Weight Loss In Group Research Articles

Cancer cachexia and weight loss before CAR T-cell therapy for lymphoma are independently associated with poor outcomes

AbstractChimeric antigen receptor (CAR) T-cell therapy has transformed the care of lymphoma, yet many patients relapse. Several prognostic markers have been associated with CAR T-cell outcomes, such as tumor burden, response to bridging chemotherapy, and laboratory parameters at the time of lymphodepletion or infusion. The effect of cancer cachexia and weight loss before CAR T cells on toxicity and outcomes is not well understood. Here, we present a retrospective single-institution cohort study of 259 patients with lymphoma treated with CAR T cells between 2017 and 2023. We observed that patients with >5% decrease in their body mass index in the 3 months preceding CAR T-cell treatment (weight loss group; all meeting one of the commonly accepted definitions of cancer cachexia) had higher disease burden and inflammatory parameters (C-reactive protein, ferritin, interleukin-6, and tumor necrosis factor α) at the time of lymphodepletion and CAR T-cell infusion. Patients with weight loss experienced higher rates of grade 3+ neurotoxicity and early hematotoxicity, but those effects were not seen upon multivariable adjustment. However, in both univariate and multivariable analysis, patients with weight loss had worse response rates, overall survival, and event-free survival, indicating that weight loss is an independent poor prognostic factor. Our data suggest that weight loss in the 3 months preceding CAR T-cell therapy represents a worrisome “alarm signal” and a potentially modifiable factor, alongside tumor burden and inflammation, and warrants further investigation in patients treated with CAR T-cell therapy.

Glucose-lowering medication associated with weight loss may limit the progression of diabetic neuropathy in type 2 diabetes.

Obesity is a major risk factor for diabetic peripheral neuropathy (DPN) in type 2 diabetes (T2D). This study investigated the effect of glucose lowering medication associated with weight change on DPN. Participants with T2D were grouped based on whether their glucose lowering medications were associated with weight gain (WG) or weight loss (WL). They underwent clinical, metabolic testing and assessment of neuropathic symptoms, vibration perception threshold (VPT), sudomotor function and corneal confocal microscopy (CCM) at baseline and follow-up between 4 and 7 years. Of 76 participants, 69.7% were on glucose lowering medication associated with WG, and 30.3% were on glucose lowering medication associated with WL. At baseline, participants in the WG group had a significantly longer duration of diabetes (p < .01), higher douleur neuropathique en 4 (DN4) score (p < .0001) and VPT (p = .01) compared with those in the WL group. Over a 56-month period, participants in the WG group showed no significant change in body weight (p = .11), HbA1c (p = .18), triglycerides (p = .42), DN4 (p = .11), VPT (p = .15) or Sudoscan (p = .43), but showed a decline in corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD) and corneal nerve fiber length (CNFL) (p < .0001). Participants in the WL group showed a reduction in weight (p = .01) and triglycerides (p < .05), no change in DN4 (p = .30), VPT (p = .31) or Sudoscan (p = .17) and a decline in the corneal nerve branch density (p < .01). Participants treated with glucose lowering medication associated with weight gain had worse neuropathy and greater loss of corneal nerves during follow-up, compared to patients treated with medication associated with weight loss.

Effect of Time-Restricted Eating on Circulating Levels of IGF1 and Its Binding Proteins in Obesity: An Exploratory Analysis of a Randomized Controlled Trial

Obesity is associated with alterations in circulating IGF1, IGF1-binding proteins (IGFBPs), insulin, inflammatory markers, and hormones implicated in cardiovascular disease, diabetes, cancer, and aging. However, the effects of 4 and 6 h time-restricted eating (TRE) on circulating IGF1 and IGFBPs is uncertain. Objective: This study aimed to investigate the effects of TRE on plasma IGF1, IGFBP1, IGFBP2, and IGFBP3, and whether these effects were mediated by weight loss or body composition changes. Insulin sensitivity, glucose control, adipokines, and inflammatory markers were also examined. Design: An exploratory analysis of an 8-week randomized controlled trial implementing a daily TRE intervention was carried out. Participants/Setting: This study was conducted at the University of Illinois at Chicago in 2019. Participants with obesity were randomized to 4 or 6 h TRE (n = 35) or a control (n = 14) group. Plasma biomarkers were measured by ELISA at baseline and week 8. In a sub-analysis, participants were stratified into higher- (&gt;3.5%) and lower- (≤3.5%) weight-loss groups. Intervention: Participants fasted daily from 7 p.m. to 3 p.m. in the 4 h TRE group (20 h) and from 7 p.m. to 1 p.m. in the 6 h TRE group (18 h), followed by ad libitum eating for the remainder of the day. Controls received no dietary recommendations. Main outcome measures: IGF1, IGFBPs, hsCRP, and adipokines were the main outcome measures of this analysis. Statistical Analysis: Repeated measures ANOVA and mediation analysis were conducted. Results: Body weight significantly decreased with TRE (−3.6 ± 0.3%), contrasting with controls (+0.2 ± 0.5%, p &lt; 0.001). Significant effects of TRE over time were observed on plasma IGFBP2, insulin, HOMA-IR, and 8-isoprostane levels, without affecting other biomarkers. In the sub-analysis, IGFBP2 increased while leptin and 8-isoprostane decreased significantly only in the “higher weight loss” subgroup. Changes in insulin and HOMA-IR were related to TRE adherence. Conclusions: Eight-week daily 4 to 6 h TRE did not affect IGF1, IGFBP1, or IGFBP3 levels but improved insulin, HOMA-IR, and 8-isoprostane. IGFBP2 increased and leptin decreased when weight loss exceeded 3.5% of baseline.

