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Relative dose intensity of first-line chemotherapy and overall survival in patients with advanced non-small-cell lung cancer

Support Care Cancer

2019 Lyman, Gary H, MD, MPH Gary Lyman

PURPOSE: The effects of chemotherapy dose intensity on survival in patients with advanced non-small-cell lung cancer (NSCLC) are poorly understood. We retrospectively analyzed dose delays/reduction, relative dose intensity (RDI), and the association between chemotherapy intensity and survival in advanced NSCLC. METHODS: This retrospective cohort study included adults with advanced lung cancer who received first-line myelosuppressive platinum-based chemotherapy (January 2007-December 2010) in ~ 230 US Oncology Network community practices. Dose delays >/= 7 days, dose reductions >/= 15%, and RDI relative to standard regimens were described. Overall survival (OS) was measured using Kaplan-Meier and Cox proportional hazard (PH) models. RESULTS: Among 3866 patients with advanced NSCLC, 32.4% experienced dose delays >/= 7 days, 50.1% experienced dose reductions >/= 15%, and 40.4% had RDI < 85%. Reduced RDI was also common regardless of baseline ECOG PS (ECOG PS >/= 2, 56.2%; ECOG PS 0, 33.6%) and tumor subgroup (squamous cell carcinoma, 52.2%; adenocarcinoma, 36.0%). When stratified by chemotherapy intensity measures, significant OS differences were observed only for dose delays. Median (95% CI) OS was 1.02 years (0.96-1.12) for dose delays >/= 7 days and 0.71 years (0.66-0.77) for dose delays < 7 days. In multivariable Cox PH analysis, dose delays >/= 7 days (HR = 0.71; 95% CI = 0.63-0.80) and RDI >/= 85% (HR = 1.18; 95% CI = 1.05-1.32) were significantly associated with decreased mortality. CONCLUSIONS: Dose delays, dose reductions, and reduced RDI were common, and dose delays >/= 7 days and high RDI were significantly associated with decreased mortality. These results can help identify potential risk factors and characterize the effect of chemotherapy dose modification strategies on mortality.

Reimbursing Patients for Participation in Cancer Clinical Trials

JAMA Oncol

2019 Unger, Joseph M, PhD, MS Joseph Unger


Traditional cardiovascular risk factors and individual prediction of cardiovascular events in childhood cancer survivors

J Natl Cancer Inst

2019 Leisenring, Wendy M, ScD Wendy m Leisenring

BACKGROUND: Childhood cancer survivors have an increased risk of heart failure, ischemic heart disease, and stroke. They may benefit from prediction models that account for cardiotoxic cancer treatment exposures combined with information on traditional cardiovascular risk factors such as hypertension, dyslipidemia, and diabetes. METHODS: Childhood Cancer Survivor Study participants (n = 22,643) were followed through age 50y for incident heart failure, ischemic heart disease, and stroke. Siblings (n = 5,056) served as a comparator. Participants were assessed longitudinally for hypertension, dyslipidemia, and diabetes based on self-reported prescription medication use. Half the cohort was used for discovery; the remainder for replication. Models for each outcome were created for survivors ages 20y, 25y, 30y, and 35y at the time of prediction (n = 12 models). RESULTS: For discovery, risk scores based on demographic, cancer treatment, hypertension, dyslipidemia, and diabetes information achieved areas under the receiver operating characteristic curve (AUC) and concordance (C) statistics >/=0.70 in 9 and 10 of the 12 models, respectively. For replication, AUCs and C-statistics >/=0.70 were observed in 7 and 9 of the models, respectively. Across outcomes, the most influential exposures were anthracycline, radiotherapy, diabetes, and hypertension. Survivors were then assigned to statistically distinct moderate- and high-risk groups corresponding to age 50y cumulative incidences of each target outcome <3% and approximately >/=10%, respectively. Siblings had cumulative incidences </=1% for all outcomes. CONCLUSIONS: Traditional cardiovascular risk factors remain important for predicting risk of cardiovascular disease among adult-aged survivors of childhood cancer. These prediction models provide a framework to base future surveillance strategies and interventions.

