Pesticide exposure and risk of aggressive prostate cancer among private pesticide applicators.

BACKGROUND: Prostate cancer (PCa) is one of the most commonly diagnosed cancers among men in developed countries; however, little is known about modifiable risk factors. Some studies have implicated organochlorine and organophosphate insecticides as risk factors (particularly the organodithioate class) and risk of clinically significant PCa subtypes. However, few studies have evaluated other pesticides. We used data from the Agricultural Health Study, a large prospective cohort of pesticide applicators in North Carolina and Iowa, to extend our previous work and evaluate 39 additional pesticides and aggressive PCa. METHODS: We used Cox proportional hazards models, with age as the time scale, to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between ever use of individual pesticides and 883 cases of aggressive PCa (distant stage, poorly differentiated grade, Gleason score ≥ 7, or fatal prostate cancer) diagnosed between 1993 and 2015. All models adjusted for birth year, state, family history of PCa, race, and smoking status. We conducted exposure-response analyses for pesticides with reported lifetime years of use. RESULTS: There was an increased aggressive PCa risk among ever users of the organodithioate insecticide dimethoate (n = 54 exposed cases, HR = 1.37, 95% CI = 1.04, 1.80) compared to never users. We observed an inverse association between aggressive PCa and the herbicide triclopyr (n = 35 exposed cases, HR = 0.68, 95% CI = 0.48, 0.95), with the strongest inverse association for those reporting durations of use above the median (≥ 4 years; n = 13 exposed cases, HR=0.44, 95% CI=0.26, 0.77). CONCLUSION: Few additional pesticides were associated with prostate cancer risk after evaluation of extended data from this large cohort of private pesticide applicators.

Cancer incidence in the Agricultural Health Study after 20 years of follow-up.

PURPOSE: To evaluate cancer incidence in the Agricultural Health Study (AHS), a cohort of private pesticide applicators, their spouses, and commercial applicators, based on 12,420 cancers, adding 5,989 cancers, and 9 years of follow-up since last evaluation. METHODS: We calculated age, year, sex, and race-adjusted standardized incidence ratios (SIR) and 95% confidence intervals (CI) for cancer sites in the AHS relative to the general population. RESULTS: Overall AHS cancer incidence was lower than the general population (SIRprivate = 0.91, CI 0.89-0.93; SIRspouse = 0.89, CI 0.86-0.92; SIRcommercial = 0.83, CI 0.76-0.92), with notable deficits across applicators and spouses for oral cavity, pancreas, and lung cancers. Cancer excesses included prostate cancer, lip cancer, certain B-cell lymphomas (e.g., multiple myeloma), acute myeloid leukemia (AML), thyroid cancer, testicular cancer, and peritoneal cancer. The lung cancer deficit was strongest among applicators reporting potential exposure to endotoxin at study enrollment (tasks such as raising animals and handling stored grain). CONCLUSIONS: Although an overall deficit in cancer was observed, there were notable exceptions, including newly observed excesses for AML, thyroid, testicular, and peritoneal cancers. Furthermore, endotoxin exposure may, in part, account for observed lung cancer incidence deficits. Cancer incidence patterns in the AHS suggest farm exposures' relevance to cancer etiology.

Overall and cause-specific mortality in a cohort of farmers and their spouses.

OBJECTIVES: Lower mortality rates compared with the general population have been reported for Agricultural Health Study (AHS) participants (enrolled 1993-1997) followed through 2007. We extended analysis of mortality among AHS participants (51 502 private pesticide applicators, their 31 867 spouses and 4677 commercial pesticide applicators from North Carolina and Iowa) through 2015 and compared results using several analytical approaches. METHODS: We calculated standardised mortality ratios (SMRs), causal mortality ratios (CMR) and relative SMRs (rSMR) using state-specific mortality rates of the general populations as the referent. RESULTS: Over the average 16 years of follow-up (1999-2015), 9305 private applicators, 3384 spouses and 415 commercial applicators died. SMRs and CMRs, with expected deaths calculated using the person-time among the cohort and the general population, respectively, indicated lower overall mortality in all study subgroups (SMRs from 0.61 to 0.69 and CMRs from 0.74 to 0.89), although CMRs indicated elevated mortality in private applicators from North Carolina and in ever-smokers. In SMR analyses, there were fewer than expected deaths from many causes, but deaths from some external causes including transportation-related injuries and mechanical forces were elevated in private applicators. CMRs indicated higher than expected deaths from prostate cancer, lymphohaematopoietic cancers, Parkinson's and Alzheimer's disease, and chronic glomerulonephritis in private applicators, and non-Hodgkin's lymphoma in spouses (from 1.19 to 1.53). rSMR results were generally elevated, similar to CMR findings. CONCLUSIONS: AHS participants experienced lower overall mortality than the general population.Mortality from a few specific causes was increased in private applicators, specifically when CMR and rSMR approaches were used.

