Assessment of the Addition of Oxaliplatin to Fluoropyrimidine-Based Adjuvant Chemotherapy in Patients With High-Risk Stage II Colon Cancer: An ACCENT Pooled Analysis.

PURPOSE: The adjuvant treatment for stage III colon cancer (CC) is chemotherapy combining fluoropyrimidine (FP) and oxaliplatin (OX). FP regimen plus OX (FPOX) may benefit in high-risk stage II CC. We performed a pooled analysis of pivotal MOSAIC and C-07 studies evaluating FPOX for the treatment of high-risk stage II CC according to prognostic factors, number of high-risk factors, and current clinicopathologic risk classification on the basis of T stage, tumor perforation, and number of lymph nodes examined. PATIENTS AND METHODS: One thousand five hundred and ninety-five patients with stage II CC receiving FP or FPOX were pooled. The overall survival (OS) benefit of OX was analyzed using Kaplan-Meier curves and unadjusted Cox models stratified by study. Three thousand and fifty-nine patients with stage III CC were used only for interaction tests between the allocated chemotherapy and stage. RESULTS: In the pooled analysis of stage II patients, independent prognostic factors in multivariable analysis were sex, age, perforation/obstruction, and tumor sidedness. There was a significant interaction in OS between stage and allocated chemotherapy with hazard ratios (HRs) of 1.03 for stage II (95% CI, 0.82 to 1.29; P = .813) and 0.82 for stage III (95% CI, 0.73 to 0.92; P = .001; Pint = .073). There was no benefit from the addition of OX to FP for any of the prognostic factors. The number of high-risk factors tested was not predictive of OX benefit. According to the currently agreed clinicopathologic risk classification, no OS benefit of OX was observed, as HR was 0.86 (95% CI, 0.63 to 1.18; P = .349). CONCLUSION: No OS benefit of adjuvant OX was found in high-risk stage II CC, regardless of the definition used to characterize tumors as having a high risk for recurrence. Hence, our analysis suggests that OX should not be the standard of care for adjuvant chemotherapy for stage II CC, even in high-risk patients.

Single-cell AI-based detection and prognostic and predictive value of DNA mismatch repair deficiency in colorectal cancer.

Testing for DNA mismatch repair deficiency (MMRd) is recommended for all colorectal cancers (CRCs). Automating this would enable precision medicine, particularly if providing information on etiology not captured by deep learning (DL) methods. We present AIMMeR, an AI-based method for determination of mismatch repair (MMR) protein expression at a single-cell level in routine pathology samples. AIMMeR shows an area under the receiver-operator curve (AUROC) of 0.98, and specificity of ≥75% at 98% sensitivity against pathologist ground truth in stage II/III in two trial cohorts, with positive predictive value of ≥98% for the commonest pattern of somatic MMRd. Lower agreement with microsatellite instability (MSI) testing (AUROC 0.86) reflects discordance between MMR and MSI PCR rather than AIMMeR misclassification. Analysis of the SCOT trial confirms MMRd prognostic value in oxaliplatin-treated patients; while MMRd does not predict differential benefit of chemotherapy duration, it correlates with difference in relapse by regimen (PInteraction = 0.04). AIMMeR may help reduce pathologist workload and streamline diagnostics in CRC.

Community Health Workers' Targeting of Women For Health and Nutrition Home Visits in Rural Tanzania: A Mixed-Methods Study.

Background: Community health workers (CHWs) are utilized in many health systems to provide education and messaging to families in their catchment areas. However, CHWs responsible for large geographic areas often must make important decisions about whom to visit. Factors that influence these decisions are understudied. Objectives: This study assessed coverage and targeting for home visits by CHWs within a large social and behavioral change health program in rural Tanzania. Methods: This implementation research was a cross-sectional, mixed-methods study. Data collection included a census with households and surveys with females, surveys with CHWs, and interviews with CHWs. Survey data also included the collection of household location data for females and CHWs. Quantitative data were analyzed using linear probability models, and qualitative data were analyzed using inductive thematic analysis. Results: Only 13% of eligible households in our study sites reported receiving a home visit from a CHW. Although CHWs were more likely to reach households with infants, other program priority populations, such as poor and food insecure households, were frequently missed. Global positioning system data showed that distance was 1 of the greatest barriers for CHWs in providing home visits. Qualitative data indicated that although CHWs were motivated and engaged to improve maternal and child health in their communities, they faced challenges in visiting households that were further away or lacked economic resources to improve their health behaviors. CHWs also found it difficult to provide health education during home visits to mothers with no formal schooling. Conclusions: Programs relying on community volunteers need to set realistic workloads, especially when volunteer CHWs also work full-time in their primary occupations. Implementation could also be strengthened by providing extra support for CHWs so that they can effectively provide services to community members who are more difficult to visit but may be the most in need.

