A phase I study of veliparib with cyclophosphamide and veliparib combined with doxorubicin and cyclophosphamide in advanced malignancies
PURPOSE/OBJECTIVE:Veliparib (V), an oral poly(ADP-ribose) polymerase (PARP) inhibitor, potentiates effects of alkylating agents and topoisomerase inhibitors in preclinical tumor models. We conducted a phase I trial of V with iv cyclophosphamide (C) and V plus iv doxorubicin (A) and C. METHODS:) Day 3 in 21-day cycles. In Group 3, patients received AC Day 1 plus V Days 1-7, and in Group 4, AC Day 1 plus V Days 1-14 was given in 21-day cycles to evaluate effects on Î³H2AX foci. RESULTS:Eighty patients were enrolled. MTD was not reached for V and C. MTD for V and AC was V 100 mg every 12 h Days 1-4 with AC (60/600 mg/m2) Day 3 every 21 days. V PK appears to be dose-dependent and has no effect on the PK of C. Overall, neutropenia and anemia were the most common adverse events. Objective response in V and AC treated groups was 22% (11/49). Overall clinical benefit rate was 31% (25/80). PAR decreased in PBMCs. Percentage of Î³H2AX-positive CTCs increased after treatment with V and AC. CONCLUSION/CONCLUSIONS:V and AC can be safely combined. Activity was observed in patients with metastatic breast cancer.
Enhancing Reach Out and Read With a Video and Text Messages: A Randomized Trial in a Low-Income Predominantly Latino Sample
OBJECTIVE:To determine the effect of adding a video and text messages to Reach Out and Read (ROR) on parent-reported literacy activities compared to the standard version. STUDY DESIGN/METHODS:We conducted a mixed methods hybrid type I effectiveness-implementation randomized trial in a community health center that serves low-income Latino families. We assessed shared reading frequency and the StimQ Reading subscale, at enrollment and 6-month follow-up and the StimQ Parent Verbal Responsivity subscale, Parent Reading Belief Inventory, and Survey of Wellbeing of Young Children-Milestones at follow-up. We randomized 160 parent-child dyads to ROR or ROR plus video and text messages (enhanced ROR). We collected process data on ROR and engagement with texts. We interviewed 15 enhanced ROR participants. We analyzed quantitative data using regression and qualitative data using immersion/crystallization. RESULTS:One hundred thirty-seven parent-child dyads completed the study (87% Latino, mean child age 9 months). We found differences in the StimQ Reading subscale (BÂ =Â 0.32; P = .034) and marginal differences in attitudes about reading favoring enhanced ROR. Between-group differences for shared reading frequency, verbal responsivity, and developmental delay were not significant. Qualitative themes provided insight into the enhanced ROR including how it encouraged parents, remaining barriers like competing priorities and lack of social support, and unanticipated benefits (ie, parent appreciation for attention on their families' wellbeing). CONCLUSIONS:A video and text message enhancement to ROR resulted in modest improvements in the home literacy environment over ROR alone. Additional strategies are needed to overcome potent barriers faced by low-income families.
HIV-associated Burkitt lymphoma: outcomes from a US-UK collaborative analysis
Data addressing prognostication in patients with HIV related Burkitt lymphoma (HIV-BL) currently treated remain scarce. We present an international analysis of 249 (United States: 140; United Kingdom: 109) patients with HIV-BL treated from 2008 to 2019 aiming to identify prognostic factors and outcomes. With a median follow up of 4.5 years, the 3-year progression-free survival (PFS) and overall survival (OS) were 61% (95% confidence interval [CI] 55% to 67%) and 66% (95%CI 59% to 71%), respectively, with similar results in both countries. Patients with baseline central nervous system (CNS) involvement had shorter 3-year PFS (36%) compared to patients without CNS involvement (69%; P < .001) independent of frontline treatment. The incidence of CNS recurrence at 3 years across all treatments was 11% with a higher incidence observed after dose-adjusted infusional etoposide, doxorubicin, vincristine, prednisone, cyclophosphamide (DA-EPOCH) (subdistribution hazard ratio: 2.52; P = .03 vs other regimens) without difference by CD4 count 100/mm3. In multivariate models, factors independently associated with inferior PFS were Eastern Cooperative Oncology Group (ECOG) performance status 2-4 (hazard ratio [HR] 1.87; P = .007), baseline CNS involvement (HR 1.70; P = .023), lactate dehydrogenase >5 upper limit of normal (HR 2.09; P < .001); and >1 extranodal sites (HR 1.58; P = .043). The same variables were significant in multivariate models for OS. Adjusting for these prognostic factors, treatment with cyclophosphamide, vincristine, doxorubicin, and high-dose methotrexate, ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) was associated with longer PFS (adjusted HR [aHR] 0.45; P = .005) and OS (aHR 0.44; P = .007). Remarkably, HIV features no longer influence prognosis in contemporaneously treated HIV-BL.
