Systematic literature review of the epidemiology of glyphosate and neurological outcomes.

PURPOSE: Human health risk assessments of glyphosate have focused on animal toxicology data for determining neurotoxic potential. Human epidemiological studies have not yet been systematically reviewed for glyphosate neurotoxicity hazard identification. The objective of this systematic literature review was to summarize the available epidemiology of glyphosate exposure and neurological outcomes in humans. METHODS: As of December 2021, 25 eligible epidemiological studies of glyphosate exposure and neurological endpoints were identified and assessed for five quality dimensions using guidance from the U.S. Environmental Protection Agency. Studies that assessed personal use of glyphosate were prioritized, whereas those assessing indirect exposure (other than personal use) were rated as low quality, since biomonitoring data indicate that indirect metrics of glyphosate exposure almost always equate to non-detectable glyphosate doses. RESULTS: Overall, the scientific evidence on glyphosate and neurotoxicity in humans is sparse and methodologically limited, based on nine included epidemiological studies of neurodegenerative outcomes (two high quality), five studies of neurobehavioral outcomes (two high quality), six studies of neurodevelopmental outcomes (none high quality), and five studies of other and mixed neurological outcomes (one high quality). The five high-quality studies showed no association between glyphosate use and risk of depression, Parkinson disease, or peripheral nerve conduction velocity. Results were mixed among the eight moderate-quality studies, which did not demonstrate consistent associations with any neurological endpoints or categories. Low-quality studies were considered uninformative about possible neurotoxic effects due primarily to questionable assessments of indirect exposure. CONCLUSIONS: No association has been demonstrated between glyphosate and any neurological outcomes in humans. To move the state of science forward, epidemiological studies should focus on scenarios involving direct and frequent use of glyphosate while collecting information on validated health outcomes, concomitant agricultural exposures, and relevant personal characteristics.

Glyphosate epidemiology expert panel review: a weight of evidence systematic review of the relationship between glyphosate exposure and non-Hodgkin's lymphoma or multiple myeloma.

We conducted a systematic review of the epidemiologic literature for glyphosate focusing on non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM) - two cancers that were the focus of a recent review by an International Agency for Research on Cancer Working Group. Our approach was consistent with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews. We evaluated each relevant study according to a priori criteria for study quality: adequacy of study size, likelihood of confounding, potential for other biases and adequacy of the statistical analyses. Our evaluation included seven unique studies for NHL and four for MM, all but one of which were case control studies for each cancer. For NHL, the case-control studies were all limited by the potential for recall bias and the lack of adequate multivariate adjustment for multiple pesticide and other farming exposures. Only the Agricultural Health (cohort) Study met our a priori quality standards and this study found no evidence of an association between glyphosate and NHL. For MM, the case control studies shared the same limitations as noted for the NHL case-control studies and, in aggregate, the data were too sparse to enable an informed causal judgment. Overall, our review did not find support in the epidemiologic literature for a causal association between glyphosate and NHL or MM.

A review of the carcinogenic potential of glyphosate by four independent expert panels and comparison to the IARC assessment.

The International Agency for Research on Cancer (IARC) published a monograph in 2015 concluding that glyphosate is "probably carcinogenic to humans" (Group 2A) based on limited evidence in humans and sufficient evidence in experimental animals. It was also concluded that there was strong evidence of genotoxicity and oxidative stress. Four Expert Panels have been convened for the purpose of conducting a detailed critique of the evidence in light of IARC's assessment and to review all relevant information pertaining to glyphosate exposure, animal carcinogenicity, genotoxicity, and epidemiologic studies. Two of the Panels (animal bioassay and genetic toxicology) also provided a critique of the IARC position with respect to conclusions made in these areas. The incidences of neoplasms in the animal bioassays were found not to be associated with glyphosate exposure on the basis that they lacked statistical strength, were inconsistent across studies, lacked dose-response relationships, were not associated with preneoplasia, and/or were not plausible from a mechanistic perspective. The overall weight of evidence from the genetic toxicology data supports a conclusion that glyphosate (including GBFs and AMPA) does not pose a genotoxic hazard and therefore, should not be considered support for the classification of glyphosate as a genotoxic carcinogen. The assessment of the epidemiological data found that the data do not support a causal relationship between glyphosate exposure and non-Hodgkin's lymphoma while the data were judged to be too sparse to assess a potential relationship between glyphosate exposure and multiple myeloma. As a result, following the review of the totality of the evidence, the Panels concluded that the data do not support IARC's conclusion that glyphosate is a "probable human carcinogen" and, consistent with previous regulatory assessments, further concluded that glyphosate is unlikely to pose a carcinogenic risk to humans.

