Romain Coriat

Background: Optimal sequencing of rectal and liver resection for patients with resectable synchronous liver metastases (SLM) from rectal cancer remains controversial, and rectal-specific evidence is limited. Methods: A nationwide target trial (METASYNC-R) was emulated using the French national discharge database (2014–2023). Adults undergoing both rectal and liver resection for rectal cancer with SLM were eligible. Combined resection was compared with staged strategies (rectum- or liver-first within 14 weeks). Inverse probability of treatment weighting (IPTW) estimated the average treatment effect. Thirty-day severe complications (Clavien–Dindo grade ≥III) were analysed using marginal logistic regression with robust variance; overall survival was analysed using IPTW Cox proportional hazards models with cluster-robust standard errors. Landmark analyses at 3, 6, 12, and 24 months addressed potential immortal time bias. Results: Among 9632 patients undergoing both resections, 3057 had SLM and 1872 met the eligibility criteria (median age of 64 years); 1365 (73%) underwent combined resection and 507 (27%) underwent staged resection. Severe complications occurred in 39.7% versus 45.3% (P = 0.20); combined surgery was not associated with an increased risk of severe complications (adjusted OR 0.82 (95% c.i. 0.58 to 1.16); P = 0.27). Major hepatectomy independently increased the risk of severe complications (adjusted OR 1.81 (95% c.i. 1.06 to 3.08); P = 0.029). Thirty-day mortality was similar (1.8% versus 1.5%). Median overall survival was 52.4 months (combined) versus 57.3 months (staged) (P = 0.30). Combined surgery was not associated with worse survival (adjusted HR 0.88 (95% c.i. 0.65 to 1.19); P = 0.40), with consistent findings across landmark analyses. Conclusion: In this nationwide rectal cancer cohort, combined and staged strategies were associated with comparable morbidity and long-term survival. Surgical sequencing should be individualized within multidisciplinary decision-making.

Neuroendocrine tumors (NETs) are often associated with paraneoplastic features including carcinoid syndrome in up to 30% to 40% of cases. However, paraneoplastic thrombocytosis is a rare NET-associated condition. We report the case of a 59-year-old woman referred for significant and unexplained weight loss. Biological evaluation revealed thrombocytosis (900 × 109/L). A thoracoabdominal and pelvic computed tomography (CT) scan revealed multiple liver and bone lesions, suggestive of metastatic disease. Colonoscopic evaluation identified a well-differentiated NET as the primary tumor. Hematologic explorations revealed no underlying hematological condition explaining thrombocytosis. Cold somatostatin analogue treatment was started and resulted in initial stabilization of the disease. However, follow-up CT scan showed liver progression after 2 years concomitant with worsening thrombocytosis. 68Ga-DOTATOC positron emission tomography showed intense uptake of all known tumoral lesions; the patient was then treated with 177Lu-DOTATATE. Under 177Lu-DOTATATE treatment, platelet counts gradually decreased until normalization 8 weeks after the first injection, remaining within the normal range for up to 18 months, in parallel with clinical improvement. In conclusion, we report a rare case of paraneoplastic thrombocytosis associated with a small bowel NET showing rapid biological resolution from the first cycle of 177Lu-DOTATATE.

Objective: The rising incidence of neuroendocrine tumors (NETs) and delayed motherhood raise concerns about pregnancy outcomes and management, yet data remain scarce. Methods: This national cohort study, conducted through the GTE and RENATEN–ENDOCAN networks, included 17 women with NETs who experienced 26 pregnancies, resulting in 27 births. Maternal and fetal outcomes were analyzed based on tumor status, presence of carcinoid syndrome, and treatments during pregnancy. Early postpartum tumor evolution was evaluated using mRECIST on CT scans at 1 and 6 months after delivery. Results: Median maternal age at first pregnancy was 31. Among women with resected localized NETs, 71.4% remained in remission post-pregnancy, while 28.6% experienced recurrence. In metastatic NETs, disease remained stable in 50% of cases, with 21.4% showing progression. Most progression was observed on 1-month postpartum scans. No worsening of carcinoid syndrome symptoms occurred. The overall cesarean rate was 16.7%, increasing to 25% in those with carcinoid syndrome. Live birth rates were high: 94.4% under surveillance and 91% under somatostatin analog (SSA) therapy. Intrauterine growth restriction rate was higher in patients receiving SSA therapy, while birth weight and length were not affected. No developmental issues were observed by age 2. Conclusion: Pregnancy is generally safe and successful in women with NETs. No major safety concerns were observed with SSA; however, these findings should be interpreted cautiously given the small sample size. Their use should remain individualized within a multidisciplinary approach, with early postpartum tumor assessment to optimize fetal and maternal outcomes.

