Predicting Hyperglycemia Among Patients Receiving Alpelisib Plus Fulvestrant for Metastatic Breast Cancer.

BACKGROUND: Hyperglycemia is recognized as a common adverse event for patients receiving alpelisib but has been little studied outside of clinical trials. We report the frequency of alpelisib-associated hyperglycemia in a real-world setting and evaluate proposed risk factors. PATIENTS AND METHODS: We retrospectively identified patients with PIK3CA-mutated, hormone receptor-positive, metastatic breast cancer who initiated treatment with alpelisib plus fulvestrant between August 2019 and December 2021. Ordinal logistic regression evaluated 5 characteristics (diabetes, prediabetes, body mass index [BMI], age, and Asian ancestry) as independent risk factors for ALP-associated hyperglycemia grades 2-4. Risk of error from multiple hypothesis testing was controlled using the false discovery rate method. RESULTS: The study included n = 92 subjects, all but 1 female, mean age 59.9 (+11.9) years with 50% non-Hispanic White, 15% Hispanic/Latino, 13% Asian, 9% African/Black, and 13% other/unknown. In total 34% of patients had diabetes, 10% had pre-diabetes, and 56% had normoglycemia. Thirty-six percent were obese, 32% were overweight, 25% were normal weight, and 7% were lean. Frequency of grades 1-4 hyperglycemia in current subjects (64.1%) was similar to hyperglycemia reported in the SOLAR-1 trial (63.7%). Our subjects' risk of grades 2-4 hyperglycemia was independently increased by pre-existing diabetes (Odds ratio 3.75, 95% CI, 1.40-10.01), pre-diabetes (6.22, 1.12-34.47), Asian ancestry (7.10, 1.75-28.84), and each unit of BMI above 20 (1.17, 1.07-1.28). CONCLUSION: While receiving alpelisib, patients of Asian ancestry, as well as patients with pre-existing hyperglycemia and/or BMI above 20, should be closely monitored for hyperglycemia. The mechanism underlying the current association of alpelisib-associated hyperglycemia with Asian ancestry is independent of BMI and merits further study. The high incidence of hyperglycemia resulted in a change in practice to include consultation with a diabetes nurse educator or endocrinologist at the start of alpelisib.

Germline mutations and age at onset of lung adenocarcinoma.

BACKGROUND: To identify additional at-risk groups for lung cancer screening, which targets persons with a long history of smoking and thereby misses younger or nonsmoking cases, the authors evaluated germline pathogenic variants (PVs) in patients with lung adenocarcinoma for an association with an accelerated onset. METHODS: The authors assembled a retrospective cohort (1999-2018) of oncogenetic clinic patients with lung adenocarcinoma. Eligibility required a family history of cancer, data on smoking, and a germline biospecimen to screen via a multigene panel. Germline PVs (TP53/EGFR, BRCA2, other Fanconi anemia [FA] pathway genes, and non-FA DNA repair genes) were interrogated for associations with the age at diagnosis via an accelerated failure time model. RESULTS: Subjects (n = 187; age, 28-89 years; female, 72.7%; Hispanic, 11.8%) included smokers (minimum of 5 pack-years; n = 65) and nonsmokers (lighter ever smokers [n = 18] and never smokers [n = 104]). Overall, 26.7% of the subjects carried 1 to 2 germline PVs: TP53 (n = 5), EGFR (n = 2), BRCA2 (n = 6), another FA gene (n = 11), or another DNA repair gene (n = 28). After adjustment for smoking, sex, and ethnicity, the diagnosis of lung adenocarcinoma was accelerated 12.2 years (95% confidence interval [CI], 2.5-20.6 years) by BRCA2 PVs, 9.0 years (95% CI, 0.5-16.5 years) by TP53/EGFR PVs, and 6.1 years (95% CI, -1.0 to 12.6 years) by PVs in other FA genes. PVs in other DNA repair genes showed no association. Germline associations did not vary by smoking. CONCLUSIONS: Among lung adenocarcinoma cases, germline PVs (TP53, EGFR, BRCA2, and possibly other FA genes) may be associated with an earlier onset. With further study, the criteria for lung cancer screening may need to include carriers of high-risk PVs, and findings could influence precision therapy and reduce lung cancer mortality by earlier stage diagnosis.