Metformin continuation post-metabolic bariatric surgery and relapse of diabetes.

To evaluate the association of metformin continuation with relapse of diabetes after metabolic bariatric surgery (MBS) in patients with type 2 diabetes and obesity who achieved an HbA1c level of less than 6.5%. This observational, retrospective cohort study included Clalit Health Service members aged 24 years or older with obesity and diabetes, who were treated with metformin, underwent MBS during 2005-2020 and achieved an HbA1c level of less than 6.5% up to 6 months after surgery (index date). Patients who continued metformin treatment (> 2 prescriptions filled, n = 122) after the index date were matched (1:2) on age, sex and HbA1c level at index date and compared with those who stopped treatment (no filled prescriptions, n = 244). The outcome was relapse of diabetes as measured by an HbA1c level of 6.5% or higher (yes/no). The two matched groups maintained a mean HbA1c level of less than 6.5% during the follow-up (mean ~ 5 years). An adjusted Cox proportional hazards model revealed no significant association of metformin continuation after MBS with relapse of diabetes (adjusted hazard ratio = 1.70, 95% confidence interval: 0.98-2.94). No significant differences were observed between the two groups in weight loss and filled prescriptions for other diabetes medications during the follow-up period. Among individuals living with obesity and diabetes who achieved diabetes remission post-MBS, metformin continuation was not associated with relapse of diabetes. This lack of an association indicates that metformin did not provide an additional benefit for maintaining glycaemic control or weight reduction during an average of 5 years postsurgery.

Weight loss rather than weight gain has a detrimental effect on successful aging in older adults: A 4-year longitudinal study in China

This study explored the effect of weight change on successful aging in older adults. A total of 1865 adults (≥65 years) were divided into the weight gain group (weight gain ≥5 %), the weight loss group (weight loss ≥5 %), and the weight stable group (weight change <5 %) according to weight changes over 4 years. Results showed that compared to the stable weight, the weight loss is associated with a lower rate of successful aging (OR=0.64, 95 % CI: 0.49-0.83), and the association was found greater in women (OR=0.61, 95 % CI: 0.43-0.86) and young-old adults (OR=0.66, 95 % CI: 0.41-0.88) than their counterparts. However, no significant association was found between weight gain and successful aging. The findings suggest that weight loss rather than weight gain in older adults has a detrimental impact on successful aging, and this detrimental impact is greater in women and young-old adults.

Systemic Metabolic and Volumetric Assessment via Whole-Body [18F]FDG-PET/CT: Pancreas Size Predicts Cachexia in Head and Neck Squamous Cell Carcinoma.

Background/Objectives: Cancer-associated cachexia in head and neck squamous cell carcinoma (HNSCC) is challenging to diagnose due to its complex pathophysiology. This study aimed to identify metabolic biomarkers linked to cachexia and survival in HNSCC patients using [18F]FDG-PET/CT imaging and machine learning (ML) techniques. Methods: We retrospectively analyzed 253 HNSCC patients from Vienna General Hospital and the MD Anderson Cancer Center. Automated organ segmentation was employed to quantify metabolic and volumetric data from [18F]FDG-PET/CT scans across 29 tissues and organs. Patients were categorized into low weight loss (LoWL; grades 0-2) and high weight loss (HiWL; grades 3-4) groups, according to the weight loss grading system (WLGS). Machine learning models, combined with Cox regression, were used to identify survival predictors. Shapley additive explanation (SHAP) analysis was conducted to determine the significance of individual features. Results: The HiWL group exhibited increased glucose metabolism in skeletal muscle and adipose tissue (p = 0.01), while the LoWL group showed higher lung metabolism. The one-year survival rate was 84.1% in the LoWL group compared to 69.2% in the HiWL group (p < 0.01). Pancreatic volume emerged as a key biomarker associated with cachexia, with the ML model achieving an AUC of 0.79 (95% CI: 0.77-0.80) and an accuracy of 0.82 (95% CI: 0.81-0.83). Multivariate Cox regression confirmed pancreatic volume as an independent prognostic factor (HR: 0.66, 95% CI: 0.46-0.95; p < 0.05). Conclusions: The integration of metabolic and volumetric data provided a strong predictive model, highlighting pancreatic volume as a key imaging biomarker in the metabolic assessment of cachexia in HNSCC. This finding enhances our understanding and may improve prognostic evaluations and therapeutic strategies.

