Safety and feasibility of chemotherapy followed by liver transplantation for patients with definitely unresectable colorectal liver metastases: insights from the TransMet randomised clinical trial.

Background: Despite the increasing efficacy of chemotherapy (C), the 5-year survival rate for patients with unresectable colorectal liver metastases (CLM) remains around 10%. Liver transplantation (LT) might offer a curative approach for patients with liver-only disease, yet its superior efficacy compared to C alone remains to be demonstrated. Methods: The TransMet randomised multicentre clinical trial (NCT02597348) compares the curative potential of C followed by LT versus C alone in patients with unresectable CLM despite stable or responding disease on C. Patient eligibility criteria proposed by local tumour boards had to be validated by an independent committee via monthly videoconferences. Outcomes reported here are from a non-specified interim analysis. These include the eligibility of patients to be transplanted for non resectable colorectal liver metastases, as well as the feasibility and the safety of liver transplantation in this indication. Findings: From February 2016 to July 2021, 94 (60%) of 157 patients from 20 centres in 3 countries submitted to the validation committee, were randomised. Reasons for ineligibility were mainly tumour progression in 50 (32%) or potential resectability in 13 (8%). The median delay to LT after randomisation was 51 (IQR 30-65) days. Nine of 47 patients (19%, 95% CI: 9-33) allocated to the LT arm failed to undergo transplantation because of intercurrent disease progression. Three of the 38 transplanted patients (8%) were re-transplanted, one of whom (3%) died post-operatively from multi-organ failure. Interpretation: The selection process of potential candidates for curative intent LT for unresectable CLM in the TransMet trial highlighted the critical role of an independent multidisciplinary validation committee. After stringent selection, the feasibility of LT was 81%, as 19% had disease progression while on the waiting list. These patients should be given high priority for organ allocation to avoid dropout from the transplant strategy. Funding: No source of support or funding from any author to disclose for this work. The trial was supported by the Assistance Publique - Hôpitaux de Paris (AP-HP).

The colibactin-producing Escherichia coli alters the tumor microenvironment to immunosuppressive lipid overload facilitating colorectal cancer progression and chemoresistance.

Intratumoral bacteria flexibly contribute to cellular and molecular tumor heterogeneity for supporting cancer recurrence through poorly understood mechanisms. Using spatial metabolomic profiling technologies and 16SrRNA sequencing, we herein report that right-sided colorectal tumors are predominantly populated with Colibactin-producing Escherichia coli (CoPEC) that are locally establishing a high-glycerophospholipid microenvironment with lowered immunogenicity. It coincided with a reduced infiltration of CD8+ T lymphocytes that produce the cytotoxic cytokines IFN-γ where invading bacteria have been geolocated. Mechanistically, the accumulation of lipid droplets in infected cancer cells relied on the production of colibactin as a measure to limit genotoxic stress to some extent. Such heightened phosphatidylcholine remodeling by the enzyme of the Land's cycle supplied CoPEC-infected cancer cells with sufficient energy for sustaining cell survival in response to chemotherapies. This accords with the lowered overall survival of colorectal patients at stage III-IV who were colonized by CoPEC when compared to patients at stage I-II. Accordingly, the sensitivity of CoPEC-infected cancer cells to chemotherapies was restored upon treatment with an acyl-CoA synthetase inhibitor. By contrast, such metabolic dysregulation leading to chemoresistance was not observed in human colon cancer cells that were infected with the mutant strain that did not produce colibactin (11G5∆ClbQ). This work revealed that CoPEC locally supports an energy trade-off lipid overload within tumors for lowering tumor immunogenicity. This may pave the way for improving chemoresistance and subsequently outcome of CRC patients who are colonized by CoPEC.

Colibactin-producing Escherichia coli enhance resistance to chemotherapeutic drugs by promoting epithelial to mesenchymal transition and cancer stem cell emergence.

Human colorectal cancers (CRCs) are readily colonized by colibactin-producing E. coli (CoPEC). CoPEC induces DNA double-strand breaks, DNA mutations, genomic instability, and cellular senescence. Infected cells produce a senescence-associated secretory phenotype (SASP), which is involved in the increase in tumorigenesis observed in CRC mouse models infected with CoPEC. This study investigated whether CoPEC, and the SASP derived from CoPEC-infected cells, impacted chemotherapeutic resistance. Human intestinal epithelial cells were infected with the CoPEC clinical 11G5 strain or with its isogenic mutant, which is unable to produce colibactin. Chemotherapeutic resistance was assessed in vitro and in a xenograft mouse model. Expressions of cancer stem cell (CSC) markers in infected cells were investigated. Data were validated using a CRC mouse model and human clinical samples. Both 11G5-infected cells, and uninfected cells incubated with the SASP produced by 11G5-infected cells exhibited an increased resistance to chemotherapeutic drugs in vitro and in vivo. This finding correlated with the induction of the epithelial to mesenchymal transition (EMT), which led to the emergence of cells exhibiting CSC features. They grew on ultra-low attachment plates, formed colonies in soft agar, and overexpressed several CSC markers (e.g. CD133, OCT-3/4, and NANOG). In agreement with these results, murine and human CRC biopsies colonized with CoPEC exhibited higher expression levels of OCT-3/4 and NANOG than biopsies devoid of CoPEC. Conclusion: CoPEC might aggravate CRCs by inducing the emergence of cancer stem cells that are highly resistant to chemotherapy.

