Safety and dose modification for patients receiving niraparib

Abstract

Background

Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor approved in the United States and Europe for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. In the pivotal ENGOT-OV16/NOVA trial, the dose reduction rate due to TEAE was 68.9%, and the discontinuation rate due to TEAE was 14.7%, including 3.3% due to thrombocytopenia. A retrospective analysis was performed to identify clinical parameters that predict dose reductions.

Patients and methods

All analyses were performed on the safety population, comprising all patients who received at least one dose of study drug. Patients were analyzed according to the study drug consumed (ie, as treated). A predictive modeling method (decision trees) was used to identify important variables for predicting the likelihood of developing grade ≥3 thrombocytopenia within 30 days after the first dose of niraparib and determine cutoff points for chosen variables.

Results

Following dose modification, 200 mg was the most commonly administered dose in the ENGOT-OV16/NOVA trial. Baseline platelet count and baseline body weight were identified as risk factors for increased incidence of grade ≥3 thrombocytopenia. Patients with a baseline body weight <77 kg or a baseline platelet count <150,000/μL in effect received an average daily dose approximating 200 mg (median = 207 mg) due to dose interruption and reduction. Progression-free survival in patients who were dose reduced to either 200 mg or 100 mg was consistent with that of patients who remained at the 300 mg starting dose.

Conclusions

The analysis presented suggests that patients with baseline body weight of < 77 kg or baseline platelets of < 150,000/μL may benefit from a starting dose of 200 mg per day.(ClinicalTrials.gov ID: NCT01847274)

Treatment of The Myeloid/lymphoid neoplasm with FGFR1 rearrangement with FGFR1 Inhibitor

Neoadjuvant Score in locally advancer rectal cancer: Integrating downstaging in risk assessment and looking for new valuable end-points

Randomized phase 3 study of docetaxel plus bavituximab in previously treated advanced non-squamous non-small-cell lung cancer

Abstract

Background

Bavituximab is a monoclonal antibody that targets phosphatidylserine in the presence of β₂ glycoprotein 1 (β2GP1) to exert an anti-tumor immune response. This phase 3 trial determined the efficacy of bavituximab combined with docetaxel in patients with previously treated advanced non-small cell lung cancer (NSCLC).

Patients and Methods

Key eligibility criteria included advanced non-squamous NSCLC with disease progression after treatment with platinum-based doublet chemotherapy, evidence of disease control after at least two cycles of first-line therapy, presence of measurable disease, ECOG performance status 0 or 1, adequate bone marrow and organ function, and no recent history of clinically significant bleeding. Eligible patients were randomized 1:1 to receive up to six 21-day cycles of docetaxel plus either weekly bavituximab 3 mg/kg or placebo until progression or toxicity. The primary endpoint was overall survival (OS).

Results

A total of 597 patients were enrolled. Median OS was 10.5 months in the docetaxel + bavituximab arm and was 10.9 months in the docetaxel + placebo arm (HR 1.06; 95% CI, 0.88-1.29; P=0.533). There was no difference in PFS (HR 1.00; 95% CI, 0.82-1.22; P=0.990). Toxicities were manageable and similar between arms. In subset analysis, among patients with high baseline serum β2GP1 levels ≥200 µg/mL, a non-significant OS trend favored the bavituximab arm (HR 0.82; 95% CI 0.63-1.06; P=0.134). Among patients who received post-study immune checkpoint inhibitor therapy, OS favored the bavituximab arm (HR 0.46; 95% CI 0.26-0.81; P=0.006).

Conclusions

The combination of bavituximab plus docetaxel is not superior to docetaxel in patients with previously treated advanced NSCLC. The addition of bavituximab to docetaxel does not meaningfully increase toxicity. The potential benefit of bavituximab observed in patients with high β2GP1 levels and in patients subsequently treated with immune checkpoint inhibitors requires further investigation.NCT01999673

Identification of etiology-specific diarrhea associated with linear growth faltering in Bangladeshi infants