Les formes réactives de l’oxygène (FRO) ont un rôle bien établi dans l’oncogénèse et le fonctionnement des cellules tumorales en augmentant les capacités de prolifération et d’invasion cellulaire. Les FRO présentent une moindre toxicité dans les cellules normales où le niveau de stress oxydant est bas et les systèmes d’oxydoréduction opérationnels. Une modulation pharmacologique de l’équilibre d’oxydoréduction permet d’améliorer l’efficacité des molécules cytotoxiques qui agissent sur les FRO. L’activité anti tumorale de la chimiothérapie étant médiée en partie par le stress oxydant, nous nous sommes dans un premier temps intéressé aux variations du stress oxydant lors d’un traitement par le sorafenib (Nexavar©), un inhibiteur de tyrosine kinases. Nous avons mis en évidence une activité anti tumorale du sorafenib liée à l’augmentation de la production d’anion superoxyde par les cellules. Ce phénomène nous a permis d’identifier un marqueur prédictif d’efficacité du sorafenib, le dosage des Produits d’Oxydation Avancée des Protéines (AOPP), dans le sérum des patients cirrhotiques développant un carcinome hépatocellulaire. Sachant que l’efficacité anti tumorale des chimiothérapies conventionnelles passe en partie par l’induction de FRO, nous nous sommes intéressés dans un deuxième temps au mangafodipir, un modulateur du stress oxydant, qui est connu pour augmenter l’index thérapeutique des agents cytotoxiques in vivo. Le mangafodipir diminue les effets toxiques du stress oxydatif dans des cellules non tumorales et potentialise l’activité anti tumorale de l’oxaliplatine. Ces données nous ont conduits à explorer in vivo et in vitro le mécanisme de la neurotoxicité induite par l’oxaliplatine et le rôle protecteur du mangafodipir. Nous avons ainsi observé dans un modèle murin que le mangafodipir prévient la neurotoxicité induite par l’oxaliplatine au niveau de la gaine de myéline. Nous avons confirmé ces résultats chez l’homme lors d’une étude de phase II. Compte tenu des taux plus élevés de FRO dans les cellules tumorales par rapport aux cellules normales, plusieurs stratégies ont été proposées pour cibler sélectivement les tumeurs sans endommager les tissus sains avec des modulateurs du stress oxydant. Notre troisième axe de travail a eu pour objectif d’identifier et de valider de nouvelles molécules liées à la modulation des FRO. Cette étude a été réalisée dans le cadre d’un projet du programme Européen Pierre et Marie Curie (International Training Network 7-FP7-2007-1-1-ITN201114), au sein du réseau REDCAT. Cette collaboration a permis de concevoir et de synthétiser de nouveaux agents thérapeutiques, les organochalcogenes. Nous avons mis en évidence in vitro et in vivo le potentiel anti tumoral de cette nouvelle classe thérapeutique et principalement celui du composé LAB027. Le LAB027 présente une activité anti tumorale seul ou associé à l’oxaliplatine. L’ensemble de ces travaux nous a permis d’envisager l’évaluation précoce de l’efficacité du sorafenib par un marqueur du stress oxydant, les AOPP, de mettre en évidence l’effet anti-neurotoxique d’un mimétique de la superoxyde dismutase, le mangafodipir et d’identifier une nouvelle classe médicamenteuse en oncologie, les organochalcogènes. Ces optimisations thérapeutiques permettent d’envisager une meilleure prise en charge des malades traités par chimiothérapie afin d’optimiser l’efficacité des traitements utilisés en oncologie.

