TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis.

TRIM21 is a RING finger domain-containing ubiquitin E3 ligase whose expression is elevated in autoimmune disease. While TRIM21 plays an important role in immune activation during pathogen infection, little is known about its inherent cellular function. Here we show that TRIM21 plays an essential role in redox regulation by directly interacting with SQSTM1/p62 and ubiquitylating p62 at lysine 7 (K7) via K63-linkage. As p62 oligomerizes and sequesters client proteins in inclusions, the TRIM21-mediated p62 ubiquitylation abrogates p62 oligomerization and sequestration of proteins including Keap1, a negative regulator of antioxidant response. TRIM21-deficient cells display an enhanced antioxidant response and reduced cell death in response to oxidative stress. Genetic ablation of TRIM21 in mice confers protection from oxidative damages caused by arsenic-induced liver insult and pressure overload heart injury. Therefore, TRIM21 plays an essential role in p62-regulated redox homeostasis and may be a viable target for treating pathological conditions resulting from oxidative damage.

Interstitial Lung Disease and Progressive Pulmonary Fibrosis: a World Trade Center Cohort 20-Year Longitudinal Study.

PURPOSE: World Trade Center (WTC) exposure is associated with obstructive airway diseases and sarcoidosis. There is limited research regarding the incidence and progression of non-sarcoidosis interstitial lung diseases (ILD) after WTC-exposure. ILD encompasses parenchymal diseases which may lead to progressive pulmonary fibrosis (PPF). We used the Fire Department of the City of New York's (FDNY's) WTC Health Program cohort to estimate ILD incidence and progression. METHODS: This longitudinal study included 14,525 responders without ILD prior to 9/11/2001. ILD incidence and prevalence were estimated and standardized to the US 2014 population. Poisson regression modeled risk factors, including WTC-exposure and forced vital capacity (FVC), associated with ILD. Follow-up time ended at the earliest of incident diagnosis, end of study period/case ascertainment, transplant or death. RESULTS: ILD developed in 80/14,525 FDNY WTC responders. Age, smoking, and gastroesophageal reflux disease (GERD) prior to diagnosis were associated with incident ILD, though FVC was not. PPF developed in 40/80 ILD cases. Among the 80 cases, the average follow-up time after ILD diagnosis was 8.5 years with the majority of deaths occurring among those with PPF (PPF: n = 13; ILD without PPF: n = 6). CONCLUSIONS: The prevalence of post-9/11 ILD was more than two-fold greater than the general population. An exposure-response gradient could not be demonstrated. Half the ILD cases developed PPF, higher than previously reported. Age, smoking, and GERD were risk factors for ILD and PPF, while lung function was not. This may indicate that lung function measured after respirable exposures would not identify those at risk for ILD or PPF.

PTEN functions by recruitment to cytoplasmic vesicles.

PTEN is proposed to function at the plasma membrane, where receptor tyrosine kinases are activated. However, the majority of PTEN is located throughout the cytoplasm. Here, we show that cytoplasmic PTEN is distributed along microtubules, tethered to vesicles via phosphatidylinositol 3-phosphate (PI(3)P), the signature lipid of endosomes. We demonstrate that the non-catalytic C2 domain of PTEN specifically binds PI(3)P through the CBR3 loop. Mutations render this loop incapable of PI(3)P binding and abrogate PTEN-mediated inhibition of PI 3-kinase/AKT signaling. This loss of function is rescued by fusion of the loop mutant PTEN to FYVE, the canonical PI(3)P binding domain, demonstrating the functional importance of targeting PTEN to endosomal membranes. Beyond revealing an upstream activation mechanism of PTEN, our data introduce the concept of PI 3-kinase signal activation on the vast plasma membrane that is contrasted by PTEN-mediated signal termination on the small, discrete surfaces of internalized vesicles.

Cancer incidence in World Trade Center-exposed and non-exposed male firefighters, as compared with the US adult male population: 2001-2016.