Gender differences in perceptions of "joint" decision-making about spending money among couples in rural Tanzania.

Family and cultural contexts can constrain the effectiveness of evidence-based interventions designed to improve the health and wellbeing of women and their children. Unequal power relationships within the household may underlie the failure of many programs targeting women to achieve their intended impact. To reduce these unequal power dynamics within the households, many programs or interventions aim to both assess and improve the gender dynamics between husbands and wives within the household. Decision-making is one important facet of these dynamics and has been linked to health outcomes for women and children. However, household decision-making is rarely observed and often difficult to capture. This study aimed to use qualitative research to further understand one aspect of decision-making, namely on how to spend money. In two regions of Tanzania, we used surveys and interviews to explore different perspectives on spending and allocation of resources among 58 couples in rural farming households. While many men and women initially reported that they made decisions jointly, most women stated they would often concede if there was a disagreement or argument around spending. These results highlight the different perceptions of joint decision-making between men and women. We compared these results to survey responses on decision-making and found differences within and between couples across interview and survey responses. Based on the differences in qualitative and survey responses within couples and how they reported dealing with disagreement, our study found households were on a spectrum from no cooperation in decision-making to full cooperation. Our results highlight challenges for assessing decision-making on spending and ultimately improving these decision-making dynamics within the household. These challenges are especially important for maternal and child behavioral change and provide insights on why many interventions aimed at improving women's decision- making power on money may not reach their full potential.

Time From Colorectal Cancer Surgery to Adjuvant Chemotherapy: Post Hoc Analysis of the SCOT Randomized Clinical Trial.

Importance: The timing of adjuvant chemotherapy after surgery for colorectal cancer and its association with long-term outcomes have been investigated in national cohort studies, with no consensus on the optimal time from surgery to adjuvant chemotherapy. Objective: To analyze the association between the timing of adjuvant chemotherapy after surgery for colorectal cancer and disease-free survival. Design, Setting, and Participants: This is a post hoc analysis of the phase 3 SCOT randomized clinical trial, from 244 centers in 6 countries, investigating the noninferiority of 3 vs 6 months of adjuvant chemotherapy. Patients with high-risk stage II or stage III nonmetastatic colorectal cancer who underwent curative-intended surgery were randomized to either 3 or 6 months of adjuvant chemotherapy consisting of fluoropyrimidine and oxaliplatin regimens. Those with complete information on the date of surgery, treatment type, and long-term follow-up were investigated for the primary and secondary end points. Data were analyzed from May 2022 to February 2024. Intervention: In the post hoc analysis, patients were grouped according to the start of adjuvant chemotherapy being less than 6 weeks vs greater than 6 weeks after surgery. Main Outcomes and Measures: The primary end point was disease-free survival. The secondary end points were adverse events in the total treatment period or the first cycle of adjuvant chemotherapy. Results: A total of 5719 patients (2251 [39.4%] female; mean [SD] age, 63.4 [9.3] years) were included in the primary analysis after data curation; among them, 914 were in the early-start group and 4805 were in the late-start group. Median (IQR) follow-up was 72.0 (47.3-88.1) months, with a median (IQR) of 56 (41-66) days from surgery to chemotherapy. Five-year disease-free survival was 78.0% (95% CI, 75.3%-80.8%) in the early-start group and 73.2% (95% CI, 72.0%-74.5%) in the late-start group. In an adjusted Cox regression analysis, the start of adjuvant chemotherapy greater than 6 weeks after surgery was associated with worse disease-free survival (hazard ratio, 1.24; 95% CI, 1.06-1.46; P = .01). In adjusted logistic regression models, there was no association with adverse events in the total treatment period (odds ratio, 0.82; 95% CI, 0.65-1.04; P = .09) or adverse events in the first cycle of treatment (odds ratio, 0.77; 95% CI, 0.56-1.09; P = .13). Conclusions and Relevance: In this international population of patients with high-risk stage II and stage III colorectal cancer, starting adjuvant chemotherapy more than 6 weeks after surgery was associated with worse disease-free survival, with no difference in adverse events between the groups. Trial Registration: isrctn.org Identifier: ISRCTN59757862.