Physical Activity in Cancer Prevention and Survival: A Systematic Review

Medicine and science in sports and exercise

2019 McTiernan, Anne M, MD, PhD Anne McTiernan

PURPOSE: This article reviews and updates the evidence on the associations between physical activity and risk for cancer, and for mortality in persons with cancer, as presented in the 2018 Physical Activity Guidelines Advisory Committee Scientific Report. METHODS: Systematic reviews of meta-analyses, systematic reviews, and pooled analyses were conducted through December 2016. An updated systematic review of such reports plus original research through February 2018 was conducted. This article also identifies future research needs. RESULTS: In reviewing 45 reports comprising hundreds of epidemiologic studies with several million study participants, the report found strong evidence for an association between highest versus lowest physical activity levels and reduced risks of bladder, breast, colon, endometrial, esophageal adenocarcinoma, renal, and gastric cancers. Relative risk reductions ranged from approximately 10% to 20%. Based on 18 systematic reviews and meta-analyses, the report also found moderate or limited associations between greater amounts of physical activity and decreased all-cause and cancer-specific mortality in individuals with a diagnosis of breast, colorectal, or prostate cancer, with relative risk reductions ranging almost up to 40% to 50%. The updated search, with five meta-analyses and 25 source articles reviewed, confirmed these findings. CONCLUSIONS: Levels of physical activity recommended in the 2018 Guidelines are associated with reduced risk and improved survival for several cancers. More research is needed to determine the associations between physical activity and incidence for less common cancers and associations with survival for other cancers. Future studies of cancer incidence and mortality should consider these associations for population subgroups, to determine dose-response relationships between physical activity and cancer risk and prognosis, and to establish mechanisms to explain these associations.

Brief Report: Cofactors of Mortality Among Hospitalized HIV-Infected Children Initiating Antiretroviral Therapy in Kenya

J Acquir Immune Defic Syndr

2019 Richardson, Barbra A, PhD Barbra Richardson

OBJECTIVES: Identifying factors associated with mortality among acutely ill HIV-infected children presenting with advanced HIV disease may help clinicians optimize care for those at highest risk of death. DESIGN: Using data from a randomized controlled trial (NCT02063880), we determined baseline sociodemographic, clinical, and laboratory cofactors of mortality among HIV-infected children in Kenya. METHODS: We enrolled hospitalized, HIV-infected, antiretroviral therapy-naive children (0-12 years), initiated antiretroviral therapy, and followed up them for 6 months. We used Cox proportional hazards regression to estimate hazard ratios (HRs) for death and 95% confidence intervals (CIs). RESULTS: Of 181 enrolled children, 39 (22%) died. Common diagnoses at death were pneumonia or suspected pulmonary tuberculosis [23 (59%)] and gastroenteritis [7 (18%)]. Factors associated with mortality in univariate analysis included age <2 years [HR 3.08 (95% CI: 1.50 to 6.33)], orphaned or vulnerable child (OVC) [HR 2.05 (95% CI: 1.09 to 3.84)], weight-for-age Z score <-2 [HR 2.29 (95% CI: 1.05 to 5.00)], diagnosis of pneumonia with hypoxia [HR 5.25 (95% CI: 2.00 to 13.84)], oral thrush [HR 2.17 (95% CI: 1.15 to 4.09)], persistent diarrhea [HR 3.81 (95% CI: 1.89 to 7.69)], and higher log10 HIV-1 viral load [HR 2.16 (95% CI: 1.35 to 3.46)] (all P < 0.05). In multivariable analysis, age <2 years and OVC status remained significantly associated with mortality. CONCLUSIONS: Young age and OVC status independently predicted mortality. Hypoxic pneumonia, oral thrush, and persistent diarrhea are important clinical features that predict mortality. Strategies to enhance early diagnosis in children and improve hospital management of critically ill HIV-infected children are needed.