Abstract

Childhood diarrhea in low-resource settings has been variably linked to linear growth shortfalls. However, the association between etiology-specific diarrhea and growth has not been comprehensively evaluated. We tested diarrheal stools collected from the Performance of Rotavirus and Oral Polio Vaccines in Developing Countries study from 2011-2013 in Dhaka, Bangladesh by quantitative polymerase chain reaction for a broad range of enteropathogens to characterize diarrhea etiology and examine the association between etiology-specific diarrhea and linear growth and systemic inflammation. Pathogen-specific burdens of diarrhea were determined using attributable fractions. Linear regression was used to examine associations of pathogen-specific diarrhea with length-for-age z-scores (LAZ) and serum C-reactive protein. There was no relationship between all-cause diarrhea and length at 12 months (-0.01 change in 12-month LAZ per episode; 95% confidence interval: -0.06, 0.03). However, Cryptosporidium (-0.23 change in 12-month LAZ per attributable episode; 95% CI: -0.50, 0.03), Campylobacter jejuni/coli (-0.16; 95% CI: -0.32, -0.01) and Shigella/enteroinvasive E. coli diarrhea (-0.12; 95% CI: -0.26, 0.03) were associated with linear growth deficits. C. jejuni/coli and Shigella/enteroinvasive E. coli attributable diarrhea were associated with elevated C-reactive protein. The association between diarrhea and linear growth appears to be pathogen specific, reinforcing the need for pathogen-specific interventions.

Drug Side Effects and Retention on HIV Treatment: a Regression Discontinuity Study of Tenofovir Implementation in South Africa and Zambia

Abstract

Tenofovir is less toxic than other nucleoside reverse transcriptase inhibitors used in antiretroviral therapy (ART) and may improve retention of HIV-infected patients on ART. We assessed the impact of national guideline changes in South Africa (2010) and Zambia (2007) recommending tenofovir in first-line ART. We applied regression discontinuity in a prospective cohort of 52,294 HIV-infected adults initiating first-line ART within ±12-months of each guideline change. We compared outcomes in patients presenting just before/after the guideline changes using local linear regression and estimated intention-to-treat effects on initiation of tenofovir, retention in care, and other treatment outcomes at 24-months. We assessed complier causal effects among patients starting tenofovir. The new guidelines increased the percentage of patients initiating tenofovir in South Africa (risk difference (RD): 81%; 95% confidence interval (CI): 73, 89) and Zambia (RD: 42%; 95% CI: 38, 45). With the guideline change, single-drug substitutions decreased substantially in South Africa (RD: −15%; 95% CI:−18, −12). Starting tenofovir also reduced attrition in Zambia (intent-to-treat RD: −1.8%; 95% CI: −3.5, −0.1, complier relative risk = 0.74) but not in South Africa (RD: −0.9%; 95% CI: −5.9, 4.1, Complier Relative Risk = 0.94). These results highlight the importance of reducing side effects for increasing retention in care, as well as the differences in population impact of policies with heterogeneous treatment effects implemented in different contexts.

Prospects for Tuberculosis Elimination in the United States: Results of a Transmission Dynamic Model

Abstract

We estimated long-term tuberculosis (TB) trends in the US population and assessed prospects for TB elimination. We used a detailed simulation model allowing for changes in TB transmission, immigration, and other TB risk determinants. We evaluated 5 hypothetical scenarios from 2017 to 2100: 1) maintain current TB prevention and treatment activities (base-case), 2) provision of latent TB infection testing and treatment for new legal immigrants, 3) increased uptake of latent TB infection screening and treatment among high-risk populations, including a 3-month isoniazid-rifapentine regimen, 4) improved TB case detection, 5) improved TB treatment quality. Under the base-case, we estimate that by 2050 TB incidence will decline to 14 cases per million, a 52% (95% interval: 35, 67) reduction from 2016, and 82% (78, 86) of incident TB will be among non-US-born persons. Intensified TB control could reduce incidence by 77% (66, 85) by 2050. By 2100, we predict TB may be eliminated in the US-born but not the non-US-born. Results were sensitive to numbers entering the US with latent or active TB, and robust to alternative interpretations of epidemiologic evidence. TB elimination in the US remains a distant goal. However, strengthening TB prevention and treatment could produce important health benefits.