Clinical Impact of Weight Loss During Hospitalization on Prognosis After Pancreatic Surgery.

Purpose This study aimed to elucidate the relationship between early-stage weight loss (WL) during hospitalization after pancreatic surgery and prognosis and investigate risk factors affecting WL. Methods We included 68 patients diagnosed with pancreatic ductal adenocarcinoma (PDAC) who underwent radical surgery. The %WL value was calculated based on the percentage of body weight at discharge compared with the body weight at admission. High WL was defined as %WL >10%. We initially evaluated the association between %WL and postoperative survival using the Kaplan-Meier method. Subsequently, we analyzed the factors affecting %WL using a logistic regression model. Results In terms of overall survival (OS), the high %WL group exhibited a significantly worse prognosis than the low %WL group (p=0.043). Univariate analysis revealed a hazard ratio of 2.244 (95% confidence interval (CI), 1.006-5.006; p=0.048) for high %WL in relation to overall survival. Multivariate analysis identified an operative time >450 min (odds ratio, 17.8; 95% confidence interval, 1.01-312.42; p=0.049) and postoperative complications (odds ratio, 12.1; 95% confidence interval, 2.01-72.79; p<0.01) as independent risk factors for high %WL. Conclusion Preventing high %WL by streamlining surgical procedures, minimizing postoperative complications, and implementing medical nutritional therapy (MNT) is imperative to improve the prognosis of patients with PDAC.

Association of dietary diversity and weight change with cognitive impairment among Chinese elderly: A prospective national cohort study

BackgroundDietary diversity is reported to be beneficial for cognitive function, while the effect may be offset by weight change status. We aimed to examine the association of dietary diversity and weight change with cognitive impairment among older adults. MethodsWe used three waves from 2008 to 2014 of the Chinese Longitudinal Survey of Health and Longevity, which included 16,954 participants for the subsequent screening and analysis. Dietary diversity information was collected from the food frequency questionnaire. Cognitive function was assessed using the Mini Mental State Examination. The relation of dietary diversity and weight change with cognitive impairment was investigated using Cox proportional hazards models and cubic spline regression. ResultsCompared with those reported poor dietary diversity at baseline, participants with good dietary diversity had a 16 % (hazard ratio [HR] = 0.84, 95 % confidence interval [CI]: 0.71–0.99) lower risk of cognitive impairment. The HR and 95 % CI of participants with consistently good dietary diversity from 2008 to 2011 was 0.71 (0.57–0.89) for cognitive impairment compared to those with consistently poor dietary diversity. Compared with the weight stable group, the HRs and 95 % CI for cognitive impairment were 1.34 (1.10–1.64) in weight loss group, and 1.08 (0.88–1.33) in weight gain group. Restricted cubic splines showed the risk of cognitive impairment decreased with higher dietary diversity score or less weight change, though no significant interaction between dietary diversity and weight change was found. LimitationGiven the observational nature of this study, there might be a reverse causation for the observed association. ConclusionEstablishing and maintaining good dietary diversity were associated with a lower risk of cognitive impairment regardless of weight change status, whereas weight loss was associated with increased cognitive impairment risk independently among older Chinese adults.

The Effect Of Weight Loss With Lifestyle Changes On LDL Cholesterol: Retrospective Cohort Study

Aim: This study aimed to investigate the rate of decrease in lipid levels with effective lifestyle changes (LC) and the minimum body weight loss necessary for effective lipid reduction in obese patients. Method: The study is a retrospective cohort study. The study included 71 patients who were followed up in the obesity clinic, who were diagnosed with hyperlipidemia but did not use any hyperlipidemia treatment. The patients' high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglyceride, body fat ratio and mass, body mass index (BMI), height and weight information were recorded at the first visit and the 6th month. In our study, patients were divided into two groups (based on the weight loss rates in the 6-month follow-up) those who lost less than 10% of their previous weight and those who lost 10% or more weight and their lipid parameters were compared. Results: LDL-C reduction rates of patients classified according to their weight loss rates were found to be statistically significantly (p=0.011) higher in those with 10% or more weight loss than (group 1=18.48%) in those with less than 10% weight loss (group 2=13.04%). Total cholesterol reduction rates were also significantly (p=0.015) higher in the 1st group than in the 2nd group. According to the findings of our study, at least 10% weight loss is required to decrease total cholesterol and LDL-C significantly. Conclusion: Implementation of primary and secondary prevention strategies to reduce the risk of cardiovascular disease is important in the context of primary care. To reach the targeted LDL-C values, the weight monitoring of obese patients should be considered, and the importance of losing at least 10% of weight as one of the first steps should be emphasized.