OBJECTIVE: To compare cancer incidence in Fire Department of the City of New York (FDNY) firefighters who worked at the World Trade Center (WTC) site to incidence in a population of non-WTC-exposed firefighters, the Career Firefighter Health Study (CFHS) cohort, and to compare rates from each firefighter cohort to rates in demographically similar US males. METHODS: FDNY (N=10 786) and CFHS (N=8813) cohorts included male firefighters who were active on 11 September 2001 (9/11) and were followed until death or 31 December 2016. Cases were identified from 15 state cancer registries. Poisson regression models assessed cancers in each group (FDNY and CFHS) versus US males, and associations between group and cancer rates; these models estimated standardised incidence ratios (SIRs) and adjusted relative rates (RRs), respectively. Secondary analyses assessed surveillance bias and smoking history. RESULTS: We identified 915 cancer cases in 841 FDNY firefighters and 1002 cases in 909 CFHS firefighters. FDNY had: higher rates for all cancers (RR=1.13; 95% CI 1.02 to 1.25), prostate (RR=1.39; 95% CI 1.19 to 1.63) and thyroid cancer (RR=2.53; 95% CI 1.37 to 4.70); younger median ages at diagnosis (55.6 vs 59.4; p<0.001, all cancers); and more cases with localised disease when compared with CFHS. Compared with US males, both firefighter cohorts had elevated SIRs for prostate cancer and melanoma. Control for surveillance bias in FDNY reduced most differences. CONCLUSIONS: Excess cancers occurred in WTC-exposed firefighters relative to each comparison group, which may partially be explained by heightened surveillance. Two decades post-9/11, clearer understanding of WTC-related risk requires extended follow-up and modelling studies (laboratory or animal based) to identify workplace exposures in all firefighters.

Vps34 regulates Rab7 and late endocytic trafficking through recruitment of the GTPase-activating protein Armus.

The class III phosphoinositide 3-kinase (PI3K) Vps34 (also known as PIK3C3 in mammals) produces phosphatidylinositol 3-phosphate [PI(3)P] on both early and late endosome membranes to control membrane dynamics. We used Vps34-deficient cells to delineate whether Vps34 has additional roles in endocytic trafficking. In Vps34-/- mouse embryonic fibroblasts (MEFs), transferrin recycling and EEA1 membrane localization were unaffected despite elevated Rab5-GTP levels. Strikingly, a large increase in Rab7-GTP levels, an accumulation of enlarged late endosomes, and decreased EGFR degradation were observed in Vps34-deficient cells. The hyperactivation of Rab7 in Vps34-deficient cells stemmed from the failure to recruit the Rab7 GTPase-activating protein (GAP) Armus (also known as TBC1D2), which binds to PI(3)P, to late endosomes. Protein-lipid overlay and liposome-binding assays reveal that the putative pleckstrin homology (PH) domain in Armus can directly bind to PI(3)P. Elevated Rab7-GTP led to the failure of intraluminal vesicle (ILV) formation and lysosomal maturation. Rab7 silencing and Armus overexpression alleviated the vacuolization seen in Vps34-deficient cells. Taken together, these results demonstrate that Vps34 has a previously unknown role in regulating Rab7 activity and late endosomal trafficking.

Incidence and prevalence of antibody to hepatitis C virus in FDNY first responders before and after work at the World Trade Center disaster site.

BACKGROUND: The goals of this study were to assess the impact of work at the World Trade Center (WTC) site in relation to new, post-9/11/2001 (9/11) antibody to hepatitis C Virus (anti-HCV); and, evaluate secular trends in WTC-exposed male Fire Department of New York City (FDNY) Firefighters and Emergency Medical Services (EMS) responders. METHODS: FDNY monitors responder health through physical exams and routine blood work. We used descriptive statistics to compare trans-9/11 and post-9/11 incidence and to assess trends in prevalence from 2000 to 2012. RESULTS: Trans-9/11 incidence of new anti-HCV was 0.42 per 100 persons compared with post-9/11 incidence of 0.34 (P = 0.68). Overall seroprevalence was 1.3%; rates declined from 1.79 per 100 to 0.49 per 100 over time (P < 0.0001). CONCLUSIONS: Work at the WTC was not associated with new infection. Biennial seroprevalence in responders declined over time, supporting the FDNY decision to discontinue routine annual testing in this cohort.

Post-9/11 cancer incidence in World Trade Center-exposed New York City firefighters as compared to a pooled cohort of firefighters from San Francisco, Chicago and Philadelphia (9/11/2001-2009).