Evaluation of an ICD-10 algorithm to detect osteonecrosis of the jaw among cancer patients in the Danish National Registry of Patients.

PURPOSE: This study aimed to validate a predefined algorithm for osteonecrosis of the jaw (ONJ) among cancer patients in the Danish National Registry of Patients and to assess the nature of clinical information recorded in medical charts of ONJ patients. METHODS: We identified potential ONJ cases recorded in 2005-2010 among cancer patients at the hospital Departments of Oral and Maxillofacial Surgery (DOMS) in three Danish regions, using a set of codes from the International Classification of Diseases, 10th revision (ICD-10). We abstracted DOMS charts of the potential cases, had the ONJ status adjudicated by an expert ONJ adjudication committee (ONJAC), and computed positive predictive values. For patients with ONJAC-confirmed ONJ, we abstracted the charts for information on ONJ clinical course. Sensitivity of the algorithm was computed using a separate sample of 101 known ONJ cases accrued in 2005-2011. RESULTS: We identified 212 potential ONJ cases, of which 197 (93%) had charts available for abstraction. Eighty-three potential cases were confirmed by ONJAC, with a positive predictive value of 42% (95% confidence interval [CI] 35%-49%). DOMS charts of these 83 cases contained complete information on ONJ clinical course. Information about antiresorptive treatment was recorded for 84% of the patients. Among the 101 known ONJ cases, 74 had at least one prespecified ICD-10 code recorded in the Danish National Registry of Patients within ±90 days of the ONJ diagnosis (sensitivity 73%; 95%CI [64%-81%]). CONCLUSIONS: The predefined algorithm is not adequate for monitoring ONJ in pharmacovigilance studies. Additional case-finding approaches, coupled with adjudication, are necessary to estimate ONJ incidence accurately.

Epidemiologic studies of glyphosate and non-Hodgkin's lymphoma: A review with consideration of exposure frequency, systemic dose, and study quality.

I reviewed the epidemiologic literature for glyphosate and non-Hodgkin's lymphoma (NHL) in the context of the frequency of exposure in each epidemiologic study, systemic dose from biomonitoring studies of applicators, and aspects of study quality. Nine studies were identified, 7 case control and 2 cohort, by a literature search and a review of reference lists from published studies and recent regulatory evaluations. All but one study involved exposure scenarios that were so infrequent that they are not credible for cancer causation. Most studies failed to address potential confounding from other pesticides. Only one study - the US Agricultural Health Study (AHS) - included individuals with relatively frequent exposure to glyphosate and involved comprehensive statistical analyses to address potential confounding by personal factors and other pesticide exposures. The AHS did not find an association between glyphosate and NHL, even among the most frequently exposed participants (≥ 109 days of use) (RR = 0.80, 95% CI 0.60, 1.06). These findings are consistent with observations that glyphosate systemic doses from agricultural applications are many orders of magnitude less than daily lifetime doses considered by regulatory agencies to impart no excess risk of deleterious health effects, even for sensitive subpopulations.

Timing of androgen deprivation therapy use and fracture risk among elderly men with prostate cancer in the United States.

PURPOSE: Fractures are a recognized consequence of androgen deprivation therapy (ADT); however, less is known about the incidence of fracture in relation to the timing of ADT use or the impact of fracture on mortality in men with prostate cancer. METHODS: Using data from the Surveillance, Epidemiology, and End Results-Medicare linked database, we estimated adjusted hazard ratios (aHRs) using time-dependent Cox regression for fracture incidence related to the recency of exposure and dose among prostate cancer patients on gonadotropin-releasing hormone (GnRH) agonists, as well as mortality associated with fractures. RESULTS: In our cohort of 80 844 patients, ADT was associated with an increased rate of fracture in both non-metastatic patients (aHR = 1.34; 95% confidence interval [CI] = 1.29-1.39) and metastatic patients (aHR = 1.51; 95%CI = 1.36-1.67). Fracture rates increased with increasing cumulative GnRH dose but decreased with increasing number of months since last use in each dose category. The mortality rate doubled for men experiencing a fracture after their diagnosis compared with that for men who did not experience a fracture (aHR = 2.05; 95%CI = 1.98-2.12). CONCLUSIONS: ADT in elderly men with prostate cancer increased the incidence of fractures, and the effect appears to diminish with increasing time since the last dose of a GnRH agonist. Experiencing a fracture after the diagnosis of prostate cancer was associated with decreased survival.

