Total neoadjuvant therapy (TNT) has become a cornerstone in the treatment of locally advanced rectal cancer, improving systemic control and increasing the potential for organ preservation. However, current trials and guidelines continue to treat rectal cancer as a homogeneous entity, overlooking the significant anatomic and therapeutic differences between mid- and low-rectal tumors. This uniform approach fails to reflect the impact of tumor location on both oncologic outcomes and functional consequences. Low-rectal cancers-defined as tumors located < 1 cm from the anal ring-pose distinct anatomic and functional challenges. These include more complex lymphatic drainage, higher risks of positive margins, and greater impact on continence. By contrast, mid-rectal tumors are generally more amenable to standard resection with preserved function and may benefit from treatment deintensification, particularly regarding radiotherapy. Drawing on data from over 80 studies and clinical trials, this review argues that mid- and low-rectal cancers should be considered distinct clinical entities requiring tailored treatment strategies. We examine evidence supporting radiotherapy de-escalation for mid-rectal tumors and intensified TNT for low-rectal tumors when organ and sphincter preservation is essential. Adopting a location-specific, patient-centered approach can better align treatment intensity with oncologic risk and individual functional priorities, ultimately improving both outcomes and quality of life.

Pancreatic ductal adenocarcinoma remains one of the deadliest malignancies, characterized by late diagnosis, aggressive biology and limited therapeutic success. Advances in multiagent chemotherapy have improved outcomes across disease stages, whereas precision medicine approaches are reshaping treatment paradigms. Personalized RNA vaccines and oncogenic KRAS-directed agents represent emerging immunological and molecular frontiers. Multimodal treatment regimens and surgical innovations, including vessel-oriented and minimally invasive techniques, have enhanced complete resection rates and enabled conversion of initially unresectable locally advanced pancreatic cancer into resectable disease. Increasingly, multidisciplinary, biology-guided strategies define resectability and the sequence of systemic and local therapies. The tumour microenvironment’s complex stromal and immune ecology remains central to therapeutic resistance but also offers opportunities for rational combination therapy. Early detection and risk-adapted surveillance for high-risk individuals are advancing, as are artificial intelligence-assisted imaging and liquid biopsy approaches. Despite persistent challenges, the convergence of mechanistic insights, precision therapeutics and supportive care provides a framework for transforming pancreatic ductal adenocarcinoma from an inevitably lethal disease towards a better manageable condition. In this Primer, Roth et al. discuss the epidemiology, current knowledge of pathophysiology, diagnosis, management and quality of life of individuals with pancreatic ductal adenocarcinoma, which remains one of the deadliest malignancies globally.

PURPOSE:This multi-national cross-sectional study assessed socio-demographic and clinical determinants of satisfaction with cancer care in patients enrolled from hospital inpatient and outpatient settings. METHODS:Six hundred ninety consecutive patients with any cancer type or stage including 558 outpatients were approached between October 2019 and October 2023 in 12 countries (20 cancer centres) from Asia, Europe, the Middle East and South America. Among them, 675 (98%) and 521 (93%) completed the EORTC PATSAT-C33 and the OUT-PATSAT7, respectively. Multi-level analyses were performed accounting for institutional differences in satisfaction with care. RESULTS:Self-reported quality of life was positively related to all thirteen PATSAT-C33 and OUT-PATSAT7 satisfaction with care domains. Treatment toxicities and the absence of comorbidity predicted lower satisfaction with nine and ten care domains, respectively. Patients in day hospitals were significantly less satisfied with nurses' availability, care coordination and health professionals' information. Tumour site predicted satisfaction with care transition hospital-home. Not being married/with a partner and shorter travels to the hospital predicted less satisfaction with five and two care domains, respectively. CONCLUSION:This study illustrates the value of collecting patients' feedback on their cancer care experience. It informs health policy, pointing out targets for improving satisfaction with cancer care across several institutions and cultures worldwide. TRIAL REGISTRATION:ClinicalTrials.gov under ID: NCT05989191, August 2, 2023.

