkpoint markers were distributed broadly from 0 to 99 or 100. CD276 and NOS2 had the highest (68th percentile) and lowest (13.5 percentile) median rank values, respectively. When rank values were categorized to “Low” (0-24), “Intermediate” (25-74), and “High” (75-100), 41.6% of patients showed high expression of CD276 while only 13% showed high expression of PD-L1. Each patient had a distinctive protfolio of the categorical expression levels of 16 checkpoint markers. Several checkpoint markers, especially NOS2, showed a significant correlation with cancer type. (median rank values in colorectal, stomach, pancreatic, and breast cancer were 79, 76, 5 and 0 respectively, p < 0.001) Five markers (IDO1, LAG3, PD-1, PD-L1, and TIGIT) showed significant correlation with MSI, while seven markers (CTLA4, IDO1, LAG3, PD-1, PD-L1, PD-L2, and TIGIT) were significantly associated with positive PD-L1 status. However, no significant association was seen based on TMB or tissue-specific grouping of patients. Conclusions: The expression of immune checkpoint markers varies from patient to patient, though transcript expression of several markers correlates with cancer type, MSI, and PD-L1 status. Clinical trials with patient selection based on the expression level of checkpoint markers matched to the corresponding ICB drug are warranted.

Background Emerging evidence suggests that sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with decreased risk of cardiovascular and renal events in type 2 diabetes mellitus (DM) patients. However, no study to date has compared the effect of SGLT-2 inhibitors with that of GLP-1 RAs in type 2 DM patients with chronic kidney disease (CKD). We herein investigated the benefits of SGLT-2 inhibitors and GLP-1 RAs in CKD patients. Methods We performed a systematic literature search through November 2020. We selected randomized control trials that compared the risk of major adverse cardiovascular events (MACE) and a composite of renal outcomes. We performed a network meta-analysis to compare SGLT-2 inhibitors with GLP-1 RAs indirectly. Risk ratios (RRs) with corresponding 95% confidence intervals (CI) were synthesized. Results Thirteen studies were selected with a total of 32,949 patients. SGLT-2 inhibitors led to a risk reduction in MACE and renal events (RR [95% CI]; 0.85 [0.75–0.96] and 0.68 [0.59–0.78], respectively). However, GLP-1 RAs did not reduce the risk of cardiovascular or renal adverse events (RR 0.91 [0.80–1.04] and 0.86 [0.72–1.03], respectively). Compared to GLP-1 RAs, SGLT-2 inhibitors did not demonstrate a significant difference in MACE (RR 0.94 [0.78–1.12]), while SGLT-2 inhibitors were associated with a lower risk of renal events compared to GLP-1 RAs (RR 0.79 [0.63–0.99]). A sensitivity analysis revealed that GLP-1 analogues significantly decreased MACE when compared to placebo treatment (RR 0.81 [0.69–0.95]), while exendin-4 analogues did not (RR 1.03 [0.88–1.20]). Conclusions In patients with type 2 DM and CKD, SGLT-2 inhibitors were associated with a decreased risk of cardiovascular and renal events, but GLP-1 RAs were not. SGLT-2 inhibitors significantly decreased the risk of renal events compared to GLP-1 RAs. Among GLP-1 RAs, GLP-1 analogues showed a positive impact on cardiovascular and renal outcomes, while exendin-4 analogues did not.

The outbreak of coronavirus disease 2019 (COVID-19) emerged in late 2019 in Wuhan, China, and has been spreading rapidly. As the infection has become widespread, concern for the influence of COVID-19 on patients with cancer has grown. Zhang et al.1Zhang L. Zhu F. Xie L. et al.Clinical characteristics of COVID-19-infected cancer patients: a retrospective case study in three hospitals within Wuhan, China.Ann Oncol. 2020; 31: 894-901Abstract Full Text Full Text PDF PubMed Scopus (306) Google Scholar reported a retrospective case study of 28 COVID-19-infected cancer patients with an astonishingly high mortality rate (28.6%). However, as Oh2Oh W.K. COVID-19 infection in cancer patients: early observations and unanswered questions.Ann Oncol. 2020; 31: 838-839Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar pointed out, the result cannot be applied to other countries with different cancer epidemiology and practice. We herein sought to determine whether patients with cancer in the USA have a poorer prognosis of COVID-19 by analyzing the electronic medical records of Mount Sinai Health System (MSHS) in New York City.

