Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study.

BACKGROUND: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only. METHODS: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or Tany N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual. FINDINGS: Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group vs none in the surgery only group), anaemia (seven [2%] vs nine [2%]), increased alanine aminotransferase (ten [3%] vs one [<1%]), abdominal pain (four [1%] vs six [2%]), and increased serum amylase (nine [2%] vs none). 177 (48%) patients in the nivolumab plus surgery group and 93 (24%) in the surgery only group had grade 3-5 adverse events due to any cause, the most common of which were anaemia (23 [6%] vs 19 [5%]), hypertension (27 [7%] vs nine [2%]), and elevated lipase (18 [5%] vs six [2%]). 48 (12%) of 404 patients in the nivolumab group and 40 (10%) of 415 in the surgery only group died, of which eight (2%) and three (1%), respectively, were determined to be treatment-related. INTERPRETATION: Perioperative nivolumab before nephrectomy followed by adjuvant nivolumab did not improve recurrence-free survival versus surgery only followed by surveillance in patients with high-risk renal cell carcinoma. FUNDING: US National Institutes of Health National Cancer Institute and Bristol Myers Squibb.

An Exploration of How Mexican American WIC Mothers Obtain Information About Behaviors Associated With Childhood Obesity Risk.

OBJECTIVE: To explore how a sample of Mexican American mothers with preschool-aged children recruited from a Midwestern Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) clinic obtained information about 4 behaviors associated with childhood obesity risk: eating, physical activity, screen time, and sleep. DESIGN: One-on-one structured interviews in which participants were asked how they communicated with family, learned to take care of their first infant, and obtained information about the 4 targeted behaviors for their preschool-aged child. SETTING: An urban WIC clinic in the Midwest. PARTICIPANTS: Forty Mexican-descent mothers enrolled in WIC with children aged 3-4 years. PHENOMENON OF INTEREST: Exposure to information about the 4 targeted behaviors among Mexican-descent mothers participating in WIC. ANALYSIS: Quantitative and qualitative data were used to characterize and compare across participants. RESULTS: Participants primarily obtained information from their child's maternal grandmother during their first child's infancy and from health professionals for their preschool-aged child. Participants typically obtained information through interpersonal communication, television, and magazines. Participants were most interested in healthy eating information and least interested in screen time information. Some participants did not seek information. CONCLUSIONS AND IMPLICATIONS: Participants engaged in different patterns of information seeking across their child's development and the 4 behaviors, which suggests that future research should be behaviorally specific. Findings from this study suggest several hypotheses to test in future research.

A Tale of Two Stories: An Exploration of Identification, Message Recall, and Narrative Preferences Among Low-Income, Mexican American Women.

Additional research is needed to guide the design of narratives for use in practice-oriented, naturalistic settings to maximize health behavior change, particularly among populations affected by health disparities. This mixed-methods study explored the influence of cultural tailoring and emotional arousal on identification and message recall in narratives promoting childhood obesity prevention among 40 Mexican American mothers. Participants were also asked about narrative exposure, narrative preferences, and beliefs about the purpose of a story. Participants were randomly assigned to listen to two stories: (a) a story tailored on noncultural or cultural variables, and (b) a story designed to enhance or minimize emotional arousal. Participants reported high engagement and identification with all stories. Participants generally envisioned protagonists as Latina, despite limited cues, and identified with protagonists in four ways: sharing personal characteristics; having similar thoughts and feelings; engaging in similar actions; and experiencing similar situations. Mothers were most interested in narratives that helped them to improve their lives. Findings from this study yield several hypotheses for consideration in future study, including ways in which story setting and message enactment may moderate message recall.

Eat, play, view, sleep: Exploring Mexican American mothers' perceptions of decision making for four behaviors associated with childhood obesity risk.

