Safety and efficacy outcomes of early cessation of anti-PD1 therapy in patients 80 years or older: A retrospective cohort study.

Older patients have similar immune checkpoint inhibitor efficacy and rates of adverse events as younger patients, but appear to have decreased tolerability, particularly in the oldest patient cohort (>80 years), often leading to early cessation of therapy. We aimed to determine whether early discontinuation impacts efficacy of anti-PD-1 therapy in patients ≥80 years old. In this retrospective, multicenter, international cohort study, we examined 773 patients with 4 tumor types who were at least 80 years old and treated with anti-PD-1 therapy. We determined response rate, overall survival (OS), and progression-free survival (PFS) in patients who discontinued therapy early (<12 months) for reasons other than progression or death. We used descriptive statistics for demographics, response, and toxicity rates. Survival statistics were described using Kaplan Meier curves. Median (range) age at anti-PD-1 initiation was 83.0 (75.8-97.0) years. The cancer types included were melanoma (n = 286), non-small cell lung cancer (NSCLC) (n = 345), urothelial cell carcinoma (UCC) (n = 108), and renal cell carcinoma (RCC) (n = 34). Of these, 102 met the primary endpoint of <12 months to discontinuation for reasons other than death or progression. Median PFS and OS, respectively, for these patients were 34.4 months and 46.6 months for melanoma, 15.8 months and 23.4 months for NSCLC, and 10.4 months and 15.8 months for UCC. This study suggests geriatric patients who have demonstrated therapeutic benefit and discontinued anti-PD-1 therapy at less than 12 months of duration for reasons other than progression may have durable clinical benefit without additional therapy.

Positive Associations of Perfluoroalkyl and Polyfluoroalkyl Substances With Hypertension May Be Attenuated by Endogenous Sex Hormones: A Nationally Representative Cross-Sectional Study.

BACKGROUND: Perfluoroalkyl and polyfluoroalkyl substance (PFAS) has endocrine-disrupting properties and may affect blood pressure. Endogenous hormones also play a crucial role in the progression of hypertension. However, their interaction with hypertension remains to be explored. METHODS: This study included 10 794 adults aged ≥18 years from the China National Human Biomonitoring program. Weighted multiple logistic regression and linear regression were used to examine the associations of serum PFAS with hypertension, diastolic blood pressure, and systolic blood pressure. Joint effects of PFAS mixtures on hypertension, diastolic blood pressure, and systolic blood pressure were evaluated using quantile-based g-computation. Additive and multiplicative interactions were used to assess the role of PFAS with testosterone and estradiol on hypertension. RESULTS: The prevalence of hypertension in Chinese adults was 35.50%. Comparing the fourth quartile with the first quartile, odds ratio (95% CI) of hypertension were 1.53 (1.13-2.09) for perfluorononanoic acid, 1.40 (1.03-1.91) for perfluorodecanoic acid, 1.34 (1.02-1.78) for perfluoroheptane sulfonic acid, and 1.46 (1.07-1.99) for perfluorooctane sulfonic acid. Moreover, PFAS mixtures, with perfluorononanoic acid contributing the most, were positively associated with hypertension, diastolic blood pressure, and systolic blood pressure. PFAS and endogenous hormones had an antagonistic interaction in hypertension. For example, the relative excess risk ratio, attributable proportion, and synergy index for perfluorononanoic acid and estradiol were -3.61 (-4.68 to -2.53), -1.65 (-2.59 to -0.71), and 0.25 (0.13-0.47), respectively. CONCLUSIONS: Perfluorononanoic acid, perfluorodecanoic acid, perfluoroheptane sulfonic acid, perfluorooctane sulfonic acid, and PFAS mixtures showed positive associations with hypertension, systolic blood pressure, and diastolic blood pressure. Positive associations of PFAS with hypertension might be attenuated by increased levels of endogenous sex hormones.

Dietary seafood as a potential modifier in the relationship between per- and polyfluoroalkyl substances (PFASs) burden and prediabetes/diabetes: Insights from a nationally representative cross-sectional study.