A copula model for joint modeling of longitudinal and time-invariant mixed outcomes.

Motivated by a preclinical study in a mouse model of breast cancer, we suggest a joint modeling framework for outcomes of mixed type and measurement structures (longitudinal versus single time/time-invariant). We present an approach based on the time-varying copula models, which is used to jointly model longitudinal outcomes of mixed types via a time-varying copula, and extend the scope of these models to handle outcomes with mixed measurement structures. Our framework allows the parameters corresponding to the longitudinal outcome to be time varying and thereby enabling researchers to investigate how the response-predictor relationships change with time. We investigate the finite sample performance of this new approach via a Monte Carlo simulation study and illustrate its usefulness by an empirical analysis of the motivating preclinical study, comparing the effect of various treatments on tumor volume (longitudinal continuous response) and the number of days until tumor volume triples (time-invariant count response). Through the real-life application and the simulation study, we demonstrate that, compared with marginal modeling, the joint modeling framework offers more precision in the estimation of model parameters.

Objective physical and mental markers of self-reported fatigue in women undergoing (neo)adjuvant chemotherapy for early-stage breast cancer.

BACKGROUND: Objective, treatment-independent markers of cancer-related fatigue are needed to advance clinical trials. In the current study, the authors evaluated physical, neurocognitive, and serologic markers for correlation with self-reported fatigue before and after (neo)adjuvant chemotherapy for patients with early-stage breast cancer. METHODS: Women with AJCC TNM Stage I-III breast cancer consented to assessment before and after the completion of 4 cycles of dose-dense doxorubicin and cyclophosphamide. Assessment included self-reported fatigue (using the Brief Fatigue Inventory), depression (using the Center for Epidemiologic Studies-Depression Scale [CES-D]), Pittsburgh Sleep Quality Index, and 28 objective measures (grip strength in dominant and nondominant hands, 6-minute walk, daily total energy expenditure, 14 neurocognitive tests, and 10 serologic markers). Generalized linear regression models of fatigue were constructed (1 model per marker), and adjusted for depression, timing before/after chemotherapy, menopausal status, obesity, and educational level. P values were adjusted to control the False Discovery Rate. RESULTS: Of 28 subjects, 3 withdrew without completing baseline assessments. Prechemotherapy and postchemotherapy data were available for the evaluation of physical measures (25 subjects aged 50.6 ± 9.5 years), neurocognitive tests (22 subjects), and serologic markers (10 subjects). On covariate-adjusted analysis, interleukin (IL)-12 was found to be associated with fatigue at both assessments (P<.01). Serum eotaxin (P < .01), IL-1RA (P < .01), monocyte chemoattractant protein 1 (MCP-1) (P<.01), and performance on 2 neurocognitive (Trail Making) tests (P<.01 and P = .02, respectively) were found to be inversely associated with fatigue before chemotherapy but not afterward, whereas daily energy expenditure, serum MCP-1, and serum macrophage inflammatory protein 1a (MIP-1a) were found to be associated with fatigue after receipt of chemotherapy but not before (P<.01 for each). The association between energy expenditure and fatigue was detectable only if an actively athletic subject with outlier values of energy expenditure was excluded. CONCLUSIONS: Serum IL-12 merits confirmatory testing as an objective, treatment-independent measure of fatigue in patients with early-stage breast cancer. Cancer 2017;123:1810-1816. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Screening endoscopy finds high prevalence of Helicobacter pylori and intestinal metaplasia in Korean American with limited access to health care.