BACKGROUND: We previously reported a modest excess of cancer in World Trade Center (WTC)-exposed firefighters versus the general population. This study aimed to separate the potential carcinogenic effects of firefighting and WTC exposure by comparing to a cohort of non-WTC-exposed firefighters. METHODS: Relative rates (RRs) for all cancers combined and individual cancer subtypes from 9/11/2001 to 12/31/2009 were modeled using Poisson regression comparing 11,457 WTC-exposed firefighters to 8,220 urban non-WTC-exposed firefighters. RESULTS: Compared with non-WTC-exposed firefighters, there was no difference in the RR of all cancers combined for WTC-exposed firefighters (RR = 0.96, 95%CI: 0.83-1.12). Thyroid cancer was significantly elevated (RR = 3.82, 95%CI: 1.07-20.81) from 2001 to 2009; this was attenuated (RR = 3.43, 95%CI: 0.94-18.94) and non-significant when controlling for possible surveillance bias. Prostate cancer was elevated during the latter half (2005-2009; RR = 1.38, 95%CI: 1.01-1.88). CONCLUSIONS: Further follow-up is needed to assess the relationship between WTC exposure and cancers with longer latency periods. Am. J. Ind. Med. 59:722-730, 2016. © 2016 Wiley Periodicals, Inc.

Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function.

A critical regulator of autophagy is the Class III PI3K Vps34 (also called PIK3C3). Although Vps34 is known to play an essential role in autophagy in yeast, its role in mammals remains elusive. To elucidate the physiological function of Vps34 and to determine its precise role in autophagy, we have generated Vps34(f/f) mice, in which expression of Cre recombinase results in a deletion of exon 4 of Vps34 and a frame shift causing a deletion of 755 of the 887 amino acids of Vps34. Acute ablation of Vps34 in MEFs upon adenoviral Cre infection results in a diminishment of localized generation of phosphatidylinositol 3-phosphate and blockade of both endocytic and autophagic degradation. Starvation-induced autophagosome formation is blocked in both Vps34-null MEFs and liver. Liver-specific Albumin-Cre;Vps34(f/f) mice developed hepatomegaly and hepatic steatosis, and impaired protein turnover. Ablation of Vps34 in the heart of muscle creatine kinase-Cre;Vps34(f/f) mice led to cardiomegaly and decreased contractility. In addition, while amino acid-stimulated mTOR activation was suppressed in the absence of Vps34, the steady-state level of mTOR signaling was not affected in Vps34-null MEFs, liver, or cardiomyocytes. Taken together, our results indicate that Vps34 plays an essential role in regulating functional autophagy and is indispensable for normal liver and heart function.

Refractory sarcoid arthritis in World Trade Center-exposed New York City firefighters: a case series.

OBJECTIVE: The objective of this study was to describe cases of sarcoid arthritis in firefighters from the Fire Department of the City of New York (FDNY) who worked at the World Trade Center (WTC) site. METHODS: All WTC-exposed FDNY firefighters with sarcoidosis and related chronic inflammatory arthritis (n = 11) are followed jointly by the FDNY-WTC Health Program and the Rheumatology Division at the Hospital for Special Surgery. Diagnoses of sarcoidosis were based on clinical, radiographic, and pathological criteria. Patient characteristics, WTC exposure information, smoking status, date of diagnosis, and pulmonary findings were obtained from FDNY-WTC database. Joint manifestations (symptoms and duration, distribution of joints involved), radiographic findings, and treatment responses were obtained from chart review. RESULTS: Nine of 60 FDNY firefighters who developed sarcoidosis since 9/11/2001 presented with polyarticular arthritis. Two others diagnosed pre-9/11/2001 developed sarcoid arthritis after WTC exposure. All 11 were never cigarette smokers, and all performed rescue/recovery at the WTC site within 3 days of the attacks. All had biopsy-proven pulmonary sarcoidosis, and all required additional disease-modifying antirheumatic drugs for adequate control (stepwise progression from hydroxychloroquine to methotrexate to anti-tumor necrosis factor α agents) of their joint manifestations. CONCLUSIONS: Chronic inflammatory polyarthritis appears to be an important manifestation of sarcoidosis in FDNY firefighters with sarcoidosis and WTC exposure. Their arthritis is chronic and, unlike arthritis in non-WTC-exposed sarcoid patients, inadequately responsive to conventional oral disease-modifying antirheumatic drugs, often requiring anti-tumor necrosis factor α agents. Further studies are needed to determine the generalizability of these findings to other groups with varying levels of WTC exposure or with other occupational/environmental exposures.

