Prevalence and predictors of colon and prostate cancer screening among volunteer firefighters: The United States Firefighter Cancer Assessment and Prevention Study.

BACKGROUND: Although firefighters have increased risk for colon and prostate cancer, limited information exists on screening practices for these cancers in volunteer firefighters who compose two-thirds of the US fire service. We estimated the prevalence of colon and prostate cancer screening among volunteer firefighters using eligibility criteria from 4 evidence-based screening recommendations and evaluated factors influencing screening. METHODS: We evaluated colon (n = 569) and prostate (n = 498) cancer screening prevalence in a sample of US volunteer firefighters using eligibility criteria from the US Preventive Services Taskforce (USPSTF), National Fire Protection Association, American Cancer Society, and National Comprehensive Cancer Network. We assessed associations with fire service experience, demographics, and cancer risk perception based on USPSTF guidelines. RESULTS: For those eligible based on USPSTF guidelines, colon and prostate cancer screening prevalence was 51.7% (95% CI: 45.7, 57.8) and 48.8% (95% CI: 40.0, 57.6), respectively. Higher odds of colon and prostate cancer screening were observed with older age and with some college education compared to those with less education. Fire service experience and cancer risk perception were not associated with screening practices. CONCLUSION: This is the first large study to assess colon and prostate cancer screening among US volunteer firefighters based on different screening guidelines. Our findings suggest gaps in cancer prevention efforts in the US volunteer fire service. Promoting cancer screening education and opportunities for volunteer firefighters by their fire departments, healthcare professionals, and public health practitioners, may help to address the gaps.

Male recognition of conspecific female chemical cues in a diverse clade of freshwater fishes.

Where orangethroat darters (Etheostoma: Ceasia) and rainbow darters (Etheostoma caeruleum) co-occur, males prefer conspecific over heterospecific females. The cues males use to identify conspecific females remain unclear. We conducted behavioral trials to ask whether chemical cues function in conspecific recognition. We found that males from three orangethroat darter species preferentially associate with female scent over a control. Our results support the use of olfaction in conspecific identification in the orangethroat clade and contribute to our understanding of signals that may facilitate species recognition and underlie the evolution of behavioral isolation.

Lifeboat ethics, risk, and therapeutic opportunity: an appeal for equitable psychedelic therapy access in the "high-risk" addiction patient.

Psychedelic-assisted treatment (PAT) for mental health is in renaissance. Psilocybin and MDMA stand near FDA approval, and US cities and states are decriminalizing or regulating the non-clinical use of psilocybin. However, neither FDA indications nor a regulated use model sufficiently address the complex needs and opportunities for an improved treatment of addiction. When paired with disability and social dispossession, addiction increasingly burdens informal care networks, public safety, and particularly healthcare systems. Stigma and mistreatment alienate people from opportunities for care and multiply the costs of providing care. This dynamic worsens socially determined resource limitations, enforcing stark ethical choices and perpetuating socioeconomic inequities, isolation, mental illness, medical illness, overdose, suicide, and violence. In order for psychedelic treatments to achieve their greatest utility to population health, we must intentionally develop regulatory, clinical, and payment systems supporting clinical research, rigorous safety monitoring, and implementation to address these immense needs and reduce the barriers to engagement for those who now bear the costs, including those who work at the front lines of addiction care. To achieve full fruition, I advocate for a collaborative approach, built from within networks of mutual social support but linked and accountable to public institutions charged with the equitable dissemination of these therapies for the greatest social and health equities. Rather than relegating PAT to the needs of the commercially insured or wellness markets, this is the moment to learn from ancient traditions of ritualized sacramental use, organized around faith in our mutual dependency and accountability, and to capture an opportunity to improve population health and equity. To miss this opportunity is to accept the status quo in the midst of a growing emergency, for lack of moral vision and intention to change our habits.

Effects of Silent Intervals on the Extraction of Human Frequency-Following Responses Using Non-Negative Matrix Factorization.