BACKGROUND: Gastric cancer (GC) is the leading cause of cancer death among Korean Americans. Prevention and early detection is improved by screening. METHODS: Between September 2013 and March 2015, ethnic Koreans age 40 or older without history or symptoms of GC and without upper endoscopy (UE) during previous 3 years were enrolled. Participants were offered screening with GC risk assessment followed by UE with biopsies. RESULTS: Risk assessment was provided to 146 participants (age 55.6 ± 8.3 years; 52.1% female; 92.5% uninsured), of whom 99 (67.8%) returned for UE. Undergoing UE was independently associated with family history of GC (OR 12.33, 95% CI:1.52-100.17), being a former smoker (6.68,1.42-31.32), and Hp-negative status (0.25,0.11-0.57). Among UE recipients, half (49.5%) had intestinal metaplasia (IM) only (n = 24), Hp only (n = 12), or both (n = 13). No case of GC was found. Adjusted for age, IM was independently associated with male sex (2.89,1.12-7.42), current Hp (2.90,0.99-8.51), unmarried status (single or divorced) (4.23,1.23-14.56). CONCLUSIONS: High prevalence of risk factors associated with gastric carcinogenesis including Hp infection and IM exists in Korean Americans who underwent upper endoscopic screening. Acceptance of GC screening is informed by personal risk factors. These findings support the need to improve access to screening UE among KAs.

Toxicity profile of repeated doses of PEG-asparaginase incorporated into a pediatric-type regimen for adult acute lymphoblastic leukemia.

Despite having been long regarded as too toxic for adult patients, pediatric-like regimens containing L-asparaginase have resulted in improved outcomes for adults with acute lymphoblastic leukemia (ALL). To characterize the spectrum of toxicity of repeated doses of polyethylene glycolated-asparaginase (PEG-asp) in adults, we reviewed all doses (2000 IU/m(2) ) administered as part of a pediatric-inspired regimen in adult ALL at our center. Subjects aged 18-60 yr with ALL (n = 152, 69.1% male) contributed 522 dose cycles to the study. Hepatotoxicity was the most common adverse event: grades 3-4 transaminitis and hyperbilirubinemia occurred in 53.9% and 23.7% of subjects, respectively. Hepatotoxicity was reversible; no cases of fulminate hepatic failure were observed. Other toxicities affecting at least 5% of subjects were grades 3-4 triglyceridemia in 50.9%, hypofibrinogenemia (<100 mg/dL) in 47.9%, clinical pancreatitis in 12.6%, venous thromboembolism in 11.2%, allergic reaction in 7.2%, and any grade bleeding in 5.3%. PEG-asp was always discontinued after grades 3-4 pancreatitis or allergic reaction. Otherwise, toxicities did not preclude administration of additional cycles of the drug. Our results suggest that repeated PEG-asp dosing is safe in adults aged 18-60 yr, even after occurrence of a drug-related toxicity.

Incidence of inflammatory breast cancer in women, 1992-2009, United States.

BACKGROUND: The annual incidence of inflammatory breast cancer (IBC) in the United States reportedly increased during the last quarter of the twentieth century. We investigated whether that increase has continued into the twenty-first century. METHODS: We queried the Surveillance Epidemiology and End Results database for all cases of IBC in women age 20 and older between 1992 and 2009. Cases were breast tumors with at least one of the following codes: extent of disease size 998, extension 70, or ICD-3-O morphology 8530 or 8533. Age-adjusted incidence was also examined. RESULTS: During 1992-2009, the annual incidence of IBC did not increase over time in any age group, nor did it vary significantly from year to year, except between 2003 and 2004, when there was a jump from 1.6 (95 % confidence interval 1.4-1.8) to 3.1 (2.8-3.4) cases per 100,000 women. Similar changes occurred in all age and racial groups before gradually returning to prejump levels. Overall, the incidence of IBC rose steeply with age until reaching a plateau at age 65. The incidence was greatest among black women (3.0; 2.8-3.2), intermediate among white women (2.1; 2.1-2.2), and lowest among Asian women (1.4; 1.3-1.6). CONCLUSIONS: The incidence of IBC has remained essentially stable for nearly two decades. A transient jump in 2003-2004 occurred in all age and racial groups, suggesting adjustment to coding changes at that time. Often described as a disease of younger women, IBC in fact disproportionately affects older women. Racial/ethnic variation in the incidence of IBC suggests that dietary, lifestyle, or genetic factors contribute to its pathogenesis.