We report that two widely-used drugs for erectile dysfunction, tadalafil and vardenafil, trigger bone gain in mice through a combination of anabolic and antiresorptive actions on the skeleton. Both drugs were found to enhance osteoblastic bone formation in vivo using a unique gene footprint and to inhibit osteoclast formation. The target enzyme, phosphodiesterase 5A (PDE5A), was found to be expressed in mouse and human bone as well as in specific brain regions, namely the locus coeruleus, raphe pallidus, and paraventricular nucleus of the hypothalamus. Localization of PDE5A in sympathetic neurons was confirmed by coimmunolabeling with dopamine β-hydroxylase, as well as by retrograde bone-brain tracing using a sympathetic nerve-specific pseudorabies virus, PRV152. Both drugs elicited an antianabolic sympathetic imprint in osteoblasts, but with net bone gain. Unlike in humans, in whom vardenafil is more potent than tadalafil, the relative potencies were reversed with respect to their osteoprotective actions in mice. Structural modeling revealed a higher binding energy of tadalafil to mouse PDE5A compared with vardenafil, due to steric clashes of vardenafil with a single methionine residue at position 806 in mouse PDE5A. Collectively, our findings suggest that a balance between peripheral and central actions of PDE5A inhibitors on bone formation together with their antiresorptive actions specify the osteoprotective action of PDE5A blockade.

Background Measuring emotional status objectively is challenging, but voice pattern analysis has been reported to be useful in the study of emotion. Objective The purpose of this pilot study was to investigate the association between specific sleep measures and the change of emotional status based on voice patterns measured before and after nighttime sleep. Methods A total of 20 volunteers were recruited. Their objective sleep measures were obtained using a portable single-channel electroencephalogram system, and their emotional status was assessed using MIMOSYS, a smartphone app analyzing voice patterns. The study analyzed 73 sleep episodes from 18 participants for the association between the change of emotional status following nighttime sleep (Δvitality) and specific sleep measures. Results A significant association was identified between total sleep time and Δvitality (regression coefficient: 0.036, P=.008). A significant inverse association was also found between sleep onset latency and Δvitality (regression coefficient: –0.026, P=.001). There was no significant association between Δvitality and sleep efficiency or number of awakenings. Conclusions Total sleep time and sleep onset latency are significantly associated with Δvitality, which indicates a change of emotional status following nighttime sleep. This is the first study to report the association between the emotional status assessed using voice pattern and specific sleep measures.

New York City emerged as an epicenter of the coronavirus disease 2019 (COVID-19) pandemic. To describe the clinical characteristics and risk factors associated with mortality in a large patient population in the USA. Retrospective cohort study. 6493 patients who had laboratory-confirmed COVID-19 with clinical outcomes between March 13 and April 17, 2020, who were seen in one of the 8 hospitals and/or over 400 ambulatory practices in the New York City metropolitan area Clinical characteristics and risk factors associated with in-hospital mortality. A total of 858 of 6493 (13.2%) patients in our total cohort died: 52/2785 (1.9%) ambulatory patients and 806/3708 (21.7%) hospitalized patients. Cox proportional hazard regression modeling showed an increased risk of in-hospital mortality associated with age older than 50 years (hazard ratio [HR] 2.34, CI 1.47–3.71), systolic blood pressure less than 90 mmHg (HR 1.38, CI 1.06–1.80), a respiratory rate greater than 24 per min (HR 1.43, CI 1.13–1.83), peripheral oxygen saturation less than 92% (HR 2.12, CI 1.56–2.88), estimated glomerular filtration rate less than 60 mL/min/1.73m2 (HR 1.80, CI 1.60–2.02), IL-6 greater than 100 pg/mL (HR 1.50, CI 1.12–2.03), D-dimer greater than 2 mcg/mL (HR 1.19, CI 1.02–1.39), and troponin greater than 0.03 ng/mL (HR 1.40, CI 1.23–1.62). Decreased risk of in-hospital mortality was associated with female sex (HR 0.84, CI 0.77–0.90), African American race (HR 0.78 CI 0.65–0.95), and hydroxychloroquine use (HR 0.53, CI 0.41–0.67). Among patients with COVID-19, older age, male sex, hypotension, tachypnea, hypoxia, impaired renal function, elevated D-dimer, and elevated troponin were associated with increased in-hospital mortality and hydroxychloroquine use was associated with decreased in-hospital mortality.