Physical Activity to Prevent and Treat Hypertension: A Systematic Review

Medicine and science in sports and exercise

2019 McTiernan, Anne M, MD, PhD Anne McTiernan

PURPOSE: This systematic umbrella review examines and updates the evidence on the relationship between physical activity (PA) and blood pressure (BP) presented in the 2008 Physical Activity Guidelines Advisory Committee Scientific Report. METHODS: We performed a systematic review to identify systematic reviews and meta-analyses involving adults with normal BP, prehypertension, and hypertension published from 2006 to February 2018. RESULTS: In total, 17 meta-analyses and one systematic review with 594,129 adults >/=18 yr qualified. Strong evidence demonstrates: 1) an inverse dose-response relationship between PA and incident hypertension among adults with normal BP; 2) PA reduces the risk of cardiovascular disease (CVD) progression among adults with hypertension; 3) PA reduces BP among adults with normal BP, prehypertension, and hypertension; and 4) the magnitude of the BP response to PA varies by resting BP, with greater benefits among adults with prehypertension than normal BP. Moderate evidence indicates the relationship between resting BP and the magnitude of benefit does not vary by PA type among adults with normal BP, prehypertension, and hypertension. Limited evidence suggests the magnitude of the BP response to PA varies by resting BP among adults with hypertension. Insufficient evidence is available to determine if factors such as sex, age, race/ethnicity, socioeconomic status, and weight status or the frequency, intensity, time, and duration of PA influence the associations between PA and BP. CONCLUSIONS: Future research is needed that adheres to standard BP measurement protocols and classification schemes to better understand the influence of PA on the risk of comorbid conditions, health-related quality of life, and CVD progression and mortality; the interactive effects between PA and antihypertensive medication use; and the immediate BP-lowering benefits of PA.

Screening flexible sigmoidoscopy versus colonoscopy for reduction of colorectal cancer mortality

Int J Colorectal Dis

2019 Weiss, Noel S, MD, PhD Noel Weiss

PURPOSE: Colonoscopy and flexible sigmoidoscopy are both recommended colorectal cancer (CRC) screening strategies, but their relative effectiveness is unclear. We sought to evaluate the ability of each of these two modalities to reduce CRC mortality. METHODS: We conducted a case-control study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Cases were persons aged 70-85 years who died of CRC and were matched to up to three non-CRC controls. Receipt of endoscopy was ascertained from Medicare claims and endoscopy indication assigned using a validated algorithm. Conditional logistic regression models were developed to estimate the association between screening colonoscopy or sigmoidoscopy and CRC mortality. We conducted secondary analyses by race, sex, and endoscopist characteristics, and with varying duration of the look-back period. RESULTS: In the initial analysis using all available look-back years, screening flexible sigmoidoscopy was associated with a 35% reduction in CRC mortality (OR 0.65, 95% CI 0.48, 0.89), while screening colonoscopy was associated with a 74% reduction (OR 0.26, 95% CI 0.23, 0.30). Sigmoidoscopy was not associated with any reduction in proximal CRC mortality. The association between colonoscopy and reduced CRC mortality was stronger in the distal than the proximal colon. Results were similar in analyses using a 5-year look-back period. CONCLUSIONS: Screening colonoscopy was associated with greater reductions in CRC mortality than screening sigmoidoscopy, and with a greater reduction in the distal than the proximal colon. These results provide additional information on the relative benefits of screening for CRC with sigmoidoscopy and colonoscopy.

Associating somatic mutations to clinical outcomes: a pan-cancer study of survival time

Genome medicine

2019 Sun, Wei, PhD Wei Sun

We developed subclone multiplicity allocation and somatic heterogeneity (SMASH), a new statistical method for intra-tumor heterogeneity (ITH) inference. SMASH is tailored to the purpose of large-scale association studies with one tumor sample per patient. In a pan-cancer study of 14 cancer types, we studied the associations between survival time and ITH quantified by SMASH, together with other features of somatic mutations. Our results show that ITH is associated with survival time in several cancer types and its effect can be modified by other covariates, such as mutation burden. SMASH is available at .