Early assessment of cancer outcomes in New York City firefighters after the 9/11 attacks: an observational cohort study.

BACKGROUND: The attacks on the World Trade Center (WTC) on Sept 11, 2001 (9/11) created the potential for occupational exposure to known and suspected carcinogens. We examined cancer incidence and its potential association with exposure in the first 7 years after 9/11 in firefighters with health information before 9/11 and minimal loss to follow-up. METHODS: We assessed 9853 men who were employed as firefighters on Jan 1, 1996. On and after 9/11, person-time for 8927 firefighters was classified as WTC-exposed; all person-time before 9/11, and person-time after 9/11 for 926 non-WTC-exposed firefighters, was classified as non-WTC exposed. Cancer cases were confirmed by matches with state tumour registries or through appropriate documentation. We estimated the ratio of incidence rates in WTC-exposed firefighters to non-exposed firefighters, adjusted for age, race and ethnic origin, and secular trends, with the US National Cancer Institute Surveillance Epidemiology and End Results (SEER) reference population. CIs were estimated with overdispersed Poisson models. Additional analyses included corrections for potential surveillance bias and modified cohort inclusion criteria. FINDINGS: Compared with the general male population in the USA with a similar demographic mix, the standardised incidence ratios (SIRs) of the cancer incidence in WTC-exposed firefighters was 1·10 (95% CI 0·98-1·25). When compared with non-exposed firefighters, the SIR of cancer incidence in WTC-exposed firefighters was 1·19 (95% CI 0·96-1·47) corrected for possible surveillance bias and 1·32 (1·07-1·62) without correction for surveillance bias. Secondary analyses showed similar effect sizes. INTERPRETATION: We reported a modest excess of cancer cases in the WTC-exposed cohort. We remain cautious in our interpretation of this finding because the time since 9/11 is short for cancer outcomes, and the reported excess of cancers is not limited to specific organ types. As in any observational study, we cannot rule out the possibility that effects in the exposed group might be due to unidentified confounders. Continued follow-up will be important and should include cancer screening and prevention strategies. FUNDING: National Institute for Occupational Safety and Health.

Performance of Risk Factor-Based Guidelines and Model-Based Chest CT Lung Cancer Screening in World Trade Center-Exposed Fire Department Rescue/Recovery Workers.

BACKGROUND: Lung cancer is a leading cause of cancer incidence and death in the United States. Risk factor-based guidelines and risk model-based strategies are used to identify patients who could benefit from low-dose chest CT (LDCT) screening. Few studies compare guidelines or models within the same cohort. We evaluate lung cancer screening performance of two risk factor-based guidelines (US Preventive Services Task Force 2014 recommendations [USPSTF-2014] and National Comprehensive Cancer Network Group 2 [NCCN-2]) and two risk model-based strategies, Prostate Lung Colorectal and Ovarian Cancer Screening (PLCOm2012) and the Bach model) in the same occupational cohort. RESEARCH QUESTION: Which risk factor-based guideline or model-based strategy is most accurate in detecting lung cancers in a highly exposed occupational cohort? STUDY DESIGN AND METHODS: Fire Department of City of New York (FDNY) rescue/recovery workers exposed to the September 11, 2001 attacks underwent LDCT lung cancer screening based on smoking history and age. The USPSTF-2014, NCCN-2, PLCOm2012 model, and Bach model were retrospectively applied to determine how many lung cancers were diagnosed using each approach. RESULTS: Among the study population (N = 3,953), 930 underwent a baseline scan that met at least one risk factor or model-based LDCT screening strategy; 73% received annual follow-up scans. Among the 3,953, 63 lung cancers were diagnosed, of which 50 were detected by at least one LDCT screening strategy. The NCCN-2 guideline was the most sensitive (79.4%; 50/63). When compared with NCCN-2, stricter age and smoking criteria reduced sensitivity of the other guidelines/models (USPSTF-2014 [44%], PLCOm2012 [51%], and Bach[46%]). The 13 missed lung cancers were mainly attributable to smoking less and quitting longer than guideline/model eligibility criteria. False-positive rates were similar across all four guidelines/models. INTERPRETATION: In this cohort, our findings support expanding eligibility for LDCT lung cancer screening by lowering smoking history from ≥30 to ≥20 pack-years and age from 55 years to 50 years old. Additional studies are needed to determine its generalizability to other occupational/environmental exposed cohorts.