Weight loss-induced adipose macrophage memory improves local Staphylococcus aureus clearance in male mice.

Different stimuli can induce innate immune memory to improve pathogen defense or worsen cardiometabolic disease. However, it is less clear if the same stimuli can induce both the protective and detrimental effects of innate immune memory. We previously showed that weight loss induces innate immune memory in adipose macrophages that correlates with worsened diabetes risk after weight regain. In this study, we investigated the effect of weight loss on macrophage cytokine production and overall survival in a mouse model of infection. Male C57Bl/6J mice were put on high-fat or low-fat diets over 18 weeks to induce weight gain or weight loss. Lean mice served as controls. All mice were then infected IV with 2.5×10^6 CFU Staphylococcus aureus . Tissues were collected from 10 mice/group at day 3 and the remaining animals were followed for survival. Weight gain mice had the highest blood neutrophils and the highest bacterial burden in the kidney. However, there was no significant difference in survival. The weight loss group had the highest plasma TNF-α and a significant reduction in bacterial burden in the adipose tissue that correlated with increased adipose macrophage cytokine production. Thus, weight loss-induced adipose macrophage memory may both improve local S.aureus clearance and worsen diabetes risk upon weight regain. Collectively, these findings support the notion that innate immune memory is an evolutionarily protective mechanism that also contributes to the development of cardiometabolic diseases.

Potential of using an engineered indole lactic acid producing Escherichia coli Nissle 1917 in a murine model of colitis

The gut microbiome is a significant factor in the pathophysiology of ulcerative colitis (UC), prompting investigations into the use of probiotic therapies to counter gastrointestinal inflammation. However, while much attention has been given to the therapeutic potential of microbes at the species and strain level, the discovery and application of their metabolic products may offer more precise and controlled solutions in battling disease. In this work, we examined the therapeutic potential of indole lactic acid (ILA) to alleviate inflammation in a murine model of colitis. A previously constructed ILA-producing Escherichia coli Nissle 1917 strain (EcN aldh) and its isogenic non-ILA producing counterpart (EcN) were studied in a murine model of Dextran Sodium Sulfate (DSS) induced colitis. The colitic animals suffered from severe colitic symptoms, with no differentiation between the groups in body weight loss and disease activity index. However, three days after cessation of DSS treatment the EcN aldh–treated mice showed signs of reduced intestinal inflammation, as manifested by lower concentrations of fecal lipocalin-2. Additionally, expression analysis of the inflamed tissue revealed distinct effects of the EcN aldh strain on proteins associated with intestinal health, such as TFF3, occludin and IL-1β expression. These results show no impact of EcN or EcN aldh on acute DSS-induced colitis, but suggest that in particular EcN aldh may assist recovery from intestinal inflammation.

The effectiveness of diet and exercise in the management of obesity

Background and objectives: Obesity is a growing global health problem and is becoming a significant challenge in the clinical and public health fields. One of the main concerns is the impact on an individual's quality of life. This review aims to evaluate the effectiveness of various interventions, including physical activity and diet, in the management of obesity. Methodology: The selected studies involved a population of adults who were obese (aged 18 years and over) and had made lifestyle modifications through pattern changes, eating, physical activity, or both. A total of 324 articles were screened, of which 25 were duplicates. After a screening process for suitability, 261 articles were excluded. A further 27 articles were excluded due to inappropriate study design or incomplete data. A total of 11 full-text articles were then reviewed and included in our analysis. The results showed that participants who followed a milk-based diet recorded a significant decrease in body weight of -1.16 kg (confidence interval -1.66, -0.66 kg; p &lt; 0.001) as well as a decrease in body fat mass of -1.49 kg (confidence interval -2.06, -0.92 kg; p &lt; 0.001). Participants who adopted an alternate day fasting (ADF) eating pattern achieved an average weight loss of -0.9% ± 0.6% in the low weight loss group and -9.9% ± 1.1% in the low weight loss group. Meanwhile, participants who restricted calorie intake (Caloric Restriction/CR) recorded a weight loss of -1.3% ± 0.7% in the low weight loss group and -9.2% ± 1.2% in the weight loss group tall body. Combining approximately 175 minutes of intense physical activity per week with a controlled diet results in significant weight loss of up to 5%. In conclusion, this systematic review confirms that the most effective approach in the management of obesity in adults is a combination of strength and cardiovascular training of at least 175 minutes per week and a low-calorie diet tailored to the individual's metabolic needs and health condition. Keywords: Obesity management; diet and exercise efficacy; obesity treatment; physical activity and weight loss

Postpartum Weight Change Association With Readmission and Blood Pressure Trend Among Individuals With Hypertensive Disorders of Pregnancy.