Socioeconomic and clinical factors are key to uncovering disparity in accrual onto therapeutic trials for breast cancer.

To monitor and address disparity in accrual, patient participation in cancer clinical trials is routinely summarized by race/ethnicity. To investigate whether confounding obscures racial/ethnic disparity in participation, all women with breast cancer treated by medical oncologists at City of Hope Comprehensive Cancer Center from 2004 through 2009 were classified by birthplace and self-reported race/ethnicity, and followed for accrual onto therapeutic trials through 2010. Undetectable on univariate analysis, significantly reduced participation by subjects of African, Asian, Eastern European, Latin American, and Middle Eastern ancestries was revealed after accounting for age, socioeconomic factors, tumor and oncologist characteristics, and intrapractice clustering of patients.

Order of patient entry and outcomes in phase II clinical trials: A meta-analysis of individual patient data.

BACKGROUND: Prior meta-analysis of stem-cell transplantation trials for renal-cell carcinoma observed that clinical outcomes vary by subjects' order of entry, specifically their quartile of accrual. We test this hypothesis using meta-analysis of individual patient data from diverse Phase II trials conducted by an oncology consortium. METHODS: Eligible were all Phase II trials in hematologic or solid tumors opened and closed by California Cancer Consortium during 2005-2020. Excluded were trials closed in first quartile or currently embargoed pending publication and subjects ineligible per protocol or untreated on study. The primary risk factor was entry by quartile of planned sample size. As a cross-protocol endpoint, primary outcome was time to discontinuation of intervention. One-stage meta-analysis used a shared frailty model with trial as random effect. As covariates, stepwise selection retained tumor type, obesity, their interaction, calendar year, entry at least 3 years post-diagnosis, and performance status but rejected age, sex, randomized design, and class of drug. RESULTS: Twenty trials (including 8 terminated early, 2 not published) included n = 923 subjects. Most (90.6%) subjects discontinued intervention, usually for disease progression or toxicity. Independently of covariates, risk of discontinuation increased (p < 0.0001) with each quartile of entry (Hazards Ratio 1.13, 95% CI 1.06-1.22), culminating at Quartile 4 (HR 1.46, 1.36-1.57). The 95% prediction interval for the Hazards Ratio in future trials was (1.04-1.24). Progression-free survival similarly worsened by quartile of entry. CONCLUSION: In Phase II trials, clinical outcome worsens with quartile of entry. This finding merits independent replication, and the cause of this phenomenon merits investigation.

Inflammation-related proteins as biomarkers of treatment-related behavioral symptoms: A longitudinal study of breast cancer patients and age-matched controls.