Joint environmental and social benefits from diversified agriculture.

Agricultural simplification continues to expand at the expense of more diverse forms of agriculture. This simplification, for example, in the form of intensively managed monocultures, poses a risk to keeping the world within safe and just Earth system boundaries. Here, we estimated how agricultural diversification simultaneously affects social and environmental outcomes. Drawing from 24 studies in 11 countries across 2655 farms, we show how five diversification strategies focusing on livestock, crops, soils, noncrop plantings, and water conservation benefit social (e.g., human well-being, yields, and food security) and environmental (e.g., biodiversity, ecosystem services, and reduced environmental externalities) outcomes. We found that applying multiple diversification strategies creates more positive outcomes than individual management strategies alone. To realize these benefits, well-designed policies are needed to incentivize the adoption of multiple diversification strategies in unison.

Oxaliplatin-Based Adjuvant Chemotherapy in Older Patients With Stage III Colon Cancer: An ACCENT/IDEA Pooled Analysis of 12 Trials.

PURPOSE: A number of studies suggest that older patients may have reduced or no benefit from the addition of oxaliplatin to fluoropyrimidines as adjuvant chemotherapy for stage III colon cancer (CC). MATERIALS AND METHODS: We studied the prognostic impact of age, as well as treatment adherence/toxicity patterns according to age, in patients with stage III CC who received 3 or 6 months of infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (CAPOX) on the basis of data collected from trials from the ACCENT and IDEA databases. Associations between age and time to recurrence (TTR), disease-free survival (DFS), overall survival (OS), survival after recurrence (SAR), and cancer-specific survival (CSS) were assessed by a Cox model or a competing risk model, stratified by studies and adjusted for sex, performance status, T and N stage, and year of enrollment. RESULTS: A total of 17,909 patients were included; 24% of patients were age older than 70 years (n = 4,340). Patients age ≥70 years had higher rates of early treatment discontinuation. Rates of grade ≥3 adverse events were similar between those older and younger than 70 years, except for diarrhea and neutropenia that were more frequent in older patients treated with CAPOX (14.2% v 11.2%; P = .01 and 12.1% v 9.6%; P = .04, respectively). In multivariable analysis, TTR was not significantly different between patients <70 years and those ≥70 years, but DFS, OS, SAR, and CSS were significantly shorter in those patients ≥70 years. CONCLUSION: In patients ≥70 years with stage III CC fit enough to be enrolled in clinical trials, oxaliplatin-based adjuvant chemotherapy was well tolerated and led to similar TTR compared with younger patients, suggesting similar efficacy. TTR may be a more appropriate end point for efficacy in this patient population.

Prognostic and Predictive Value of Immunoscore in Stage III Colorectal Cancer: Pooled Analysis of Cases From the SCOT and IDEA-HORG Studies.