Total Versus Subtotal Gastrectomy for Distal Gastric Poorly Cohesive Carcinoma.

BACKGROUND: Gastric poorly cohesive carcinoma (PCC) in advanced stages has a poor prognosis. Total gastrectomy (TG) remains the common treatment for distal gastric PCC, but subtotal gastrectomy (SG) may improve quality of life without compromising outcomes. Currently, no clear recommendation on the best surgical strategy for distal PCC is available. This study aimed to compare overall survival (OS) and disease-free survival (DFS) at 5 years for patients with antropyloric PCC treated by total versus subtotal gastrectomy. METHODS: A large retrospective European multicenter cohort study analyzed 2131 patients treated for gastric cancer between 2007 and 2017 by members of the French Association of Surgery (AFC). The study compared a group of patients who underwent TG with a group who underwent SG for antropyloric PCC. The primary outcomes were 5 year OS and DFS. RESULTS: The study enrolled 269 patients: 140 (52.0%) in the TG group and 129 (48.0%) in the SG group. The baseline characteristics and pTNM stage were similar between the two groups. According to Dindo-Claven classification, the patients treated with TG had more postoperative complications than the patients treated with SG (p < 0.001): grades I to IIIa (77.1% vs 59.5%) and grades IIIb to IVb (14.4% vs 9.0%). No difference in 5-year OS was observed between TG (53.8%; 95 % confidence interval [CI], 43.2-63.3%) and SG (53.0%; 95% CI, 41.4-63.3%) (hazard ratio [HR], 0.94; 95% CI, 0.68-1.29). The same was observed for 5-year DFS: TG (46.0%; 95% CI, 35.9-55.5%) versus SG (45.3%; 95% CI, 34.3-55.6%) (HR, 0.97; 95% CI, 0.70-1.34). CONCLUSIONS: At 5 years, SG was not associated with worse OS and DFS than TG for distal PCC. Surgical morbidity was higher after TG. Subtotal gastrectomy is a valuable option for distal PCC gastric cancer.

A phase-II study based on dose adjustment according to UGT1A1 polymorphism: is irinotecan underdosed in first-line FOLFIRI regimen for mCRC?

PURPOSE: Irinotecan has considerable importance in the treatment of metastatic colorectal cancer (mCRC). UDP-glucoronyltransferase (UGT) 1A1 is responsible for the inactivation of SN-38, a metabolite of irinotecan. Depending on UGT1A1 polymorphism, the activity of the UGT enzyme can be reduced leading to more frequent occurrence of adverse events related to irinotecan. The present study aimed to assess the safety and efficacy of different doses of irinotecan adjusted according to UGT1A1 polymorphism. METHODS: Thirty-four patients treated with FOLFIRI as first-line treatment for mCRC were included in this study. The irinotecan dosage was adapted on the basis of UGT1A1 polymorphisms: *1/*1 (370 mg/m2); *1/*28 (310 mg/m2), and *28/*28 (180 mg/m2). The incidence of grades 3 and 4 toxicities (neutropenia, febrile neutropenia, and diarrhoea) was recorded. Response was assessed according to the RECIST 1.1 criteria. RESULTS: On the basis of UGT1A1 genotyping, 20 patients were *1/*1 (58.8%), 12 were *1/*28 (35.3%) and 2 were *28/*28 (5.9%). Seven patients experienced at least one severe toxicity, i.e., 21% of the population, amounting to eleven adverse events. Concerning the response rate, 15 patients (44%) had partial or complete response. CONCLUSION: This study demonstrates that mCRC patients treated with FOLFIRI can tolerate a higher dose of irinotecan than the standard dose, i.e., > 180 mg/m2, on the basis of their UGT1A1 genotype, without increased toxicities. TRIAL REGISTRATION: NCT01963182 (registered on 16/10/2013, Clermont-Ferrand, France).

Combination of CDX2 H-score quantitative analysis with CD3 AI-guided analysis identifies patients with a good prognosis only in stage III colon cancer.