Evaluation of Medical Surveillance and Incidence of Post-September 11, 2001, Thyroid Cancer in World Trade Center-Exposed Firefighters and Emergency Medical Service Workers.

Importance: Elevated incidence rates of thyroid cancer among World Trade Center (WTC)-exposed individuals may be associated with the identification of asymptomatic cancers during medical surveillance. Objective: To examine the association between WTC exposure and thyroid cancer among Fire Department of the City of New York (hereafter, Fire Department) rescue/recovery workers as well as the association with medical surveillance. Design, Setting, and Participants: This closed-cohort study classified the method of detection (asymptomatic and symptomatic) of thyroid cancers in 14 987 men monitored through the Fire Department-WTC Health Program diagnosed from September 12, 2001, to December 31, 2018. Age-, sex-, and histologic-specific Fire Department incidence rates were calculated and compared with demographically similar men in Olmsted County, Minnesota, from the Rochester Epidemiology Project using age-standardized rates, relative rates (RRs), and 95% CIs. The secondary analysis was restricted to papillary carcinomas. Exposures: World Trade Center exposure was defined as rescue/recovery work at the WTC site from September 11, 2001, to July 25, 2002. Main Outcomes and Measures: The outcomes evaluated comprised (1) number of incident thyroid cancers and their detection method categorizations in the Fire Department and Rochester Epidemiology Project cohorts; (2) Fire Department, Rochester Epidemiology Project, and Surveillance, Epidemiology, and End Results-21 age-standardized incidence rates of thyroid cancer; and (3) RRs comparing Fire Department and Rochester Epidemiology Project overall and by detection method categorization. Results: Seventy-two post-9/11 Fire Department cases of thyroid cancer were identified. Among the 65 cases (90.3%) with a categorized detection method, 53 cases (81.5%) were asymptomatic and 12 cases (18.5%) were symptomatic. Median (interquartile range) age at diagnosis was 50.2 (44.0-58.6) vs 46.6 (43.9-52.9) years for asymptomatic vs symptomatic cases. Associated primarily with asymptomatic cancers, the overall age-standardized incidence of Fire Department thyroid cancers (24.7; 95% CI, 17.4-52.3) was significantly higher than the Rochester Epidemiology Project (10.4; 95% CI, 8.5-12.7) and Surveillance, Epidemiology, and End Results-21 (9.1; 95% CI, 9.0-9.1) per 100 000 person-years. Furthermore, the RR of thyroid cancer among symptomatic men in Fire Department cases was not significantly different from that of men in the Rochester Epidemiology Project (0.8; 95% CI, 0.4-1.5); however, the rate of asymptomatic cancers was more than 3-fold that of the Rochester Epidemiology Project rate (RR, 3.1; 95% CI, 2.1-4.7). Conclusions and Relevance: Excess asymptomatic thyroid cancer in Fire Department WTC-exposed rescue/recovery workers is apparently attributable to the identification of occult lesions during medical surveillance. Among WTC-exposed cohorts and the general population, these findings appear to have important implications for how thyroid cancer incidence rates are interpreted and how diagnoses should be managed.

Long-term Cardiovascular Disease Risk Among Firefighters After the World Trade Center Disaster.