While seafood is recognized for its beneficial effects on glycemic control, concerns over elevated levels of per- and polyfluoroalkyl substances (PFASs) may deter individuals from its consumption. This study aims to elucidate the relationship between seafood intake, PFASs exposure, and the odds of diabetes. Drawing from the China National Human Biomonitoring data (2017-2018), we assessed the impact of PFASs on the prevalence of prediabetes and diabetes across 10851 adults, including 5253 individuals (48.1%) reporting seafood consumption. Notably, seafood consumers exhibited PFASs levels nearly double those of non-consumers. Multinomial logistic regression identified significant positive associations between serum PFASs concentrations and prediabetes (T3 vs. T1: ORPFOA: 1.64 [1.08-2.49], ORPFNA: 1.59 [1.19-2.13], ORPFDA: 1.56 [1.13-2.17], ORPFHxS: 1.58 [1.18-2.12], ORPFHpS: 1.73 [1.24-2.43], ORPFOS: 1.51 [1.15-1.96], OR6:2 Cl-PFESA: 1.58 [1.21-2.07]). Significant positive association were also found between PFHpS, PFOS, and diabetes. RCS curves indicated significant non-linear relationships between log-transformed PFOA, PFUnDA, PFOS, 6:2 Cl-PFESA, and FBG levels. Subgroup analyses revealed that seafood consumption significantly mitigated the associations between PFASs burdens and prediabetes/diabetes. These findings suggest a protective role of dietary seafood against the adverse effects of PFASs exposure on glycemic disorders, offering insights for dietary interventions aimed at mitigating diabetes risks associated with PFASs.

Heavy metals and metalloids exposure and liver function in Chinese adults - A nationally representative cross-sectional study.

BACKGROUND: In China, the effects of heavy metals and metalloids (HMMs) on liver health are not consistently documented, despite their prevalent environmental presence. OBJECTIVE: Our research assessed the association between HMMs and liver function biomarkers in a comprehensive sample of Chinese adults. METHODS: We analyzed data from 9445 participants in the China National Human Biomonitoring survey. Blood and urine were evaluated for HMM concentrations, and liver health was gauged using serum albumin (ALB), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) metrics. Various statistical methods were employed to understand the relationship between 11 HMMs and liver function, adjusting for multiple factors. We also explored interactions with alcohol intake, gender, and age. RESULTS: Among HMMs, selenium in blood [weighted geometric mean (GM) = 95.56 µg/L] and molybdenum in urine (GM = 46.44 µg/L) showed the highest concentrations, while lead in blood (GM = 21.92 µg/L) and arsenic in urine (GM = 19.80 µg/L) had the highest levels among risk HMMs. Manganese and thallium consistently indicated potential risk factor to liver in both sample types, while selenium displayed potential liver protection. Blood HMM mixtures were negatively associated with ALB (ß = -0.614, 95% CI: -0.809, -0.418) and positively with AST (ß = 0.701, 95% CI: 0.290, 1.111). No significant associations were found in urine HMM mixtures. Manganese, tin, nickel, and selenium were notable in blood mixture associations, with selenium and cobalt being significant in urine. The relationship of certain HMMs varied based on alcohol consumption. CONCLUSION: This research highlights the complex relationship between HMM exposure and liver health in Chinese adults, particularly emphasizing metals like manganese, thallium, and selenium. The results suggest a need for public health attention to low dose HMM exposure and underscore the potential benefits of selenium for liver health. Further studies are essential to establish causality.

Association between urinary polycyclic aromatic hydrocarbons and unexplained recurrent spontaneous abortion from a case-control study.

Polycyclic aromatic hydrocarbons (PAHs) have been reported to be associated with adverse pregnancy outcomes. However, there is limited knowledge regarding the effects of single or mixed PAHs exposure on unexplained recurrent spontaneous abortion (URSA). This study aimed to investigate the association between monohydroxylated polycyclic aromatic hydrocarbons (OH-PAHs) and URSA in a case-control study. The results showed that 1-NAP, 2-NAP, 9-FLU, and 1-PYR were detected in 100% of the subjects among measured all sixteen OH-PAHs. Compared with those in the lowest quartiles, participants in the highest quartiles of 3-BAA were associated with a higher risk of URSA (OR (95%CI) = 3.56(1.28-9.85)). With each one-unit increase of ln-transformed 3-BAA, the odds of URSA increased by 41% (OR (95%CI) = 1.41(1.05-1.89)). Other OH-PAHs showed negative or non-significant associations with URSA. Weighted quantile sum (WQS) regression, Bayesian kernel machine regression (BKMR), and quantile-based g-computation (qgcomp) analyses consistently identified 3-BAA as the major contributor to the mixture effect of OH-PAHs on URSA. Our findings suggest that exposure to 3-BAA may be a potential risk factor for URSA. However, further prospective studies are needed to validate our findings in the future.