Source-Separation Non-Negative Matrix Factorization (SSNMF) is a mathematical algorithm recently developed to extract scalp-recorded frequency-following responses (FFRs) from noise. Despite its initial success, the effects of silent intervals on algorithm performance remain undetermined. Our purpose in this study was to determine the effects of silent intervals on the extraction of FFRs, which are electrophysiological responses that are commonly used to evaluate auditory processing and neuroplasticity in the human brain. We used an English vowel /i/ with a rising frequency contour to evoke FFRs in 23 normal-hearing adults. The stimulus had a duration of 150 ms, while the silent interval between the onset of one stimulus and the offset of the next one was also 150 ms. We computed FFR Enhancement and Noise Residue to estimate algorithm performance, while silent intervals were either included (i.e., the WithSI condition) or excluded (i.e., the WithoutSI condition) in our analysis. The FFR Enhancements and Noise Residues obtained in the WithoutSI condition were significantly better (p < .05) than those obtained in the WithSI condition. On average, the exclusion of silent intervals produced a 11.78% increment in FFR Enhancement and a 20.69% decrement in Noise Residue. These results not only quantify the effects of silent intervals on the extraction of human FFRs, but also provide recommendations for designing and improving the SSNMF algorithm in future research.

Prevalence and predictors of skin cancer screening among a sample of US volunteer firefighters.

BACKGROUND: Firefighters have a higher risk of melanoma incidence and mortality compared to the general population. In the United States (US), the National Fire Protection Association recommends all firefighters receive annual skin cancer screening through visual skin examination by a clinician. However, there is limited information on skin cancer screening practices among volunteer firefighters who comprise two-thirds of the US fire service. METHODS: This cross-sectional study of 552 US volunteer firefighters estimated the prevalence of skin cancer screening and evaluated associations with their fire service experience, demographics, sun protection practices, and cancer risk perception. RESULTS: The prevalence of receiving skin cancer screening among volunteer firefighters was 26.1% (95% confidence interval [CI]: 22.4, 29.8). The odds of being screened for skin cancer, compared to not being screened, were twice as high for firefighters who used sunscreen (odds ratio [OR]: 2.35, 95% CI: 1.48, 3.73) and who perceived their skin likely to burn with prolonged sun exposure (OR: 1.81, 95% CI: 1.10, 3.00). Older age, some college education, and family history of skin cancer were also positively associated with skin cancer screening. A positive exposure-response relationship was observed between more monthly firefighting calls and receiving screening. Cancer risk perception was not associated with screening. CONCLUSION: To our knowledge, this is the first large study to assess skin cancer screening among US volunteer firefighters. Our findings suggest gaps in skin cancer prevention efforts in the volunteer fire service. Additional assessment of skin cancer prevention practices within volunteer fire departments could help address these gaps.

Multianalyte Prognostic Signature Including Circulating Tumor DNA and Circulating Tumor Cells in Patients With Advanced Pancreatic Adenocarcinoma.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is associated with a poor prognosis. Multianalyte signatures, including liquid biopsy and traditional clinical variables, have shown promise for improving prognostication in other solid tumors but have not yet been rigorously assessed for PDAC. MATERIALS AND METHODS: We performed a prospective cohort study of patients with newly diagnosed locally advanced pancreatic cancer (LAPC) or metastatic PDAC (mPDAC) who were planned to undergo systemic therapy. We collected peripheral blood before systemic therapy and assessed circulating tumor cells (CTCs), cell-free DNA concentration (cfDNA), and circulating tumor KRAS (ctKRAS)-variant allele fraction (VAF). Association of variables with overall survival (OS) was assessed in univariate and multivariate survival analysis, and comparisons were made between models containing liquid biopsy variables combined with traditional clinical prognostic variables versus models containing traditional clinical prognostic variables alone. RESULTS: One hundred four patients, 40 with LAPC and 64 with mPDAC, were enrolled. CTCs, cfDNA concentration, and ctKRAS VAF were all significantly higher in patients with mPDAC than patients with LAPC. ctKRAS VAF (cube root; 0.05 unit increments; hazard ratio, 1.11; 95% CI, 1.03 to 1.21; P = .01), and CTCs ≥ 1/mL (hazard ratio, 2.22; 95% CI, 1.34 to 3.69; P = .002) were significantly associated with worse OS in multivariate analysis while cfDNA concentration was not. A model selected by backward selection containing traditional clinical variables plus liquid biopsy variables had better discrimination of OS compared with a model containing traditional clinical variables alone (optimism-corrected Harrell's C-statistic 0.725 v 0.681). CONCLUSION: A multianalyte prognostic signature containing CTCs, ctKRAS, and cfDNA concentration outperformed a model containing traditional clinical variables alone suggesting that CTCs, ctKRAS, and cfDNA provide prognostic information complementary to traditional clinical variables in advanced PDAC.

