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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Carried by 1 in 8 patients with lung adenocarcinoma who have a family history of cancer, germline pathogenic variants of TP53, EGFR, BRCA2, and other Fanconi anemia genes are associated with earlier onset of lung cancer in nonsmokers and smokers alike. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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/m2) 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The intensity and persistence of treatment-related symptoms among breast cancer survivors is incompletely understood. Objective: The objective of the study was to estimate prevalence of severe symptoms well after initial treatment for breast cancer, to test whether symptom intensity diminishes with time or varies by treatment received. Design, setting, subjects: This was a cross-sectional survey of female survivors of stage I-III invasive breast cancer, seen for routine follow-up a year or more after diagnosis. Measurements: Data was derived from three validated questionnaires indicating physical and emotional domains. Symptoms rated in the top two levels of four- or five-item Likert scales were 'severe.' Associations with symptom intensity were tested using multivariate linear regression. Results: Survey response was 68.5% (50/73). Respondents were age 55.4 (±9.1) years, median 2.2 (1.0-13.1) years since diagnosis; 64% were receiving endocrine therapy. Severe levels of hot flashes (42% of respondents), weight gain (32%), low libido (32%), and joint pain (30%) were common; (36%) of respondents rated sleep 'fairly poor' or 'very bad;' 30% were fatigued at least half the day. For 34%, health typically limited vigorous activities 'a lot.' Most (84%) respondents were experiencing at least one severe symptom. Symptom intensity did not vary with time since diagnosis. Of seven symptoms, three (hot flashes, weight gain, low libido) were more intense when systemic treatment had included endocrine therapy. Time in past month feeling down, nervous, or worn out increased with intensity of physical symptoms. Conclusions: Given their severity, persistence, and association with emotional burden, treatment-related symptoms among breast cancer survivors (BCS) merit greater attention toward clinical management, patient education, and longitudinal study. [ABSTRACT FROM AUTHOR]

Stress hyperglycemia and acute graft- versus-host disease (GVHD), the major early complication of hematopoietic stem cell transplantation (HSCT), are both associated with excessive release of inflammatory cytokines. We investigated whether new-onset hyperglycemia immediately after HSCT predicts acute GVHD. We studied nondiabetic adult recipients of human leukocyte antigen-matched HSCT (peripheral blood stem cells) for acute leukemia. Using mean morning serum glucose on Days 1-10, we classified hyperglycemia as: mild (6.11-8.33 mmol/L), moderate (8.34-9.98), and severe (minimum of 9.99). Subjects who were GVHD-free on Day 10 were followed during Days 11-100 for grades II-IV acute GVHD or competing event. Evaluation utilized cumulative incidence-based proportional hazards regression. Subjects ( n = 328) were age 18-74, median of 49 years. Per body mass index (BMI)-25.0 % were obese (BMI, 30-48), 33.8 % overweight (25 to <30), 30.8 % normal weight (21 to <25), and 10.4 % lean (18 to <21). Mild, moderate, or severe hyperglycemia occurred during Days 1-10 in 50.0, 21.3, and 16.8 % of subjects, respectively. Cumulative incidence on Day 100 was 44.8 (±2.8) % acute GVHD and 7.9 (±1.5) % competing event. Among normal-to-overweight subjects ( n = 212), severe hyperglycemia developed in 14.2 % ( n = 30) and more than doubled the risk of acute GVHD (hazards ratio, 2.71; 95 % CI, 1.58-4.65-adjusted for donor/recipient characteristics, prophylactic regimen, and mucositis). In contrast, among obese subjects ( n = 82), severe hyperglycemia developed in 30.5 % ( n = 25) but did not significantly affect risk of GVHD. (No lean subjects ( n = 34) developed severe hyperglycemia.) Hyperglycemia that was less than severe had an effect indistinguishable from normoglycemia. In nondiabetic patients, severe hyperglycemia immediately after allogeneic HSCT indicates increased likelihood of acute GVHD. This association is absent in obese patients, who may be primed by obesity-induced inflammation to develop severe hyperglycemia even without experiencing the cytokine storm that is essential to GVHD pathogenesis. [ABSTRACT FROM AUTHOR]

The article presents a study to investigate the risk of COPD among nonsmokers. Using data from a national health examination, the current study identifies and compares risk factors for mild and moderate-to-severe COPD among nonsmokers. The current study confirmed findings from earlier COPD studies not restricted to nonsmokers, specifically independent associations with increasing age and asthma but not with allergy alone. The magnitude of the association between asthma and COPD was currently shown to increase with the severity of COPD. Limitations of the current study include its cross-sectional nature, limited numbers of nonsmokers with moderate and severe COPD, and nonsampling of nursing home residents and homeless persons.