Pesticide use and incident hyperthyroidism in farmers in the Agricultural Health Study.

BACKGROUND: Few studies have evaluated associations between pesticides and hyperthyroidism. OBJECTIVE: We evaluated associations between specific pesticides and incident hyperthyroidism in private pesticide applicators in the Agricultural Health Study. METHODS: We used Cox proportional hazards models to estimate HRs and 95% CIs for associations between pesticide use at enrolment and hyperthyroidism (n=271) in 35 150 applicators (mostly men), adjusting for potential confounders. RESULTS: Ever use of several pesticides (organophosphate insecticide malathion, fungicide maneb/mancozeb, herbicides dicamba, metolachlor, and atrazine in overall sample and chlorimuron ethyl among those ≤62 years) was associated with reduced hyperthyroidism risk, with HRs ranging from 0.50 (95% CI 0.30 to 0.83) for maneb/mancozeb to 0.77 (95% CI 0.59 to 1.00) for atrazine. Hyperthyroidism risk was lowest among those with higher intensity-weighted lifetime days of using carbofuran and chlorpyrifos (ptrend ≤0.05). CONCLUSIONS: Observed associations between pesticides and decreased risk of hyperthyroidism warrant further investigation.

Occupational pesticide exposure and subclinical hypothyroidism among male pesticide applicators.

OBJECTIVES: Animal studies suggest that exposure to pesticides may alter thyroid function; however, few epidemiologic studies have examined this association. We evaluated the relationship between individual pesticides and thyroid function in 679 men enrolled in a substudy of the Agricultural Health Study, a cohort of licensed pesticide applicators. METHODS: Self-reported lifetime pesticide use was obtained at cohort enrolment (1993-1997). Intensity-weighted lifetime days were computed for 33 pesticides, which adjusts cumulative days of pesticide use for factors that modify exposure (eg, use of personal protective equipment). Thyroid-stimulating hormone (TSH), thyroxine (T4), triiodothyronine (T3) and antithyroid peroxidase (anti-TPO) autoantibodies were measured in serum collected in 2010-2013. We used multivariate logistic regression to estimate ORs and 95% CIs for subclinical hypothyroidism (TSH >4.5 mIU/L) compared with normal TSH (0.4-<4.5 mIU/L) and for anti-TPO positivity. We also examined pesticide associations with TSH, T4 and T3 in multivariate linear regression models. RESULTS: Higher exposure to the insecticide aldrin (third and fourth quartiles of intensity-weighted days vs no exposure) was positively associated with subclinical hypothyroidism (ORQ3=4.15, 95% CI 1.56 to 11.01, ORQ4=4.76, 95% CI 1.53 to 14.82, ptrend <0.01), higher TSH (ptrend=0.01) and lower T4 (ptrend=0.04). Higher exposure to the herbicide pendimethalin was associated with subclinical hypothyroidism (fourth quartile vs no exposure: ORQ4=2.78, 95% CI 1.30 to 5.95, ptrend=0.02), higher TSH (ptrend=0.04) and anti-TPO positivity (ptrend=0.01). The fumigant methyl bromide was inversely associated with TSH (ptrend=0.02) and positively associated with T4 (ptrend=0.01). CONCLUSIONS: Our results suggest that long-term exposure to aldrin, pendimethalin and methyl bromide may alter thyroid function among male pesticide applicators.

A nested case-control study of polychlorinated biphenyls, organochlorine pesticides, and thyroid cancer in the Janus Serum Bank cohort.