AIM: Stratification of colon cancer (CC) of patients with stage II and III for risk of relapse is still needed especially to drive adjuvant therapy administration. Our study evaluates the prognostic performance of two known biomarkers, CDX2 and CD3, standalone or their combined information in stage II and III CC. PATIENTS AND METHODS: CDX2 and CD3 expression was evaluated in Prodige-13 study gathering 443 stage II and 398 stage III primary CC on whole slide colectomy. We developed for this study an H-score to quantify CDX2 expression and used our artificial intelligence (AI)-guided tissue analysis ColoClass to detect CD3 in tumour core and invasive margin. Association between biomarkers and relapse-free survival was investigated. RESULTS: Univariate analysis showed that the combined variable CD3-TC and CD3-IM was associated with prognosis in both stage II and stage III. CDX2, on the contrary, was associated with prognosis only in stage III. We subsequently associated CDX2 and combined immune parameters only in stage III. This multivariate analysis allowed us to distinguish a proportion of stage III CC harbouring a high CDX2 expression and a high immune infiltration with a particularly good prognosis compared to their counterpart. CONCLUSION: This study validated the prognostic role of CDX2 and CD3 evaluated with immunohistochemistry procedures in stage III but not in stage II. This association would be conceivable in a routine pathology laboratory and could help oncologist to consider chemotherapy de-escalation for a part of stage III patients.

Efficacy of donepezil for the treatment of oxaliplatin-induced peripheral neuropathy: DONEPEZOX, a protocol of a proof of concept, randomised, triple-blinded and multicentre trial.

BACKGROUND: The use of oxaliplatin in digestive tract cancers could induce severe peripheral neuropathy (OIPN) decreasing the quality of life of patients and survivors. There is currently, no univocal treatment for these peripheral neuropathies. Donepezil, a reversible inhibitor of cholinesterase, used to treat Alzheimer's disease and dementia, is reported to have a good safety profile in humans, and preclinical data have provided initial evidence of its effectiveness in diminishing neuropathic symptoms and related comorbidities in OIPN animal models. METHODS: The DONEPEZOX trial will be a proof-of-concept, randomised, triple-blinded, and multicentre study. It will be the first clinical trial evaluating the efficacy and safety of donepezil for the management of OIPN. Adult cancer survivors with OIPN that report sensory neuropathy according to QLQ-CIPN20 sensory score (equivalence of a grade ≥ 2), at least 6 months after the end of an oxaliplatin-based chemotherapy will be included. Eighty patients will be randomly assigned to receive either donepezil or placebo over 16 weeks of treatment. The primary endpoint will be the rate of responders (neuropathic grade decreases according to the QLQ-CIPN20 sensory score) in the donepezil arm. The severity of OIPN will be assessed by the QLQ-CIPN20 sensory scale before and after 16 weeks of treatment. The comparison versus the placebo arm will be a secondary objective. The other secondary endpoints will be tolerance to donepezil, the severity and features of OIPN in each arm before and after treatment, related-comorbidities and quality of life. Fleming's one-stage design will be used for sample size estimation. This design yields a type I error rate of 0.0417 and power of 91% for a responder rate of at least 30% in donepezil arm. A total of 80 randomized patients is planned. DISCUSSION: This study will allow, in the case of positive results, to initiate a phase 3 randomized and placebo-controlled (primary endpoint) clinical study to assess the therapeutic interest of donepezil to treat OIPN. TRIAL REGISTRATION: NCT05254639 , clincialtrials.gov, Registered 24 February 2022.

Gastric Pneumatosis with Portal Venous Gas can be Treated Non-operatively: A Retrospective Multi-institutional Study.

BACKGROUND: Gastric pneumatosis (GP) is a rare radiologic finding with an unpredictable prognosis. The aim of this study was to identify mortality risk factors from patients presenting with GP on computed tomography (CT), and to develop a model which would allow us to predict which patients would benefit most from operative management. METHODS: Between 2010 and 2020, all CT-scan reports in four tertiary centers were searched for the following terms: "gastric pneumatosis," "intramural gastric air" or "emphysematous gastritis." The retrieved CT scans were reviewed by a senior surgeon and a senior radiologist. Relevant clinical and laboratory data for these patients were extracted from the institutions' medical records. RESULTS: Among 58 patients with GP, portal venous gas and bowel ischemia were present on CT scan in 52 (90%) and 17 patients (29%), respectively. The 30-day mortality rate was 31%. Univariate analysis identified the following variables as predictive of mortality at the time of the diagnosis of GP: abdominal guarding, hemodynamic instability, arterial lactate level >2 mmol/l, and the absence of gastric dilatation. Multivariable analysis identified the following variables as independent predictors of mortality: arterial lactate level (OR: 1.39, 95% CI: 1.07-1.79) and the absence of gastric dilatation (OR: 0.07, 95% CI: 0.01-0.79). None of the patients presenting with a baseline lactate rate<2 mmol/l died within 30 days following diagnosis, and no more than 17 patients out of 58 had bowel ischemia (29%). CONCLUSIONS: GP could be managed non-operatively, even in the presence of portal venous gas. However, patients with arterial lactate level>2 mmol/l, or the absence of gastric dilation should be surgically explored due to a non-negligible risk of mortality.

A multicentre, prospective cohort study of handsewn versus stapled intracorporeal anastomosis for robotic hemicolectomy.