Importance: Published studies examining the association between World Trade Center (WTC) exposure on and after September 11, 2001, and longer-term cardiovascular disease (CVD) outcomes have reported mixed findings. Objective: To assess whether WTC exposure was associated with elevated CVD risk in Fire Department of the City of New York (FDNY) firefighters. Design, Settings, and Participants: In this cohort study, the association between WTC exposure and the risk of CVD was assessed between September 11, 2001, and December 31, 2017, in FDNY male firefighters. Multivariable Cox regression analyses were used to estimate CVD risk in association with 2 measures of WTC exposure: arrival time to the WTC site and duration of work at the WTC site. Data analyses were conducted from May 1, 2018, to March 8, 2019. Main Outcomes and Measures: The primary CVD outcome included myocardial infarction, stroke, unstable angina, coronary artery surgery or angioplasty, or CVD death. The secondary outcome (all CVD) included all primary outcome events or any of the following: transient ischemic attack; stable angina, defined as either use of angina medication or cardiac catheterization without intervention; cardiomyopathy; and other CVD (aortic aneurysm, peripheral arterial vascular intervention, and carotid artery surgery). Results: There were 489 primary outcome events among 9796 male firefighters (mean [SD] age on September 11, 2001, was 40.3 [7.4] years and 7210 individuals [73.6%] were never smokers). Age-adjusted incident rates of CVD were higher for firefighters with greater WTC exposure. The multivariable adjusted hazard ratio (HR) for the primary CVD outcome was 1.44 (95% CI, 1.09-1.90) for the earliest arrival group compared with those who arrived later. Similarly, those who worked at the WTC site for 6 or more months vs those who worked less time at the site were more likely to have a CVD event (HR, 1.30; 95% CI, 1.05-1.60). Well-established CVD risk factors, including hypertension (HR, 1.41; 95% CI, 1.10-1.80), hypercholesterolemia (HR, 1.56; 95% CI, 1.28-1.91), diabetes (HR, 1.99; 95% CI, 1.33-2.98), and smoking (current: HR, 2.13; 95% CI, 1.68-2.70; former: HR, 1.55; 95% CI, 1.23-1.95), were significantly associated with CVD in the multivariable models. Analyses with the all-CVD outcome were similar. Conclusions and Relevance: The findings of the study suggest a significant association between greater WTC exposure and long-term CVD risk. The findings appear to reinforce the importance of long-term monitoring of the health of survivors of disasters.

Genetic Variants Associated with FDNY WTC-Related Sarcoidosis.

Sarcoidosis is a systemic granulomatous disease of unknown etiology. It may develop in response to an exposure or inflammatory trigger in the background of a genetically primed abnormal immune response. Thus, genetic studies are potentially important to our understanding of the pathogenesis of sarcoidosis. We developed a case-control study which explored the genetic variations between firefighters in the Fire Department of the City of New York (FDNY) with World Trade Center (WTC)-related sarcoidosis and those with WTC exposure, but without sarcoidosis. The loci of fifty-one candidate genes related to granuloma formation, inflammation, immune response, and/or sarcoidosis were sequenced at high density in enhancer/promoter, exonic, and 5' untranslated regions. Seventeen allele variants of human leukocyte antigen (HLA) and non-HLA genes were found to be associated with sarcoidosis, and all were within chromosomes 1 and 6. Our results also suggest an association between extrathoracic involvement and allele variants of HLA and non-HLA genes found not only on chromosomes 1 and 6, but also on chromosomes 16 and 17. We found similarities between genetic variants with WTC-related sarcoidosis and those reported previously in sporadic sarcoidosis cases within the general population. In addition, we identified several allele variants never previously reported in association with sarcoidosis. If confirmed in larger studies with known environmental exposures, these novel findings may provide insight into the gene-environment interactions key to the development of sarcoidosis.

Estimation of Future Cancer Burden Among Rescue and Recovery Workers Exposed to the World Trade Center Disaster.