Impact of Centers for Medicare & Medicaid Services national coverage determination on erythropoiesis-stimulating agent and transfusion use in chemotherapy-treated cancer patients.

PURPOSE: In July 2007, the Centers for Medicare & Medicaid Services released a national coverage determination (NCD) for erythropoiesis-stimulating agent (ESA) use in cancer patients, mandating payment restrictions likely to reduce ESA use and possibly increase red blood cell transfusions. We aimed to quantify ESA and transfusion use pre-NCD and post-NCD. METHODS: Medicare 5% sample data, 2005-2007, were used. Patients were 66 years or older, had lung, breast, or colorectal cancer or lymphomas, and initiated chemotherapy in pre-NCD and post-NCD periods (September-November 2006, September-November 2007). ESA use and transfusions were identified from claims. Differences in proportions of patients using ESAs and receiving transfusions pre-NCD and post-NCD were evaluated using logistic regression; differences in transfusion event rates were evaluated using a Poisson model. RESULTS: The pre-NCD cohort included 1897 patients and the post-NCD cohort 1877. In the pre-NCD cohort, 31% of patients had lung cancer, 29% lymphoma, 20% colorectal cancer, and 20% breast cancer; distribution was similar in the post-NCD cohort. Overall, ESA use decreased from 35.0% pre-NCD to 15.2% post-NCD. Transfusion use increased from 9.3% to 10.4%, and transfusion event rates from 19.0 to 21.8 per 100 patient-quarters. Results adjusted for baseline characteristics and comorbid conditions were similar. ESA use reduction achieved statistical significance; transfusion use and rate increases did not. CONCLUSIONS: ESA use decreased sharply post-NCD. This was accompanied by an estimated 1.1% (95% confidence interval -0.8% to 3.0%) absolute increase in transfusion use.

Registry-based cohort study of alpha-1 antitrypsin deficiency prevalence, incidence and mortality in Denmark 2000-2018.

OBJECTIVE: To estimate the prevalence of diagnosed alpha-1 antitrypsin deficiency (dAATD) in Denmark as of 31 December 2018, and dAATD incidence and mortality from 1 January 2000 to 31 December 2018. STUDY DESIGN AND SETTING: We used the Danish National Patient Registry to identify patients with dAATD based on the International Classification of Diseases, 10th Revision (ICD-10) code E88.0A and the Danish Civil Registration System (CRS) for population counts and vital status. We estimated dAATD prevalence, incidence and mortality. We compared mortality among patients with dAATD and an age-matched and sex-matched cohort extracted from the Danish CRS. We conducted a sensitivity analysis to examine whether coding changes during 2000-2018, from a general to a more specific ICD-10 code for AATD, and left truncation affected results appreciably. RESULTS: The prevalence of dAATD was 12.9 (95% CI 11.9 to 13.8) per 100 000 persons. The age distribution was bimodal, with peaks at ages ≤12 and ≥45 years. The incidence rate per 100 000 person-years was 0.90 (95% CI 0.85 to 0.96), again with a bimodal age distribution. Mortality was higher for patients with dAATD than for the general population (mortality rate ratio (mRR) 4.7, 95% CI 4.1 to 5.3), especially for children (mRR 33.8, 95% CI 6.8 to 167.4). The sensitivity analysis indicated that dAATD prevalence might have been as high as 19.7 per 100 000 persons due to less specific ICD-10 coding for AATD early in the study period or 21.4 per 100 000 persons correcting for left truncation. CONCLUSION: Diagnosed AATD was associated with increased mortality, especially for children. The finding for children was based on few deaths and had very wide 95% CIs.