PURPOSE The choice of adjuvant chemotherapy in pancreatic ductal adenocarcinoma (PDAC) is mainly guided by patients' general condition. We hypothesized that tumor morphology may predict differential treatment benefit and tested whether deep learning applied to histology images could derive a biomarker of relative benefit from gemcitabine (GEM) versus modified FOLFIRINOX (mFOLFIRINOX) in resected PDAC. PATIENTS AND METHODS Standard whole-slide images from a retrospective multicentric series of 231 patients who underwent curative-intent pancreatectomy and received adjuvant mFOLFIRINOX (n = 54) or GEM (n = 177) were used to train regimen-specific histology models on disease-free survival (DFS), which were then combined into PANCprAId, a biomarker estimating personalized relative benefit from adjuvant GEM versus mFOLFIRINOX. External validation was performed in the randomized PRODIGE-24/CCTG PA6 trial (n = 313). RESULTS In PRODIGE-24/CCTG PA6, the treatment-specific histology scores used to construct PANCprAId stratified outcomes among patients treated with GEM (hazard ratio [HR], 1.69 [95% CI, 1.04 to 2.73]; P = .03) and mFOLFIRINOX (HR, 2.02 [95% CI, 1.4 to 3.0]; P < .001). When combined into PANCprAId, the biomarker identified subgroups with differential relative benefit from adjuvant GEM versus mFOLFIRINOX, with significant treatment interactions for DFS (interaction P = .003) and cancer-specific survival (interaction P = .001). Predicted sensitivity to each regimen was associated with distinct epithelial and stromal features. CONCLUSION Histology-based deep learning can derive a predictive biomarker of relative benefit from adjuvant GEM versus mFOLFIRINOX in resected PDAC.

ABSTRACT Background Pancreatic cancer remains one of the most lethal cancers despite extensive efforts and research conducted over the past decades. To effectuate groundbreaking improvements in pancreatic cancer treatment, interdisciplinary and international collaboration is essential. Evidence‐based guidelines, including state‐of‐the‐art evidence and expert opinion, are crucial to guide medical specialists, researchers, and patients, especially on issues where consensus is still lacking. This article describes the methodological protocol for the development of the European Multidisciplinary Evidence‐Based Guideline on Pancreatic Cancer. The guideline aims to identify current knowledge gaps on pancreatic cancer management, develop questions based on these knowledge gaps, and answer these questions with evidence‐based recommendations supplemented, when evidence is lacking, with expert advice for treatment and future research. Methods This guideline development protocol is developed according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. The process is structured into six stages: First, 13 theme‐based multidisciplinary working groups are established, comprising representatives from 30 European medical and patient societies. Second, these working groups identify the most relevant current knowledge gaps on pancreatic cancer within their theme and formulate key questions. Third, the available evidence to answer these key questions is obtained through systematic reviews and the certainty of evidence is assessed using the GRADE approach. Fourth, recommendations are developed based on the available evidence. Fifth, all participants reach consensus on the recommendations through a modified Delphi process. Sixth, the recommendations are discussed during an open conference, including an external validation committee. Discussion This methodological protocol of the European Multidisciplinary Evidence‐Based Guideline on Pancreatic Cancer is designed to identify key knowledge gaps across 13 themes and formulate evidence‐based recommendations. This guideline initiative unites 30 European medical and patient societies for pancreatic cancer.

Objective:To investigate the correlation between positive resection margins and outcomes in patients with pancreatic ductal adenocarcinoma who underwent surgery and adjuvant chemotherapy according to the pivotal trial PRODIGE 24-CCTG PA-6. Background:The primary focus is on elucidating the prognostic significance of specific resection margins, including those associated with the superior-mesenteric vein, medial, and posterior pancreas. Methods:The analysis involved 400 patients across multiple centers in France and Canada. Surgical resection and subsequent adjuvant chemotherapy were core interventions. This study assessed the prognostic impact of resection margins, highlighting the significance of standardized pathology assessments. In addition, the influence of chemotherapy regimen choice, comparing gemcitabine to mFOLFIRINOX, on the implications of positive resection margins was examined. Results:Only 3 margins, superior-mesenteric vein [hazard ratio (HR) = 1.48 (95% CI: 1.11; 1.96); P < 0.001], medial [HR = 1.92 (95% CI: 1.36; 2.73); P < 0.001] and posterior [HR = 1.65 (95% CI: 1.21; 2.24); P = 0.002], had a significant prognostic impact on disease-free survival and were sufficient compared with the 7 recommended margins (Kappa = 0.90; 95% CI: 0.87; 0.94). R1 status was a significant independent prognostic factor for poorer survival in gemcitabine-treated patients [HR = 1.97 (95% CI: 1.23; 3.16); P = 0.005] but lost its significance with mFOLFIRINOX [HR = 1.46 (95% CI: 0.91; 2.35); P = 0.114]. Conclusions:All efforts should be made to evaluate the 3 margins of the highest prognostic value, with the others being secondary. A key finding of this study is the likely effect of mFOLFIRINOX on local invasion in operated patients, which seems to correct the impairment related to margin involvement, probably explaining the improvements in disease-free survival and overall survival.