PURPOSE: Immunoscore (IS) is prognostic in stage III colorectal cancer (CRC) and may predict benefit of duration (6 v 3 months) of adjuvant infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. We sought to determine IS prognostic and predictive value in stage-III CRC treated with adjuvant FOLFOX or oral capecitabine and infusional oxaliplatin (CAPOX) in the SCOT and IDEA-HORG trials. METHODS: Three thousand sixty-one cases had tumor samples, of which 2,643 (1,792 CAPOX) were eligible for IS testing. Predefined cutoffs (IS-Low and IS-High) were used to classify cases into two groups for analysis of disease-free survival (3-year DFS) and multivariable-adjusted hazard ratios (mvHRs) by Cox regression. RESULTS: IS was determined in 2,608 (99.5%) eligible cases, with 877 (33.7%) samples classified as IS-Low. IS-Low tumors were more commonly high-risk (T4 and/or N2; 52.9% IS-Low v 42.2% IS-High; P < .001) and in younger patients (P = .024). Patients with IS-Low tumors had significantly shorter DFS in the CAPOX, FOLFOX, and combined cohorts (mvHR, 1.52 [95% CI, 1.28 to 1.82]; mvHR, 1.58 [95% CI, 1.22 to 2.04]; and mvHR, 1.55 [95% CI, 1.34 to 1.79], respectively; P < .001 all comparisons), regardless of sex, BMI, clinical risk group, tumor location, treatment duration, or chemotherapy regimen. IS prognostic value was greater in younger (≤65 years) than older (>65 years) patients in the CAPOX cohort (mvHR, 1.92 [95% CI, 1.50 to 2.46] v 1.28 [95% CI, 1.01 to 1.63], PINTERACTION = .026), and in DNA mismatch repair proficient than deficient mismatch repair disease (mvHR, 1.68 [95% CI, 1.41 to 2.00] v 0.67 [95% CI, 0.30 to 1.49], PINTERACTION = .03), although these exploratory analyses were uncorrected for multiple testing. Adding IS to a model containing all clinical variables significantly improved prediction of DFS (likelihood ratio test, P < .001) regardless of MMR status. CONCLUSION: IS is prognostic in stage III CRC treated with FOLFOX or CAPOX, including within clinically relevant tumor subgroups. Possible variation in IS prognostic value by age and MMR status, and prediction of benefit from extended adjuvant therapy merit validation.

Suitability of Alternative Protein Foods for Agroecological Approaches to Address Nutrition in Low- and Middle-Income Countries.

Agroecology has been proposed as a holistic approach to transform food systems that meet global food requirements with favorable environmental and social impacts. Agroecology relies on science, practices, and social movements that emphasize ecological principles, local knowledge, culture, and traditions to increase the sustainability and equity of the food system. Agroecological practices have demonstrated positive outcomes on food security and nutrition in low- and middle-income countries (LMICs). Agroecology principles can be applied across the food system and could facilitate the integration of certain alternative protein (AP) foods to address multiple issues. In this perspective, agroecological principles were analyzed to compare the suitability of different AP sources: unprocessed/minimally processed legumes, plant-based meats, edible insects, macroalgae (seaweed), fungal biomass, and cultivated meat. Considerations were identified for the feasibility of AP adoption in LMICs within an agroecological framework to provide nutrient-rich and sustainable diets while addressing other principles such as fairness and economic diversity. From this analysis, legumes, simplified plant-based meat analogs such as texturized plant proteins with minimal additives, edible insects, and macroalgae (location dependent) would make excellent nutritional contributions alongside animal-sourced food within LMICs within an agroecological framework. In contrast, highly processed plant-based meats, fungal biomass, and cultivated meat do not align well with agroecological principles for large-scale human consumption within LMICs. Furthermore, the production facilities to make these foods require robust capital investment and there may be issues related to who owns the intellectual property of these technologies. The NOVA classification system categorizes food based on the degree of processing. Our assessment suggests that foods with lower NOVA classification of unprocessed and minimally processed best fit the agroecological principles related to nutrition, agroecosystem, and societal demands for sustainable food systems.

Multiplex analysis of intratumoural immune infiltrate and prognosis in patients with stage II-III colorectal cancer from the SCOT and QUASAR 2 trials: a retrospective analysis.