Association of Body Mass Index, Central Obesity, and Body Composition With Mortality Among Black Breast Cancer Survivors
Importance/UNASSIGNED:Obesity disproportionately affects Black women, who also have a higher risk of death after a breast cancer diagnosis compared with women of other racial/ethnic groups. However, few studies have evaluated the association of measures of adiposity with mortality among Black breast cancer survivors. Objective/UNASSIGNED:To assess the association of measures of adiposity with survival after a breast cancer diagnosis among Black women. Design, Setting, and Participants/UNASSIGNED:This prospective population-based cohort study comprised 1891 women with stage 0 to IV breast cancer who self-identified as African American or Black and were ages 20 to 75 years. The New Jersey State Cancer Registry was used to identify women living in 10 counties in New Jersey who were recruited from March 1, 2006, to February 29, 2020, and followed up until September 2, 2020. Exposures/UNASSIGNED:Measures of adiposity, including body mass index, body fat distribution (waist circumference and waist-to-hip ratio), and body composition (percent body fat and fat mass index), were collected during in-person interviews at approximately 10 months after breast cancer diagnosis. Main Outcomes and Measures/UNASSIGNED:All-cause and breast cancer-specific mortality. Results/UNASSIGNED:Among 1891 women, the mean (SD) age at breast cancer diagnosis was 54.5 (10.8) years. During a median follow-up of 5.9 years (range, 0.5-14.8 years), 286 deaths were identified; of those, 175 deaths (61.2%) were associated with breast cancer. A total of 1060 women (56.1%) had obesity, and 1291 women (68.3%) had central obesity. Higher adiposity, particularly higher waist-to-hip ratio, was associated with worse survival. Women in the highest quartile of waist-to-hip ratio had a 61% increased risk of dying from any cause (hazard ratio [HR], 1.61; 95% CI, 1.12-2.33) and a 68% increased risk of breast cancer death (HR, 1.68; 95% CI, 1.04-2.71) compared with women in the lowest quartile. The risks of all-cause and breast cancer-specific death were similarly high among women in the highest quartile for waist circumference (HR, 1.74 [95% CI, 1.26-2.41] and 1.64 [95% CI, 1.08-2.48], respectively), percent body fat (HR, 1.53 [95% CI, 1.09-2.15] and 1.81 [95% CI, 1.17-2.80]), and fat mass index (HR, 1.57 [95% CI, 1.11-2.22] and 1.74 [95% CI, 1.10-2.75]); however, the risk was less substantial for body mass index (HR, 1.26 [95% CI, 0.89-1.79] and 1.33 [95% CI, 0.84-2.10]). In analyses stratified by estrogen receptor status, menopausal status, and age, a higher waist-to-hip ratio was associated with a higher risk of all-cause death among women who had estrogen receptor-negative tumors (HR, 2.24; 95% CI, 1.14-4.41), women who were postmenopausal (HR, 2.15; 95% CI, 1.28-3.61), and women who were 60 years or older at diagnosis (HR per 0.10-U increase, 1.76; 95% CI, 1.37-2.26). Conclusions and Relevance/UNASSIGNED:In this population-based cohort study, central obesity and higher adiposity were associated with higher all-cause and breast cancer-specific mortality among Black breast cancer survivors. Simple measures of body fat distribution and body composition were found to be useful tools for identifying Black women with a higher risk of death after a breast cancer diagnosis.