BACKGROUND: Polychlorinated biphenyls (PCBs) and organochlorine pesticides have been associated with altered thyroid hormone levels in humans, but their relationship with thyroid cancer is unknown. METHODS: We conducted a nested case-control study of thyroid cancer in the Norwegian Janus Serum Bank cohort using pre-diagnostic blood samples from 1972 to 1985. Incident thyroid cancer (n = 108) was ascertained through 2008. Controls were matched 2:1 by age, date of blood draw, gender, and county. We used gas chromatography/mass spectrometry to quantify 36 PCB congeners and metabolites of pesticides DDT, chlordane, hexachlorocyclohexane, and hexachlorobenzene. PCBs and pesticide metabolites were evaluated individually and summed by degree of chlorination and parent compound, respectively. Odds ratios (OR) and 95% confidence intervals (CI) were computed using conditional logistic regression per specified increase in lipid-adjusted concentration. We additionally stratified analyses by birth cohort (1923-1932, 1933-1942, 1943-1957). RESULTS: Increasing concentration of DDT metabolites (ORper 1000 ng/g = 0.80, 95%CI = 0.66-0.98) was inversely associated with thyroid cancer. Associations for PCBs were null or in inverse direction. We observed interactions for total PCBs, moderately-chlorinated PCBs, and chlordane metabolites with birth cohort (p ≤ 0.04). Among participants born 1943-1957, total PCBs (ORper 100 ng/g = 1.25, 95%CI = 1.00-1.56), moderately-chlorinated PCBs (ORper 100 ng/g = 1.31, 95%CI = 1.01-1.70), and chlordane metabolites (ORper 10 ng/g = 1.78, 95%CI = 1.09-2.93) were positively associated with thyroid cancer. For individuals born before 1943, associations were generally null or in the inverse direction. CONCLUSIONS: Emissions of PCBs and OC pesticides varied over time. Different risk patterns by birth cohort suggest the potential importance of timing of exposure in thyroid cancer risk. Further evaluation of these associations is warranted.

Greater Coronary Heart Disease Risk With Lower Intensity and Longer Duration Smoking Compared With Higher Intensity and Shorter Duration Smoking: Congruent Results Across Diverse Cohorts.

INTRODUCTION: Relative risks (RRs) for coronary heart disease (CHD) by cigarettes/day exhibit a concave pattern, implying the RR increase with each additional cigarette/day consumed decreases with greater intensity. Interpreting this pattern faces limitations, since cigarettes/day alone does not fully characterize smoking-related exposure. A more complete understanding of smoking and CHD risk requires a more comprehensive representation of smoking. METHODS: Using Poisson regression, we applied a RR model in pack-years and cigarettes/day to analyze two diverse cohorts, the US Agricultural Health Study, with 4396 CHD events and 1 425 976 person-years of follow-up, and the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, with 5979 CHD events and 486 643 person-years. RESULTS: In both cohorts, the concave RR pattern with cigarettes/day was consistent with cigarettes/day modifying a linear RR association for CHD by pack-years within categories of cigarettes/day, indicating that strength of the pack-years association depended on cigarettes/day (p < .01). For example, at 50 pack-years (365 000 total cigarettes), estimated RRs of CHD were 2.1 for accrual at 20 cigarettes/day and 1.5 for accrual at 50 cigarettes/day. CONCLUSIONS: RRs for CHD increased with pack-years with smoking intensities affecting the strength of association. For equal pack-years, smoking fewer cigarettes/day for longer duration was more deleterious than smoking more cigarettes/day for shorter duration. We have now observed inverse smoking intensity effects in multiple cohorts with differing smoking patterns and other characteristics, suggesting a common underlying phenomenon. IMPLICATIONS: Risk of CHD increases with pack-years of smoking, but accrual intensity strongly influences the strength of the association, such that smoking fewer cigarettes/day for longer duration is more deleterious than smoking more cigarettes/day for shorter duration. This observation offers clues to better understanding biological mechanisms, and reinforces the importance of cessation rather than smoking less to reduce CHD risk.

A prospective study of cancer risk among Agricultural Health Study farm spouses associated with personal use of organochlorine insecticides.