Background: Behavioral symptoms in breast cancer (BC) survivors have been attributed to cancer treatment and resulting inflammation. However, studies linking behavioral symptoms to BC treatment have observed patients only after some treatment. Our prospective study with pre-treatment baseline investigates post-treatment changes in inflammation-related biomarkers and whether those changes correlate with changes in symptoms. Methods: Participants were postmenopausal women, newly-diagnosed with stage 0-3 BC before any treatment (n = 173 "patients"), and age-matched women without cancer (n = 77 "controls"), who were assessed on plasma markers [soluble tumor necrosis factor receptor type 2 (sTNF-RII), interleukin (IL)-6, IL-1 receptor antagonist (IL-1RA), C-reactive protein (CRP)]) and symptoms (Physical Functioning, Pain, Attention/concentration, Perceived Cognitive Problems, Fatigue, Sleep Insufficiency, Depression). Participants were assessed again 1 month, 1 year, and 2 years after completing primary treatment or similar interval in controls. Generalized linear mixed models tested 4 treatments (surgery alone or with chemotherapy, radiation, or both) for association with change per marker. Joint models tested change per marker for association with change per symptom. Models considered demographic, socioeconomic, and clinical covariates. False Discovery Rate method controlled risk of error from multiple hypotheses. Results: At one month post-completion of treatment, sTNF-RII and IL-6 were elevated by all BC treatments, as were IL-1RA and CRP after surgery alone (all, p < 0.05). By 1 year, markers' average values returned to baseline. Throughout 2-year follow-up, increase-from-baseline in sTNF-RII, IL-1RA, and IL-6 coincided with worsened Physical Functioning, and increase-from-baseline in sTNF-RII coincided with increased Pain (all, p < 0.01). These biomarker-symptom associations (excepting IL-6) were exclusive to patients. No other symptoms worsened, and baseline Fatigue and Depression improved in all participants. Conclusions: BC treatment, even surgery, is associated with transient elevation in inflammatory markers. In patients post-treatment, increase-from-baseline in sTNF-RII accompanies increased Pain and decreased Physical Functioning, suggesting that sTNF-RII merits development as a clinical biomarker in BC patients.

HER2-targeted antibody-drug conjugates for breast cancer: ancestry and dose adjustment for thrombocytopenia.

BACKGROUND: Thrombocytopenia is a common adverse event on HER2-targeted therapies, fam-trastuzumab deruxtecan (T-DXd) and ado-trastuzumab emtansine (T-DM1). A reported association of Asian ancestry with this event merits investigation to rule out potential confounding. METHODS: Subjects in this retrospective cohort were female patients with HER2 positive breast cancer, of Asian or non-Hispanic White ancestry, who initiated T-DM1 or T-DXd from January 2017 through October 2021. Follow-up closed in January 2022. Primary endpoint was dose adjustment for thrombocytopenia. Competing endpoints were discontinuation of drug for other toxicity, disease progression, or for completion of prescribed cycles. The association between Asian ancestry and thrombocytopenia-related dose adjustment was tested at p < 0.01 in a proportional hazards model for the sub-distributions of 4 (primary and competing) endpoints. Covariates examined as potential confounders were age, metastatic disease, specific HER2-targeted drug, and prior drug switching for toxicity. RESULTS: Among 181 subjects, 48 reported Asian ancestry. Incidence of dose adjustment for thrombocytopenia was higher in patients with Asian ancestry and among patients switched to T-DXd after experiencing thrombocytopenia on T-DM1. Independent of specific drug and prior drug switching, Asian ancestry was associated with dose adjustment for thrombocytopenia (hazards ratio 2.95, 95% confidence interval 1.41-6.18) but not with competing endpoints. Among participants of Asian ancestry, the ancestral origin was usually China or the Philippines (where Chinese ancestry is common). CONCLUSIONS: The association between Asian ancestry and thrombocytopenia on HER2-targeted therapy is independent of age, metastatic disease, drug, and history of similar toxicity. This association may have a genetic basis linked to Chinese ancestry.

Tumor Epigenetic Signature and Survival in Resected Gastric Cancer Patients.