PURPOSE:Predicting recurrence of pancreatic cancer after surgery could inform clinical decision making, including adjuvant therapies and follow-up. This study aimed to develop and validate a deep learning model using digitized whole-slide images (WSI) of histopathology. METHODS:Publicly available WSI of pancreatic ductal adenocarcinoma resections from three cohorts were used for training. The model consisted of a pan-cancer foundation model to generate embeddings, mean-pooling across tissue patches, and then a fully connected neural network. Model predictions were compared with human-labeled histopathologic features and genomic alterations. The model was externally validated in a meta-analysis of a single-center cohort from Princess Margaret Cancer Centre, a multicenter cohort from France, and the PRODIGE 24 trial of adjuvant chemotherapy. RESULTS:The deep learning model was trained on 12,594 tissue patches from 257 patients. High-risk classifications were associated with squamous morphology, reactive stroma, tumor cellularity, and necrosis, whereas low-risk classifications were associated with tubulopapillary and conventional morphologies, as well as deserted stroma. High-risk cancers were enriched for basal-like gene expression profiles and distinct oncogenic pathways. In a meta-analysis of the external cohorts, the hazard ratio (HR) for death comparing high-versus low-risk cancers was 1.49 (95% CI, 1.25 to 1.79, P < .001), whereas the HR for recurrence or death was 1.41 (95% CI, 1.19 to 1.68, P < .001). The classifications remained prognostic among moderately differentiated cancers. CONCLUSION:An open-source deep learning model using WSI from pancreatic cancer resections generated risk classifications that correlated with histopathologic and genomic features. Classifications were externally validated in a meta-analysis of three cohorts. This model could be applied to WSI to provide individualized prognostic information for patients.

PURPOSE:Modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX/mFFX) is the standard adjuvant chemotherapy for resected pancreatic ductal adenocarcinoma (PDAC), offering survival benefits over gemcitabine (GEM). However, the contribution of molecular biomarkers to treatment selection remains unclear. Here, we characterize the molecular landscape of tumors from the PRODIGE-24/CCTG PA6 trial and assess the clinical impact of genomic alterations and molecular subtypes. PATIENTS AND METHODS:Tumor DNA sequencing was successfully performed in 317/350 tumors (168 mFFX; 149 GEM), complemented by transcriptomic subtyping using the PurIST classifier. Mutational status of four key PDAC driver genes and 24 homologous recombination repair (HRR)-associated genes was analyzed, alongside single-base substitution (SBS) mutational signatures. Primary and secondary end points were disease-free survival (DFS) and cancer-specific survival (CSS), respectively. RESULTS:In the mFFX group, the PurIST subtype was prognostic, with classical tumors showing superior DFS compared with basal-like tumors (stratified hazard ratio [sHR], 0.48 [95% CI, 0.31 to 0.77]). Among KRAS-mutated patients, mFFX significantly improved DFS compared with GEM (sHR, 0.60 [95% CI, 0.45 to 0.79]; P < .001), while no benefit was observed in KRAS wild-type tumors (interaction test, Pint. = 0.010). HRR and BRCA status were not predictive (Pint. = .568 and Pint. = .785, respectively). The benefit of mFFX was consistent across SBS-positive and SBS-negative subgroups. CONCLUSION:Overall, these results do not support a change in current adjuvant treatment strategies. mFFX remains the standard adjuvant regimen in PDAC, and the observed lack of benefit in KRAS wild-type tumors should be considered hypothesis-generating and warrants further investigation.

Background: Genome and transcriptome analysis has enhanced the characterisation of pancreatic ductal adenocarcinoma (PDAC), paving the way for targeted therapies. Tumours KRAS wild type (WT) represent a unique subgroup. Objectives: Characterise the population and molecular abnormalities present in KRAS WT PDAC. Design: Clinical and molecular data from a large retrospective cohort of KRAS WT PDAC were analysed. Methods: Next-generation sequencing (NGS) was used to analyse DNAs and RNAs, allowing molecular and transcriptomic characterisation. Results: We identified 93/1059 (9%) KRAS WT PDAC, among which eight had druggable fusions ( n = 8/30 contributive samples), six had BRAF mutations and 19 ( n = 19/47) had mutations in homologous recombination (HR) pathway genes. Potential molecular targets in this series may be underestimated due to many non-contributive results. Clinical characteristics and survival did not differ between patients with KRAS WT and KRAS- mutated tumours. Transcriptomic data were available for 350 samples. Their analysis shows a difference in phenotype between mutated and WT tumours, with a molecular profile that appears to be better prognostic for KRAS WT tumours. Conclusion: KRAS WT tumours are enriched with molecular abnormalities of therapeutic interest. These include oncogene driver alterations (gene fusions and mutations) and mutations in genes of the HR pathway. Targeted therapy strategies for PDAC rely on molecular testing beyond RAS , but further research is needed to identify new therapeutic approaches that improve outcomes in PDAC.