Conventional stroke risks are thought responsible for most cerebral ischemic events (CIE) in adult cancer patients. Also suspected as a risk is cisplatin chemotherapy, alone or in combination with tumor angiogenesis inhibitor. We investigated whether treatment or tumor characteristics, independently of conventional stroke risks, are associated with CIE in a retrospective cohort study of 1,559 patients with advanced non-small cell lung cancer or hormone-refractory prostate cancer followed during 3 clinical trials of matrix metalloprotease inhibitor (prinomastat) versus placebo, with chemotherapy (gemcitabine/cisplatin, paclitaxel/carboplatin or mitoxantrone/prednisone). During 11,907 patient-months, 28 CIE (17 cerebral infarction, 11 transient ischemic attack) were diagnosed in 24 patients, all but 1 over 55 years. Neither prinomastat, platinum-based chemotherapy nor their combination was associated with CIE after age 55. However, such events were predicted by the presence of distant metastases in the liver or lungs and not in distant lymph nodes (hazard estimate 4.6, 95% CI 2.0–10.5, adjusted for conventional stroke risks). Further studies are needed to verify this preliminary finding and determine its generalizability to advanced tumors other than lung or prostate cancer. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

purpose To identify factors affecting visual acuity and its decrease in eyes with subfoveal choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD). methods Distance visual acuity was recorded at screening and up to five follow-up visits during the first year of a randomized, double-blind, placebo-controlled trial of oral prinomastat. Subjects had AMD in both eyes and neovascular AMD in at least one eye. Analysis employed a generalized linear mixed model. results Of 158 eligible subjects (age 56-90), 125 (79.1%) received prinomastat. Visual acuity was independently affected by relative acuity of the fellow eye, whether the study eye had been the first or second to develop CNV, age, current smoking, leakage area, and prior photocoagulation. Decrease in visual acuity score, unaffected by prinomastat, was less steep in eyes that had been second to develop CNV. Such eyes had a comparable time since CNV onset to other study eyes. conclusion Fellow eye features independently affect visual acuity and its decrease in eyes with classic neovascular AMD. [ABSTRACT FROM AUTHOR]

Study objectives: To estimate the incidence of acute respiratory failure (ARF) in the United States and to analyze 31-day hospital mortality among a cohort of patients with ARF. Design and setting: Retrospective cohort drawn from the Nationwide Inpatient Sample of 6.4 million discharges from 904 representative nonfederal hospitals during 1994. Patients: All 61,223 patients in the sample whose discharge records indicated all of the following: acute respiratory distress or failure, mechanical ventilation, ≥ 24 h of hospitalization, and age ≥ 5 years. Results: An estimated 329,766 patients discharged from nonfederal hospitals nationwide in 1994 met study criteria for ARF. The incidence of ARF was 137.1 hospitalizations per 100,000 US residents age ≥ 5 years. Incidence increased nearly exponentially each decade until age 85 years. Overall, 35.9% of patients with ARF did not survive to hospital discharge. At 31 days, hospital mortality was 31.4%. According to the proportional hazards model, significant mortality hazards included age (≥ 80 years and ≥ 30 years), multiorgan system failure (MOSF), HIV, chronic liver disease, and cancer. Hospital admission for coronary artery bypass, drug overdose, or trauma other than head injury or burns was associated with a reduced mortality hazard. Interaction was present between age and MOSF, trauma, and cancer. A point system derived from the hazard model classified patients into seven groups with distinct 31-day survival probabilities ranging from 24 to 99%. Conclusions: The incidence of ARF increases markedly with age and is especially high among persons ≥ 65 years of age. Nonpulmonary hazards explain short-term (31-day) survival. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]