BACKGROUND: Precision oncology can identify patient-specific molecular signatures to better inform the prognosis and management of surgical cancer patients. Specifically, microRNAs (miRs) hold promise as prognostic biomarkers because dysregulation of individual miRs is implicated in tumorigenesis, progression, and metastases of various malignancies, including gastric adenocarcinoma (GC). STUDY DESIGN: To identify miRs prognostic of survival after radical gastrectomy, we studied GC patients within The Cancer Genome Atlas (TCGA) who had undergone R0 or R1 resection and had data on clinical characteristics, overall survival (OS), and tumor miR expression. The miRs expressed by at least 15% of tumors were eligible for study. From 10 replicate samples, each with 80% of patients, miRs were selected using age-adjusted proportional hazards regression with stepwise selection. Cross-validated miRs (selected by multiple replicates) were retained if they optimized an accelerated failure-time model of OS using all patients. RESULTS: In this GC cohort (n = 270), half (916/1,870) of miRs screened met our criteria for evaluation. Cross-validation identified 20 miRs as prognostic, of which 14 (miR-129-1, miR-373, miR-490, miR-597, miR-1185-2, miR-3943, miR-4756, miR-5683, miR-6510, miR-6733, miR-6808, miR-6855, miR-6882, miR-8072) were independently informative. The age-adjusted 14-miRNA panel remained significantly associated with OS after adjustment for pathologic prognostic factors (number of lymph nodes examined, number of positive lymph nodes) and other clinical covariates (TNM stage, residual tumor, tumor microsatellite instability, targeted molecular therapy, sex, race, ethnicity). Panel-predicted survival estimates below the upper tertile cut-off were associated with worse outcome (30% vs 74% OS at 3 years, p < 0.0001). CONCLUSIONS: In surgically resected GC patients, an epigenetic signature of miRs associated with survival has the potential to improve prognostication.

Donor and recipient CMV serostatus and outcome of pediatric allogeneic HSCT for acute leukemia in the era of CMV-preemptive therapy.

In the era of cytomegalovirus (CMV)-preemptive therapy, it is unclear whether CMV serostatus of donor or recipient affects outcome of allogeneic hematopoietic stem cell transplantation (HSCT) among children with leukemia. To investigate, consecutive patients aged 0-18 who underwent primary HSCT for acute leukemia in 1997-2007 (HLA-matched sibling or unrelated donor, myeloablative conditioning, unmanipulated bone marrow or peripheral blood, preemptive therapy, no CMV prophylaxis) were followed retrospectively through January 2008. Treatment failure (relapse or death) was analyzed using survival-based proportional hazards regression. Competing risks (relapse and nonrelapse mortality, NRM) were analyzed using generalized linear models of cumulative incidence-based proportional hazards. Excluding 4 (2.8%) patients lacking serostatus of donor or recipient, there were 140 subjects, of whom 50 relapsed and 24 died in remission. Pretransplant CMV seroprevalence was 55.7% in recipients, 57.1% in donors. Thirty-five (25.0%) grafts were from seronegative donor to seronegative recipient (D-/R-). On univariate analysis, D-/R- grafts were associated with shorter relapse-free survival (RFS) than other grafts (median 1.06 versus 3.15 years, P < .05). Adjusted for donor type, diagnosis, disease stage, recipient and donor age, female-to-male graft, graft source, and year, D-/R- graft was associated with relapse (hazards ratio 3.15, 95% confidence interval 1.46-6.76) and treatment failure (2.45, 1.46-4.12) but not significantly with NRM (2.00, 0.44-9.09). In the current era, children who undergo allogeneic HSCT for acute leukemia have reduced risk of relapse and superior RFS when recipient and/or donor is CMV-seropositive before transplantation. However, no net improvement in RFS would be gained from substituting seropositive unrelated for seronegative sibling donors.

Are associations between psychosocial stressors and incident lung cancer attributable to smoking?

PURPOSE: To learn whether reported associations between major psychosocial stressors and lung cancer are independent of smoking history. METHODS: Subjects were at least 25 years old and without lung cancer at enrollment in the United States Census Bureau's National Longitudinal Mortality Survey in 1995-2008. Follow-up via Surveillance Epidemiology and End Results and National Death Index continued until lung cancer diagnosis, death, or December 2011. Involuntary unemployment, widowhood, and divorce, stratified by sex, were tested for association with subsequent lung cancer using proportional hazards regression for competing risks. Smoking status, years smoked, cigarettes per day, and years since quitting were imputed when missing. RESULTS: At enrollment, subjects (n = 100,733, 47.4% male, age 49.1(±15.8) years) included 17.6% current smokers, 23.5% former smokers. Of men and women, respectively, 11.3% and 15.0% were divorced/separated, 2.9% and 11.8% were widowed, and 2.9% and 2.3% were involuntarily unemployed. Ultimately, 667 subjects developed lung cancer; another 10,071 died without lung cancer. Adjusted for age, education, and ancestry, lung cancer was associated with unemployment, widowhood, and divorce/separation in men but not women. Further adjusted for years smoked, cigarettes per day, and years since quitting, none of these associations was significant in either sex. CONCLUSIONS: Once smoking is accounted for, psychosocial stressors in adulthood do not independently promote lung cancer. Given their increased smoking behavior, persons experiencing stressors should be referred to effective alternatives to smoking and to support for smoking cessation.