Binding Heterogeneity of Plasmodium falciparum to Engineered 3D Brain Microvessels Is Mediated by EPCR and ICAM-1


2019 Zheng, Ying Ying Chen

Cerebral malaria is a severe neurological complication associated with sequestration of Plasmodium falciparum-infected erythrocytes (IE) in the brain microvasculature, but the specific binding interactions remain under debate. Here, we have generated an engineered three-dimensional (3D) human brain endothelial microvessel model and studied P. falciparum binding under the large range of physiological flow velocities that occur in both health and disease. Perfusion assays on 3D microvessels reveal previously unappreciated phenotypic heterogeneity in parasite binding to tumor necrosis factor alpha (TNF-alpha)-activated brain endothelial cells. While clonal parasite lines expressing a group B P. falciparum erythrocyte membrane protein 1 (PfEMP1) present an increase in binding to activated 3D microvessels, P. falciparum -IE expressing DC8-PfEMP1 present a decrease in binding. The differential response to endothelium activation is mediated by surface expression changes of endothelial protein C receptor (EPCR) and intercellular adhesion molecule 1 (ICAM-1). These findings demonstrate heterogeneity in parasite binding and provide evidence for a parasite strategy to adapt to a changing microvascular environment during infection. The engineered 3D human brain microvessel model provides new mechanistic insight into parasite binding and opens opportunities for further studies on malaria pathogenesis and parasite-vessel interactions.IMPORTANCE Cerebral malaria research has been hindered by the inaccessibility of the brain. Here, we have developed an engineered 3D human brain microvessel model that mimics the blood flow rates and architecture of small blood vessels to study how P. falciparum -infected human erythrocytes attach to brain endothelial cells. By studying parasite lines with different adhesive properties, we show that the malaria parasite binding rate is heterogeneous and strongly influenced by physiological differences in flow and whether the endothelium has been previously activated by TNF-alpha, a proinflammatory cytokine that is linked to malaria disease severity. We also show the importance of human EPCR and ICAM-1 in parasite binding. Our model sheds new light on how P. falciparum binds within brain microvessels and provides a powerful method for future investigations of recruitment of human brain pathogens to the blood vessel lining of the brain.

Docetaxel, Oxaliplatin, and 5-Fluorouracil (DOF) in Metastatic and Unresectable Gastric/Gastroesophageal Junction Adenocarcinoma: A Phase II Study with Long-Term Follow-Up


2019 Shankaran, Veena, MD Veena Shankaran

LESSONS LEARNED: Adding docetaxel to the modified FOLFOX7 backbone (DOF) is a feasible three-drug combination therapy for advanced gastric cancer with high activity, providing evidence that leucovorin is not necessary in this setting.The DOF regimen represents an alternative to the FLOT (5-FU 2,600 mg/m(2) as 24-hour infusion with leucovorin 200 mg/m(2), oxaliplatin 85 mg/m(2), and docetaxel 50 mg/m(2)) regimen that can be considered in select patients with advanced gastric cancer and is a potential choice in the curative setting. BACKGROUND: The combination of docetaxel, cisplatin, and 5-fluorouracil (5-FU) demonstrates high response rates in advanced gastric cancer, albeit with increased toxicity. Given the efficacy of platinum-taxane-fluoropyrimidine regimens, this phase II study evaluated the efficacy and toxicity of docetaxel, oxaliplatin, and 5-FU (DOF) for the treatment of metastatic or unresectable gastric or gastroesophageal junction (GEJ) adenocarcinoma. METHODS: Patients with metastatic or unresectable gastric or GEJ adenocarcinoma with no prior therapy for metastatic disease received docetaxel 50 mg/m(2) on day 1, oxaliplatin 85 mg/m(2) on day 1, and 5-FU 2,400 mg/m(2) continuous intravenous infusion over 46 hours; cycles were repeated every 2 weeks. The primary endpoint was overall response rate (ORR). RESULTS: Forty-four patients were enrolled. Assessment of treatment response and toxicity was feasible in 41 and 43 patients, respectively. ORR was 73.2% (68.3% partial response; 4.9% complete response). Therapy was discontinued for progressive disease in 53%, toxicity in 26%, and death on treatment in 16%. Two patients underwent surgical resection. Thirty-three patients (76.7%) received at least seven cycles (7-34). Grade 3-4 toxicities occurred in 31 patients (72.1%), including neutropenia (23.3%), neurologic (20.9%), and diarrhea (14.0%). Median overall survival was 10.3 months. CONCLUSION: DOF demonstrates a high response rate, expected safety profile, and prolonged survival and remains an option for select patients with unresectable or metastatic gastric or GEJ adenocarcinoma.