BACKGROUND: Organochlorine insecticides (OCs) have historically been used worldwide to control insects, although most have now been banned in developed countries. Evidence for an association between OC exposures and cancer predominantly comes from occupational and population based-studies among men. We evaluated the association between the use of specific OCs and cancer among the female spouses of pesticide applicators in the Agricultural Health Study. METHODS: At enrollment (1993-1997), spouses of private applicators in the cohort provided information about their own use of pesticides, including seven OCs (aldrin, chlordane, dieldrin, DDT, heptachlor, lindane, and toxaphene), and information on potential confounders. We used Poisson regression to estimate relative risks (RRs) and 95% confidence intervals (CIs) for cancers (n ≥ 3 exposed cases) reported to state cancer registries from enrollment through 2012 (North Carolina) and 2013 (Iowa), and use of the individual OCs, as well as use of any of the specific OCs. RESULTS: Among 28,909 female spouses, 2191 (7.58%) reported ever use of at least one OC, of whom 287 were diagnosed with cancer. Most cancers were not associated with OC use. Risk of glioma was increased among users of at least one OC (Nexposed = 11, RR = 3.52, 95% CI 1.72-7.21) and specifically among lindane users (Nexposed = 3, RR = 4.45, 95% CI 1.36-14.55). Multiple myeloma was associated with chlordane (Nexposed = 6, RR = 2.71, 95% CI 1.12-6.55). Based on 3 exposed cases each, there were also positive associations between pancreatic cancer and lindane, and ER-PR- breast cancer and dieldrin. No other associations with breast cancer were found. CONCLUSIONS: Overall, there were some associations with OC use and cancer incidence, however we were limited by the small number of exposed cancer cases. Future research should attempt to expand on these findings by assessing environmental sources of OC exposures, to fully evaluate the role of OC exposures on cancer risk in women.

Use of Dietary Vitamin Supplements and Risk of Thyroid Cancer: A Population-Based Case-Control Study in Connecticut.

Certain dietary supplements have been reported to increase the risk of some cancers. Over half of the US population regularly uses dietary supplements. Thyroid cancer incidence has increased over the past several decades. However, few studies have investigated the association between dietary supplements and thyroid cancer. Thus, it is essential to clarify any association between dietary supplements and risk of thyroid cancer. MATERIALS AND METHODS: A population-based case-control study in Connecticut was conducted during 2010-2011 among 462 histologically confi rmed incident thyroid cancer cases and 498 population-based controls. Dietary supplement intake was ascertained through in-person interviews and a food frequency questionnaire. Multivariate unconditional logistic regression models were used to estimate the risk of thyroid cancer and dietary supplement use. RESULTS: Overall, no statistically signifi cant associations were observed between dietary supplementation and thyroid cancer risk. Stratifi ed analyses revealed a suggestive protective effect on risk of papillary microcarcinoma among longterm (> 10 years) use of multivitamins (OR = 0.59, 95 % CI: 0.33, 1.04) and calcium supplementation (OR = 0.45, 95 % CI: 0.22, 0.93). An increased risk of large papillary thyroid cancers (tumor size > 1 cm) was observed among short-term (< 5 years) users of calcium supplements (OR = 2.24, 95 % CI: 1.30, 3.88). DISCUSSION: No signifi cant associations were observed between supplementation and overall thyroid cancer risk. The different associations between calcium supplements and risk of papillary thyroid cancer by tumor size warrant further investigation.

Use of acetochlor and cancer incidence in the Agricultural Health Study.

Since its registration in 1994 acetochlor has become a commonly used herbicide in the US, yet no epidemiologic study has evaluated its carcinogenicity in humans. We evaluated the use of acetochlor and cancer incidence among licensed pesticide applicators in the Agricultural Health Study. In telephone interviews administered during 1999-2005, participants provided information on acetochlor use, use of other pesticides and additional potential confounders. We used Poisson regression to estimate relative risks (RR) and 95% confidence intervals (95% CI) for cancers that occurred from the time of interview through 2011 in Iowa and 2010 in North Carolina. Among 33,484 men, there were 4,026 applicators who used acetochlor and 3,234 incident cancers, with 304 acetochlor-exposed cases. Increased risk of lung cancer was observed among acetochlor users (RR = 1.74; 95% CI: 1.07-2.84) compared to nonusers, and among individuals who reported using acetochlor/atrazine product mixtures (RR = 2.33; 95% CI: 1.30-4.17), compared to nonusers of acetochlor. Colorectal cancer risk was significantly elevated among the highest category of acetochlor users (RR = 1.75; 95% CI: 1.08-2.83) compared to never users. Additionally, borderline significantly increased risk of melanoma (RR = 1.61; 95% CI: 0.98-2.66) and pancreatic cancer (RR = 2.36; 95% CI: 0.98-5.65) were observed among acetochlor users. The associations between acetochlor use and lung cancer, colorectal cancer, melanoma and pancreatic cancer are suggestive, however the lack of exposure-response trends, small number of exposed cases and relatively short time between acetochlor use and cancer development prohibit definitive conclusions.