Prospective Study of Cancer Genetic Variants: Variation in Rate of Reclassification by Ancestry.

Background: In germline genetic testing, variants from understudied ancestries have been disproportionately classified as being of uncertain significance. We hypothesized that the rate of variant reclassification likewise differs by ancestry. Methods: Nonbenign variants in actionable genes were collected from consenting subjects undergoing genetic testing at two Southern California sites from September 1996 through December 2016. Variant reclassifications were recorded as they were received, until February 2017 or reclassification to benign. Excluding duplicate variants (same ancestry, laboratory, classification), generalized linear models for the hereditary breast cancer genes (BRCA1/2) and other variants investigated whether rate of reclassification differed for seven categories of ancestry compared with non-Hispanic European. Models took into account laboratory, year, gene, sex, and current classification (handled as a time-dependent covariate) and were adjusted for multiple hypothesis testing. Results: Among 1483 nonbenign variants, 693 (46.7%) involved BRCA1/2. Overall, 268 (18.1%) variants were reclassified at least once. Few (9.7%) reclassified variants underwent a net upgrade in pathogenicity. For BRCA1/2 variants, reclassification rates varied by ancestry and increased over time, more steeply for ancestries with lower initial rates (African, Ashkenazi, Chinese) than for ancestries whose initial rates were high (Middle Eastern) or similar to non-Hispanic European (non-Chinese Asian, Native American, Hispanic). In contrast, reclassification rates of non-BRCA1/2 variants did not vary over time but were elevated for most minority ancestries except non-Chinese Asian and Native American. Conclusions: For nonbenign variants in cancer-related genes, the rates at which reclassifications are issued vary by ancestry in ways that differ between BRCA1/2 and other genes.

Hyperglycemia among persons with hepatitis C: not the classical diabetic phenotype.

Using data from the Third National Health and Nutrition Examination Survey (United States, 1988-1994), we compared clinical phenotypes of hepatitis C virus (HCV)-seropositive and seronegative adults aged 20-89 years with hyperglycemia (impaired fasting glucose (IFG) or type 2 diabetes, n=3566 including 86 with HCV). Seroprevalence was higher among younger persons (3.4% for ages 20-59 versus 0.9% for ages 60-89, p=0.002), while traditional correlates of diabetes (hypertension, coronary heart disease) were more prevalent among older persons (both comparisons, p<0.0001). To prevent confounding by age, younger and older persons were analyzed separately. In both age groups, HCV was associated with signs of hepatic impairment and B-cell clonal expansion (higher alanine aminotransferase (ALT) and serum globulin, lower total cholesterol and platelet count). Only among younger persons, however, was HCV also associated with a marker for advanced hepatic fibrosis (elevated serum ferritin) and absence of the classical diabetic phenotype (overweight, coronary heart disease). In addition, among younger persons, HCV was currently associated with family history of diabetes, positively in persons with diabetes and inversely in those with IFG, suggesting that family history of diabetes may serve as a cofactor for progression from HCV-associated IFG to diabetes.

Mild and moderate-to-severe COPD in nonsmokers: distinct demographic profiles.