While the concept of predictive imaging is not entirely new, advanced analytic tools such as radiomics and machine learning have laid the foundation for a new generation of predictive imaging, which goes far beyond what is visible to the human eye. Predictive imaging has emerged as a transformative tool in abdominal oncology, offering the potential to personalize cancer detection and diagnosis, staging, treatment planning, monitoring and prognostication. A growing trend in predictive imaging is the creation of integrated models that combine multimodal imaging data, clinical parameters, genomic and molecular biomarkers. These integrated models can potentially offer superior prognostic capabilities and better risk stratification than traditional models in patients with abdominal cancers. Predictive imaging powered by radiomics and delta radiomics, artificial intelligence, and multimodal data integration is on the way for reshaping abdominal oncology. When current challenges are overcome, it is presumable that predictive imaging will offer powerful, noninvasive means to guide individualized care for patients with abdominal cancers, translating imaging data into actionable clinical insights. The purpose of this article was to provide an overview of the capabilities of predictive imaging in hepatic, pancreatic, colorectal, and gastric cancers.

Background: In RAS wild-type (WT) metastatic colorectal cancer (mCRC), preliminary data have suggested that circulating tumor DNA (ctDNA) may select patients for anti-EGFR rechallenge therapy. Methods: RASINTRO is a prospective nonrandomized study evaluating anti-EGFR rechallenge strategy in third and later line treatment in RAS/BRAF WT mCRC. Liquid biopsies for ctDNA analysis were collected before the first (C1) and second (C2) cycles of anti-EGFR rechallenge therapy. The primary endpoint was the progression-free survival (PFS) according to RAS/BRAF mutational status on ctDNA at C1. Results: Among 74 patients screened between November 2017 and March 2020, 62 were enrolled: median age, 66.1 years; median number of previous lines of therapy, 3; panitumumab or cetuximab rechallenge alone (66.2%) or with chemotherapy (33.8%); ctDNA RAS/BRAF status at C1, 42 WT (67.7%) and 20 mutated (32.3%). Median PFS (3.3 vs 1.9 months: hazard ratio (HR) = 0.43; P <.01) and overall survival (OS) (7.9 vs 4.9 months; HR = 0.46; P =.01) were significantly longer for patients with ctDNA RAS/BRAF WT vs mutated at C1. Among the 32 patients with ctDNA RAS/BRAF WT at C1 and available blood samples at C2, those who have experienced an early decrease of >50% in ctDNA concentration (n = 15) had a significantly longer median PFS (4.2 vs 2.8 months; HR = 0.39; P =.01) and OS (10.2 vs 4.2 months; HR = 0.39; P =.02). Conclusion: This study showed that anti-EGFR rechallenge therapy in refractory disease is more effective in patients with RAS/BRAF WT on ctDNA, and in those who experienced an early decrease of >50% in ctDNA concentration Trial Registration: ClinicalTrials.gov Identifier: NCT03259009.

As FDA‐approved platinum (Pt) anticancer drugs (e.g. cisplatin, oxaliplatin and carboplatin) grapple with clinical challenges including chemoresistance and systemic side‐effects, Pt(IV) prodrugs have emerged as potent alternative chemotherapies. In this work, a novel bimetallic dual‐action Pt(IV) prodrug bearing a manganese (Mn) superoxide dismutase mimic (SODm) is presented, demonstrating high stability in solution. The prodrug displays intrinsic antisuperoxide properties and in vitro comparable cytotoxic activities to that of oxaliplatin in 2‐ and 3D colorectal cancer cellular models, as well as an increase in intracellular reactive oxygen species (ROS) production. The prodrug is further evaluated in an in vivo mice model for colorectal cancer, demonstrating a similar performance to that of oxaliplatin. Additionally, a total tumor remission is reached with a PEGylated micellar encapsulation of the prodrug. This novel formulation increases the lifetime of the prodrug and therefore its tumoral uptake and plasma content with respect to the unencapsulated drug. This enhanced activity suggests the therapeutic potential of said formulation.