Importance: Elevated rates of cancer have been reported in individuals exposed to the World Trade Center (WTC) disaster, including Fire Department of the City of New York (FDNY) rescue and recovery workers. Objective: To project the future burden of cancer in WTC-exposed FDNY rescue and recovery workers by estimating the 20-year cancer incidence. Design, Setting, and Participants: A total of 14 474 WTC-exposed FDNY employees who were cancer-free on January 1, 2012; subgroup analyses were conducted of the cohort's white male population (n = 12 374). In this closed-cohort study, we projected cancer incidence for the January 1, 2012, to December 31, 2031, period. Simulations were run using demographic-specific New York City (NYC) cancer and national mortality rates for each individual, summed for the whole cohort, and performed 1000 times to produce mean estimates. Additional analyses in the subgroup of white men compared case counts produced by using 2007-2011 FDNY WTC Health Program (FDNY-WTCHP) cancer rates vs NYC rates. Average and 20-year aggregate costs of first-year cancer care were estimated using claims data. Exposures: World Trade Center disaster exposure defined as rescue and recovery work at the WTC site at any time from September 11, 2001, to July 25, 2002. Main Outcomes and Measures: (1) Projected number of incident cancers in the full cohort, based on NYC cancer rates; (2) cancer incidence estimates in the subgroup projected using FDNY-WTCHP vs NYC rates; and (3) estimated first-year treatment costs of incident cancers. Results: On January 1, 2012, the cohort was 96.8% male, 87.1% white, and had a mean (SD) age of 50.2 (9.2) years. The projected number of incident cancer cases was 2960 (95% CI, 2883-3037). In our subgroup analyses using FDNY-WTCHP vs NYC cancer rates, the projected number of new cases in white men was elevated (2714 [95% CI, 2638-2786] vs 2596 [95% CI, 2524-2668]). Accordingly, we expect more prostate (1437 [95% CI, 1383-1495] vs 863 [95% CI, 816-910]), thyroid (73 [95% CI, 60-86] vs 57 [95% CI, 44-69]), and melanoma cases (201 [95% CI, 179-223] vs 131 [95% CI, 112-150), but fewer lung (237 [95% CI, 212-262] vs 373 [95% CI, 343-405]), colorectal (172 [95% CI, 152-191] vs 267 [95% CI, 241-292]), and kidney cancers (66 [95% CI, 54-80] vs 132 [95% CI, 114-152]) (P < .001 for all comparisons). The estimated 20-year cost of first-year treatment was $235 835 412 (95% CI, $187 582 227-$284 088 597). Conclusions and Relevance: We project that the FDNY-WTCHP cohort will experience a greater cancer burden than would be expected from a demographically similar population. This underscores the importance of cancer prevention efforts and routine screening in WTC-exposed rescue and recovery workers.

Clinical Course of Sarcoidosis in World Trade Center-Exposed Firefighters.

BACKGROUND: Sarcoidosis is believed to represent a genetically primed, abnormal immune response to an antigen exposure or inflammatory trigger, with both genetic and environmental factors playing a role in disease onset and phenotypic expression. In a population of firefighters with post-World Trade Center (WTC) 9/11/2001 (9/11) sarcoidosis, we have a unique opportunity to describe the clinical course of incident sarcoidosis during the 15 years postexposure and, on average, 8 years following diagnosis. METHODS: Among the WTC-exposed cohort, 74 firefighters with post-9/11 sarcoidosis were identified through medical records review. A total of 59 were enrolled in follow-up studies. For each participant, the World Association of Sarcoidosis and Other Granulomatous Diseases organ assessment tool was used to categorize the sarcoidosis involvement of each organ system at time of diagnosis and at follow-up. RESULTS: The incidence of sarcoidosis post-9/11 was 25 per 100,000. Radiographic resolution of intrathoracic involvement occurred in 24 (45%) subjects. Lung function for nearly all subjects was within normal limits. Extrathoracic involvement increased, most prominently joints (15%) and cardiac (16%) involvement. There was no evidence of calcium dysmetabolism. Few subjects had ocular (5%) or skin (2%) involvement, and none had beryllium sensitization. Most (76%) subjects did not receive any treatment. CONCLUSIONS: Extrathoracic disease was more prevalent in WTC-related sarcoidosis than reported for patients with sarcoidosis without WTC exposure or for other exposure-related granulomatous diseases (beryllium disease and hypersensitivity pneumonitis). Cardiac involvement would have been missed if evaluation stopped after ECG, 48-h recordings, and echocardiogram. Our results also support the need for advanced cardiac screening in asymptomatic patients with strenuous, stressful, public safety occupations, given the potential fatality of a missed diagnosis.

Multiple Myeloma and Its Precursor Disease Among Firefighters Exposed to the World Trade Center Disaster.