Skeletal-related events (SREs) are significant contributors to the morbidity and mortality in patients with bone metastasis from breast cancer. Thus, bone-modifying agents (BMAs) are recommended in this population. However, the baseline risk factors of SREs in patients with bone metastasis from breast cancer receiving BMAs are not well understood. We analyzed the patient-level data from a controlled arm of a clinical trial comparing denosumab with zoledronate in patients with bone metastases from breast cancer (ClinicalTrial.gov ID: NCT00321464) available at Project Data Sphere, a broad-access research platform that collects and curates patient-level data from completed, phase III cancer trials. The primary endpoint was the first SRE after the inclusion to the trial. The time to the first on study SRE was analyzed using Cox proportional hazards model based on patients’ baseline characteristics including age, race, ECOG performance status (PS), histology and immunohistochemistry of breast cancer, and urine and serum laboratory data. Among 756 patients in the zoledronate arm of the trial, we excluded 64 patients with a documented history of osteopenia or osteoporosis. The median age of the patients was 56 years old, the median follow-up was 553 days, and 249 patients (36%) had SREs. The univariate analysis showed that black or African American heritage, ECOG PS > 0, human epidermal growth factor receptor 2 (HER2) positivity, high urine N-telopeptide cross-links / creatinine ratio (NTx/Cre), and elevated serum alkaline phosphatase (ALP) are significant baseline risk factors for SREs. Patients with the characteristics of ECOG PS > 0, HER2 positivity, and elevated ALP also showed a significantly higher hazard ratio of SREs in multivariate analysis. We determined risk factors for SREs in patients with bone metastasis from breast cancer.

Parathyroid disorders include hyperparathyroidism, hypoparathyroidism, and parathyroid resistance. Hyperparathyroidism is primarily caused by neoplasia of the parathyroid gland or abnormal calcium sensing system. Hypocalcemia can cause secondary hyperparathyroidism and eventually tertiary hyperparathyroidism. Hypoparathyroidism is caused by deficient parathyroid development, altered calcium sensing system, or the destruction of parathyroid gland. Abnormality in PTH signaling leads to parathyroid resistance.

An imbalance in bone formation and bone resorption results in the bone loss that characterizes osteoporosis. An absolute or relative increase in bone resorption by osteoclasts can significantly contribute to this bone loss. Cathepsin K is a lysosomal protease responsible for bone degradation by osteoclasts. Pharmacological use of cathepsin K inhibitors such as odanacatib for osteoporosis has shown benefit, though the clinical development of these agents had to be discontinued due to potential adverse events. Preclinical and clinical studies on cathepsin K and its inhibitors have shown the potential for an adjuvant antiresorptive agent, and continue to guide future research.

A gas emitted from marine diesel engines has high particle concentration. Therefore, re-entrainment phenomenon occurs in a conventional electrostatic precipitator (ESP). A new hole-type ESP was developed to overcome the re-entrainment in the ESP. The hole-type ESP utilizes the ionic wind and Coulomb force to induce particle motion into the hole. To understand this mechanism, visualization of particle behavior is important. In this study, the particle behavior, the particle velocity, and the influx rate of particle in the hole were investigated. Particle image velocimetry (PIV) was used especially to analyze the ionic wind and particle behavior in the hole-type ESP. The ESP model was made of clear acrylic. The high-voltage electrode was a stainless needle electrode, and the ground electrode was a plate electrode with a hole in its center. It was confirmed that the particles flowed into the hole with discharge current of 3 μ A. In order to confirm quantitatively whether particles are flowing into the hole, the influx rate of particle in the hole was calculated. The influx rate of particle in the hole was improved by moving the position of the needle electrode toward the ESP inlet direction.