BACKGROUND: Tumour-infiltrating CD8+ cytotoxic T cells confer favourable prognosis in colorectal cancer. The added prognostic value of other infiltrating immune cells is unclear and so we sought to investigate their prognostic value in two large clinical trial cohorts. METHODS: We used multiplex immunofluorescent staining of tissue microarrays to assess the densities of CD8+, CD20+, FoxP3+, and CD68+ cells in the intraepithelial and intrastromal compartments from tumour samples of patients with stage II-III colorectal cancer from the SCOT trial (ISRCTN59757862), which examined 3 months versus 6 months of adjuvant oxaliplatin-based chemotherapy, and from the QUASAR 2 trial (ISRCTN45133151), which compared adjuvant capecitabine with or without bevacizumab. Both trials included patients aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1. Immune marker predictors were analysed by multiple regression, and the prognostic and predictive values of markers for colorectal cancer recurrence-free interval by Cox regression were assessed using the SCOT cohort for discovery and QUASAR 2 cohort for validation. FINDINGS: After exclusion of cases without tissue microarrays and with technical failures, and following quality control, we included 2340 cases from the SCOT trial and 1069 from the QUASAR 2 trial in our analysis. Univariable analysis of associations with recurrence-free interval in cases from the SCOT trial showed a strong prognostic value of intraepithelial CD8 (CD8IE) as a continuous variable (hazard ratio [HR] for 75th vs 25th percentile [75vs25] 0·73 [95% CI 0·68-0·79], p=2·5 × 10-16), and of intrastromal FoxP3 (FoxP3IS; 0·71 [0·64-0·78], p=1·5 × 10-13) but not as strongly in the epithelium (FoxP3IE; 0·89 [0·84-0·96], p=1·5 × 10-4). Associations of other markers with recurrence-free interval were moderate. CD8IE and FoxP3IS retained independent prognostic value in bivariable and multivariable analysis, and, compared with either marker alone, a composite marker including both markers (CD8IE-FoxP3IS) was superior when assessed as a continuous variable (adjusted [a]HR75 vs 25 0·70 [95% CI 0·63-0·78], p=5·1 × 10-11) and when categorised into low, intermediate, and high density groups using previously published cutpoints (aHR for intermediate vs high 1·68 [95% CI 1·29-2·20], p=1·3 × 10-4; low vs high 2·58 [1·91-3·49], p=7·9 × 10-10), with performance similar to the gold-standard Immunoscore. The prognostic value of CD8IE-FoxP3IS was confirmed in cases from the QUASAR 2 trial, both as a continuous variable (aHR75 vs 25 0·84 [95% CI 0·73-0·96], p=0·012) and as a categorical variable for low versus high density (aHR 1·80 [95% CI 1·17-2·75], p=0·0071) but not for intermediate versus high (1·30 [0·89-1·88], p=0·17). INTERPRETATION: Combined evaluation of CD8IE and FoxP3IS could help to refine risk stratification in colorectal cancer. Investigation of FoxP3IS cells as an immunotherapy target in colorectal cancer might be merited. FUNDING: Medical Research Council, National Institute for Health Research, Cancer Research UK, Swedish Cancer Society, Roche, and Promedica Foundation.

Accounting for intensity variation in image analysis of large-scale multiplexed clinical trial datasets.

Multiplex immunofluorescence (mIF) imaging can provide comprehensive quantitative and spatial information for multiple immune markers for tumour immunoprofiling. However, application at scale to clinical trial samples sourced from multiple institutions is challenging due to pre-analytical heterogeneity. This study reports an analytical approach to the largest multi-parameter immunoprofiling study of clinical trial samples to date. We analysed 12,592 tissue microarray (TMA) spots from 3,545 colorectal cancers sourced from more than 240 institutions in two clinical trials (QUASAR 2 and SCOT) stained for CD4, CD8, CD20, CD68, FoxP3, pan-cytokeratin, and DAPI by mIF. TMA slides were multi-spectrally imaged and analysed by cell-based and pixel-based marker analysis. We developed an adaptive thresholding method to account for inter- and intra-slide intensity variation in TMA analysis. Applying this method effectively ameliorated inter- and intra-slide intensity variation improving the image analysis results compared with methods using a single global threshold. Correlation of CD8 data derived by our mIF analysis approach with single-plex chromogenic immunohistochemistry CD8 data derived from subsequent sections indicates the validity of our method (Spearman's rank correlation coefficients ρ between 0.63 and 0.66, p ≪ 0.01) as compared with the current gold standard analysis approach. Evaluation of correlation between cell-based and pixel-based analysis results confirms equivalency (ρ > 0.8, p ≪ 0.01, except for CD20 in the epithelial region) of both analytical approaches. These data suggest that our adaptive thresholding approach can enable analysis of mIF-stained clinical trial TMA datasets by digital pathology at scale for precision immunoprofiling.

Women's empowerment, production choices, and crop diversity in Burkina Faso, India, Malawi, and Tanzania: a secondary analysis of cross-sectional data.