Incidence of solid tumours among pesticide applicators exposed to the organophosphate insecticide diazinon in the Agricultural Health Study: an updated analysis.

OBJECTIVE: Diazinon, a common organophosphate insecticide with genotoxic properties, was previously associated with lung cancer in the Agricultural Health Study (AHS) cohort, but few other epidemiological studies have examined diazinon-associated cancer risk. We used updated diazinon exposure and cancer incidence information to evaluate solid tumour risk in the AHS. METHODS: Male pesticide applicators in Iowa and North Carolina reported lifetime diazinon use at enrolment (1993-1997) and follow-up (1998-2005); cancer incidence was assessed through 2010(North Carolina)/2011(Iowa). Among applicators with usage information sufficient to evaluate exposure-response patterns, we used Poisson regression to estimate adjusted rate ratios (RRs) and 95% CI for cancer sites with ≥10 exposed cases for both lifetime (LT) exposure days and intensity-weighted (IW) lifetime exposure days (accounting for factors impacting exposure). RESULTS: We observed elevated lung cancer risks (N=283) among applicators with the greatest number of LT (RR=1.60; 95% CI 1.11 to 2.31; P(trend)=0.02) and IW days of diazinon use (RR=1.41; 95% CI 0.98 to 2.04; P(trend)=0.08). Kidney cancer (N=94) risks were non-significantly elevated (RR(LT) days=1.77; 95% CI 0.90 to 3.51; P(trend)=0.09; RR(IW) days 1.37; 95% CI 0.64 to 2.92; P(trend)=0.50), as were risks for aggressive prostate cancer (N=656). CONCLUSIONS: Our updated evaluation of diazinon provides additional evidence of an association with lung cancer risk. Newly identified links to kidney cancer and associations with aggressive prostate cancer require further evaluation.

Organophosphate insecticide use and cancer incidence among spouses of pesticide applicators in the Agricultural Health Study.

OBJECTIVES: Organophosphates (OPs) are among the most commonly used insecticides. OPs have been linked to cancer risk in some epidemiological studies, which have been largely conducted in predominantly male populations. We evaluated personal use of specific OPs and cancer incidence among female spouses of pesticide applicators in the prospective Agricultural Health Study cohort. METHODS: At enrolment (1993-1997), spouses provided information about ever use of specific pesticides, including 10 OPs, demographic information, reproductive health history and other potential confounders. We used Poisson regression to estimate relative risks (RRs) and 95% CIs for all cancers diagnosed through 2010 for North Carolina and through 2011 for Iowa. RESULTS: Among 30,003 women, 25.9% reported OP use, and 718 OP-exposed women were diagnosed with cancer during the follow-up period. Any OP use was associated with an elevated risk of breast cancer (RR=1.20, 95% CI 1.01 to 1.43). Malathion, the most commonly reported OP, was associated with increased risk of thyroid cancer (RR=2.04, 95% CI 1.14 to 3.63) and decreased risk of non-Hodgkin lymphoma (RR=0.64, 95% CI 0.41 to 0.99). Diazinon use was associated with ovarian cancer (RR=1.87, 95% CI 1.02 to 3.43). CONCLUSIONS: We observed increased risk with OP use for several hormonally-related cancers, including breast, thyroid and ovary, suggesting potential for hormonally-mediated effects. This study represents the first comprehensive analysis of OP use and cancer risk among women, and thus demonstrates a need for further evaluation.

Insurance status and distant-stage disease at diagnosis among adolescent and young adult patients with cancer aged 15 to 39 years: National Cancer Data Base, 2004 through 2010.