Mediating Role of Liver Dysfunction in the Association between Arsenic Exposure and Diabetes in Chinese Adults: A Nationwide Cross-Sectional Study of China National Human Biomonitoring (CNHBM) 2017-2018.

Inconsistent results have been reported regarding the association between low-to-moderate arsenic (As) exposure and diabetes. The effect of liver dysfunction on As-induced diabetes remains unclear. The cross-sectional study included 10,574 adults from 2017-2018 China National Human Biomonitoring. Urinary total As (TAs) levels were analyzed as markers of As exposure. Generalized linear mixed models and restricted cubic splines models were used to examine the relationships among TAs levels, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentrations, and diabetes prevalence. Mediating analysis was performed to assess whether liver dysfunction mediated the association between TAs and diabetes. Overall, the OR (95% CI) of diabetes in participants in the second, third, and fourth quartiles of TAs were 1.08 (0.88, 1.33), 1.17 (0.94, 1.45), and 1.52 (1.22, 1.90), respectively, in the fully adjusted models compared with those in the lowest quartile. Serum ALT was positively associated with TAs and diabetes. Additionally, mediation analyses showed that ALT mediated 4.32% of the association between TAs and diabetes in the overall population and 8.86% in the population without alcohol consumption in the past year. This study suggested that alleviating the hepatotoxicity of As could have implications for both diabetes and liver disease.

Serum per- and polyfluoroalkyl substances and abnormal lipid metabolism: A nationally representative cross-sectional study.

BACKGROUND: The associations of legacy per- and polyfluoroalkyl substances (PFAS) with lipid metabolism are controversial, and there is little information about the impact of emerging PFAS (6:2 Cl-PFESA) on lipid metabolism in China. OBJECTIVES: We aimed to explore the associations of legacy and emerging PFAS with lipid profiles and dyslipidemia in Chinese adults. METHODS: We included 10,855 Chinese participants aged 18 years and above in the China National Human Biomonitoring. The associations of 8 PFAS with 5 lipid profiles and 4 dyslipidemia were investigated using weighted multiple linear regression or weighted logistic regression, and the dose-response associations were investigated using restricted cubic spline model. RESULTS: Among the 8 PFAS, the concentration of PFOS was the highest, with a geometric mean of 5.15 ng/mL, followed by PFOA and 6:2 Cl-PFESA, which were 4.26 and 1.63 ng/mL, respectively. Legacy (PFOA, PFOS, PFUnDA) or emerging (6:2 Cl-PFESA) PFAS were associated with lipid profiles (TC, LDL-C, HDL-C, non HDL-C) and dyslipidemia (high LDL-C, high TC, low HDL-C), and their effects on TC were most obvious. TC concentration increased by 0.595 mmol/L in the highest quartile (Q4) of PFOS when compared with the lowest quartile (Q1), (95 % CI:0.396, 0.794). Restricted cubic spline models showed that PFAS are nonlinearly associated with TC, non HDL-C, LDL-C and HDL-C, and that the lipid concentrations tend to be stable when PFOS and PFOA were > 20 ng/mL well as when the 6:2 Cl-PFESA level was > 10 ng/mL. The positive associations between PFAS mixtures and lipid profiles were also significant. CONCLUSIONS: Single and mixed exposure to PFAS were positively associated with lipid profiles, and China's unique legacy PFAS substitutes (6:2 Cl-PFESA) contributed less to lipid profiles than legacy PFAS. In the future, cohort studies will be needed to confirm our findings.

Association of urinary nickel levels with diabetes and fasting blood glucose levels: A nationwide Chinese population-based study.