OBJECTIVE: This mixed methods study sought to understand who makes decisions about whether preschool-aged Mexican American children engage in eating, outdoor play, sleep, and screen time behaviors. METHODS: Forty Mexican American mothers of children ages 3-4 participated in two interviews, during which both closed- and open-ended questions elicited perceptions of who made decisions for the four behaviors, as well as who was present, mealtime rules, and food choice values. Interviews were transcribed, coded for emergent themes, and compared across participants. RESULTS: Participants generally perceived themselves to be primary decision makers for all four behaviors; however, food decisions often seemed to be made collaboratively with the child. Fathers were most likely to participate in evening television decisions. Other family members were rarely mentioned. Selecting foods that children liked was a strong food choice value, while cost was rarely mentioned. Participants appeared to have low perceived control over their child's behaviors relative to their perceived roles in decision making. CONCLUSIONS: Mothers may be the primary audience for obesity prevention messages for preschool-aged, Mexican American children; however, health promotion programs may need to increase mothers' awareness of their control over children's behaviors. Understanding how children's behaviors are regulated is an important aspect of obesity prevention for low-income, Mexican American children.

"It Hurts a Latina When They Tell Us Anything About Our Children": Implications of Mexican-Origin Mothers' Maternal Identities, Aspirations, and Attitudes About Cultural Transmission for Childhood Obesity Prevention.

BACKGROUND: This qualitative study explored values, attitudes, and beliefs held by Mexican-origin mothers of preschool-aged children to enhance understanding of cultural influences on behaviors associated with childhood obesity risk. METHODS: During face-to-face interviews, 39 Mexican-origin mothers of preschool-aged children discussed their hopes for their children, their image of the perfect mother, Mexican and American foods, why they taught their children about these foods, and their opinions about television (TV) viewing language. RESULTS: Participants wanted their children to become successful, "good" people, which necessitated doing well in school. Mothers also wanted their children to know them, which required understanding the mothers' Mexican backgrounds. Mothers wanted their children to maintain Mexican values and identities. Some mothers viewed American culture as harmful. Many participants prepared their child for going to Mexico by exposing them to Mexican culture and foods. Some mothers fed their children American foods to prepare them for school. Perceptions of American foods generally reflected stereotypical unhealthy foods. TV helped teach children Spanish and English. Being a good mother was core to participants' identities; thus, hearing about child overweight made some mothers feel like failures. CONCLUSIONS: Health promotion programs may be more salient to mothers if they: underscore how a healthy weight can help children in school; teach mothers to prepare healthy American foods that their children will encounter in kindergarten; assist mothers in teaching their children about Mexico; and present information about childhood obesity in ways that reinforce what mothers are doing well, enhance mothers' self-efficacy, and allay feelings of failure.

Reduced-intensity allogeneic hematopoietic stem cell transplantation for relapsed multiple myeloma.

Despite recent advances, multiple myeloma (MM) remains incurable, and most patients eventually develop progressive disease. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) offers a potentially curative option in 10%-20% of patients with relapsed or refractory disease. We evaluated the outcome of patients undergoing allo-HSCT with reduced-intensity conditioning (RIC) for relapsed and/or refractory MM at our institution. The study cohort included 51 patients with heavily pretreated, relapsed MM who underwent RIC allo-HSCT between 1996 and 2006. The median time from diagnosis to allo-HSCT was 34 months, and median follow-up in surviving patients was 27 months (range, 3-98 months). Cumulative transplantation-related mortality at 1 year was 25%. Progression-free survival (PFS) and overall survival (OS) at 2 years were 19% and 32%, respectively. The incidences of grade II-IV acute and chronic graft-versus-host disease were 27% and 47%, respectively. At the time of this analysis, 12 patients (24%) were alive, 7 of whom (14%) were in remission for up to 6 years after allo-HSCT. A lower beta2 microglobulin level (<3.3) and previous autologous HSCT were predictive of lower nonrelapse mortality and longer PFS and OS. Our findings indicate that allo-HSCT with RIC is associated with acceptable toxicity and durable remission and survival in relapsed or refractory MM. The use of RIC allo-HSCT earlier in the course of the disease may offer the greatest benefit.

A coalescent simulation of marker selection strategy for candidate gene association studies.