BACKGROUND: The percentage of adolescent and young adult (AYA) patients with cancer (those aged 15-39 years) diagnosed at a distant stage of disease did not significantly change between 1975 and 2004. It has been hypothesized that a lack of health insurance may be a significant risk factor for a diagnosis of distant-stage disease among AYA patients, but to the authors' knowledge this has not been examined in a national sample. METHODS: The National Cancer Data Base, a hospital-based cancer registry, was used to obtain data regarding incident cancer cases among patients aged 15 years to 39 years who were diagnosed between 2004 and 2010. After all exclusions, a total of 285,448 cases were available for analysis; all AYA cancer sites were included. A retrospective study was conducted to assess the association between insurance status and stage of disease at diagnosis. RESULTS: After adjusting for age, race/ethnicity, facility type, ZIP code-based income and education levels, and US Census region, it was found that among males, uninsured patients were 1.51 times more likely to be diagnosed at a distant stage of disease compared with patients with private insurance (95% confidence interval, 1.46-1.55). Among females, the effect of insurance was stronger, with uninsured patients found to be 1.86 times more likely to be diagnosed at a distant stage (95% confidence interval, 1.79-1.94). The effect of insurance status was substantially stronger for malignancies that are more amenable to early detection (melanoma, thyroid carcinoma, breast carcinoma, genitourinary carcinoma), and substantially weaker for those that are less amenable to early detection (lung carcinoma, adrenocortical carcinoma, Wilms tumor). CONCLUSIONS: In a large national sample of AYA patients with cancer, insurance status was found to be a strong independent risk factor for distant-stage disease at the time of diagnosis.

Trends in new and persistent opioid use in older adults with and without cancer.

BACKGROUND: The impact of ongoing efforts to decrease opioid use on patients with cancer remains undefined. Our objective was to determine trends in new and additional opioid use in patients with and without cancer. METHODS: This retrospective cohort study used data from Surveillance, Epidemiology, and End Results program-Medicare for opioid-naive patients with solid tumor malignancies diagnosed from 2012 through 2017 and a random sample of patients without cancer. We identified 238 470 eligible patients with cancer and further focused on 4 clinical strata: patients without cancer, patients with metastatic cancer, patients with nonmetastatic cancer treated with surgery alone ("surgery alone"), and patients with nonmetastatic cancer treated with surgery plus chemotherapy or radiation therapy ("surgery+"). We identified new, early additional, and long-term additional opioid use and calculated the change in predicted probability of these outcomes from 2012 to 2017. RESULTS: New opioid use was higher in patients with cancer (46.4%) than in those without (6.9%) (P < .001). From 2012 to 2017, the predicted probability of new opioid use was more stable in the cancer strata (relative declines: 0.1% surgery alone; 2.4% surgery+; 8.8% metastatic cancer), than in the noncancer stratum (20.0%) (P < .001 for each cancer to noncancer comparison). Early additional use declined among surgery patients (‒14.9% and ‒17.5% for surgery alone and surgery+, respectively) but was stable among patients with metastatic disease (‒2.8%, P = .50). CONCLUSIONS: Opioid prescribing declined over time at a slower rate in patients with cancer than in patients without cancer. Our study suggests important but tempered effects of the changing opioid climate on patients with cancer.

FDA Approval Summary: Eflornithine for High-Risk Neuroblastoma Following Prior Multiagent, Multimodality Therapy.

On December 13, 2023, the U.S. Food and Drug Administration (FDA) approved eflornithine (IWILFIN, US WorldMeds) to reduce the risk of relapse in adult and pediatric patients with high-risk neuroblastoma who have demonstrated at least a partial response to prior multiagent, multimodality therapy including anti-GD2 immunotherapy. The approval was based on an externally controlled trial (ECT) consisting of a single-arm trial, Study 3(b), compared to an external control derived from a National Cancer Institute (NCI)/Children's Oncology Group (COG)-sponsored clinical trial (Study ANBL0032) and supported by confirmatory evidence. In the protocol-specified primary analysis, the event-free survival (EFS) hazard ratio (HR) was 0.48 (95% confidence interval [CI]: 0.27, 0.85) and overall survival (OS) HR was 0.32 (95% CI: 0.15, 0.70). The most common adverse reactions (≥5%) were hearing loss, otitis media, pyrexia, pneumonia, and diarrhea. Notably, this is the first oncology drug approval which relies on an ECT as the primary clinical data to support substantial evidence of effectiveness. This was made possible by a distinctly high-quality, comparable external control dataset with consistent treatment effect estimations demonstrated in multiple sensitivity and supportive analyses. Eflornithine's manageable safety profile and strong nonclinical and mechanistic data provided further support for the approval, and the evidentiary package was evaluated in the context of high unmet need in a rare, life-threatening cancer.

Perspectives on drug development for the treatment of chronic myeloid leukemia in pregnant patients and patients who are breastfeeding.