AIM: Robotic right hemicolectomy is gaining in popularity due to the recognized technical benefits associated with the robotic platform. However, there is a lack of standardization regarding the optimal anastomotic technique in this cohort of patients, namely stapled or handsewn intra- or extra-corporeal anastomosis. The ergonomic benefit associated with the robotic platform lends itself to intracorporeal anastomosis (ICA). The aim of this study was to compare the short-term clinical outcomes of stapled versus handsewn ICA. METHOD: A multicentre prospective cohort study was undertaken across four high-volume robotic centres in France between September 2018 and December 2020. All adult patients undergoing an elective robotic right hemicolectomy with an ICA performed and a minimum postoperative follow-up of 30 days were included. The primary endpoint of our study was anastomotic leak within 30 days postoperatively. RESULTS: A total of 144 patients underwent robotic right hemicolectomy: 92 (63.8%) had a stapled ICA and 52 (36.1%) a handsewn ICA. The operative indication was adenocarcinoma in 90% with a stapled ICA compared with 62% in the handsewn ICA group (p < 0.001). The overall operating time was longer in the handsewn ICA group compared with the stapled ICA group (219 min vs. 193 min; p = 0.001). The anastomotic leak rate was 3.3% in stapled ICA and 3.8% in handsewn ICA (p = 1.00). There was no difference in the rate or severity of postoperative morbidity. CONCLUSION: ICA robotic hemicolectomy is technically safe and is associated with low rates of anastomotic leak overall and equivalent clinical outcomes between the two techniques.

Prediction of recurrence after surgery in colorectal cancer patients using radiomics from diagnostic contrast-enhanced computed tomography: a two-center study.

OBJECTIVES: To assess the value of contrast-enhanced (CE) diagnostic CT scans characterized through radiomics as predictors of recurrence for patients with stage II and III colorectal cancer in a two-center context. MATERIALS AND METHODS: This study included 193 patients diagnosed with stage II and III colorectal adenocarcinoma from 1 July 2008 to 15 March 2017 in two different French University Hospitals. To compensate for the variability in two-center data, a statistical harmonization method Bootstrapped ComBat (B-ComBat) was used. Models predicting disease-free survival (DFS) were built using 3 different machine learning (ML): (1) multivariate regression (MR) with 10-fold cross-validation after feature selection based on least absolute shrinkage and selection operator (LASSO), (2) random forest (RF), and (3) support vector machine (SVM), both with embedded feature selection. RESULTS: The performance for both balanced and 95% sensitivity models was systematically higher after our proposed B-ComBat harmonization compared to the use of the original untransformed data. The most clinically relevant performance was achieved by the multivariate regression model combining a clinical variable (postoperative chemotherapy) with two radiomics shape descriptors (compactness and least axis length) with a BAcc of 0.78 and an MCC of 0.6 associated with a required sensitivity of 95%. The resulting stratification in terms of DFS was significant (p = 0.00021), especially compared to the use of unharmonized original data (p = 0.17). CONCLUSIONS: Radiomics models derived from contrast-enhanced CT could be trained and validated in a two-center cohort with a good predictive performance of recurrence in stage II et III colorectal cancer patients. KEY POINTS: • Adjuvant therapy decision in colorectal cancer can be a challenge in medical oncology. • Radiomics models, derived from diagnostic CT, trained and validated in a two-center cohort, could predict recurrence in stage II and III colorectal cancer patients. • Identifying patients with a low risk of recurrence, these models could facilitate treatment optimization and avoid unnecessary treatment.

Tailored Strategy for Locally Advanced Rectal Carcinoma (GRECCAR 4): Long-term Results From a Multicenter, Randomized, Open-Label, Phase II Trial.