Some epidemiological studies support a relationship between nickel exposure and diabetes in the general population. To address this, we tested the association of nickel exposure with diabetes in 10,890 adults aged ≥ 18 years old from the China National Human Biomonitoring study conducted in 2017-2018. Urinary nickel concentrations and fasting blood glucose (FBG) were measured, and lifestyle and demographic data were collected. Weighted logistic and linear regressions were used to estimate the associations of urinary nickel levels with diabetes prevalence and FBG. Restricted cubic splines (RCS) were used to test for the dose-response relationship. The odd ratio (95% confidence interval [CI]) of diabetes for the highest versus lowest quartiles of urinary nickel concentrations was 1.74 (1.28, 2.36) in the multivariate model (p trend =0.001). Each one-unit increase in log-transformed urinary nickel concentrations was associated with a 0.36 (0.17, 0.55) mmol/L elevation in FBG. The RCS curves showed a monotonically increasing dose-response relationship of urinary nickel with diabetes as well as FBG levels, and then tended to flatten after about 4.75 µg/L of nickel exposure. The nickel-diabetes association was stronger in individuals with lower than those with higher rice consumption (OR: 2.39 vs. 1.72). Our study supports a positive association between nickel exposure and diabetes prevalence in Chinese adults, especially in individuals with lower rice consumption. Further large-scale prospective studies are needed to validate our findings.

Cadmium exposure is associated with testosterone levels in men: A cross-sectional study from the China National Human Biomonitoring.

BACKGROUND: Sex hormone disorders can cause adverse health consequences. While experimental data suggests that cadmium (Cd) disrupts the endocrine system, little is known about the link between Cd exposure and sex hormones in men. METHODS: We measured blood cadmium (B-Cd), urine cadmium (U-Cd), serum testosterone and serum estradiol in men aged ≥18 years old participating in the China National Human Biomonitoring program, from 2017 to 2018. Urine cadmium adjusted for creatinine (Ucr-Cd) and the serum testosterone to serum estradiol ratio (T/E2) were calculated. The association of Cd exposure to serum testosterone and T/E2 in men was analyzed with multiple linear regression models. RESULTS: Among Chinese men ≥18 years old, the weighted geometric mean (95% CI) of B-Cd and Ucr-Cd levels were 1.23 (1.12-1.35) µg/L and 0.53 (0.47-0.59) µg/g, respectively. The geometric means (95% CI) of serum testosterone and T/E2 were 18.56 (17.92-19.22) nmol/L and 143.86 (137.24-150.80). After adjusting for all covariates, each doubling of B-Cd level was associated with a 5.04% increase in serum testosterone levels (ß = 0.071; 95%CI: 0.057-0.086) and a 4.03% increase in T/E2 (ß = 0.057; 95%CI: 0.040-0.075); similar findings were found in Ucr-Cd. CONCLUSIONS: In Chinese men, Cd may be an endocrine disruptor, which is positively associated with serum testosterone and T/E2.

Comparison of the Seventh and Eighth Edition of American Joint Committee on Cancer (AJCC) Staging for Selected and Nonselected Oropharyngeal Squamous Cell Carcinomas.

OBJECTIVES: The eighth edition American Joint Committee on Cancer (AJCC) Staging incorporates significant changes to the seventh edition in the staging of oropharyngeal squamous cell carcinomas (OPSCC). An important change was the inclusion of OPSCC associated with the human papilloma virus (HPV). Our goal is to compare the performance of both staging systems for patients with HPV-selected and unselected clinical characteristics for OPSCC. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database, 2004-2016, we identified patients with likely HPV-associated OPSCC based on surrogate markers (white males aged <65 years old with squamous cell carcinomas of the tonsil and base of tongue), excluding those who underwent surgery. We re-classified these patients using seventh and eighth edition staging for HPV-selected OPSCC and compared the prediction performance of both staging editions for overall survival (OS) and disease-specific survival (DSS). We performed the same analysis for clinically unselected patients with OPSCC. RESULTS: Our analysis included 9554 patients with a median follow-up of 67 months. Comparing the eighth versus seventh edition for our HPV-selected cohort, clinical staging changed for 92.3% of patients and 10-year OS was 62.2%, 61.2%, 35.3%, and 15.5% for Stage I, II, III, and IV, versus 52.9%, 59.2%, 61.6%, 55.1%, 38.3%, and 15.5% for stage I, II, III, IVA, IVB, and IVC, respectively. A similar pattern was observed for 10-year DSS. The concordance statistics for our HPV-selected cohort were improved for both AJCC 7 (0.6260) and AJCC 8 (0.6846) compared with the unselected cohort, 0.5860 and 0.6457 for AJCC 7 and 8, respectively. CONCLUSION: The overall performance of discrimination improved from AJCC 7 to AJCC 8 for both clinically selected and unselected patients, but more notably for our HPV-selected cohort. Despite the lack of statistically significant differentiation between Stages I and II in AJCC 8 in either groups, markedly improved discrimination was observed between Stages I/II, III, and IV in the HPV-selected cohort.