Tyrosine kinase inhibitors (TKI) have improved the outcome and life expectancy of patients with chronic myeloid leukemia (CML). Patients are diagnosed with CML at younger ages, and patients treated for CML may become pregnant or choose to breastfeed. The information available to date on the safety of TKIs during pregnancy and lactation and the optimal management of these patients is largely anecdotal, based on personal or small-group experience, and heterogeneous. A panel of interested parties was convened by US Food and Drug Administration (FDA) to analyze the current data and discuss possible solutions. Possible solutions include prospective data collection, in clinical trials and in routine clinical practice, a more uniform and specific data collection, and greater coordination among involved entities. Since patients with cancer are living longer, frequently receiving therapies for extended periods of time (or for life), data on appropriate management of patients through different reproductive phases of life are needed. It is thus time to change our approach for how to study treatment of cancer (including CML) during pregnancy or breastfeeding to develop evidence-based guidelines for safe and effective patient care.

Comparison of cases captured in the national cancer data base with those in population-based central cancer registries.

BACKGROUND: The National Cancer Data Base (NCDB) is a large, geographically diverse hospital-based cancer registry that has been used to study factors related to cancer diagnosis, treatment, and survival. The primary purpose of this study was to compare the case counts and characteristics of patients in NCDB with population-based registries reported in the United States Cancer Statistics (USCS). METHODS: Cancer case counts from NCDB were compared to case counts from USCS to measure NCDB's case coverage, or the percentage of cases captured. Case coverage was examined by a variety of characteristics, including state of residence, race/ethnicity, age, and primary cancer site. RESULTS: The overall NCDB case coverage was 67.4 %, ranging from a high of 88.7 % for Delaware to a low of 27.1 % for Arizona. Case coverage for white, black, and Asian/Pacific Islander cases was high (64.7 % to 67.4 %), but it was much lower for American Indians/Alaskan Natives (32.8 %) and those of Hispanic ethnicity (51.1 %). Among the elderly (aged 65 + years), case coverage is much lower compared to persons younger than 65 (63.0 % and 73.0 %, respectively). Case coverage also varied widely by site, with the highest being cervix (77.9 %) and the lowest being melanoma (50.6 %). CONCLUSIONS: This study highlights the geographic- and site-specific variation in NCDB case coverage, primarily as a result of NCDB facility presence and data collection and processing protocols. These findings illustrate the strengths and limitations of NCDB as a resource for nationwide data on cancer diagnosis, treatment, and survival.

Lifetime Pesticide Use and Monoclonal Gammopathy of Undetermined Significance in a Prospective Cohort of Male Farmers.

BACKGROUND: Farmers have a higher incidence of multiple myeloma, and there is suggestive evidence of an elevated prevalence of its precursor, monoclonal gammopathy of undetermined significance (MGUS), relative to the general population. Pesticide exposures are suspected to play a role; however, the biologic plausibility for associations with multiple myeloma remains unclear. OBJECTIVES: Our objectives were to examine the prevalence of MGUS and evaluate associations with a wide range of pesticides in a large sample of farmers. METHODS: We obtained sera and assessed MGUS among 1,638 male farmers ≥50 years of age in the Agricultural Health Study (AHS), a prospective cohort in Iowa and North Carolina. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed to estimate associations with MGUS for recent use (within the 12 months before phlebotomy) and cumulative intensity-weighted lifetime days of use of specific pesticides. RESULTS: The age-standardized MGUS prevalence was significantly elevated among AHS farmers (7.7%) compared with demographically similar men in the National Health and Nutrition Examination Survey (2.8%) or Olmsted County, Minnesota (3.8%; p<0.001). Recent use of permethrin was associated with MGUS [recent use vs. no recent use, OR=1.82 (95% CI: 1.06, 3.13)], especially among those who had also used it in the past [recent and past use vs. never use, OR=2.49 (95% CI: 1.32, 4.69)]. High intensity-weighted lifetime use of the organochlorine insecticides aldrin and dieldrin was associated with MGUS relative to those who never used either of these pesticides [OR=2.42 (95% CI: 1.29, 4.54); ptrend=0.006]. We also observed a positive association with high lifetime use of petroleum oil/distillates as an herbicide, as well as an inverse association with fonofos use. DISCUSSION: This is the largest investigation of MGUS in farmers and the first to identify an association with MGUS for permethrin, a pyrethroid insecticide previously associated with multiple myeloma. Given the continued widespread use of permethrin in various residential and commercial settings, our findings may have important implications for exposed individuals in the general population. https://doi.org/10.1289/EHP6960.