Optimization of Sources of Circulating Cell-Free DNA Variability for Downstream Molecular Analysis.

Circulating cell-free DNA (ccfDNA) is used increasingly as a cancer biomarker for prognostication, as a correlate for tumor volume, or as input for downstream molecular analysis. Determining optimal blood processing and ccfDNA quantification are crucial for ccfDNA to serve as an accurate biomarker as it moves into the clinical realm. Whole blood was collected from 50 subjects, processed to plasma, and used immediately or frozen at -80°C. Plasma ccfDNA was extracted and concentration was assessed by real-time quantitative PCR (qPCR), fluorimetry, and droplet digital PCR (ddPCR). For the 24 plasma samples from metastatic pancreatic cancer patients, the variant allele fractions (VAF) of KRAS G12/13 pathogenic variants in circulating tumor DNA (ctDNA) were measured by ddPCR. Using a high-speed (16,000 × g) or slower-speed (4100 × g) second centrifugation step showed no difference in ccfDNA yield or ctDNA VAF. A two- versus three-spin centrifugation protocol also showed no difference in ccfDNA yield or ctDNA VAF. A higher yield was observed from fresh versus frozen plasma by qPCR and fluorimetry, whereas a higher yield was observed for frozen versus fresh plasma by ddPCR, however, no difference was observed in ctDNA VAF. Overall, our findings suggest factors to consider when implementing a ccfDNA extraction and quantification workflow in a research or clinical setting.

Serial Monitoring of Circulating Tumor DNA by Next-Generation Gene Sequencing as a Biomarker of Response and Survival in Patients With Advanced NSCLC Receiving Pembrolizumab-Based Therapy.

Although the majority of patients with metastatic non-small-cell lung cancer (mNSCLC) lacking a detectable targetable mutation will receive pembrolizumab-based therapy in the frontline setting, predicting which patients will experience a durable clinical benefit (DCB) remains challenging. MATERIALS AND METHODS: Patients with mNSCLC receiving pembrolizumab monotherapy or in combination with chemotherapy underwent a 74-gene next-generation sequencing panel on blood samples obtained at baseline and at 9 weeks. The change in circulating tumor DNA levels on-therapy (molecular response) was quantified using a ratio calculation with response defined by a > 50% decrease in mean variant allele fraction. Patient response was assessed using RECIST 1.1; DCB was defined as complete or partial response or stable disease that lasted > 6 months. Progression-free survival and overall survival were recorded. RESULTS: Among 67 patients, 51 (76.1%) had > 1 variant detected at a variant allele fraction > 0.3% and thus were eligible for calculation of molecular response from paired baseline and 9-week samples. Molecular response values were significantly lower in patients with an objective radiologic response (log mean 1.25% v 27.7%, P < .001). Patients achieving a DCB had significantly lower molecular response values compared to patients with no durable benefit (log mean 3.5% v 49.4%, P < .001). Molecular responders had significantly longer progression-free survival (hazard ratio, 0.25; 95% CI, 0.13 to 0.50) and overall survival (hazard ratio, 0.27; 95% CI, 0.12 to 0.64) compared with molecular nonresponders. CONCLUSION: Molecular response assessment using circulating tumor DNA may serve as a noninvasive, on-therapy predictor of response to pembrolizumab-based therapy in addition to standard of care imaging in mNSCLC. This strategy requires validation in independent prospective studies.

Combining radiomic phenotypes of non-small cell lung cancer with liquid biopsy data may improve prediction of response to EGFR inhibitors.