Purpose Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies, largely due to chemoresistance arising from prominent cellular heterogeneity and a complex tumor microenvironment. Given this challenge, understanding the mechanisms of driving chemoresistance is essential for guiding our chemotherapeutic choice. Emerging evidence suggests that methylglyoxal (MG), a reactive glycolytic byproduct, may play a role in modulating tumor behavior and therapy response, offering a novel angle for patient stratification. Our recent study indicates that the accumulation of MG in PDAC cells leads to MG-induced cellular stress associated with gemcitabine (GEM) resistance. The primary objective of this study was to identify a predictive transcriptomic signature associated with MG stress in PDAC and compare it to the recently reported GemPred signature. Patients and methods MG stress classification was applied to the Puleo et al. cohort (n=309), enabling differential gene expression analysis and the development of a prognostic 16-gene MG-GEM signature through LASSO Cox regression. The signature was validated for survival prediction and diagnostic performance using cross-validation and ROC analysis. Results The prognostic significance and predictive performance of the signature were validated in both internal and external cohorts, including this from the phase III PRODIGE-24/CCTG PA6 trial, composed of 167 GEM and 183 FOLFIRINOX (mFFX) patients. Importantly, the MG-GEM signature demonstrated independent and complementary predictive value relative to GemPred. Conclusion We present a novel clinically actionable 16-gene transcriptomic signature reflecting MG-induced stress that enables robust stratification of PDAC patients likely to benefit from adjuvant GEM therapy. This model supports the development of personalized treatment strategies in pancreatic cancer. Key Objective Can metabolic gemcitabine (GEM) resistant inducer methylglyoxal stress be used to predict resistance to adjuvant GEM through a transcriptomic signature? Knowledge Generated The transcriptomic MG-GEM signature demonstrated the ability to distinguish between GEM sensitive and GEM resistant patients in the internal cohorts from Erasme University Hospital. MG-GEMs predictive capacity was further validated in the independent PRODIGE-24/CCTG PA6 clinical trial data. When compared to the established GemPred transcriptomic signature, MG-GEM exhibited an independent predictive behaviour. Moreover, combining both independent signatures enhanced the identification of GEM sensitive and GEM resistant patient subgroups. This combined approach may be particularly valuable in identifying patient subsets with treatment- specific responses. ### Competing Interest Statement The authors have declared no competing interest. National Fund for Scientific Research (FNRS), PDR T0011.22, J.0068.22 Fondation Belge contre le cancer, FCC 2020-072 Les Amis de l’Institut Bordet / L’Association Jules Bordet, 2024-20] La Ligue, L’Institut National du Cancer (INCa), and CHUGAI Pharma France L’Institut National du Cancer (INCa) La Direction Générale de l’Offre de Soins

Advances in cancer care require ongoing monitoring of patient satisfaction using rigorous questionnaires. The EORTC Quality of Life Group has cross-culturally developed a patient satisfaction core questionnaire (PATSAT-C33) to be used in any hospital cancer care settings and an outpatient satisfaction module (OUT-PATSAT7) to address specific aspects of ambulatory care. This multi-center international prospective study aimed to validate the PATSAT-C33 and OUT-PATSAT7, including assessing its acceptability. Patients (N = 690) affected by any cancer site or stage equally distributed by age and gender, were enrolled in in- and out-patient cancer settings from 20 institutions, 12 countries and 5 geographic/cultural areas. Among them, 675 completed the PATSAT-C33 alongside the EORTC QLQ-C30, Oberst’s perception of care quality 5-item, and ‘intention to recommend the hospital’ 1-item. Among the 532 outpatients, 526 also completed the OUT-PATSAT7. A subset completed a two-week retest (N = 120 96 for the PATSAT-C33 OUT-PATSAT7, respectively) or one-year responsiveness-to-change assessment (RCA) (N = 166 155). Comprehensive psychometric testing was performed. Full item completion was high (85