The aim of this study was to evaluate the association between early postpartum weight change and (1) hospital readmission and (2) 2-week blood pressure trajectory. This retrospective study cohort included 1365 individuals with a hypertensive disorder of pregnancy enrolled in a postpartum hypertension remote monitoring program. Exposure was percentage weight change from delivery to first weight recorded within 10 days postpartum. We first modeled likelihood of hospital readmission within 8 weeks postpartum using logistic regression adjusting for age, race, insurance, type of hypertensive disorder of pregnancy, early body mass index, gestational weight gain, mode of delivery, and any discharge antihypertensive medications. We then performed case-control analysis additionally matching in a 1:3 ratio on breastfeeding, early body mass index, discharge on antihypertensive medications, and days between weight measurements. Both analytic approaches were repeated, limiting to readmissions attributable to hypertension or heart failure. Finally, we compared blood pressure trajectories over first 2 weeks postpartum. Individuals who did not lose weight in the early postpartum period had more admissions compared with weight loss groups (group 3: 14.1% versus group 2: 5.8% versus group 1: 4.5%). These individuals had 4 times the odds of postpartum readmissions (adjusted odds ratio [aOR], 3.9 [95% CI, 1.8-8.6]) to 7 (aOR, 7.8 [95% CI, 2.3-26.5]) compared with those with the most weight loss. This association strengthened when limited to hypertension or heart failure readmissions. These individuals also had more adverse postpartum blood pressure trajectories, with significant differences by weight change group. Weight change is readily accessible and may identify individuals at high risk for postpartum readmission following a hypertensive disorder of pregnancy who could benefit from targeted interventions.

Relationships of Weight Change from 20 Years of Age with the Risks of All-Cause and Cardiovascular Mortality in Patients with Chronic Kidney Disease.

Weight changes from a young age are known to be associated with poor life outcomes in the general population. However, little is known about the association between weight change from a young age and life expectancy in patients with chronic kidney disease (CKD). Data of 2,806 nondialysis CKD patients who participated in the Fukuoka Kidney Disease Registry (FKR) Study, a multicenter observational study, were analyzed. The primary outcome was all-cause death, whereas the secondary outcome was cardiovascular mortality. The covariate of interest was weight change, defined as the difference between body weight at study enrollment and at 20 years old. Cox proportional-hazards models were used to estimate the risks of mortality for participants with weight changes of ≥ 5 or ＜5 kg compared with those with stable weights. During the 5-year observation period, 243 participants died from all causes and 62 from cardiovascular disease. The risk of all-cause mortality in the weight-loss group was significantly higher than that in the stable-weight group (multivariable-adjusted hazard ratio, 2.11; 95% confidence interval [CI], 1.52-2.93). Conversely, the risk of cardiovascular mortality in the weight-loss group was significantly higher than that in the stable-weight group (multivariable-adjusted hazard ratio, 2.48; 95% CI, 1.32-4.64). However, no significant association was observed between weight gain and the risks of all-cause and cardiovascular mortalities. Weight loss from 20 years of age was found to be associated with higher risks of all-cause and cardiovascular mortalities in patients with CKD.

E4bp4-Cyp3a11 axis in high-fat diet-induced obese mice with weight fluctuation

ObjectiveWeight regain after weight loss is a challenge in obesity management. The metabolic changes and underlying mechanisms in obese people with weight fluctuation remain to be elucidated. In the present study, we aimed to profile the features and clinical significance of liver transcriptome in obese mice with weight regain after weight loss.MethodsThe male C57BL/6J mice were fed with standard chow diet or high-fat diet (HFD). After 9 weeks, the HFD-induced obese mice were randomly divided into weight gain (WG), weight loss (WL) and weight regain (WR) group. After 10 weeks of dietary intervention, body weight, fasting blood glucose (FBG), intraperitoneal glucose tolerance, triglycerides (TG), total cholesterol (T-CHO) and low-density lipoprotein cholesterol (LDL-C) were measured. Morphological structure and lipid droplet accumulation in the liver were observed by H&E staining and oil red O staining, respectively. The liver transcriptome was detected by RNA sequencing. Protein expressions of liver cytochrome P450 3a11 (Cyp3a11) and E4 promoter-binding protein 4 (E4bp4) were determined by Western blot.ResultsAfter 10 weeks of dietary intervention, the body weight, FBG, glucose area under the curve, T-CHO and LDL-C in WL group were significantly lower than those in WG group (P < 0.05). At 4 weeks of HFD re-feeding, the mice in WR group presented body weight and T-CHO significantly lower than those in WG group, whereas higher than those in WL group (P < 0.05). Hepatic vacuolar degeneration and lipid droplet accumulation in the liver were significantly alleviated in WL group and WR group, compared to those in WG group. The liver transcriptome associated with lipid metabolism was significantly altered during weight fluctuation in obese mice. Compared with those in WG group, Cyp3a11 in the liver was significantly upregulated, and E4bp4 was significantly downregulated in WL and WR groups.ConclusionObese mice experience weight regain after weight loss by HFD re-feeding, but their glucose and lipid metabolism disorders are milder than those induced by the persistence of obesity. Downregulated E4bp4 and upregulated Cyp3a11 are detected in obese mice after weight loss, suggesting that the E4bp4-Cyp3a11 axis may involved in metabolic mechanisms underlying weight regulation.Graphical

