Impact of Positive Resection Margins on Recurrence and Survival Following Resection and Adjuvant Chemotherapy in Pancreatic Cancer: Results of the PRODIGE 24-CCTG PA-6 Randomized Controlled Trial.

OBJECTIVE: This study investigated 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 (SMV), 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. Additionally, the influence of chemotherapy regimen choice, comparing gemcitabine to mFOLFIRINOX, on the implications of positive resection margins was examined. RESULTS: Only three margins, SMV (HR=1.48 95% CI [1.11;1.96], P<.001), medial (HR=1.92 95% CI [1.36;2.73], P<.001) and posterior (HR=1.65 95% CI [1.21;2.24], P=.002), had a significant prognostic impact on disease-free survival and were sufficient compared with the seven recommended margins (Kappa=0.90 95% CI [0.87; 0.94]). R1 status was significant independent prognostic factor for poorer survival in gemcitabine-treasted patients (HR=1.97 95% CI [1.23;3.16], P=.005) but lost its significance with mFOLFIRINOX (HR=1.46 95% CI [0.91;2.35], P=.114). CONCLUSIONS: All efforts should be made to evaluate the three 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 DFS and OS.

Distal Pancreatectomy for Body Pancreatic Ductal Adenocarcinoma: Is Splenectomy Necessary? A Propensity Score Matched Study.

BACKGROUND: The value of splenectomy for body localization (≥ 5 cm from spleen hilum) of pancreatic ductal adenocarcinoma (B-PDAC) is uncertain. This study assessed spleen-preserving distal pancreatectomy (SPDP) results for B-PDAC. PATIENTS AND METHODS: This single-center study included patients who underwent SPDP (Warshaw's technique) or distal splenopancreactomy (DSP) for B-PDAC from 2008 to 2019. Propensity score matching was performed to balance SPDP and DSP patients regarding sex, age, American Society of Anesthesiologists (ASA), body mass index (BMI), laparoscopy, pathological features [American Joint Committee on Cancer (AJCC)/tumor node metastasis classification (TNM)], margins, and neoadjuvant/adjuvant therapies. RESULTS: A total of 129 patients (64 male, median age 68 years, median BMI 24 kg/m2) were enrolled with a median follow-up of 63 months (95% CI 52-96 months), including 59 (46%) SPDP and 70 (54%) DSP patients. A total of 39 SPDP patients were matched to 39 DSP patients. SPDP patients had fewer harvested nodes (19 vs 22; p = 0.038) with a similar number of positive nodes (0 vs 0; p = 0.237). R0 margins were achieved similarly in SPDP and DSP patients (75% vs 71%; p = 0.840). SPDP patients were associated with decreased comprehensive complication index (CCI, 8.7 vs 16.6; p = 0.004), rates of grade B/C postoperative pancreatic fistula (POPF, 14% vs 29%; p = 0.047), and hospital stay (11 vs 16 days; p < 0.001). SPDP patients experienced similar disease-free survival (DFS, 5 years: 38% vs 32%; p = 0.180) and overall survival (OS, 5 years 54% vs 44%; p = 0.710). After matching, SPDP patients remained associated with lower CCI (p = 0.034) and hospital stay (p = 0.028) while not associated with risks of local recurrence (HR 0.85; 95% CI 0.28-2.62; p = 0.781), recurrence (HR 1.04; 95% CI 0.61-1.78; p = 0.888), or death (HR 1.20; 95% CI 0.68-2.11; p = 0.556). CONCLUSION: SPDP for B-PDAC is associated with less postoperative morbidity than DSP, without impairing oncological outcomes.

Reappraising imaging features of pancreatic acinar cystic transformation: be aware of differential diagnoses.

OBJECTIVES: Imaging features of pancreatic acinar cystic transformation (ACT) have been published. We aimed to describe the clinical and radiological characteristics of patients with a presumed pancreatic ACT diagnosis, reappraising the value of these published imaging criteria. MATERIALS AND METHODS: Single-center retrospective study (2003-2021) of consecutive patients with a presumed diagnosis of ACT as suggested by the local expert multidisciplinary case review board. Patients without available imaging (CT or MRI) for review were excluded. Patients were classified into "certain" ACT (if ≥ 2 imaging criteria and no differential diagnosis) or "uncertain" ACT (if ≥ 1 imaging criteria and suggested differential diagnoses). RESULTS: Sixty-four patients (35 males, [55%]) were included. ACT was considered "certain" for 34 patients (53%) and "uncertain" for 30 patients (47%). The number of ACT criteria did not differ between groups, with 91.2% of patients with ≥ 3 ACT imaging criteria in the "certain" group vs 93.3% in the "uncertain" group (p = 0.88). In the "uncertain" group, the main suggested differentials were branch-duct intraductal papillary mucinous neoplasm (18/30 patients, 60%), calcifying chronic pancreatitis (8/30 patients, 27%), both (three patients, 10%) and serous cystadenoma (one patient, 3%). Calcifications were significantly more frequent in the "uncertain" group (89% vs 63% in the "certain" group, p = 0.02). CONCLUSION: Published ACT imaging criteria are frequently associated with features suggesting differential diagnoses. They appear insufficient to reach a final diagnosis in a subset of patients. CLINICAL RELEVANCE STATEMENT: ACT displays a heterogeneous morphological imaging presentation challenging the non-invasive diagnostic work-up. Physicians' and radiologists' awareness of this entity is important to better understand its natural history and improve non-invasive diagnostic criteria. KEY POINTS: The criteria to help diagnose ACT are frequently associated with features suggestive of differentials. The main alternatives suggested when ACT diagnosis was "uncertain" were branch-duct intraductal papillary mucinous neoplasm and calcifying chronic pancreatitis. Published ACT diagnostic imaging criteria can be insufficient for a definite non-invasive diagnosis.