Importance: The World Trade Center (WTC) attacks on September 11, 2001, created an unprecedented environmental exposure to known and suspected carcinogens suggested to increase the risk of multiple myeloma. Multiple myeloma is consistently preceded by the precursor states of monoclonal gammopathy of undetermined significance (MGUS) and light-chain MGUS, detectable in peripheral blood. Objective: To characterize WTC-exposed firefighters with a diagnosis of multiple myeloma and to conduct a screening study for MGUS and light-chain MGUS. Design, Setting, and Participants: Case series of multiple myeloma in firefighters diagnosed between September 11, 2001, and July 1, 2017, together with a seroprevalence study of MGUS in serum samples collected from Fire Department of the City of New York (FDNY) firefighters between December 2013 and October 2015. Participants included all WTC-exposed FDNY white, male firefighters with a confirmed physician diagnosis of multiple myeloma (n = 16) and WTC-exposed FDNY white male firefighters older than 50 years with available serum samples (n = 781). Exposures: WTC exposure defined as rescue and/or recovery work at the WTC site between September 11, 2001, and July 25, 2002. Main Outcomes and Measures: Multiple myeloma case information, and age-adjusted and age-specific prevalence rates for overall MGUS (ie, MGUS and light-chain MGUS), MGUS, and light-chain MGUS. Results: Sixteen WTC-exposed white male firefighters received a diagnosis of multiple myeloma after September 11, 2001; median age at diagnosis was 57 years (interquartile range, 50-68 years). Serum/urine monoclonal protein isotype/free light-chain data were available for 14 cases; 7 (50%) had light-chain multiple myeloma. In a subset of 7 patients, myeloma cells were assessed for CD20 expression; 5 (71%) were CD20 positive. In the screening study, we assayed peripheral blood from 781 WTC-exposed firefighters. The age-standardized prevalence rate of MGUS and light-chain MGUS combined was 7.63 per 100 persons (95% CI, 5.45-9.81), 1.8-fold higher than rates from the Olmsted County, Minnesota, white male reference population (relative rate, 1.76; 95% CI, 1.34-2.29). The age-standardized prevalence rate of light-chain MGUS was more than 3-fold higher than in the same reference population (relative rate, 3.13; 95% CI, 1.99-4.93). Conclusions and Relevance: Environmental exposure to the WTC disaster site is associated with myeloma precursor disease (MGUS and light-chain MGUS) and may be a risk factor for the development of multiple myeloma at an earlier age, particularly the light-chain subtype.

Post-9/11 sarcoidosis in WTC-exposed firefighters and emergency medical service workers.

INTRODUCTION: The World Trade Center (WTC) disaster released a huge quantity and variety of toxicants into the environment. To-date, studies from each of the three major cohorts of WTC-exposed workers have suggested "greater than expected" numbers of post-9/11 cases in some workers. We undertook this study to estimate the incidence of post-9/11 sarcoidosis in ∼13,000 male firefighters and EMS workers enrolled in The Fire Department of the City of New York (FDNY) WTC Health Program; to compare FDNY incidence to rates from unexposed, demographically similar men in the Rochester Epidemiology Project (REP); and, to examine rates by level of WTC exposure. METHODS: We calculated incidence of sarcoidosis diagnosed from 9/12/2001 to 9/11/2015, and generated expected sex- and age-specific rates based on REP rates. Standardized incidence ratios (SIR) based on REP rates, and 95% confidence intervals (95% CI) were estimated. Two sensitivity analyses limited cases to those with intra-thoracic symptoms or biopsy confirmation. RESULTS: We identified 68 post-9/11 cases in the FDNY cohort. Overall, FDNY rates were significantly higher than expected rates (SIR = 2.8; 95% CI = 2.2, 3.6). Including only symptomatic cases, the SIR decreased (SIR = 2.2; 95% CI = 1.5, 3.0), but remained significantly elevated. SIRs ranged from 2.7 (95% CI = 2.0, 3.5) in the lower WTC exposure group to 4.2 (95% CI = 1.9, 8.0) in the most highly exposed. CONCLUSIONS: We found excess incident post-9/11 sarcoidosis in WTC-exposed workers. Continued surveillance, particularly of those most highly exposed, is necessary to identify those with sarcoidosis and to follow them for possible adverse effects including functional impairments and organ damage.

CTD2 Dashboard: a searchable web interface to connect validated results from the Cancer Target Discovery and Development Network.

Database URL: https://ctd2-dashboard.nci.nih.gov/.