Acute-on-Chronic Liver Failure in China: Rationale for Developing a Patient Registry and Baseline Characteristics

Abstract

Definitions and descriptions of acute-on-chronic liver failure (ACLF) vary between Western and Eastern types, and alcoholism and hepatitis B virus(HBV) are the main etiologies, respectively. To determine whether there are unified diagnostic criteria and common treatment programs for different etiologies of ACLF, a multicenter prospective cohort with the same inclusion criteria and disease indicators as those used in the European CANONIC (Chronic liver failure-ACLF in Cirrhosis) study is urgently needed in Asia, where the prevalence of HBV is high. Fourteen nationwide liver centers from tertiary university hospitals in China were included, and 2,600 hospitalized patients with chronic liver disease (both cirrhotic and non-cirrhotic) of various etiologies with acute decompensation or acute hepatic injury were continuously recruited from January 2015 to December 2016. Data were collected during hospitalization and continuous follow-ups were performed once a month until 36 months after hospital discharge. A multicenter prospective cohort of 2,600 patients was designed (NCT no. NCT02457637). Of these patients, 71.5% had HBV-related disease, 1,833 had cirrhotic disease, and 767 had non-cirrhotic disease. The numbers and proportions of enrolled patients from each participating center and the baseline characteristics of the patients with or without cirrhosis are presented.

Complete Streets and Adult Bicyclist Fatalities: Applying G-Computation to Evaluate an Intervention That Affects the Size of a Population at Risk

Abstract

"Complete Streets" policies require transportation engineers to make provisions for pedestrians, cyclists and transit users. These policies may make bicycling safer for individual cyclists while increasing overall bicycle fatalities if more individuals cycle due to improved infrastructure. We merged county-level records of Complete Streets policies with Fatality Analysis Reporting System counts of cyclist fatalities occurring between January 2000 and December 2015. Because comprehensive county cycling estimates were not available, we used bicycle commute estimates from the American Community Survey and US Census as a proxy for the cycling population, and limited analysis to 183 counties (accounting for over half the US population) for which cycle commute estimates were consistently non-zero. We used G-computation to estimate the effect of policies on overall cyclist fatalities while also accounting for potential policy effects on the size of the cycling population. Over 16 years, 5,254 cyclists died in these counties, representing 34 fatalities per 100,000 cyclist-years. We estimated that Complete Streets policies made cycling safer, averting 0.6 fatalities per 100,000 cyclist-years (95% CI: 0.3, 1.0) by encouraging a 2.4% increase in cycling and a 0.7% increase in cyclist fatalities. G-computation is a useful tool for understanding policy impact on risk and exposure.

Using a Mixture of Bivariate Regression Model to Explore Heterogeneity of Effects of Use of Inhaled Corticosteroids on Gestational Age and Birthweight among Pregnant Women with Asthma

Abstract

Asthma is a heterogeneous disease, and responses to asthma medications vary noticeably among patients. A substantively oriented objective of this study was to explore the potential heterogeneous effects of maternal inhaled corticosteroids (ICS) exposure on gestational age (GA) at delivery and birthweight (BW) using a cohort of 6,197 pregnancies from women with asthma (Quebec, Canada, 1998-2008). A methodologically oriented objective was to comprehensively describe the application of a Bayesian two-component mixture of bivariate regressions to address this issue and estimate the effects of ICS on GA and BW jointly. Based on proposed model, no association between ICS and GA/BW was found for a large proportion of asthmatic pregnancies. However, a positive association between ICS exposure and GA/BW was revealed in a small subset of pregnancies mainly formed of preterm and low-birthweight infants. A novel application of this model was also subsequently performed using BW z-score instead of BW as outcome variable. In conclusion, the studied mixture of bivariate regressions was useful to detect heterogeneity of ICS effect on GA and BW in our population of women with asthma; these analyses pave the way for analogous uses of this model for general assessment of exposure effect heterogeneity for these perinatal outcomes.

Association of Maternal Exposure to Childhood Abuse With Elevated Risk for Attention Deficit Hyperactivity Disorder in Offspring

Abstract

Children whose mothers experienced childhood abuse are more likely to suffer various neurodevelopmental deficits. Whether an association exists specifically for attention deficit hyperactivity disorder (ADHD) is unknown. We examined the association of maternal experience of childhood abuse with ADHD in offspring, assessed by maternal report of diagnosis and validated with the ADHD Rating Scale-IV in a subsample, in the Nurses' Health Study II (n = 49,497 mothers, N offspring cases = 7,607, N offspring controls = 102,151). We examined whether ten adverse perinatal circumstances (e.g., prematurity, smoking) or socioeconomic factors accounted for a possible association. Exposure to abuse was associated with greater prevalence of ADHD in offspring (8.7% of offspring of women exposed to severe abuse vs. 5.5% of offspring of women not abused, P = 0.0001) and with greater risk for ADHD adjusted for demographic factors (male offspring, risk ratio (RR) = 1.6; 95% CI: 1.3, 1.9; female offspring, RR = 2.3, 95% CI: 1.7, 3.0). Adjusted for perinatal factors, the association of maternal childhood abuse with ADHD in offspring was slightly attenuated (male offspring, RR = 1.5; 95% CI: 1.2, 1.8; female offspring, RR = 2.1, 95% CI: 1.6, 2.8). We identified an association between maternal experience of childhood abuse and risk for ADHD in offspring, which was not explained by several important perinatal risk factors or socioeconomic status.