Declines in Blood Lead Levels Among General Population - China, 2000-2018.

What is already known about this topic?: Environmental and occupational lead exposure has generally declined in the past two decades. However, there is no large-scale monitoring of blood lead levels (BLLs) in the Chinese general population. What is added by this report?: This nationally representative study showed declines of BLLs in all ages of participants; for children aged 3-5 years, down from 78.1 µg/L to 16.9 µg/L, corresponding to 78.4% decrease in the past two decades (2000-2018). What are the implications for public health practice?: Recommendations for elevated BLLs on screening children at high risk now need to be revisited and updated from 100 µg/L to 50 µg/L in guidelines to conform with the substantial declines in China.

Clinical Outcomes and Toxic Effects of Single-Agent Immune Checkpoint Inhibitors Among Patients Aged 80 Years or Older With Cancer: A Multicenter International Cohort Study.

IMPORTANCE: Geriatric (aged ≥80 years) patients are historically underrepresented in cancer clinical trials. Little is known about the efficacy of immune checkpoint inhibitors (ICIs) in geriatric patients. These agents are associated with immune-related adverse events (irAEs), which may be particularly associated with morbidity in this population. OBJECTIVE: To provide insight into the clinical outcomes and safety of ICIs among geriatric patients (aged ≥80 years) with cancer. DESIGN, SETTING, AND PARTICIPANTS: A Multicenter, international retrospective study of 928 geriatric patients with different tumors treated with single-agent ICIs between 2010 to 2019 from 18 academic centers in the US and Europe. Analyses were conducted from January 2021 to April 2021. MAIN OUTCOMES AND MEASURES: Clinical outcomes and irAE patterns in geriatric patients treated with single-agent ICIs. RESULTS: Median (range) age of the 928 patients at ICI initiation was 83.0 (75.8-97.0) years. Most patients (806 [86.9%]) were treated with anti-programmed cell death 1 therapy. Among the full cohort, the 3 most common tumors were non-small cell lung cancer (NSCLC, 345 [37.2%]), melanoma (329 [35.5%]), and genitourinary (GU) tumors (153 [16.5%]). Objective response rates for patients with NSCLC, melanoma, and GU tumors were 32.2%, 39.3%, and 26.2%, respectively. Median PFS and OS, respectively, were 6.7 and 10.9 months (NSCLC), 11.1 and 30.0 months (melanoma), and 6.0 and 15.0 months (GU). Within histologically specific subgroups (NSCLC, melanoma, and GU), clinical outcomes were similar across age subgroups (aged <85 vs ≥85 years). Among all 928 patients, 383 (41.3%) experienced ≥1 irAE(s), including 113 (12.2%) that were reported to be grade (G) 3 to 4 based on Common Terminology Criteria for Adverse Events (version 5.0). The median time to irAE onset was 9.8 weeks; 219 (57%) occurred within the first 3 months after ICI initiation. Discontinuation of treatment with ICIs owing to irAEs occurred in 137 (16.1%) patients. There was no significant difference in the rate of irAEs among patients aged younger than 85, 85 to 89, and 90 years or older. Despite the similar rate of G3 or higher irAEs, ICIs were discontinued due to irAEs more than twice as often among patients aged 90 years or older compared with patients younger than 90 years (30.9% vs 15.1%, P = .008). CONCLUSIONS AND RELEVANCE: The findings of this international cohort study suggest that treatment with ICIs may be effective and generally well tolerated among older patients with cancer, though ICI discontinuation owing to irAEs was more frequent with increasing age.

MetaGSCA: A tool for meta-analysis of gene set differential coexpression.