BACKGROUND: Systematic preoperative radiochemotherapy and total mesorectal excision are the standard of care for locally advanced rectal carcinoma. Some patients can be over- or undertreated. OBJECTIVE: This study aimed to investigate the long-term oncological, functional, and late morbidity outcomes after tailored radiochemotherapy and induction high-dose chemotherapy. DESIGN: This is a prospective, phase II, multicenter, open-label study at 16 tertiary centers in France. SETTINGS: Patients were operated on by surgeons from the French GRECCAR group. PATIENTS: Two hundred six patients were randomly assigned to treatment: good responders after chemotherapy (≥75% tumor volume reduction) to immediate surgery (arm A) or standard radiochemotherapy (capecitabine 50) plus surgery (arm B) and poor responders to capecitabine 50 (arm C) or intensive radiochemotherapy (capecitabine 60; 60 Gy irradiation; arm D) before surgery. INTERVENTIONS: Treatment was tailored according to MRI response to induction chemotherapy. RESULTS: After induction treatment, 194 patients were classified as good (n = 30, 15%) or poor (n = 164, 85%) responders; they were included in arms A and B (16 and 14 patients) or C and D (113 and 51 patients). The primary objective was obtained: R0 resection rates (90% CI) in the 4 arms were 100% (74-100), 100% (85-100), 83% (72-91), and 88% (77-95). At 5 years, overall survival rates were 90% (47.3-98.5), 93.3% (61.3-99.0), 84.3% (71.0-91.8), and 86.1% (71.6-93.5); disease-free survival rates were 80% (40.9-94.6), 89.5% (64.1-97.3), 72.9% (58.5-82.9), and 72.8% (57.7-83.2); local recurrence rates were 0%, 0%, 2.1% (0.3-13.9), and 9.3% (3.6-23.0); and metastasis rates were 20% (5.4-59.1), 10.5% (2.7-35.9), 18% (31.8-94.6), and 18.8% (10.2-33.0). Late morbidity and quality-of-life evaluations showed no significant difference between arms. LIMITATIONS: Limitations were due to the small number of patients randomly assigned in the good responder arms, especially arm A without radiotherapy. CONCLUSION: Tailoring preoperative radiochemotherapy based on induction treatment response appears to be promising. Future prospective trials should confirm this strategy. See Video Abstract at http://links.lww.com/DCR/B761 . REGISTRATION: URL: https://www.clinicaltrials.gov ; Identifier: NCT01333709. ESTRATEGIA HECHA A MEDIDA PARA EL TRATAMIENTO DEL CARCINOMA DE RECTO LOCALMENTE AVANZADO GRECCAR RESULTADOS A LARGO PLAZO DE UN ESTUDIO ALEATRIO MULTICNTRICO Y ABIERTO DE FASE II: ANTECEDENTES:La radio-quimioterapia pré-operatoria sistemáticas y la excisión total del mesorrecto son el estándar en el tratamiento del carcinoma de recto localmente avanzado. En éste sentido, algunos pacientes podrían recibir un sobre o un infra-tratamiento.OBJETIVO:Evaluar los resultados oncológicos, funcionales y de morbilidad a largo plazo después de radio-quimioterapia personalizada y quimioterapia de inducción a dosis elevadas.DISEÑO:Estudio aleatório multicéntrico y abierto de Fase II° realizado en 16 centros terciarios en Francia.AJUSTE:Aquellos pacientes operados por cirujanos del grupo GRECCAR francés.PACIENTES:206 pacientes fueron asignados aleatoriamente al tratamiento: los buenos respondedores después de quimioterapia (reducción del volumen tumoral ≥75%) a la cirugía inmediata (brazo A) o a la radio-quimioterapia estándar (Cap 50) asociada a la cirugía (brazo B); los malos respondedores a Cap 50 (brazo C) o a la radio-quimioterapia intensiva (Cap 60 (irradiación de 60 Gy) (brazo D) previas a la cirugía.INTERVENCIONES:Tratamiento adaptado según la respuesta de la RM a la TC de inducción.RESULTADOS:Después del tratamiento de inducción, 194 pacientes fueron clasificados como buenos (n = 30, 15%) o malos (n = 164, 85%) respondedores, y se incluyeron en los brazos A y B (16 y 14 pacientes) o C y D (113 y 51 pacientes). Se alcanzó el objetivo principal: las tasas de resección R0 [intervalo de confianza del 90%] en los cuatro brazos respectivamente, fueron del 100% [74-100], 100% [85-100], 83% [72-91] y 88% [77-95]. A los 5 años, las tasas fueron: de sobrevida global 90% [47,3-98,5], 93,3% [61,3-99,0], 84,3% [71,0-91,8], 86,1% [71,6-93,5]; de sobrevida libre a la enfermedad 80% [40,9-94,6], 89,5% [64,1-97,3], 72,9% [58,5-82,9], 72,8% [57,7-83,2]; de recidiva local 0, 0, 2,1% [0,3-13,9], 9,3% [3,6-23,0]; de metástasis 20% [5,4-59,1], 10,5% [2,7-35,9], 18% [31,8-94,6], 18,8% [10,2-33,0]. La evaluación tardía de la morbilidad y la calidad de vida no mostraron diferencias significativas entre los brazos.LIMITACIONES:Debido al pequeño número de pacientes asignados al azar en los brazos de buenos respondedores, especialmente en el brazo A de aquellos sin radioterapia.CONCLUSIÓN:Parecería muy prometedor el adaptar la radio-quimioterapia pré-operatoria basada en la respuesta al tratamiento de inducción. Estudios prospectivos en el futuro podrán confirmar la presente estrategia. Consulte Video Resumen en http://links.lww.com/DCR/B761 . (Traducción-Dr. Xavier Delgadillo )IDENTIFICADOR DE CLINICALTRIALS.GOV:NCT01333709. Groupe de REcherche Chirurgicale sur le CAncer du Rectum.

Burnout in French General Practitioners: A Nationwide Prospective Study.