Prevalence of narcolepsy and other sleep disorders and frequency of diagnostic tests from 2013-2016 in insured patients actively seeking care.

STUDY OBJECTIVES: The primary objective was to describe trends in the 2-year limited duration prevalence of narcolepsy from 2013-2016 in a large insured population with claims activity. Secondary objectives were to assess the prevalence of other sleep disorders and the frequency of diagnostic sleep testing. METHODS: Nationwide medical/prescription claims (Symphony Health) were analyzed to estimate the annual prevalence per 100,000 persons of narcolepsy and other sleep disorders (obstructive sleep apnea, idiopathic hypersomnia, rapid eye movement sleep behavior disorder, periodic limb movement disorder) and the frequency of diagnostic sleep testing. Prevalence was adjusted to the age/sex distribution of the 2016 US census estimates. RESULTS: The prevalence of narcolepsy per 100,000 persons increased 14% from 38.9 in 2013 to 44.3 in 2016. Obstructive sleep apnea prevalence increased 41% over the study period from 2,429 to 3,420 per 100,000. Large increases in prevalence were also seen for idiopathic hypersomnia (32%), periodic limb movement disorder (30%), and rapid eye movement sleep behavior disorder (64%). For each sleep disorder, prevalence was higher for those with commercial insurance versus Medicare/Medicaid, and markedly lower prevalence was observed for the Northeast compared with the Midwest, South, and Western US regions. The frequency of multiple sleep latency/maintenance of wakefulness testing declined by 20%, and polysomnography declined by 15%. Conversely, home sleep apnea testing increased by 117%. CONCLUSIONS: The prevalence of narcolepsy, obstructive sleep apnea, and the other sleep disorders increased appreciably over the 2013-2016 period. It remains to be determined whether the trends seen in our analyses are due to increased incidence or increased awareness of these conditions.

Evolving statistical methods to facilitate evaluation of the causal association between erythropoiesis-stimulating agent dose and mortality in nonexperimental research: strengths and limitations.

Findings from randomized controlled trials examining the efficacy of therapy with erythropoiesis-stimulating agents (ESAs) to normalize hemoglobin levels in patients with chronic kidney disease or kidney failure have raised questions regarding the safety of this class of drugs. However, no trial to date has specifically assessed the safety of ESA-dosing algorithms used to achieve the lower hemoglobin targets typically using in clinical practice. Although a wealth of nonexperimental data is available for dialysis patients, analyses based on these data are more susceptible to confounding bias than randomized controlled trials. Conducting valid pharmacoepidemiologic studies of drug effects in hemodialysis patients is complicated by the extent of their comorbidities, frequent hospitalizations, various concomitant medications, and an exceedingly high mortality rate. The need for greater ESA doses for the treatment of anemia in sicker patients potentially and plausibly generates confounding by indication, the control of which is complicated by the presence of time-dependent confounding. Here, we describe sources of bias in nonexperimental studies of ESA therapy in hemodialysis patients and critically appraise analytical methods that may help minimize bias in such studies.

Chronic immune thrombocytopenia in Denmark, Sweden and Norway: The Nordic Country Patient Registry for Romiplostim.

BACKGROUND: Population-based cohorts of immune thrombocytopenia (ITP) are useful for understanding occurrence, clinical characteristics and long-term clinical course. This paper describes the content of the Nordic Country Patient Registry for Romiplostim (NCPRR) and provides prevalence and incidence estimates of chronic ITP (cITP). METHODS: The NCPRR, a cohort study established in 2009, includes all adult (≥ 18 years) patients in Denmark, Sweden and Norway with cITP (defined as ITP lasting > 12 months and platelet count < 100 × 109/L), combining data from national health registries and medical records. The NCPRR currently includes prevalent cITP patients diagnosed before 2009 and incident cITP patients diagnosed during 2009-2016. The registry obtains clinical information for cITP patients, including comorbidities, treatments, laboratory values, and complete follow-up for various outcomes. FINDINGS: The NCPRR currently includes 3831 patients with cITP (1258 prevalent; 2573 incident). In 2009, the prevalence of registered cITP was 10 · 0/100,000 (95%CI:9 · 1-11 · 0) adult persons in Denmark and 10 · 7/100,000 (95% CI: 9 · 9-11 · 4) adults in Sweden. During 2009-2016, the incidence rates of cITP per 100,000 person-years were 2 · 8 (95%CI: 2 · 6-3 · 0), 1 · 8 (95%CI: 1 · 7-1 · 9) and 2 · 1 (95%CI: 1 · 9-2 · 2) in Denmark, Sweden and Norway, respectively. Fifty-eight percent of cITP patients were women. At NCPRR inclusion, 30.2% were aged ≥ 70 years, 23% had a platelet count < 50 × 109/L, 17.4% were splenectomized, 41% had prior ITP therapy, and 8.6% had severe comorbidity. INTERPRETATION: The NCPRR provides population-based data on the epidemiology and characteristics of almost 4000 cITP patients and is a valuable resource for research. FUNDING: This study was partly funded by a research grant from Amgen to Aarhus University.