BACKGROUND: Bolstering farm-level crop diversity is one strategy to strengthen food system resilience and achieve global food security. Women who live in rural areas play an essential role in food production; therefore, we aimed to assess the associations between women's empowerment and crop diversity. METHODS: In this secondary analysis of cross-sectional data, we used data from four cluster-randomised controlled trials done in Burkina Faso, India, Malawi, and Tanzania. We assessed women's empowerment using indicators from the Women's Empowerment in Agriculture Index. Farm-level crop diversity measures were the number of food crops grown, number of food groups grown, and if nutrient-dense crops were grown. We used a two-stage modelling approach. First, we analysed covariate-adjusted country-specific associations between women's empowerment and crop diversity indicators using multivariable generalised linear models. Second, we pooled country-specific associations using random-effects models. FINDINGS: The final analytic sample included 1735 women from Burkina Faso, 4450 women from India, 547 women from Malawi, and 574 women from Tanzania. Across all countries, compared with households in which women provided input into fewer productive decisions, households of women with greater input into productive decisions produced more food crops (mean difference 0·36 [95% CI 0·16-0·55]), a higher number of food groups (mean difference 0·16 [0·06-0·25]), and more nutrient-dense crops (percentage point difference 3 [95% CI 3-4]). Across all countries, each additional community group a woman actively participated in was associated with cultivating a higher number of food crops (mean difference 0·20 [0·04-0·35]) and a higher number of food groups (mean difference 0·11 [0·03-0·18]), but not more nutrient-dense crops. In pooled associations from Burkina Faso and India, asset ownership was associated with cultivating a higher number of food crops (mean difference 0·08 [0·04-0·12]) and a higher number of food groups (mean difference 0·05 [0·04-0·07]), but not more nutrient-dense crops. INTERPRETATION: Greater women's empowerment was associated with higher farm-level crop diversity among low-income agricultural households, suggesting that it could help enhance efforts to strengthen food system resilience. FUNDING: Bill & Melinda Gates Foundation.

A Mixed Methods Exploration of the Role of Participation in a Nutrition-Sensitive Agroecology Intervention in Rural Tanzania.

Background: Participation is key to the successful implementation of nutrition-related interventions, but it has been relatively overlooked. Objective: We sought to describe participation intensity among smallholder farmers in a randomized nutrition-sensitive agroecology study in rural Tanzania. We explored the association between baseline characteristics and overall participation intensity (quantitatively at the individual level and qualitatively at the group level), the association of participation intensity with 2 process indicators, and the association between participation intensity and key study outcomes. Methods: Data came from 7 rounds of surveys with 295 women and 267 men across 29 months and 2 rounds of semi-structured interviews with the 20 "mentor farmers" who delivered the intervention. Participation intensity was based on the number of months of attendance at village-level project meetings or household visits (range: 0-29). Multivariable models of participation were built. Results: Women and men participated for 17.5 ± 7.2 and 13.6 ± 8.3 months, respectively. Participation intensity followed 1 latent trajectory: initially low, with a sharp increase after month 7, and plateaued after the first year. At baseline, higher participation intensity was associated with older age, higher education, level of women's empowerment, being in the middle quintile of wealth, and qualitatively, village residence. Higher participation intensity was associated with 2 process indicators - better recall of topics discussed during meetings and greater knowledge about key agroecological methods. High participation intensity was positively associated with increased use of sustainable agricultural practices among all participants, and among women, with husband's involvement in household tasks and child's dietary diversity score. Conclusions: Participation intensity covaried with key study outcomes, suggesting the value of increased attention to implementation in nutrition-related programs for providing insights into drivers of impact. We hope that investigations of participation, including participation intensity, will become more widespread so that intervention impacts, or lack thereof, can be better understood.

Non-Canonical Activin A Signaling Stimulates Context-Dependent and Cellular-Specific Outcomes in CRC to Promote Tumor Cell Migration and Immune Tolerance.