Abstract PO5-14-01: Weight loss and omega-3 polyunsaturated fatty acid intervention in overweight and obese peri- and postmenopausal women with increased breast cancer risk modifies the gut microbiome and is associated with circulating biomarkers

Abstract Background: Obesity-associated gut microbiome dysbiosis is thought to increase risk for postmenopausal breast cancer through alteration of estrogen metabolism and an increase in pro-inflammatory microbe abundance. Many studies have reported an increase in the Firmicutes/Bacteroidetes phyla ratio as a biomarker of obesity and is associated with adverse metabolic outcomes. Marine omega-3 eicosapentaenoic (EPA) and docosahexaenoic (DHA) fatty acids are thought to have favorable metabolic and inflammation resolving properties resulting in reduced risk for several epithelial cancers. One possible mechanism is the effect of EPA and DHA on the gut microbiome. We assessed the effect of weight loss and/or omega-3 supplementation on the gut microbiome and circulating molecular breast cancer risk factors. Methods: 46 peri/postmenopausal overweight and obese women at increased risk for breast cancer were enrolled into a weight-loss intervention and after 2 weeks randomized to 3.25 g/day combined EPA and DHA or placebo (PMC8416797). Fecal samples were collected at 0, 2-weeks and 6-months, with matched fecal samples for all timepoints available for 26 patients. Fecal samples at 6-months were available for 34 patients. 12M read depth metagenomic sequencing was performed on DNA isolated from feces to determine shifts in the gut microbiome. Fasting and non-fasting blood was also collected for circulating biomarker analysis. Body composition by DXA scan were also performed at baseline and 6-month time points. Results: Mean baseline BMI was 32 kg/m2. There was no significant difference between arms in age, baseline BMI, % body fat, or baseline Firmicutes/Bacteroidetes ratio. We identified gut microbiota species (A. hadrus and P. faecium) that correlated with metabolic parameters (% body fat, adiponectin/leptin ratio, and fasting insulin), species (P. dorei and B. ovatus) that correlated with estradiol levels, and mucin-degrading species (D. formicigenerans and R. gnavus) whose abundance correlated with inflammation (as measured by circulating monocyte-chemoattractant protein 1 (MCP-1)). Median 6-month weight change for all randomized subjects was -10% from baseline. Favorable change in the Firmicutes/Bacteroidetes ratio was associated both with the degree of weight loss and with omega-3 supplementation, although significant species modification differed between weight loss and omega-3 PUFA groups. Women with both &amp;gt;10% weight loss and omega-3 supplementation had a significantly reduced Firmicutes abundance and lower Firmicute/Bacteroidetes ratio than other groups. Species abundance shifts appear to differ between weight loss and omega-3 supplementation with 3 species modified by weight loss and 12 species shifted by omega-3 PUFA administration. Omega-3 PUFA supplementation significantly reduced proportional abundance of Dorea formicigenerans, which was a microbe associated with inflammation. Conclusions: Omega-3 supplementation at 3.25 g/day compared to placebo had a greater net effect on changing the gut microbiome in overweight and obese women at increased risk for breast cancer undergoing a weight loss intervention. Change in the gut microbiome may serve as a useful response biomarker in Phase II prevention trials of omega-3 fatty acid and weight loss. Citation Format: Katherine L. Cook, Erin Giles, Amy Kreutzjans, Shahid Umar, Christie Befort, Bruce Kimler, Stephen Hursting, Carol Fabian. Weight loss and omega-3 polyunsaturated fatty acid intervention in overweight and obese peri- and postmenopausal women with increased breast cancer risk modifies the gut microbiome and is associated with circulating biomarkers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-14-01.

Exploring the optimal indicator of short-term peridiagnosis weight dynamics to predict cancer survival: A multicentre cohort study.