Educational Mobility Across Generations and Depressive Symptoms Over 10 Years Among US Latinos

Abstract

Few studies have collected intergenerational data to assess the association between educational mobility across multiple generations and offspring depression. Using data from the Sacramento Area Latino Study on Aging (1998–2008), we assessed the influence of intergenerational education on depressive symptoms over 10 years among 1,786 Latino individuals (mean age = 70.6 years). Educational mobility was classified: stable-low (low parent/low offspring education), upwardly mobile (low parent/high offspring education), stable-high (high parent/high offspring education), or downwardly mobile (high parent/low offspring education). Depressive symptoms were measured with the Center for Epidemiological Studies Depression Scale (CES-D); higher scores indicated more depressive symptoms. To quantify the association between educational mobility and CES-D scores over follow-up, we used generalized estimating equations to account for repeated CES-D measurements and adjusted for identified confounders. Within individuals, depressive symptoms remained relatively stable over follow-up. Compared to stable-low education, stable-high education and upward mobility were associated with significantly lower CES-D scores (β = −2.75 and −2.18, respectively). Downwardly mobile participants had slightly lower CES-D scores than stable-low participants (β = −0.77). Our results suggest that sustained low educational attainment across generations may have adverse mental health consequences, and improved educational opportunities in under-resourced communities may counteract the adverse influence of low parental education on Latino depression.

Shorter Time to Pregnancy With Increasing Preconception Carotene Concentrations Among Women With 1 to 2 Previous Pregnancy Losses

Abstract

Although maternal nutrition may impact fecundity, associations between preconception micronutrients and time to pregnancy (TTP) has not been examined. We assessed the relationship between preconception fat-soluble micronutrient concentrations and TTP among women with 1–2 prior pregnancy losses. This is a prospective cohort study of 1,228 women set in the EAGeR Trial (US, 2007–2011), which assessed the effect of preconception-initiated daily low dose aspirin on reproductive outcomes. We measured preconception zeaxanthin, cryptoxanthin, lycopene, α- and β-carotene, and α- and γ-tocopherol in serum. We used discrete Cox regression models, accounting for left truncation and right censoring, to calculate fecundability odds ratios (FOR) and 95% confidence intervals (CI). Models were adjusted for age, body mass index, race, smoking, alcohol, physical activity, income, vitamin use, cholesterol, treatment arm, and study site. Serum α-carotene levels (FOR = 1.17, 95% CI: 1.00, 1.36, per log unit [μg/dL] increase), as well as concentrations above versus below the US average (2.92 μg/dL) were associated with shorter TTP (FOR = 1.21 95% CI: 1.02, 1.44). Compared to below the US average (187 μg/dL), γ-tocopherol concentrations above the US average were associated with longer TTP (FOR = 0.83, 95% CI: 0.69, 1.00). The potential for these nutrients to influence fecundability deserves further exploration.

Networked Individuals, Gendered Violence: A Literature Review of Cyberviolence

Violence and Gender, Ahead of Print.

Oesophageal causes of dysphagia localised only to the pharynx: Implications for the suspected head and neck cancer pathway

Clinical Otolaryngology, EarlyView.

Total glossolaryngectomy cohort study (N = 25): Survival, function and quality of life

Clinical Otolaryngology, EarlyView.

Investigation of factors influencing the immunogenicity of hCG as a potential cancer vaccine

Clinical &Experimental Immunology, EarlyView.

Sorafenib paradoxically activates the RAS/RAF/ERK pathway in polyclonal human NK cells during expansion and thereby enhances effector functions in a dose‐ and time‐dependent manner

Clinical &Experimental Immunology, EarlyView.

Psychoonkologische Versorgung von Melanompatienten in zertifizierten Hautkrebszentren

JDDG: Journal der Deutschen Dermatologischen Gesellschaft, Volume 16, Issue 5, Page 577-584, May 2018.

Chronische Urtikaria – Was bringt die neue Leitlinie?

JDDG: Journal der Deutschen Dermatologischen Gesellschaft, Volume 16, Issue 5, Page 585-595, May 2018.