Analyses of gene set differential coexpression may shed light on molecular mechanisms underlying phenotypes and diseases. However, differential coexpression analyses of conceptually similar individual studies are often inconsistent and underpowered to provide definitive results. Researchers can greatly benefit from an open-source application facilitating the aggregation of evidence of differential coexpression across studies and the estimation of more robust common effects. We developed Meta Gene Set Coexpression Analysis (MetaGSCA), an analytical tool to systematically assess differential coexpression of an a priori defined gene set by aggregating evidence across studies to provide a definitive result. In the kernel, a nonparametric approach that accounts for the gene-gene correlation structure is used to test whether the gene set is differentially coexpressed between two comparative conditions, from which a permutation test p-statistic is computed for each individual study. A meta-analysis is then performed to combine individual study results with one of two options: a random-intercept logistic regression model or the inverse variance method. We demonstrated MetaGSCA in case studies investigating two human diseases and identified pathways highly relevant to each disease across studies. We further applied MetaGSCA in a pan-cancer analysis with hundreds of major cellular pathways in 11 cancer types. The results indicated that a majority of the pathways identified were dysregulated in the pan-cancer scenario, many of which have been previously reported in the cancer literature. Our analysis with randomly generated gene sets showed excellent specificity, indicating that the significant pathways/gene sets identified by MetaGSCA are unlikely false positives. MetaGSCA is a user-friendly tool implemented in both forms of a Web-based application and an R package "MetaGSCA". It enables comprehensive meta-analyses of gene set differential coexpression data, with an optional module of post hoc pathway crosstalk network analysis to identify and visualize pathways having similar coexpression profiles.

Prognostic Clinical and Radiographic Biomarkers for BRAF-Targeted Therapy in Advanced Melanoma.

Agents blocking BRAF and MEK produce robust responses in patients with BRAFV600 -mutated melanoma; however, more accurate clinical biomarkers are needed to predict prognosis. To explore this question, we retrospectively studied 158 patients with BRAF-mutated melanoma treated with BRAF with or without MEK inhibitors. We found that the number of distinct tumor sites upon initiation of targeted therapy was associated with decreased progression-free survival but had no effect on overall survival. Serum values of lactate dehydrogenase and absolute lymphocyte count to absolute neutrophil count ratio independently had the strongest association with both progression-free survival and overall survival. Using both of these markers can help stratify prognosis of patients with metastatic melanoma receiving targeted therapy.

Mechanistic Phase II Clinical Trial of Metformin in Pulmonary Arterial Hypertension.

Background Metabolic dysfunction is highly prevalent in pulmonary arterial hypertension (PAH) and likely contributes to both pulmonary vascular disease and right ventricular (RV) failure in part because of increased oxidant stress. Currently, there is no cure for PAH and human studies of metabolic interventions, generally well tolerated in other diseases, are limited in PAH. Metformin is a commonly used oral antidiabetic that decreases gluconeogenesis, increases fatty acid oxidation, and reduces oxidant stress and thus may be relevant to PAH. Methods and Results We performed a single-center, open-label 8-week phase II trial of up to 2 g/day of metformin in patients with idiopathic or heritable PAH with the co-primary end points of safety, including development of lactic acidosis and study withdrawal, and plasma oxidant stress markers. Exploratory end points included RV function via echocardiography, plasma metabolomic analysis performed before and after metformin therapy, and RV triglyceride content by magnetic resonance spectroscopy in a subset of 9 patients. We enrolled 20 patients; 19/20 reached the target dose and all completed the study protocol. There was no clinically significant lactic acidosis or change in oxidant stress markers. Metformin did not change 6-minute walk distance but did significantly improve RV fractional area change (23±8% to 26±6%, P=0.02), though other echocardiographic parameters were unchanged. RV triglyceride content decreased in 8/9 patients (3.2±1.8% to 1.6±1.4%, P=0.015). In an exploratory metabolomic analysis, plasma metabolomic correlates of ≥50% reduction in RV lipid included dihydroxybutyrate, acetylputrescine, hydroxystearate, and glucuronate (P<0.05 for all). In the entire cohort, lipid metabolites were among the most changed by metformin. Conclusions Metformin therapy was safe and well tolerated in patients with PAH in this single-arm, open-label phase II study. Exploratory analyses suggest that metformin may be associated with improved RV fractional area change and, in a subset of patients, reduced RV triglyceride content that correlated with altered lipid and glucose metabolism markers. Registration URL: http://www.clinicaltrials.gov; Unique identifier: NCT01884051.