Among non-small cell lung cancer (NSCLC) patients with therapeutically targetable tumor mutations in epidermal growth factor receptor (EGFR), not all patients respond to targeted therapy. Combining circulating-tumor DNA (ctDNA), clinical variables, and radiomic phenotypes may improve prediction of EGFR-targeted therapy outcomes for NSCLC. This single-center retrospective study included 40 EGFR-mutant advanced NSCLC patients treated with EGFR-targeted therapy. ctDNA data included number of mutations and detection of EGFR T790M. Clinical data included age, smoking status, and ECOG performance status. Baseline chest CT scans were analyzed to extract 429 radiomic features from each primary tumor. Unsupervised hierarchical clustering was used to group tumors into phenotypes. Kaplan-Meier (K-M) curves and Cox proportional hazards regression were modeled for progression-free survival (PFS) and overall survival (OS). Likelihood ratio test (LRT) was used to compare fit between models. Among 40 patients (73% women, median age 62 years), consensus clustering identified two radiomic phenotypes. For PFS, the model combining radiomic phenotypes with ctDNA and clinical variables had c-statistic of 0.77 and a better fit (LRT p = 0.01) than the model with clinical and ctDNA variables alone with a c-statistic of 0.73. For OS, adding radiomic phenotypes resulted in c-statistic of 0.83 versus 0.80 when using clinical and ctDNA variables (LRT p = 0.08). Both models showed separation of K-M curves dichotomized by median prognostic score (p < 0.005). Combining radiomic phenotypes, ctDNA, and clinical variables may enhance precision oncology approaches to managing advanced non-small cell lung cancer with EGFR mutations.

Prevalence and Predictors of Per- and Polyfluoroalkyl Substances (PFAS) Serum Levels among Members of a Suburban US Volunteer Fire Department.

BACKGROUND: Per-and polyfluoroalkyl substances (PFAS), are ubiquitous pollutants associated with adverse health outcomes. High PFAS levels have been demonstrated among career firefighters; less is known about PFAS levels among volunteer firefighters who comprise two-thirds of US firefighters. METHODS: Volunteer fire department members completed a survey and provided blood samples. We calculated geometric means and 95% CIs for PFAS reported by the National Health and Nutrition Examination Survey (NHANES). We compared PFAS distribution and levels among non-Hispanic white adult male study participants to those in the 2015-2016 and 2017-2018 NHANES cycles. We assessed associations between PFAS serum levels and years of firefighting controlling demographics and occupation using linear regression. RESULTS: Participant's average age was 46.6 years (sd. 17.1). Perfluorododecanoic acid (PFDoA) was detected in almost half study but <3% of NHANES participants; serum levels of PFDoA, perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) were elevated among participants compared with NHANES. Serum levels of both PFDA and PFDoA were positively associated with years of firefighting. CONCLUSIONS: Volunteer firefighters may have a different serum profile and levels of PFAS than the general population. Future work in this area should include volunteer firefighters from other geographic locations and assess sources of PFAS exposure.

Perceived Health Risks Among Firefighters; The New Jersey Firefighter Health Survey.

OBJECTIVE: There is a growing literature on the risk of chronic disease among firefighters, including cardiovascular disease (CVD) and cancer. However there is little information on firefighter's perception thereof. METHODS: Firefighters attending a union convention in New Jersey completed a survey with four domains: firefighting experience; perceived additional risk for chronic diseases (six-point Likert scale); cancer screening history; demographics, and risk behaviors. RESULTS: Among 167 enrolled firefighters, all were men and 86.6% active career. Median perceived risk ranged from high risk (colon, hematologic, breast, prostate, and testicular cancers) to very high risk (CVD, pulmonary diseases, all cancers, lung and oral cancer). CONCLUSIONS: NJ Firefighters attributed considerable additional risk to acquiring chronic disease as a result of their firefighting activities. Understanding firefighter perceptions of their own morbidity and mortality will help develop future firefighter preparatory programs.

Association of plasma cell-free DNA with survival in patients with IDH wild-type glioblastoma.