We have shown that activin A (activin), a TGF-ß superfamily member, has pro-metastatic effects in colorectal cancer (CRC). In lung cancer, activin activates pro-metastatic pathways to enhance tumor cell survival and migration while augmenting CD4+ to CD8+ communications to promote cytotoxicity. Here, we hypothesized that activin exerts cell-specific effects in the tumor microenvironment (TME) of CRC to promote anti-tumoral activity of immune cells and the pro-metastatic behavior of tumor cells in a cell-specific and context-dependent manner. We generated an Smad4 epithelial cell specific knockout (Smad4-/-) which was crossed with TS4-Cre mice to identify SMAD-specific changes in CRC. We also performed IHC and digital spatial profiling (DSP) of tissue microarrays (TMAs) obtained from 1055 stage II and III CRC patients in the QUASAR 2 clinical trial. We transfected the CRC cells to reduce their activin production and injected them into mice with intermittent tumor measurements to determine how cancer-derived activin alters tumor growth in vivo. In vivo, Smad4-/- mice displayed elevated colonic activin and pAKT expression and increased mortality. IHC analysis of the TMA samples revealed increased activin was required for TGF-ß-associated improved outcomes in CRC. DSP analysis identified that activin co-localization in the stroma was coupled with increases in T-cell exhaustion markers, activation markers of antigen presenting cells (APCs), and effectors of the PI3K/AKT pathway. Activin-stimulated PI3K-dependent CRC transwell migration, and the in vivo loss of activin lead to smaller CRC tumors. Taken together, activin is a targetable, highly context-dependent molecule with effects on CRC growth, migration, and TME immune plasticity.

SCOT: Tumor Sidedness and the Influence of Adjuvant Chemotherapy Duration on Disease Free Survival (DFS).

AIM: Patients with loco-regional right-sided colorectal tumors have a worse overall survival (OS). Here we investigate the difference in disease free survival (DFS) between colorectal patients with right and left sided tumors in the SCOT study. METHODS: The SCOT study showed 3-months of oxaliplatin-containing adjuvant chemotherapy (OxFp) is non-inferior to 6-months for patients with stage III and high-risk stage II colorectal cancer. We divided the cohort into patients with left and right sided tumors, and evaluated the effect on DFS and the principle 3 versus 6-months analysis. RESULTS: 6088 patients with Stage III/high risk Stage II colorectal cancers were randomized between 27th March 2008 and 29th November 2013 from 244 centers internationally. In February 2017 (3-years FU) information on sidedness was available for 3309 patients (1238 R-sided, 2071 L-sided). Patients with right-sided tumors had a significantly worse DFS (3-year DFS right: 73.3% (se = 1.3%), left: 80.2% (se = 0.9%) HR 1.423 (95% CI 1.237-1.637; P < .0001). Adjusting for T and N-stage reduced the HR to 1.230 (95% CI 1.066-1.420, P = .005). The data did not suggest that sidedness affected the impact of chemotherapy duration on 3-year DFS (R: HR 1.024 [0.831-1.261], L: HR 0.944 [0.783-1.139]). Test for heterogeneity, P = .571. Further sub-set analysis was limited due to cohort size. CONCLUSIONS: This is the first study to show that unselected patients with right-sided tumors had a worse DFS compared to left-sided tumors. Tumor sidedness did not impact upon the 3-months versus 6-months comparison in SCOT.

Complications of Influenza A or B Virus Infection in Individuals With SCN1A-Positive Dravet Syndrome.

BACKGROUND AND OBJECTIVES: To determine the frequency and spectrum of complications of influenza infection in individuals with SCN1A-positive Dravet syndrome (SCN1A-DS). METHODS: Individuals with SCN1A-DS were identified in neurologists' care at 2 hospitals in Melbourne, Australia, with additional searches of EEG databases, the Victorian PAEDS FluCan influenza database, and the University of Melbourne Epilepsy Genetics Research Program database. Medical records were searched and families questioned to identify individuals who had an influenza infection; reported infections were confirmed by pathology report. For these individuals, we obtained baseline clinical characteristics and clinical details of the influenza infection. RESULTS: Twenty-one of 82 individuals (26%) had 24 documented influenza infections (17 influenza A and 7 influenza B) at age 0.5-25 years (median 4 years). All presented to hospital, 18/24 (75%) for status epilepticus or seizure exacerbations. Recovery was prompt in 18/24 (75%) infections, delayed but complete in 1/24 (4%) and incomplete in 5/24 (21%). One child died from influenza pneumonia, and long-term neurologic sequelae were seen with 4 infections. These individuals were poorly responsive after termination of status epilepticus. Brain imaging in 2 showed cerebral edema and 1 also having imaging features of laminar necrosis. All have ongoing neurologic deficits compared with their baseline, 1 having profound global impairment. DISCUSSION: Our data show that patients with SCN1A-DS are highly susceptible to neurologic complications during and severe sequelae after influenza infection, including moderate to severe persistent neurologic impairments and death. Safe administration of the seasonal influenza vaccine should be prioritized for this population.