BACKGROUND: We aimed to evaluate the prevalence of burnout among French general practitioners in private practice and to study the risk and protective factors of burnout. METHODS: A nationwide cross-sectional study was conducted with French GPs working in a private practice in France who were asked to fulfil an internet questionnaire. We used the secure internet application REDCap®. Exclusion criteria were only working in a hospital, substitute doctors, and internship students. There was a putative sample size of 88,886 GPs. We retrieved the Maslach Burnout Inventory (MBI), occupational characteristics (type of installation, emergency regulated shifts, night shifts, university supervisor, weekly hours worked, seniority), and personal characteristics such as age, gender, marital status, and number of children. RESULTS: We included 1926 GPs among the 2602 retrieved questionnaires. A total of 44.8% of French liberal GPs were experiencing burnout, with 4.8% (95%CI 3.9-5.9%) experiencing severe burnout. The risk factors of severe burnout were male gender (RR = 1.91, 95%CI 1.15-3.16), working in a suburban area (5.23, 2.18-12.58), and having more than 28 appointments per day (1.95, 1.19-3.19). Working more than 50 h weekly showed a tendency to increase the risk of severe burnout (1.55, 0.93-2.59, p = 0.095), with a significant increase in the risk of low and moderate burnout (1.31, 1.02-1.67 and 1.86, 1.34-2.57, respectively). Protective factors were mainly resident training, which decreased the risk of both low, moderate, and severe burnout (0.65, 0.51-0.83; 0.66, 0.48-0.92; and 0.42, 95%CI 0.23-0.76, respectively). Performing home visits decreased the risk of severe burnout (0.25, 0.13-0.47), as did group practice for intermediate level of burnout (0.71, 0.51-0.96). CONCLUSION: GPs are at a high risk of burnout, with nearly half of them in burnout, with burnout predominantly affecting males and those between the ages of 50 and 60 years old. The main risk factors were a high workload with more than 28 appointments per day or 50 h of work per week, and the main protective factors were related to social cohesion such having a teaching role and working in a group practice with back-office support.

Colorectal Cancer Survivors Suffering From Sensory Chemotherapy-Induced Peripheral Neuropathy Are Not a Homogenous Group: Secondary Analysis of Patients' Profiles With Oxaliplatin-Induced Peripheral Neuropathy.

Oxaliplatin, a pivotal drug in the management of colorectal cancer, causes chemotherapy-induced peripheral neuropathy (CIPN) in a third of cancer survivors. Based on a previous cross-sectional study assessing oxaliplatin-related sensory CIPN in colorectal cancer survivors, a secondary analysis was designed to explore the possibility that different clusters of patients may co-exist among a cohort of patients with oxaliplatin-related CIPN. Other objectives were to characterize these clusters considering CIPN severity, anxiety, depression, health-related quality of life (HRQOL), patients' characteristics and oxaliplatin treatments. Among the 96 patients analyzed, three clusters were identified (cluster 1: 52, cluster 2: 34, and cluster 3: 10 patients). Clusters were significantly different according to CIPN severity and the proportion of neuropathic pain (cluster 1: low, cluster 2: intermediate, and cluster 3: high). Anxiety, depressive disorders and HRQOL alteration were lower in cluster 1 in comparison to clusters 2 and 3, but not different between clusters 2 and 3. This study underlines that patients with CIPN are not a homogenous group, and that CIPN severity is associated with psychological distress and a decline of HRQOL. Further studies are needed to explore the relation between clusters and CIPN management.

Half of Postoperative Deaths After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Could be Preventable: A French Root Cause Analysis on 5562 Patients.

OBJECTIVE: To perform a retrospective root-cause analysis of postoperative death after CRS and HIPEC procedures. BACKGROUND: The combination of CRS and HIPEC is an effective therapeutic strategy to treat peritoneal surface malignancies, however it is associated with significant postoperative mortality. METHODS: All patients treated with a combination of CRS and HIPEC between January 2009 and December 2018 in 22 French centers and died in the hospital, were retrospectively analyzed. Perioperative data of the 101 patients were collected by a local senior surgeon with a sole junior surgeon. Three independent experts investigated the typical root cause of death and provided conclusions on whether postoperative death was preventable (PREV group) or not (NON-PREV group). A typical root cause of preventable postoperative death was classified on a cause-and-effect diagram. RESULTS: Of the 5562 CRS+HIPEC procedures performed, 101 in-hospital deaths (1.8%) were identified, of which a total of 18 patients of 70 years old and above and 20 patients with ASA score of 3. Etiology of peritoneal disease was mainly colorectal. A total of 54 patients (53%) were classified in the PREV group and 47 patients (47%) in the NON-PREV group. The results of the study show that in the PREV group, WHO performance status 1-2 was more frequent and the Median Peritoneal Cancer Index was higher compared with those of the NON-PREV group. The cause of death in the PREV group was classified as: (i) preoperatively for debatable indication (59%), (ii) intraoperatively (30%) and (iii) postoperatively in 17 patients (31%). A multifactorial cause of death was found in 11 patients (20%). CONCLUSION: More than half of the postoperative deaths after combined CRS and HIPEC may be preventable, mainly by following guidelines regarding preoperative selection of the patients and adequate intraoperative decisions.