BACKGROUND: We aimed to determine whether plasma cell-free DNA (cfDNA) concentration is associated with survival in patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma (GBM). METHODS: Pre-operative and post-chemoradiotherapy blood samples were prospectively collected from patients with newly diagnosed IDH wild-type GBM. Patients underwent surgical resection or biopsy and received adjuvant radiotherapy with concomitant temozolomide. Cell-free DNA (cfDNA) was isolated from plasma and quantified using SYBR Green-based q polymerase chain reaction (qPCR). RESULTS: Sixty-two patients were enrolled and categorized into high vs. low cfDNA groups relative to the pre-operative median value (25.2 ng/mL, range 5.7-153.0 ng/mL). High pre-operative cfDNA concentration was associated with inferior PFS (median progression-free survival (PFS), 3.4 vs. 7.7 months; log-rank P = .004; hazard ratio [HR], 2.19; 95% CI, 1.26-3.81) and overall survival (OS) (median OS, 8.0 vs. 13.9 months; log-rank P = .01; HR, 2.43; 95% CI, 1.19-4.95). After adjusting for risk factors, including O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, pre-operative cfDNA remained independently associated with PFS (HR, 2.70; 95% CI, 1.50-4.83; P = .001) and OS (HR, 2.65; 95% CI, 1.25-5.59; P = .01). Post-hoc analysis of change in cfDNA post-chemoradiotherapy compared to pre-surgery (n = 24) showed increasing cfDNA concentration was associated with worse PFS (median, 2.7 vs. 6.0 months; log-rank P = .003; HR, 4.92; 95% CI, 1.53-15.84) and OS (median, 3.9 vs. 19.4 months; log-rank P < .001; HR, 7.77; 95% CI, 2.17-27.76). CONCLUSIONS: cfDNA concentration is a promising prognostic biomarker for patients with IDH wild-type GBM. Plasma cfDNA can be obtained noninvasively and may enable more accurate estimates of survival and effective clinical trial stratification.

Blood-based gene expression signature associated with metastatic castrate-resistant prostate cancer patient response to abiraterone plus prednisone or enzalutamide.

BACKGROUND: Precision medicine approaches for managing patients with metastatic castrate-resistant prostate cancer (mCRPC) are lacking. Non-invasive approaches for molecular monitoring of disease are urgently needed, especially for patients suffering from bone metastases for whom tissue biopsy is challenging. Here we utilized baseline blood samples to identify mCRPC patients most likely to benefit from abiraterone plus prednisone (AAP) or enzalutamide. METHODS: Baseline blood samples were collected for circulating tumor cell (CTC) enumeration and qPCR-based gene expression analysis from 51 men with mCRPC beginning treatment with abiraterone or enzalutamide. RESULTS: Of 51 patients (median age 68 years [51-82]), 22 received AAP (abiraterone 1000 mg/day plus prednisone 10 mg/day) and 29 received enzalutamide (160 mg/day). The cohort was randomly divided into training (n = 37) and test (n = 14) sets. Baseline clinical variables (Gleason score, PSA, testosterone, and hemoglobin), CTC count, and qPCR-based gene expression data for 141 genes/isoforms in CTC-enriched blood were analyzed with respect to overall survival (OS). Genes with expression most associated with OS included MSLN, ARG2, FGF8, KLK3, ESRP2, NPR3, CCND1, and WNT5A. Using a Cox-elastic net model for our test set, the 8-gene expression signature had a c-index of 0.87 (95% CI [0.80, 0.94]) and was more strongly associated with OS than clinical variables or CTC count alone, or a combination of the three variables. For patients with a low-risk vs. high-risk gene expression signature, median OS was not reached vs. 18 months, respectively (HR 5.32 [1.91-14.80], p = 0.001). For the subset of 41 patients for whom progression-free survival (PFS) data was available, the median PFS for patients with a low-risk vs high-risk gene expression signature was 20 vs. 5 months, respectively (HR 2.95 [1.46-5.98], p = 0.003). CONCLUSIONS: If validated in a larger prospective study, this test may predict patients most likely to benefit from second-generation antiandrogen therapy.