Pesticide exposure and incident thyroid cancer among male pesticide applicators in agricultural health study.

BACKGROUND: Many pesticides are known to have thyroid-disrupting properties. However, few studies have evaluated the association between specific pesticide ingredients and risk of thyroid cancer. We investigated self-reported pesticide use and incident thyroid cancer in the Agricultural Health Study (AHS), a large cohort of occupationally-exposed male pesticide applicators. METHODS: The AHS is a prospective cohort of licensed pesticide applicators in Iowa and North Carolina. At enrollment (1993-1997) and follow-up (1999-2005), participants reported use of 50 pesticides. We characterized exposure as ever use (44 pesticides with ≥5 exposed cases) and by cumulative intensity-weighted lifetime days (22 pesticides with ≥10 exposed cases), a metric that accounts for factors that influence exposure. We estimated hazard ratios (HR) and 95% confidence intervals (CI) using Cox regression for incident thyroid (n = 85 cases) cancer among male participants using follow-up through 2014/2015. RESULTS: Use of the fungicide metalaxyl (HR = 2.03, CI:1.16-3.52) and the organochlorine insecticide lindane (HR = 1.74, CI:1.06-2.84) was associated with increased risk of thyroid cancer. The herbicide chlorimuron-ethyl was inversely associated with risk when we restricted to papillary thyroid cancer, the most common subtype (HR = 0.52, CI:0.28-0.96). High use of the insecticide carbaryl (>median intensity-weighted days) was inversely associated with thyroid cancer (HR = 0.20, CI:0.08-0.53, ptrend = 0.001). CONCLUSIONS: In this large cohort study, we observed increased risk of thyroid cancer associated with use of metalaxyl and lindane, and an inverse association with carbaryl. More work is needed to understand the potential role of these chemicals in thyroid carcinogenesis.

Occupational Pesticide Use and Risk of Renal Cell Carcinoma in the Agricultural Health Study.

BACKGROUND: Agricultural work and occupational pesticide use have been associated with increased risk of renal cell carcinoma (RCC), the most common form of kidney cancer. However, few prospective studies have investigated links to specific pesticides. OBJECTIVE: We evaluated the lifetime use of individual pesticides and the incidence of RCC. METHODS: We evaluated the associations between intensity-weighted lifetime days (IWDs) of 38 pesticides and incident RCC in the Agricultural Health Study, a prospective cohort of licensed pesticide applicators in Iowa and North Carolina. Among 55,873 applicators, 308 cases were diagnosed between enrollment (1993-1997) and the end of follow-up (2014-2015). We estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) using Poisson regression, controlling for potential confounding factors, with lagged and unlagged pesticide exposures. RESULTS: There was a statistically significant increased risk of RCC among the highest users of 2,4,5-T compared with never users [unlagged RRIWD Tertile 3=2.92 (95% CI: 1.65, 5.17; ptrend=0.001)], with similar risk estimates for lagged exposure [20-y lag RRIWD Tertile 3=3.37 (95% CI: 1.83, 6.22; ptrend=0.001)]. In 20-y lagged analyses, we also found exposure-response associations with chlorpyrifos [RRIWD Quartile 4=1.68 (95% CI: 1.05, 2.70; ptrend=0.01)], chlordane [RRIWD Tertile 3=2.06 (95% CI: 1.10, 3.87; ptrend=0.02)], atrazine [RRIWD Quartile 4=1.43 (95% CI: 1.00, 2.03; ptrend=0.02)], cyanazine [RRIWD Quartile 4=1.61 (95% CI: 1.03, 2.50; ptrend=0.02)], and paraquat [RRIWD>Median=1.95 (95% CI: 1.03, 3.70; ptrend=0.04)]. CONCLUSIONS: This is, to our knowledge, the first prospective study to evaluate RCC risk in relation to various pesticides. We found evidence of associations with RCC for four herbicides (2,4,5-T, atrazine, cyanazine, and paraquat) and two insecticides (chlorpyrifos and chlordane). Our findings provide insights into specific chemicals that may influence RCC risk among pesticide applicators. Confirmation of these findings and investigations of the biologic plausibility and potential mechanisms underlying the observed associations are warranted. https://doi.org/10.1289/EHP6334.