Ramucirumab in patients with previously treated advanced hepatocellular carcinoma: Impact of liver disease aetiology.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a common complication of chronic liver disease with diverse underlying aetiologies. REACH/REACH-2 were global phase III studies investigating ramucirumab in advanced HCC (aHCC) following sorafenib treatment. We performed an exploratory analysis of outcomes by liver disease aetiology and baseline serum viral load. METHODS: Meta-analysis was conducted in patients with aHCC and alpha-fetoprotein (AFP) ≥400 ng/mL (N = 542) from REACH/REACH-2 trials. Individual patient-level data were pooled with results reported by aetiology subgroup (hepatitis B [HBV] or C [HCV] and Other). Pre-treatment serum HBV DNA and HCV RNA were quantified using Roche COBAS AmpliPrep/COBAS TaqMan. Overall survival (OS) and progression-free survival (PFS) were evaluated using the Kaplan-Meier method and Cox proportional hazard model (stratified by study). RESULTS: Baseline characteristics were generally balanced between arms in each subgroup (HBV: N = 225, HCV: N = 127, Other: N = 190). No significant difference in treatment effect by aetiology subgroup was detected (OS interaction P-value = .23). Median OS (ramucirumab vs placebo) in months was 7.7 versus 4.5 (HR 0.74, 95% CI 0.55-0.99) for HBV, 8.2 versus 5.5 (HR 0.82, 95% CI 0.55-1.23) for HCV and 8.5 versus 5.4 (HR 0.56, 95% CI 0.40-0.79) for Other. Ramucirumab showed similar overall safety profiles across subgroups. Worst outcomes were noted in patients with a detectable HBV load. Use of HBV antiviral therapy, irrespective of viral load, was beneficial for survival, liver function and liver-specific adverse events. CONCLUSIONS: Ramucirumab improved survival across aetiology subgroups with a tolerable safety profile, supporting its use in patients with aHCC and elevated AFP.

Impact of BRAF mutations on clinical outcomes following liver surgery for colorectal liver metastases: An updated meta-analysis.

BACKGROUND: Data regarding clinical outcomes of patients undergoing hepatic resection for BRAF-mutated colorectal liver metastases (CRLM) are scarce. Most of the studies report an impaired median overall survival (OS) in BRAF-mutated patients, but controversial Results regarding both recurrence-free survival (RFS) and recurrence patterns. The purpose of this updated meta-analysis was to better precise the impact of BRAF mutations on clinical outcomes following liver surgery for CRLM study, especially on recurrence. METHODS: A systematic literature review was performed to identify articles reporting clinical outcomes including both OS and RFS, recurrence patterns, and clinicopathological details of patients who underwent complete liver resection for CRLM, stratified according to BRAF mutational status. RESULTS: Thirteen retrospective studies, including 5192 patients, met the inclusion criteria. The analysis revealed that both OS (OR = 1.981; 95% CI = [1.613-2.432]) and RFS (OR = 1.49; 95% CI [1.01-2.21]) were impaired following liver surgery for CRLM in BRAF-mutated patients. Risks of both hepatic (OR = 0.42; 95% CI [0.18-0.98]) and extrahepatic recurrences (OR = 0.53; 95% CI [0.33-0.83] were significantly higher in BRAF-mutated patients. These patients tended to have higher rates of right-sided colon primary tumors, primary positive lymph nodes, and multiple CRLM. CONCLUSIONS: This meta-analysis confirms that BRAF mutations impair both OS and RFS following liver surgery. Therefore, BRAF mutational status should probably be included in further prognostic scores for the assessment of the expected clinical outcomes following surgery for CRLM.

Emergency surgery for splenic flexure cancer: results of the SFC Study Group database.

BACKGROUND: The effectiveness of surgical treatment for splenic flexure carcinomas (SFCs) in emergency settings remains unexplored. This study aims to compare the perioperative and long-term outcomes of different alternatives for emergency SFC resection. METHOD: This multicenter retrospective study was based on the SFC Study Group database. For the present analysis, SFC patients were selected if they had received emergency surgical resection with curative intent between 2000 and 2018. Extended right colectomy (ERC), left colectomy (LC), and segmental left colectomy (SLC) were evaluated and compared. RESULTS: The study sample was composed of 90 SFC patients who underwent emergency ERC (n = 55, 61.1%), LC (n = 18, 20%), or SLC (n = 17, 18.9%). Bowel obstruction was the most frequent indication for surgery (n = 75, 83.3%), and an open approach was chosen in 81.1% of the patients. A higher incidence of postoperative complications was observed in the ERC group (70.9%) than in the LC (44.4%) and SLC groups (47.1%), with a significant procedure-related difference for severe postoperative complications (Dindo-Clavien ≥ III; adjusted odds ratio for ERC vs. LC:7.23; 95% CI 1.51-34.66; p = 0.013). Anastomotic leakage occurred in 8 (11.2%) patients, with no differences between the groups (p = 0.902). R0 resection was achieved in 98.9% of the procedures, and ≥ 12 lymph nodes were retrieved in 92.2% of patients. Overall and disease-free survival rates at 5 years were similar between the groups and were significantly associated with stage pT4 and the presence of synchronous metastases. CONCLUSION: In the emergency setting, ERC and open surgery are the most frequently performed procedures. ERC is associated with increased odds of severe postoperative complications when compared to more conservative SFC resections. Nonetheless, all the alternatives seem to provide similar pathologic and long-term outcomes, supporting the oncological safety of more conservative resections for emergency SFCs.

Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to cytoreductive surgery has been associated with encouraging survival results in some patients with colorectal peritoneal metastases who were eligible for complete macroscopic resection. We aimed to assess the specific benefit of adding HIPEC to cytoreductive surgery compared with receiving cytoreductive surgery alone. METHODS: We did a randomised, open-label, phase 3 trial at 17 cancer centres in France. Eligible patients were aged 18-70 years and had histologically proven colorectal cancer with peritoneal metastases, WHO performance status of 0 or 1, a Peritoneal Cancer Index of 25 or less, and were eligible to receive systemic chemotherapy for 6 months (ie, they had adequate organ function and life expectancy of at least 12 weeks). Patients in whom complete macroscopic resection or surgical resection with less than 1 mm residual tumour tissue was completed were randomly assigned (1:1) to cytoreductive surgery with or without oxaliplatin-based HIPEC. Randomisation was done centrally using minimisation, and stratified by centre, completeness of cytoreduction, number of previous systemic chemotherapy lines, and timing of protocol-mandated systemic chemotherapy. Oxaliplatin HIPEC was administered by the closed (360 mg/m2) or open (460 mg/m2) abdomen techniques, and systemic chemotherapy (400 mg/m2 fluorouracil and 20 mg/m2 folinic acid) was delivered intravenously 20 min before HIPEC. All individuals received systemic chemotherapy (of investigators' choosing) with or without targeted therapy before or after surgery, or both. The primary endpoint was overall survival, which was analysed in the intention-to-treat population. Safety was assessed in all patients who received surgery. This trial is registed with ClinicalTrials.gov, NCT00769405, and is now completed. FINDINGS: Between Feb 11, 2008, and Jan 6, 2014, 265 patients were included and randomly assigned, 133 to the cytoreductive surgery plus HIPEC group and 132 to the cytoreductive surgery alone group. After median follow-up of 63·8 months (IQR 53·0-77·1), median overall survival was 41·7 months (95% CI 36·2-53·8) in the cytoreductive surgery plus HIPEC group and 41·2 months (35·1-49·7) in the cytoreductive surgery group (hazard ratio 1·00 [95·37% CI 0·63-1·58]; stratified log-rank p=0·99). At 30 days, two (2%) treatment-related deaths had occurred in each group.. Grade 3 or worse adverse events at 30 days were similar in frequency between groups (56 [42%] of 133 patients in the cytoreductive surgery plus HIPEC group vs 42 [32%] of 132 patients in the cytoreductive surgery group; p=0·083); however, at 60 days, grade 3 or worse adverse events were more common in the cytoreductive surgery plus HIPEC group (34 [26%] of 131 vs 20 [15%] of 130; p=0·035). INTERPRETATION: Considering the absence of an overall survival benefit after adding HIPEC to cytoreductive surgery and more frequent postoperative late complications with this combination, our data suggest that cytoreductive surgery alone should be the cornerstone of therapeutic strategies with curative intent for colorectal peritoneal metastases. FUNDING: Institut National du Cancer, Programme Hospitalier de Recherche Clinique du Cancer, Ligue Contre le Cancer.

Prevention, diagnosis and management of chemotherapy-induced peripheral neuropathy: a cross-sectional study of French oncologists' professional practices.

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is challenging for oncologists. Many publications mention the high incidence of CIPN and the lack of effective preventive/management strategies and robust diagnostic tools. This cross-sectional study was aimed at assessing the practice of French oncologists for CIPN prevention, diagnosis and management. METHODS: This web-based survey was sent to French oncologists by the regional cancer networks. Incidence and impact of CIPN were assessed using visual analogue scales (VAS) and diagnostic strategies were recorded. Also recorded were the drugs used to prevent or manage CIPN and their perceived efficacy and safety (VAS). RESULTS: Among the 210 oncologists included, the perceived incidence of CIPN was about 36.2 ± 22.1% of patients. About 99.5% of oncologists declared that they assess CIPN during medical follow-up. The use of drugs to prevent CIPN was reported by 9.6% of oncologists (group B vitamins (35.0%) and calcium and magnesium infusion (25.0%)). In the case of CIPN, the therapeutic adjustment of neurotoxic anticancer drugs is performed by 99.0% of oncologists (chemotherapy change (49.8%), dose reduction (30.9%) or interruption (19.3%)). The pharmacological management of CIPN was declared by 72.9% of oncologists. The main drugs used are pregabalin (75.8%), amitriptyline (32.7%) and gabapentin (25.5%). Duloxetine (ASCO recommendation) is used by only 11.8% of oncologists. CONCLUSION: Oncologists were clearly aware of CIPN risks, but its incidence tended to be underestimated and the ASCO recommendations for the management of CIPN were not followed. The prevention, diagnosis and management of CIPN remain problematic in clinical practice in France. TRIAL REGISTRATION: ClinicalTrials.gov : NCT03854864.