Recent efforts have focused on the challenges of finding alleles that contribute to health-related phenotypes in genome-wide association studies. However, in candidate gene studies, where the genomic region of interest is small and recombination is limited, factors that affect the ability to detect disease-susceptibility alleles remain poorly understood. In particular, it is unclear how varying the number of markers on a haplotype, the type of marker (e.g., single nucleotide polymorphism (SNP), short tandem repeat (STR)), including the causative site (cs) as a genetic marker, or population demographics influences the power to detect a candidate gene. We evaluated the power of association tests using coalescent-modeled computer simulations. Results show that an effective number of markers on a haplotype is dependent on whether the cs is included as a marker. When the analyses include the cs, highest power is achieved with a single-marker association test. However, when the cs is excluded from analyses, the addition of more nonfunctional SNPs on the haplotype increases power to a certain point under most scenarios. We find a rapidly expanding population always has lower power compared to a population of constant size; although utilizing markers with a frequency of at least 5% improves the chance of detecting an association. Comparing the mutational properties of a nonfunctional SNP versus an STR, multi-allelic STRs provide more or comparable power than a bi-allelic SNP unless SNP frequencies are constrained to 10% or more. Similarly, including an STR with SNPs on a haplotype improves power unless SNP frequencies are 5% or more.

Enhanced VWF biosynthesis and elevated plasma VWF due to a natural variant in the murine Vwf gene.

Both genetic and environmental influences contribute to the wide variation in plasma von Willebrand factor (VWF) levels observed in humans. Inbred mouse strains also have highly variable plasma VWF levels, providing a convenient model in which to study genetic modifiers of VWF. Previously, we identified a major modifier of VWF levels in the mouse (Mvwf1) as a regulatory mutation in murine Galgt2. We now report the identification of an additional murine VWF modifier (Mvwf2). Mvwf2 accounts for approximately 16% of the 8-fold plasma VWF variation (or approximately 25% of the genetic variation) observed between the A/J and CASA/RkJ strains and maps to the murine Vwf gene itself. Twenty SNPs were identified within the coding regions of the A/J and CASA/RkJ Vwf alleles, and in vitro analysis of recombinant VWF demonstrated that a single SNP (+7970G>A) and the associated nonsynonymous amino acid change (R2657Q) confers a significant increase in VWF biosynthesis from the CASA/RkJ Vwf allele. This change appears to represent a unique gain of function that likely explains the mechanism of Mvwf2 in vivo. The identification of a natural Vwf gene variant among inbred mice affecting biosynthesis suggests that similar genetic variation may contribute to the wide range of VWF levels observed in humans.

A lifestyle intervention improves plasma insulin levels among Native American high school youth.

BACKGROUND: Worldwide, type 2 diabetes prevalence is increasing, with Native American populations particularly at risk. The Zuni Pueblo, with a history of wellness activities, volunteered to test the feasibility and efficacy of a high school-based diabetes prevention intervention. METHODS: This school-based intervention used a multiple cross-sectional design to evaluate outcome measures at 0, 1.5, and 3 years against an Anglo comparison group. The Zuni high school diabetes prevention program included an educational component targeting decreased consumption of sugared beverages, knowledge of diabetes risk factors, and a youth-oriented fitness center. Main outcome measures were plasma glucose and insulin measured fasting and 30 min after a 75-g glucose challenge. RESULTS: Plasma glucose levels were normal at baseline for Zuni (n = 72) and Anglo (n = 37) youth and did not significantly change throughout the study. At baseline, fasting and 30-min plasma insulin levels were significantly elevated for Zuni youth; they showed significant steady declines for both males and females throughout the study (P = 0.06 to P = 0.000 for trends using quantile regression). By Year 3, values for Zuni males (n = 29) equaled Anglo comparison values, while Zuni female (n = 26) values had declined but were still higher than Anglo comparison values. CONCLUSIONS: Among at-risk youth, an environmentally based lifestyle intervention may significantly suppress markers of type 2 diabetes risk.