Dietary Intake Among Members of a Volunteer Fire Department Compared With US Daily Dietary Recommendations.

OBJECTIVE: To characterize the diet of volunteer firefighters compared with the United States recommended dietary intake. METHODS: A survey was administered to members of volunteer fire department which collected information on demographics, behavioral risks, fire service history, and dietary intake using the Dietary Screener Questionnaire. Dietary intake was compared with US recommendations; associations between dietary intake and years of firefighting, were assessed using bi- and multivariate analysis. RESULTS: The 122 male study participants were majority non-Hispanic white (96.4%), and over 90% were overweight or obese. Participants had lower mean intakes of fruit and vegetables, whole grains, and dietary fiber, and a higher mean intake of added sugars compared with the US recommended dietary intake. CONCLUSION: Volunteer firefighters in our study had suboptimal daily dietary intake of fruits and vegetables, dietary fiber, whole grains, and added sugars.

Retrospective Assessment of Risk Factors for Head and Neck Cancer Among World Trade Center General Responders.

Objective: To assess the reliability of a questionnaire designed to reconstruct risk factors for head and neck cancer relative to the 9/11 World Trade Center (WTC) response and over the lifetime. Methods: As part of a nested case-control study, 200 WTC Health Program (WTCHP) General Responder Cohort (GRC) members completed a newly-developed study questionnaire via telephone (with a trained interviewer) or online (self-administered). We assessed agreement between measures of tobacco and alcohol use in our questionnaire results and data collected previously during WTCHP-GRC monitoring visits using Cohens Kappa (κ) and intraclass correlation coefficient (ICC) for categorical and continuous measures, respectively. We compared agreement by disease status, survey mode, and year of WTCHP enrollment. Results: We observed high agreement between measures of lifetime, pre-WTC, and post-WTC smoking prevalence (all κ > 0.85) and smoking duration (all ICC > 0.84). There was moderate agreement between measures of smoking frequency (ICC: 0.61-0.73). Agreement between measures of smoking frequency, but not duration, differed by disease status, and agreement between smoking measures was higher for participants who completed our survey by phone than by web. Among cases, there were no differences based on enrollment in the WTCHP before or after diagnosis. Conclusion: Agreement between measures was generally high, although potential reporting bias and a mode effect that should be considered when interpreting analyses of self-reported data in this population; however differential misclassification appears to be minimal. Our questionnaire may be useful for future studies examining similar behavioral risk factors among disaster-exposed populations.

A Multianalyte Panel Consisting of Extracellular Vesicle miRNAs and mRNAs, cfDNA, and CA19-9 Shows Utility for Diagnosis and Staging of Pancreatic Ductal Adenocarcinoma.

PURPOSE: To determine whether a multianalyte liquid biopsy can improve the detection and staging of pancreatic ductal adenocarcinoma (PDAC). EXPERIMENTAL DESIGN: We analyzed plasma from 204 subjects (71 healthy, 44 non-PDAC pancreatic disease, and 89 PDAC) for the following biomarkers: tumor-associated extracellular vesicle miRNA and mRNA isolated on a nanomagnetic platform that we developed and measured by next-generation sequencing or qPCR, circulating cell-free DNA (ccfDNA) concentration measured by qPCR, ccfDNA KRAS G12D/V/R mutations detected by droplet digital PCR, and CA19-9 measured by electrochemiluminescence immunoassay. We applied machine learning to training sets and subsequently evaluated model performance in independent, user-blinded test sets. RESULTS: To identify patients with PDAC versus those without, we generated a classification model using a training set of 47 subjects (20 PDAC and 27 noncancer). When applied to a blinded test set (N = 136), the model achieved an AUC of 0.95 and accuracy of 92%, superior to the best individual biomarker, CA19-9 (89%). We next used a cohort of 20 patients with PDAC to train our model for disease staging and applied it to a blinded test set of 25 patients clinically staged by imaging as metastasis-free, including 9 subsequently determined to have had occult metastasis. Our workflow achieved significantly higher accuracy for disease staging (84%) than imaging alone (accuracy = 64%; P < 0.05). CONCLUSIONS: Algorithmically combining blood-based biomarkers may improve PDAC diagnostic accuracy and preoperative identification of nonmetastatic patients best suited for surgery, although larger validation studies are necessary.