Exploring relative mortality and epoetin alfa dose among hemodialysis patients.

BACKGROUND: Confounding-by-indication is a bias in nonexperimental studies that occurs when outcomes are compared for treated and untreated patients and the treatment or medication dose is related to predictors of the outcome. Two recent publications reported that greater epoetin alfa (EPO) doses were associated with increased mortality rates. We assessed whether confounding-by-indication might account for these results. STUDY DESIGN: We used a retrospective cohort study design. SETTING & PARTICIPANTS: Hemodialysis patients were randomly selected from a large dialysis organization from July 2000 to June 2002 and were required to have completed a 9-month baseline period. PREDICTOR: EPO dose assessed during months 7 to 9 of the baseline period and monthly throughout the follow-up period. Hemoglobin (Hb) was assessed as average value during months 4 to 6 of the baseline period and monthly throughout the follow-up period. All other covariates were assessed during months 1 to 6 of the baseline period. OUTCOME: All-cause mortality during the 1 year of follow-up. Baseline Cox models were fitted with log EPO and Hb with and without adjustment for baseline patient characteristics. Time-dependent models were fitted with time-varying log EPO and Hb and, separately, lagged log EPO and Hb, with adjustment for baseline patient characteristics. RESULTS: 22,955 patients met our inclusion criteria. In the unadjusted model, we observed increased mortality risk with increasing EPO dose (hazard ratio [HR], 1.31 per log unit increase; 95% confidence interval [CI], 1.26 to 1.36). Adjustment for baseline patient characteristics resulted in an appreciably decreased HR (HR, 1.21; 95% CI, 1.15 to 1.28). In the lagged time-dependent analyses, estimates ranged from HR of 0.93 (95% CI, 0.92 to 0.95) to HR of 1.01 (95% CI, 0.99 to 1.03) for the 1- and 2-month lagged models, respectively. LIMITATIONS: This analysis was limited to prevalent hemodialysis patients, and inhospital EPO dosing information was unavailable. CONCLUSIONS: The observed mortality risk estimates associated with EPO dose in nonexperimental studies in dialysis patients may be highly sensitive to the analytic method used. This highlights the complexity of evaluating the association between EPO dose, Hb level, and mortality in these studies.

Biomonitoring of 2,4-dichlorophenoxyacetic acid exposure and dose in farm families.

OBJECTIVE: We estimated 2,4-dichlorophenoxyacetic acid (2,4-D) exposure and systemic dose in farm family members following an application of 2,4-D on their farm. METHODS: Farm families were recruited from licensed applicators in Minnesota and South Carolina. Eligible family members collected all urine during five 24-hr intervals, 1 day before through 3 days after an application of 2,4-D. Exposure profiles were characterized with 24-hr urine 2,4-D concentrations, which then were related to potential predictors of exposure. Systemic dose was estimated using the urine collections from the application day through the third day after application. RESULTS: Median urine 2,4-D concentrations at baseline and day after application were 2.1 and 73.1 microg/L for applicators, below the limit of detection, and 1.2 microg/L for spouses, and 1.5 and 2.9 microg/L for children. The younger children (4-11 years of age) had higher median post-application concentrations than the older children (> or = 12 years of age) (6.5 vs. 1.9 microg/L). The geometric mean systemic doses (micrograms per kilogram body weight) were 2.46 (applicators), 0.8 (spouses), 0.22 (all children), 0.32 (children 4-11 years of age), and 0.12 (children > or = 12 years of age). Exposure to the spouses and children was primarily determined by direct contact with the application process and the number of acres treated. Multivariate models identified glove use, repairing equipment, and number of acres treated as predictors of exposure in the applicators. CONCLUSIONS: We observed considerable heterogeneity of 2,4-D exposure among farm family members, primarily attributable to level of contact with the application process. Awareness of this variability and the actual magnitude of exposures are important for developing exposure and risk characterizations in 2,4-D-exposed agricultural populations.