STUDY OBJECTIVE: To investigate the risk of COPD among nonsmokers. DESIGN: Case-control study, logistic regression analysis. SETTING: Third National Health and Nutrition Examination Survey, from 1988 to 1994. PARTICIPANTS: Community residents 18 to 80 years of age, of white, black, or Mexican-American ethnicity. Nonsmokers included never-smokers and former smokers with a < 5 pack-year smoking history who had never smoked cigars or pipes. MEASUREMENTS: COPD (FEV1/FVC < 70%) was classified as mild (FEV1 > or = 80% predicted) or moderate to severe (FEV1 23 to 79% predicted). RESULTS: Among 13,995 examinees, 51.3 +/- 0.4% were female, mean age was 42.2 +/- 0.4 years, 48.7 +/- 0.9% were nonsmokers, 8.8 +/- 0.3% had mild COPD, and 4.1 +/- 0.3% had moderate-to-severe COPD [+/- SE]. One fourth of mild and moderate-to-severe cases were nonsmokers. Among 7,526 nonsmokers, 4.7 +/- 0.3% had mild COPD (n = 403; age, 60.9 +/- 1.3 years) and were mostly female (82.5%), while 1.9 +/- 0.3% had moderate-to-severe COPD (n = 92, age 39.3 +/- 1.3) and were mostly male (88.1%). Few nonsmokers with COPD (12.1 +/- 2.4%) had a previous diagnosis of chronic bronchitis or emphysema. Among nonsmokers, physician-diagnosed asthma increased the risk of mild and especially of moderate-to-severe COPD. Independently of asthma, risk of mild COPD in nonsmokers increased with age (doubling every 12 years), before age 60 was lower among men than women, and was inversely associated with current exposure to tobacco smoke at home and at work. In contrast, the risk of moderate-to-severe COPD in nonsmokers was markedly associated with male gender, peaked in middle age, and was inversely associated with nonwhite ethnicity. COPD risks did not vary by minimal smoking history, longest-held occupation, urban residence, income, allergies, thyroid disease, or Helicobacter pylori antibody. CONCLUSIONS: Among nonsmokers, mild and moderate-to-severe COPD are associated with asthma but otherwise have distinct demographic profiles, suggesting that moderate-to-severe disease is not a mere progression of mild COPD.

Venous thromboembolism among patients with advanced lung cancer randomized to prinomastat or placebo, plus chemotherapy.

Two clinical trials have suggested that the combination of vascular endothelial growth factor inhibitor with chemotherapy is associated with venous thromboembolism (VTE). This retrospective cohort study investigates whether a similar association exists when matrix metalloproteinase inhibitor (prinomastat) is combined with chemotherapy. Patients (n=1,023) with stage IIIB, IV, or recurrent non-small cell lung cancer (NSCLC) were followed during 2 randomized, double-blind trials of prinomastat versus placebo orally bid, plus gemcitabine/cisplatin (GC) or paclitaxel/carboplatin (PC). VTE included deep venous thrombosis (DVT) or pulmonary embolism (PE) confirmed by imaging or autopsy. Risks identified in univariate analysis (incidence densities compared by t test) were confirmed in multivariate analysis (proportional hazards model). During 7,500.3 patient-months, 58 VTE (31 PE, 27 isolated DVT) were confirmed in 54 patients. On univariate analysis, VTE was associated with central venous catheter placed within 3 months, 15 mg prinomastat plus GC, and to a lesser extent, 15 mg prinomastat plus PC, baseline performance status, and histologic type. VTE incidence was not increased by 15 mg prinomastat alone (post-discontinuation of chemotherapy), by chemotherapy plus placebo, or by 5 or 10 mg prinomastat plus chemotherapy. On multivariate analysis,VTE hazards (95% confidence interval) were 5.69 (2.61, 12.40) with recently placed central catheter, 2.78 (1.42, 5.43) with 15 mg prinomastat plus GC, and 2.06 (0.98, 4.31) with 15 mg prinomastat plus PC; performance status and histology were nonsignificant. We can conclude that combined treatment with 15 mg prinomastat plus chemotherapy approximately doubles the hazard of VTE among patients with advanced NSCLC.