Prognostic Impact of Early Treatment and Oxaliplatin Discontinuation in Patients With Stage III Colon Cancer: An ACCENT/IDEA Pooled Analysis of 11 Adjuvant Trials.

PURPOSE: Oxaliplatin-based adjuvant chemotherapy in patients with stage III colon cancer (CC) for 6 months remains a standard in high-risk stage III patients. Data are lacking as to whether early discontinuation of all treatment (ETD) or early discontinuation of oxaliplatin (EOD) could worsen the prognosis. MATERIALS AND METHODS: We studied the prognostic impact of ETD and EOD in patients with stage III CC from the ACCENT/IDEA databases, where patients were planned to receive 6 months of infusional fluorouracil, leucovorin, and oxaliplatin or capecitabine plus oxaliplatin. ETD was defined as discontinuation of treatment and EOD as discontinuation of oxaliplatin only before patients had received a maximum of 75% of planned cycles. Association between ETD/EOD and overall survival and disease-free survival (DFS) were assessed by Cox models adjusted for established prognostic factors. RESULTS: Analysis of ETD and EOD included 10,447 (20.9% with ETD) and 7,243 (18.8% with EOD) patients, respectively. Compared with patients without ETD or EOD, patients with ETD or EOD were statistically more likely to be women, with Eastern Cooperative Oncology Group performance status ≥ 1, and for ETD, older with a lower body mass index. In multivariable analyses, ETD was associated with a decrease in disease-free survival and overall survival (hazard ratio [HR], 1.61, P < .001 and HR, 1.73, P < .001), which was not the case for EOD (HR, 1.07, P = .3 and HR, 1.13, P = .1). However, patients who received < 50% of the planned cycles of oxaliplatin had poorer outcomes. CONCLUSION: In patients treated with 6 months of oxaliplatin-based chemotherapy for stage III CC, ETD was associated with poorer oncologic outcomes. However, this was not the case for EOD. These data favor discontinuing oxaliplatin while continuing fluoropyrimidine in individuals with significant neurotoxicity having received > 50% of the planned 6-month chemotherapy.

Does Crop Diversity Influence Household Food Security and Women's Individual Dietary Diversity? A Cross-Sectional Study of Malawian Farmers in a Participatory Agroecology and Nutrition Project.

BACKGROUND: Agroecological methods have the potential to impact nutrition and food security, however, to date there is limited research evaluating this approach. OBJECTIVE: A 5-year participatory research project with farming households in north and central Malawi was designed to train farmers on agroecological practices, alongside raising awareness on nutrition and gender equity. This cross-sectional study aimed to explore the relationships between crop diversity, food security at the household level, and individual diversity for women, within the context of an agroecology, nutrition education, and farmer mentoring program. METHODS: Participating farmers were trained in and experimented with different farming methods. These farmers subsequently trained other farmers on these short-term agroecological practices and provided mentorship using community-based educational methods designed to address both household food security and nutrition. In year 4 of the intervention, a cross-sectional survey assessed farm practices, food security, and individual dietary diversity of 851 participating households. RESULTS: Households with lower crop diversity were significantly less likely to be food secure (odds ratios [OR] = 0.829, P < .001). Women in households with higher crop diversity were more likely to have higher individual dietary diversity (OR = 1.120, P < .01), eat vitamin A rich foods (OR = 1.176, P < .01), and legumes, nuts, and seeds (OR = 1.141, P < .01). CONCLUSIONS: These findings suggest that within a participatory agroecological training combined with community-based nutrition education with a focus on social equity, crop diversity is associated with less household food insecurity and poorer diet quality for rural farming households. Crop diversity may improve dietary diversity by making nutritious foods more available.