Tenosynovial Giant Cell Tumor: Incidence, Prevalence, Patient Characteristics, and Recurrence. A Registry-based Cohort Study in Denmark.

OBJECTIVE: Tenosynovial giant cell tumor (TGCT) is a rare benign proliferative and inflammatory disease arising from synovia of joints, bursae, or tendon sheaths. We aimed to estimate incidence rate and prevalence of TGCT in Denmark, to describe patient characteristics and treatment modalities among patients with TGCT, and to estimate risk of TGCT recurrence. METHODS: Using registry data on pathology examinations and inpatient and outpatient hospital diagnoses, we identified adult patients with diagnoses of diffuse TGCT (D-TGCT) or localized TGCT (L-TGCT) between 1997 and 2012, followed through 2012. We described patients' characteristics, treatment modalities, and recurrence. RESULTS: We identified 2087 patients with L-TGCT and 574 patients with D-TGCT. Their incidence rates per million person-years were 30.3 (95% CI 29.1-31.7) and 8.4 (95% CI 7.7-9.1), respectively. At the end of 2012, prevalence per 100,000 persons was 44.3 (95% CI 42.4-46.3) for L-TGCT and 11.5 (95% CI 10.6-12.6) for D-TGCT. Women made up 61% of the patients with L-TGCT and 51% of the patients with D-TGCT. Median age at diagnosis was 47 years. Ten-year risk of recurrence was 9.8% (95% CI 8.4-11.3%) after L-TGCT and 19.1% (95% CI 15.7-22.7%) after D-TGCT. CONCLUSION: This study contributes evidence about epidemiology of TGCT based on routinely collected population-based data gathered in a setting of universal equal access to healthcare and complete followup.

Osteonecrosis of the jaw and survival of patients with cancer: a nationwide cohort study in Denmark.

Osteonecrosis of the jaw (ONJ) is an adverse effect of bone-targeted therapies, which are used to prevent symptomatic skeletal events following bone malignancy. We examined the association between ONJ and survival among cancer patients treated with bone-targeted agents. Using nationwide registries and databases in Denmark, we identified 184 cancer patients with incident ONJ between 2010 and 2015, and a comparison cohort of 1067 cancer patients without ONJ and with a history of hospital-administered treatment with bisphosphonates or denosumab initiating from cancer diagnosis. At the date of confirmed ONJ diagnosis, the comparison cohort was matched to the ONJ patients on age, cancer site, year of cancer diagnosis, and stage at diagnosis. The patients were followed up for survival until emigration or 15 June 2016. We computed overall survival and estimated mortality rate ratios adjusted for sex, and for the presence of distant metastases and other comorbidity at start of follow-up. A match was found for 149 of the 184 ONJ patients. The 1- and 3-year survival among all 184 cancer patients with ONJ was 70% (95% confidence interval [CI]: 63%-76%) and 42% (95% CI: 34%-51%), respectively. Among the matched patients, ONJ was associated with an adjusted mortality rate ratio of 1.31 (95% CI: 1.01-1.71). ONJ was associated with reduced survival among cancer patients treated with bone-targeted agents. ONJ may be a marker of advanced disease or of survival-related lifestyle characteristics.

Site of metastasis and breast cancer mortality: a Danish nationwide registry-based cohort study.