Ultra-Processed Foods and Incident Cardiovascular Disease in the Framingham Offspring Study
BACKGROUND:Ultra-processed foods provide 58% of total energy in the U.S. diet, yet their association with cardiovascular disease (CVD) remains understudied. OBJECTIVES/OBJECTIVE:The authors investigated the associations between ultra-processed foods and CVD incidence and mortality in the prospective Framingham Offspring Cohort. METHODS:The analytical sample included 3,003 adults free from CVD with valid dietary data at baseline. Data on diet, measured by food frequency questionnaire, anthropometric measures, and sociodemographic and lifestyle factors were collected quadrennially from 1991 to 2008. Data regarding CVD incidence and mortality were available until 2014 and 2017, respectively. Ultra-processed foods were defined according to the NOVA framework. The authors used Cox proportional hazards models to determine the multivariable association between ultra-processed food intake (energy-adjusted servings per day) and incident hard CVD, hard coronary heart disease (CHD), overall CVD, and CVD mortality. Multivariable models were adjusted for age, sex, education, alcohol consumption, smoking, and physical activity. RESULTS:During follow-up (1991 to 2014/2017), the authors identified 251, 163, and 648 cases of incident hard CVD, hard CHD, and overall CVD, respectively. On average, participants consumed 7.5 servings per day of ultra-processed foods at baseline. Each additional daily serving of ultra-processed foods was associated with a 7% (95% confidence interval [CI]: 1.03 to 1.12), 9% (95%Â CI: 1.04 to 1.15), 5% (95%Â CI: 1.02 to 1.08), and 9% (95%Â CI: 1.02 to 1.16) increase in the risk of hard CVD, hard CHD, overall CVD, and CVD mortality, respectively. CONCLUSIONS:The current findings support that higher consumption of ultra-processed foods is associated with increased risk of CVD incidence and mortality. Although additional research in ethnically diverse populations is warranted, these findings suggest cardiovascular benefits of limiting ultra-processed foods.
Trends in food consumption by degree of processing and diet quality over 17 years: results from the Framingham Offspring Study
Ultraprocessed foods provide the majority of energy content in the American diet, yet little is known regarding consumption trends over time. We determined trends in diet processing level and diet quality from 1991 to 2008 within the prospective Framingham Offspring Cohort. Dietary intakes were collected by FFQ quadrennially 1991-2008 (total of four examinations). The analytical sample included 2893 adults with valid dietary data for â‰¥3 examinations (baseline mean age = 54 years). Based on the NOVA framework, we classified foods as: unprocessed/minimally processed foods; processed culinary ingredients (salt/sugar/fats/oils); and processed foods and ultraprocessed foods. We evaluated diet quality using the Dietary Guidelines for Americans Adherence Index (DGAI) 2010. Trends in consumption of foods within each processing level (servings/d) and diet quality over the four examinations were evaluated using mixed effects models with subject-specific random intercepts. Analyses were stratified by sex, BMI (<25 kg/m2, 25-29Â·9 kg/m2, â‰¥30 kg/m2) and smoking status. Over 17 years of follow-up, ultraprocessed food consumption decreased from 7Â·5 to 6Â·0 servings/d and minimally processed food consumption decreased from 11Â·9 to 11Â·3 servings/d (Ptrend < 0Â·001). Changes in intakes of processed foods, culinary ingredients and culinary preparations were minimal. Trends were similar by sex, BMI and smoking status. DGAI-2010 score increased from 60Â·1 to 61Â·5, P < 0Â·001. The current study uniquely describes trends in diet processing level in an ageing US population, highlighting the longstanding presence of ultraprocessed foods in the American diet. Given the poor nutritional quality of ultraprocessed foods, public health efforts should be designed to limit their consumption.
Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)
In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
Burkitt lymphoma in the modern era: real-world outcomes and prognostication across 30 US cancer centers
We examined adults with untreated Burkitt lymphoma (BL) from 2009 to 2018 across 30 US cancer centers. Factors associated with progression-free survival (PFS) and overall survival (OS) were evaluated in univariate and multivariate Cox models. Among 641 BL patients, baseline features included the following: median age, 47 years; HIV+, 22%; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 to 4, 23%; >1 extranodal site, 43%; advanced stage, 78%; and central nervous system (CNS) involvement, 19%. Treatment-related mortality was 10%, with most common causes being sepsis, gastrointestinal bleed/perforation, and respiratory failure. With 45-month median follow-up, 3-year PFS and OS rates were 64% and 70%, respectively, without differences by HIV status. Survival was better for patients who received rituximab vs not (3-year PFS, 67% vs 38%; OS, 72% vs 44%; P < .001) and without difference based on setting of administration (ie, inpatient vs outpatient). Outcomes were also improved at an academic vs community cancer center (3-year PFS, 67% vs 46%, P = .006; OS, 72% vs 53%, P = .01). In multivariate models, age â‰¥ 40 years (PFS, hazard ratio [HR] = 1.70, P = .001; OS, HR = 2.09, P < .001), ECOG PS 2 to 4 (PFS, HR = 1.60, P < .001; OS, HR = 1.74, P = .003), lactate dehydrogenase > 3Ã— normal (PFS, HR = 1.83, P < .001; OS, HR = 1.63, P = .009), and CNS involvement (PFS, HR = 1.52, P = .017; OS, HR = 1.67, P = .014) predicted inferior survival. Furthermore, survival varied based on number of factors present (0, 1, 2 to 4 factors) yielding 3-year PFS rates of 91%, 73%, and 50%, respectively; and 3-year OS rates of 95%, 77%, and 56%, respectively. Collectively, outcomes for adult BL in this real-world analysis appeared more modest compared with results of clinical trials and smaller series. In addition, clinical prognostic factors at diagnosis identified patients with divergent survival rates.