Impact of body composition on outcomes from anti-PD1 +/- anti-CTLA-4 treatment in melanoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have transformed treatment for melanoma, but identifying reliable biomarkers of response and effective modifiable lifestyle factors has been challenging. Obesity has been correlated with improved responses to ICI, although the association of body composition measures (muscle, fat, etc) with outcomes remains unknown. METHODS: We performed body composition analysis using Slice-o-matic software on pretreatment CT scans to quantify skeletal muscle index (SMI=skeletal muscle area/height2), skeletal muscle density (SMD), skeletal muscle gauge (SMG=SMI × SMD), and total adipose tissue index (TATI=subcutaneous adipose tissue area + visceral adipose tissue area/height2) of each patient at the third lumbar vertebrae. We then correlated these measures to response, progression-free survival (PFS), overall survival (OS), and toxicity. RESULTS: Among 287 patients treated with ICI, body mass index was not associated with clinical benefit or toxicity. In univariable analyses, patients with sarcopenic obesity had inferior PFS (HR 1.4, p=0.04). On multivariable analyses, high TATI was associated with inferior PFS (HR 1.7, p=0.04), which was particularly strong in women (HR 2.1, p=0.03). Patients with intermediate TATI and high SMG had the best outcomes, whereas those with low SMG/high TATI had inferior PFS and OS (p=0.02 for both PFS and OS). CONCLUSIONS: Body composition analysis identified several features that correlated with improved clinical outcomes, although the associations were modest. As with other studies, we identified sex-specific associations that warrant further study.

Outcomes after progression of disease with anti-PD-1/PD-L1 therapy for patients with advanced melanoma.

BACKGROUND: Greater than one-half of patients with melanoma who are treated with antibodies blocking programmed cell death protein 1 receptor (anti-PD-1) experience disease progression. The objective of the current study was to identify prognostic factors and outcomes in patients with metastatic melanoma that progressed while they were receiving anti-PD-1 therapy. METHODS: The authors evaluated 383 consecutively treated patients who received anti-PD-1 for advanced melanoma between 2009 and 2019. Patient and disease characteristics at baseline and at the time of progression, subsequent therapies, objective response rate (ORR), overall survival, and progression-free survival were assessed. RESULTS: Of 383 patients, 247 experienced disease progression. The median survival after progression was 6.8 months. There was no difference in survival noted after disease progression based on primary tumor subtype, receipt of prior therapy, or therapy type. However, significantly improved survival after disease progression correlated with clinical features at the time of progression, including normal lactate dehydrogenase, more favorable metastatic stage (American Joint Committee on Cancer eighth edition stage IV M1a vs M1b, M1c, or M1d), mutation status (NRAS or treatment-naive BRAF V600 vs BRAF/NRAS wild-type or treatment-experienced BRAF-mutant), decreasing tumor bulk, and progression at solely existing lesions. After progression, approximately 54.3% of patients received additional systemic therapy. A total of 41 patients received BRAF/MEK inhibition (ORR of 58.6%, including 70.4% for BRAF/MEK-naive patients), 30 patients received ipilimumab (ORR of 0%), and 11 patients received ipilimumab plus nivolumab (ORR of 27.3%). CONCLUSIONS: The current study identified prognostic factors in advanced melanoma for patients who experienced disease progression while receiving anti-PD-1, including lactate dehydrogenase, stage of disease, site of disease progression, tumor size, and mutation status.

Demographic Factors Associated with Toxicity in Patients Treated with Anti-Programmed Cell Death-1 Therapy.