Survival among patients with metastatic breast cancer may vary according to the site of metastasis and receptor status. We used Danish nationwide medical registries to establish a cohort of patients with metastatic breast cancer (870 with de novo metastatic disease and 3518 with recurrent disease with distant metastasis) diagnosed during 1997-2011. We examined 1-year and >1 to 5-year mortality associated with first site of metastasis and receptor expression status of the primary tumor. Cox proportional regression was used to compute confounder-adjusted mortality rate ratios (MRRs) associated with site of metastasis, stratified by receptor status. Overall 1-year and >1 to 5-year mortality risks were 36 and 69 %, respectively. Risk of death within 1 year was highest for brain-only (62 %) and liver-only (43 %) involvement and nearly the same for patients with lung-only (32 %), bone-only (32 %) involvement, and other/combination of sites (34 %). Using bone-only metastasis as reference, women with brain-only metastasis had more than two-fold increased risk of dying. The adjusted MRR for women with liver-only metastasis also was increased, though less pronounced. Patients with lung-only [adjusted MRR 0.9 (95 % confidence interval (CI) 0.8, 1.1)] or other metastases [adjusted MRR 1.0 (95 % CI 0.9, 1.2)] had similar mortality as patients with bone-only metastasis. Positive hormonal receptor status was a favorable prognostic factor. Metastatic breast cancer has a serious prognosis. Patients with brain-only metastasis had the highest mortality. Positive hormonal receptor status on the primary tumor was a favorable prognostic factor for all metastatic sites.

Biomonitoring of exposure in farmworker studies.

Although biomonitoring has been used in many occupational and environmental health and exposure studies, we are only beginning to understand the complexities and uncertainties involved with the biomonitoring process--from study design, to sample collection, to chemical analysis--and with interpreting the resulting data. We present an overview of concepts that should be considered when using biomonitoring or biomonitoring data, assess the current status of biomonitoring, and detail potential advancements in the field that may improve our ability to both collect and interpret biomonitoring data. We discuss issues such as the appropriateness of biomonitoring for a given study, the sampling time frame, temporal variability in biological measurements to nonpersistent chemicals, and the complex issues surrounding data interpretation. In addition, we provide recommendations to improve the utility of biomonitoring in farmworker studies.

Challenges in translating endpoints from trials to observational cohort studies in oncology.

Clinical trials are considered the gold standard for examining drug efficacy and for approval of new drugs. Medical databases and population surveillance registries are valuable resources for post-approval observational research, which are increasingly used in studies of benefits and risk of new cancer drugs. Here, we address the challenges in translating endpoints from oncology trials to observational studies. Registry-based cohort studies can investigate real-world safety issues - including previously unrecognized concerns - by examining rare endpoints or multiple endpoints at once. In contrast to clinical trials, observational cohort studies typically do not exclude real-world patients from clinical practice, such as old and frail patients with comorbidity. The observational cohort study complements the clinical trial by examining the effectiveness of interventions applied in clinical practice and by providing evidence on long-term clinical outcomes, which are often not feasible to study in a clinical trial. Various endpoints can be included in clinical trials, such as hard endpoints, soft endpoints, surrogate endpoints, and patient-reported endpoints. Each endpoint has it strengths and limitations for use in research studies. Endpoints used in oncology trials are often not applicable in observational cohort studies which are limited by the setting of standard clinical practice and by non-standardized endpoint determination. Observational studies can be more helpful moving research forward if they restrict focus to appropriate and valid endpoints.

Prognostic impact of tumor MET expression among patients with stage IV gastric cancer: a Danish cohort study.

PURPOSE: We aimed to investigate the prevalence and prognostic impact of tumor mesenchymal epithelial transition factor (MET) expression in stage IV gastric cancers in a real-world clinical setting because existing evidence is sparse. METHODS: The study included archived cancer specimens from 103 stage IV gastric cancer patients (2003-2010). We analyzed MET-protein expression by immunohistochemistry (MET-positive if ≥25% of tumor cells showed MET expression). We calculated overall survival using the Kaplan-Meier method and hazard ratios comparing mortality among MET-positive and MET-negative patients using Cox regression adjusted for age, gender, and comorbidity. RESULTS: We found that 62.1% (95% confidence interval, 52.0-71.5) of patients had MET-positive tumors. Median survival was lower among patients with MET-positive tumors (3.5 months) than among patients with MET-negative tumors (9.6 months), corresponding to an adjusted hazard ratio of 2.2 (95% confidence interval, 1.3-3.7). CONCLUSIONS: Tumor MET expression is prevalent and has substantial prognostic impact in stage IV gastric cancer patients.