Body weight and its changes have been associated with cancer outcomes. However, the associations of short-term peridiagnosis weight dynamics in standardized, clinically operational time frames with cancer survival remain largely unknown. This study aimed to screen for and evaluate the optimal indicator of short-term peridiagnosis weight dynamics to predict overall survival (OS) in patients with cancer. This multicentre cohort study prospectively collected data from 7460 patients pathologically diagnosed with cancer between 2013 and 2019. Body weight data were recorded 1month before, at the time of and 1month following diagnosis. By permuting different types (point value in kg, point height-adjusted value in kg/m2, absolute change in kg or relative change in percentage) and time frames (prediagnosis, postdiagnosis or peridiagnosis), we generated 12 different weight-related indicators and compared their prognostic performance using Harrell's C-index, integrated discrimination improvement, continuous net reclassification improvement and time-dependent C-index. We analysed associations of peridiagnosis relative weight change (RWC) with OS using restricted cubic spine (RCS), Kaplan-Meier analysis and multivariable-adjusted Cox regression models. The study enrolled 5012 males and 2448 females, with a median age of 59years. During a median follow-up of 37months, 1026 deaths occurred. Peridiagnosis (1month before diagnosis to 1month following diagnosis) RWC showed higher prognostic performance (Harrell's C-index=0.601, 95% confidence interval [CI]=[0.583, 0.619]) than other types of indicators including body mass index (BMI), absolute weight change, absolute BMI change, prediagnosis RWC and postdiagnosis RWC in the study population (all P<0.05). Time-dependent C-index analysis also indicated that peridiagnosis RWC was optimal for predicting OS. The multivariable-adjusted RCS analysis revealed an N-shaped non-linear association between peridiagnosis RWC and OS (PRWC<0.001, Pnon-linear<0.001). Univariate survival analysis showed that the peridiagnosis RWC groups could represent distinct mortality risk stratifications (P<0.001). Multivariable survival analysis showed that, compared with the maintenance group (weight change<5%), the significant (gain >10%, hazard ratio [HR]=0.530, 95% CI=[0.413, 0.680]) and moderate (gain 5-10%, HR=0.588, 95% CI=[0.422, 0.819]) weight gain groups were both associated with improved OS. In contrast, the moderate (loss 5-10%, HR=1.219, 95% CI=[1.029, 1.443]) and significant (loss >10%, HR=1.280, 95% CI=[1.095, 1.497]) weight loss groups were both associated with poorer OS. The prognostic performance of peridiagnosis RWC is superior to other weight-related indicators in patients with cancer. The findings underscore the importance of expanding the surveillance of body weight from at diagnosis to both past and future, and conducting it withinclinically operational time frames, in order to identify and intervene with patients who are at risk of weight change-related premature deaths.

Impact of postpartum weight change on metabolic syndrome and its components among women with recent gestational diabetes mellitus

BackgroundWhile postpartum weight changes may affect the levels of metabolic parameters, the direct effects of weight changes in the postpartum period on changes in the prevalence rates of metabolic syndrome and its components remain unstudied. This study aimed to investigate the effects of postpartum weight changes between 6 weeks and 6 months on changes in the prevalence rates of metabolic syndrome and its components in women who have recently experienced gestational diabetes mellitus.MethodsThis prospective cohort study included 171 postpartum women with recent gestational diabetes mellitus, who underwent serial weight and metabolic risk factor assessments at 6 weeks and 6 months postpartum. Weight changes between these time points were classified as weight loss (> 2 kg), weight stability (± 2 kg), or weight gain (> 2 kg). Metabolic syndrome comprised the following metabolic risk factors: large waist circumference, elevated blood pressure, elevated fasting plasma glucose levels, high triglyceride levels, and low high-density lipoprotein cholesterol levels.ResultsOf the 171 women in our cohort, 30 women (17.5%) lost > 2 kg of body weight, while 85 (49.7%) maintained a stable weight and 56 (32.8%) gained > 2 kg. The weight loss group experienced significant changes in the prevalence rates of the following metabolic risk factors compared to the weight stability and weight gain groups: large waist circumference (% change: − 26.7 vs − 5.9 vs 5.4, respectively; p = 0.004), elevated fasting plasma glucose levels (% change: − 3.4 vs 18.9 vs 26.8, respectively; p = 0.022), and high triglyceride levels (% change: − 30.0 vs 0 vs − 7.2, respectively; p = 0.024). A significantly greater decrease in the prevalence of metabolic syndrome was also found in the weight loss group than in the other two groups (% change: − 20.0 vs 11.8 vs 14.2, respectively; p = 0.002).ConclusionsWeight changes from 6 weeks to 6 months postpartum significantly altered the prevalence rates of metabolic syndrome and its components in women with recent gestational diabetes mellitus. Early postpartum weight loss can reverse metabolic risk factors and reduce the prevalence of metabolic syndrome.Trial registrationThai Clinical Trials Registry: Registration no. TCTR20200903001. Date of registration: September 3, 2020. Date of initial participant enrolment: September 7, 2020.

Effects of Bariatric Surgery on Knee Articular Cartilage and Osteoarthritis Symptoms-A 12-Month Follow-Up Using T2 Relaxation Time and WOMAC Osteoarthritis Index.