Longitudinal dimensions of alcohol consumption and dietary intake in the Framingham Heart Study Offspring Cohort (1971-2008)
Existing studies addressing alcohol consumption have not captured the multidimensionality of drinking patterns, including drinking frequency, binge drinking, beverage preference and changes in these measures across the adult life course. We examined longitudinal trends in drinking patterns and their association with diet over four decades in ageing US adults from the Framingham Offspring Study (n 4956; baseline mean age 36Â·2 years). Alcohol intake (drinks/week, drinking frequency, beverage-specific consumption, drinks/occasion) was assessed quadrennially from examinations 1 to 8. Participants were classified as binge drinkers, moderate drinkers or heavy drinkers (4+ and 5+ drinks/occasion; â‰¤1 and â‰¤2 drinks/d and >7 and >14 drinks/week for women and men, respectively). Dietary data were collected by a FFQ from examinations 5 to 8 (1991-2008). We evaluated trends in drinking patterns using linear mixed effect models and compared dietary intake across drinking patterns using heterogeneous variance models. Alcohol consumption decreased from 1971 to 2008 (3Â·7 v. 2Â·2 oz/week; P < 0Â·05). The proportion of moderate (66 v. 59Â·3 %), heavy (18Â·4 v. 10Â·5 %) and binge drinkers (40Â·0 v. 12Â·3 %) declined (P < 0Â·05). While average wine consumption increased (1Â·4 v. 2Â·2 drinks/week), beer (3Â·4 v. 1Â·5 drinks/week) and cocktail intake (2Â·8 v. 1Â·2 drinks/week) decreased. Non-binge drinkers consumed less sugary drinks and more whole grains than binge drinkers, and the latter consumed more total fat across all examinations (P < 0Â·05). There was a significant difference in consumption trends of total grains by drinking level (P < 0Â·05). In conclusion, alcohol drinking patterns are unstable throughout adulthood. Higher intakes were generally associated with poorer diets. These analyses support the nuanced characterisation of alcohol consumption in epidemiological studies.
Early Shared Reading Is Associated with Less Harsh Parenting
OBJECTIVE:Shared reading is believed to enhance parent-child relationships, but the extent to which it reduces harsh parenting is understudied. Associations between early shared reading and subsequent harsh parenting were investigated. METHODS:Data from a national urban birth cohort were used to estimate associations between mother-reported shared reading at ages 1 and 3 years and harsh parenting-based on a composite of psychological and physical aggression subscales of a validated self-report instrument-when the children were at ages 3 and 5 years. The authors used multivariable linear regression and generalized estimating equations to account for repeated observations. Given potential inverse associations between shared reading and child disruptive behaviors, which can trigger harsh parenting, the authors investigated the extent to which children's behavior at age 3 years mediated the association between shared reading at age 1 year and harsh parenting at age 5 years. RESULTS:This study included 2165 mother-child dyads. Thirty-four percent and 52% of mothers reported daily reading at ages 1 and 3 years. In adjusted models, shared reading at age 1 year was associated with less harsh parenting at age 3 years. Similarly, shared reading at age 3 years was associated with less harsh parenting at age 5 years. These associations remained significant in lagged repeated-measures models. Decreased disruptive behaviors partially mediated the association between shared reading at age 1 year and harsh parenting at age 5 years. CONCLUSION/CONCLUSIONS:Shared reading predicted less harsh parenting in a national urban sample. These findings suggest that shared reading contributes to an important aspect of the parent-child relationship and that some of the association operates through enhanced child behaviors.