Baseline Plasma Tumor Mutation Burden Predicts Response to Pembrolizumab-based Therapy in Patients with Metastatic Non-Small Cell Lung Cancer.

PURPOSE: The role of plasma-based tumor mutation burden (pTMB) in predicting response to pembrolizumab-based first-line standard-of-care therapy for metastatic non-small cell lung cancer (mNSCLC) has not been explored. EXPERIMENTAL DESIGN: A 500-gene next-generation sequencing panel was used to assess pTMB. Sixty-six patients with newly diagnosed mNSCLC starting first-line pembrolizumab-based therapy, either alone or in combination with chemotherapy, were enrolled (Clinicaltrial.gov identifier: NCT03047616). Response was assessed using RECIST 1.1. Associations were made for patient characteristics, 6-month durable clinical benefit (DCB), progression-free survival (PFS), and overall survival (OS). RESULTS: Of 66 patients, 52 (78.8%) were pTMB-evaluable. Median pTMB was 16.8 mutations per megabase (mut/Mb; range, 1.9-52.5) and was significantly higher for patients achieving DCB compared with no durable benefit (21.3 mut/Mb vs. 12.4 mut/Mb, P = 0.003). For patients with pTMB ≥ 16 mut/Mb, median PFS was 14.1 versus 4.7 months for patients with pTMB < 16 mut/Mb [HR, 0.30 (0.16-0.60); P < 0.001]. Median OS for patients with pTMB ≥ 16 was not reached versus 8.8 months for patients with pTMB < 16 mut/Mb [HR, 0.48 (0.22-1.03); P = 0.061]. Mutations in ERBB2 exon 20, STK11, KEAP1, or PTEN were more common in patients with no DCB. A combination of pTMB ≥ 16 and absence of negative predictor mutations was associated with PFS [HR, 0.24 (0.11-0.49); P < 0.001] and OS [HR, 0.31 (0.13-0.74); P = 0.009]. CONCLUSIONS: pTMB ≥ 16 mut/Mb is associated with improved PFS after first-line standard-of-care pembrolizumab-based therapy in mNSCLC. STK11/KEAP1/PTEN and ERBB2 mutations may help identify pTMB-high patients unlikely to respond. These results should be validated in larger prospective studies.

Risk factors for head and neck cancer in the World Trade Center Health Program General Responder Cohort: results from a nested case-control study.

OBJECTIVES: Head and neck cancers (HNCs) may be among the health consequences of involvement in the World Trade Center (WTC) response on and after 11 September 2001. We conducted a nested case-control study of WTC Health Program (WTCHP) general responders to examine the effects of WTC exposures and behavioural risk factors on HNC. METHODS: We enrolled 64 cases and 136 controls, matched on age, sex and race/ethnicity within risk sets. We assessed tobacco and alcohol use, sexual activity, and occupational exposures prior to, during and after WTC exposure until case diagnosis via questionnaire. We obtained WTC exposure information (duration (first to last day), total days and location of work) from the WTCHP General Responder Data Center. We assessed associations with HNC, and interaction among exposures, using conditional logistic regression. RESULTS: Responders in protective services versus other occupations had increased odds (OR: 2.51, 95% CI 1.09 to 5.82) of HNC. Among those in non-protective services occupations, arriving to the WTC effort on versus after 11 September 2001 was significantly associated with HNC (OR: 3.77, 95% CI 1.00 to 14.11). Duration of work was not significantly associated with HNC. Lifetime and post-WTC years of cigarette smoking and post-WTC number of sex partners were positively and significantly associated with HNC, while alcohol consumption was not. CONCLUSIONS: These findings suggest opportunities for HNC risk factor mitigation (eg, smoking cessation, human papillomavirus vaccination) and contribute to a risk factor profile which may assist WTCHP clinicians with identifying high-risk responders and improve detection and treatment outcomes in this population.