Obesity is a significant risk factor for osteoarthritis (OA). The most effective treatment for morbid obesity is bariatric surgery. To study the effects of potential surgically induced weight loss on knee articular cartilage and OA symptoms of obese patients over a 12-month follow-up. Prospective longitudinal cohort study. 45 obese patients (38 female, BMI = 42.3 ± 6.5 kg/m2) who underwent gastric bypass (intervention group), and 46 age-matched conservative-care controls (37 female, BMI = 39.8 ± 4.6 kg/m2). Multiecho spin echo sequence at 3 T. Knee cartilage T2 measurements and WOMAC Indices were measured presurgery and after 12 months. The intervention group was split into successful (≥20% total weight loss (TWL)) and unsuccessful (<20% TWL) weight loss groups. T2 and WOMAC indices were also measured in controls at baseline and after 12 months. Changes among the three groups were analyzed. Analysis of variance (significance level 0.05). Twenty-six (58%) intervention patients achieved ≥20% TWL. The <20% TWL group demonstrated significantly more T2 reduction in the deep lateral femur over 12 months compared with the ≥20% TWL group (-3.83 ± 8.18 msec vs. 2.47 ± 6.54 msec, respectively), whereas no significant differences were observed on the medial femoral compartment (P = 0.385, P = 0.551, and P = 0.511 for bulk, superficial and deep regions, respectively). Changes in WOMAC indices over 12 months were significantly greater in the ≥20% TWL group compared with controls. In the <20% TWL group, pain significantly improved over 12 months compared with controls, while stiffness and function changes were not statistically significant (P = 0.063 and P = 0.051, respectively). Cartilage matrix, measured by T2, showed improvement on lateral femoral cartilage with <20% TWL compared with ≥20% TWL. Bariatric surgery provided significant improvements in knee symptoms with ≥20% TWL compared with conservative WL. This effect is also seen to some extent with <20% TWL compared with conservative WL. 2 TECHNICAL EFFICACY: Stage 4.

Abstract 2189: Tirzepatide mitigates obesity-associated metabolic dysregulation and tumor progression in a mouse model of triple-negative breast cancer

Abstract Obesity is an established risk factor for breast cancer. Dietary and surgical weight loss interventions reduce breast cancer risk but have significant limitations to their widespread use as anticancer strategies. Incretin-based pharmaceuticals safely and effectively promote weight loss, but whether these drugs exert similar protective effects against cancer is unknown. Here we test whether weight loss induced by the glucagon-like peptide 1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide limits tumor growth in an orthotopic mouse model of triple-negative breast cancer. Ten-week-old female C57BL/6NCrl mice were randomized to either a 10 kcal% low-fat diet (control; n=14) or 60 kcal% high-fat diet to promote diet-induced obesity (DIO; n=43). After 18 weeks on diet, DIO mice were randomized by body weight to either i) remain on the high-fat diet (DIO; n=15); ii) lose weight with tirzepatide (TZP; n=13); or iii) lose weight with 30% daily calorie restriction relative to control mice (CR; n=15). All mice were subcutaneously injected with either TZP or vehicle every other day for 13 weeks with the following escalating dosing schedule: 3 nmol/kg TZP in week 1; 10 nmol/kg TZP in weeks 2-3; 20 nmol/kg TZP in weeks 4-7; 30 nmol/kg TZP in weeks 8-11; and 40 nmol/kg TZP in weeks 12-13. Fasting blood glucose and body composition was assessed after 9 weeks of weight loss, and 35,000 E0771 cells were orthotopically transplanted into the 4th mammary fat pad. Tumors growth was monitored for 4 weeks. TZP-treated mice lost on average &amp;gt;20% weight loss by week 4 and remained at or below 20% weight loss for the remainder of the study. Directly prior to E0771 tumor cell injections, TZP-treated mice had lost 23.6±8.9% body weight, versus 39.7±3.6% in CR mice. Relative to DIO mice, blood glucose control was restored in both weight loss groups (DIO: 149.5±18.5 mg/dl; TZP: 124.5±15.5 mg/dl; CR: 107.6±18.8 mg/dl) and &amp;gt;87.5% of the lost weight was attributed to fat mass, rather than lean mass, for TZP-treated and CR mice. Notably, tirzepatide suppressed tumor growth relative to DIO, but the CR group had a greater anticancer effect than TZP. Reduced tumor mass in both weight loss groups was accompanied by a significant reduction in circulating IGF-1, insulin, and leptin relative to DIO mice. These findings are timely and important because i) obesity is a highly prevalent metabolic disease that increases risk and progression of breast cancer and &amp;gt;13 other cancers; ii) incretin therapies, which show promise as highly effective weight loss drugs, are increasingly being prescribed; and iii) the tumor suppressive effects of tirzepatide described herein newly suggest incretin agonism as another propitious option for breaking the obesity-cancer link. Citation Format: Elaine M. Glenny, Alyssa N. Ho, Violet A. Kiesel, Fangxin Chen, Claire E. Gates, Evan M. Paules, Ruihan Xu, C. Alex Holt, Michael F. Coleman, Stephen D. Hursting. Tirzepatide mitigates obesity-associated metabolic dysregulation and tumor progression in a mouse model of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2189.