Immune checkpoint inhibitors (ICI) are now routinely used in multiple cancers but may induce autoimmune-like side effects known as immune-related adverse events (irAE). Although classical autoimmune diseases have well-known risk factors, including age, gender, and seasonality, the clinical factors that lead to irAEs are not well-defined. To explore these questions, we assessed 455 patients with advanced melanoma treated with ICI at our center and a large pharmacovigilance database (VigiBase). We found that younger age was associated with a similar rate of any irAEs but more frequent severe irAEs and more hospitalizations (OR, 0.97 per year). Paradoxically, however, older patients had more deaths and increased length of stay (LOS) when hospitalized. This was partially due to a distinct toxicity profile: Colitis and hepatitis were more common in younger patients, whereas myocarditis and pneumonitis had an older age distribution both in our center and in VigiBase. This pattern was particularly apparent with combination checkpoint blockade with ipilimumab and nivolumab. We did not find a link between gender or seasonality on development of irAEs in univariate or multivariate analyses, although winter hospitalizations were associated with marginally increased LOS. This study identifies age-specific associations of irAEs.

The Endogenous Plasma Small RNAome of Rheumatoid Arthritis.

OBJECTIVE: Small RNA (sRNA) sequencing has revealed new sRNA classes beyond microRNAs (miRNAs). These sRNAs can regulate genes and act as biomarkers. The aim of this study was to determine if the endogenous plasma sRNA landscape is altered in patients with rheumatoid arthritis (RA) compared with control subjects and to determine its association with disease-related parameters in RA. METHODS: sRNA sequencing was performed on plasma from 165 RA and 90 control subjects who were frequency-matched for age, race, and sex. Endogenous sRNAs, such as miRNAs, isomiRs, sRNAs derived from small nuclear RNAs (snDRs), small nucleolar RNAs (snoDRs), Y RNAs (yDRs), transfer-derived RNAs (tDRs), long noncoding RNAs (lncDRs) as well as miscellaneous sRNAs (miscRNAs), were quantified using Tools for Integrative Genome analysis of Extracellular sRNAs (TIGER). Individual and categories of sRNAs were compared between RA and controls, and significantly altered sRNAs and sRNA categories were correlated with disease activity and general laboratory measures in RA. RESULTS: Patients with RA had more miRNAs (1.42-fold, P = 0.01), more tDRs (1.14-fold, P = 0.04), and fewer yDRs (-1.41-fold, P = 0.009) compared with control subjects. Disease duration was inversely associated with yDRs. Disease-related parameters, such as Disease Activity Score-28 (DAS28), swollen joint count, and inflammatory markers were significantly positively associated with tDRs and miscRNAs, and miR-22-3p and related sequences and isomiRs were most significantly associated with DAS28. CONCLUSION: Endogenous plasma sRNAs are altered in RA compared with control subjects. Although individual miRNAs have been well studied and many are excellent biomarkers in RA, several non-miRNA sRNAs were significantly associated with disease-related parameters as classes and may represent novel biomarkers for RA.

Current Perceptions of the Aesthetically Ideal Position and Size of the Male Nipple-Areola Complex.

BACKGROUND: The dimensions of the nipple-areola complex (NAC) and its location on the chest wall are important aesthetic factors in male breast surgery. OBJECTIVES: This study examines the perceptions of aesthetic surgeons and the general population for the aesthetically ideal position and size of male NAC. METHODS: An online survey was distributed to the American Society for Aesthetic Plastic Surgery (ASAPS) members and to the general population. Parameters queried included demographics for all participants and academic details for ASAPS members. Both surveys included a male model picture with 16 separate choices for the NAC position from a frontal view, 5 choices for the NAC position from a lateral view, and 6 choices for the NAC dimensions. For all 3 sets of images, the participants were asked to rank the top 3 images they considered most "aesthetically pleasing" in descending order. A weighted scoring rule was created to quantitatively evaluate image choices. Standard statistical methods were employed for analysis. RESULTS: The survey was completed by 272 ASAPS members and 4909 participants from the general population. The top 3 choices for NAC location on frontal view were the same for ASAPS members and the general population. The most popular NAC location on lateral view was the same for both groups, but the preferred locations differed between the 2 groups for the second and third choices. The most popular dimensions of the NAC were 2 cm (vertical) × 3 cm (horizontal) followed by 2 cm × 2 cm for both groups. Comparison of the 3 top image choices scores between different ethnic groups and individuals with different gender or sexual orientation demonstrated similar trends. CONCLUSIONS: This survey identified the preferred position and dimensions of the NAC on the male breast for plastic surgeons and the general population. These parameters should be considered when counseling males undergoing breast surgery.