Rationale: We report a phase II trial (OSAD93) testing CDDP with ifosfamide (IFO), without doxorubicin in neoadjuvant phase, in adult osteosarcoma with a 25 years follow-up. Patients and methods: This is a multicentric phase II study of neoadjuvant chemotherapy with IFO and CDDP in localized high-grade osteosarcoma of patients. Patients received 4 pre-operative courses of IFO 9 g/m(2) and CDDP 100 mg/m(2) on day 4 (SHOC regimen), followed by local treatment. Doxorubicin was added post-operatively (HOCA regimen) in patients with > 10 % residual tumor cells. A Good Histological Response (GHR), ie <= 10 % residual tumor cells in > 30 % of patients, was the primary objective. Disease-free survival (DFS), overall survival (OS) and toxicity were secondary objectives. Results: From Jan 1994 to Jun 1998, 60 patients were included. Median age was 27 (range: 16-63). Primary tumor sites were limbs (76 %), trunk, head or neck (24 %). After neoadjuvant SHOC, grade 3-4 and febrile neutropenia, thrombopenia, and re-hospitalization occurred in 58 %, 17 %, 17 % and 22 % of SHOC courses and in 76 %, 28 %, 47 %, 47 % of HOCA courses, respectively. GHR was obtained in 16/60 (27.5 %) patients. With a median follow-up of 322 months, the DFS and OS were 51.8 % and 64.4 % at 5 years. At 10 years, DFS and OS were 49.9 % and 64.4 %. At 25 years, DFS and OS were 47.8 % and 55.9 %. No long-term cardiac toxicity was observed. Three patients developed a second malignancy (one fatal) after 300 months. Conclusion: Though the primary endpoint of OSAD93 was not met, this pre-operative doxorubicin-free regimen led to excellent long-term survival with limited toxicity in localized osteosarcoma.

Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges in patient management due to a dismal prognosis, increasing incidence, and limited treatment options. In this regard, precision medicine, which personalizes treatments based on tumour molecular characteristics, has gained great interest. However, its widespread implementation is not fully endorsed in current recommendations. This review explores key molecular alterations in PDAC, while emphasizing differences between KRAS -mutated and KRAS -wild-type tumours. It assesses the practical application of precision medicine in clinical settings and outlines potential future directions with respect to PDAC. Actionable molecular targets are examined with the aim of enhancing our understanding of PDAC molecular biology. Insights from this analysis may contribute to a more refined and personalized approach to pancreatic cancer treatment, ultimately improving patient outcomes.

Background: The standard of care for the treatment of locally advanced rectal cancer (LARC) results in an excellent local disease control but the metastasis rates remain high. PRODIGE 23 demonstrated improved disease-free survival (DFS) and metastasis-free survival (MFS) with total neoadjuvant therapy versus standard of care in this population. Long-term analysis of overall survival (OS) is reported here. Patients and methods: The study design, participants, and primary endpoint DFS have been reported for this multicenter, randomized, open-label, phase III trial investigating the neoadjuvant chemotherapy with mFOLFIRINOX (6 cycles) followed by chemoradiotherapy, surgery, and adjuvant chemotherapy (6 cycles), versus chemoradiotherapy, surgery, and adjuvant chemotherapy (12 cycles) in patients with locally advanced rectal adenocarcinoma under peritoneal reflection fl ection on magnetic resonance imaging, and staged cT3/T4. Key secondary endpoints included OS, MFS, and local and metastatic recurrence rate. Results: With a median follow-up of 82.2 months, the 7-year DFS was 67.6% [95% confidence fi dence interval (CI) 60.7% to 73.9%] and 62.5% (95% CI 55.6% to 68.6%) [restricted mean survival time (RMST) difference 5.73 months, 95% CI 0.05-11.41 months, P = 0.048] in the neoadjuvant chemotherapy and the standard-of-care groups, respectively. The 7-year MFS was 79.2% (95% CI 73.0% to 84.4%) in the neoadjuvant chemotherapy group and 72.3% (95% CI 65.8% to 77.8%) in the standard-of-care group (RMST difference 6.1 months, 95% CI 0.93-11.37 months, P = 0.021). The 7-year OS was 81.9% (95% CI 75.8% to 86.6%) in the neoadjuvant chemotherapy group and 76.1% (95% CI 69.7% to 81.2%) in the standard-of-care group (RMST difference 4.37 months, 95% CI 0.35-8.38 months, P = 0.033). The safety profile fi le remained unchanged since the previous analysis. Conclusions: Neoadjuvant chemotherapy with mFOLFIRINOX followed by chemoradiotherapy improved OS, confirmed fi rmed long-term DFS and MFS benefits fi ts in LARC patients, and should be considered as one of the best options of care for these patients.