Outcome and survival were similar with laparoscopic and open pancreatectomy in 102 solid pseudopapillary neoplasms.

BACKGROUND: Solid pseudopapillary neoplasms of the pancreas (SPNP) are rare tumors predominantly in young women. We report the largest single-center cohort study comparing resection of SPNP by laparoscopic approach (LA) and the open approach (OA). METHOD: Between 2001 and 2021, 102 patients (84% women, median age: 30) underwent pancreatectomy for SPNP and were retrospectively studied. Demographic, perioperative, pathological, early and the long-term results were evaluated between patients operated by LA and those by OA. RESULTS: Population included 40 LA and 62 OA. There were no significant differences in demographics data between the groups. A preoperative biopsy by endoscopic ultrasound was performed in 45 patients (44%) with no difference between the groups. Pancreatoduodenectomy (PD) was less frequently performed by LA (25 vs 53%, p = 0.004) and distal pancreatectomy (DP) was more frequently performed by LA (40 vs 16%, p = 0.003). In the subgroup analysis by surgical procedure, LA-PD was associated with one mortality, less median blood loss (180 vs 200 ml, p = 0.034) and fewer harvested lymph nodes (11 vs 15, p = 0.02). LA-DP was associated with smaller median tumor size on imaging (40 vs 80mm, p = 0.048), shorter surgery (135 vs 190 min, p = 0.028), and fewer complications according to the median comprehensive complication index score (0 vs 8.7, p = 0.048). LA-Central pancreatectomy was associated with shorter surgery (160 vs 240, p = 0.037), less median blood loss (60 vs 200, p = 0.043), and less harvested lymph nodes (5 vs 2, p = 0.025). After a median follow-up of 60 months, two recurrences (2%) were observed and were unrelated to the approach. CONCLUSIONS: The LA for SPNP appears to be safe, should be applied cautiously in case of PD for large lesion, and was not associated with recurrence.

Role of the fatty pancreatic infiltration in pancreatic oncogenesis.

Although pancreatic precancerous lesions are known to be related to obesity and fatty pancreatic infiltration, the mechanisms remain unclear. We assessed the role of fatty infiltration in the process of pancreatic oncogenesis and obesity. A combined transcriptomic, lipidomic and pathological approach was used to explore neoplastic transformations. Intralobular (ILF) and extralobular (ELF) lipidomic profiles were analyzed to search for lipids associated with pancreatic intraepithelial neoplasia (PanINs) and obesity; the effect of ILF and ELF on acinar tissue and the histopathological aspects of pancreatic parenchyma changes in obese (OB) and non-obese patients. This study showed that the lipid composition of ILF was different from that of ELF. ILF was related to obesity and ELF-specific lipids were correlated to PanINs. Acinar cells were shown to have different phenotypes depending on the presence and proximity to ILF in OB patients. Several lipid metabolic pathways, oxidative stress and inflammatory pathways were upregulated in acinar tissue during ILF infiltration in OB patients. Early acinar transformations, called acinar nodules (AN) were linked to obesity but not ELF or ILF suggesting that they are the first reversible precancerous pancreatic lesions to occur in OB patients. On the other hand, the number of PanINs was higher in OB patients and was positively correlated to ILF and ELF scores as well as to fibrosis. Our study suggests that two types of fat infiltration must be distinguished, ELF and ILF. ILF plays a major role in acinar modifications and the development of precancerous lesions associated with obesity, while ELF may play a role in the progression of PDAC.

Pancreatic neuroendocrine tumors in French VHL mutation carriers: a multicentric retrospective study.

BACKGROUND: Von Hippel-Lindau disease (VHL) is a rare autosomal dominant hereditary cancer-predisposition syndrome caused by germline pathogenic variants (PV) in VHL gene. It is associated with a high penetrance of benign and malignant vascular tumors in multiples organs, including pancreatic neuroendocrine tumors (PanNETs), whose long-term natural history is ill-known. METHODS: Patients with both documented germline PV in VHL gene and PanNETs included in the French PREDIR database between 1995 and 2022 were included. Primary endpoint was the proportion of patients with PanNET-related metastases and secondary endpoint was overall survival (OS). Genotype/phenotype correlations were studied. RESULTS: We included 121 patients with 259 PanNETs. Median age at diagnosis was 38 years. Median follow-up was 89.5 months. PanNET surgical resection was performed in 51 patients. Overall, 29 patients (24%) had metastases (5 synchronous, 10 metachronous), with a higher risk in case of larger PanNET size (p=0.0089; best threshold 28 mm) and grade 2 PanNET (p=0.048), and a pejorative prognostic impact (p=0.043). Patients with PV in VHL exon 1 had larger PanNETs (p=0.018), more often metastatic disease (48% vs 11.5%; p < 0.001) and a trend toward shorter OS (p=0.16). CONCLUSION: The risk of metastases associated to VHL-related PanNETs remains low (24%) but increases with tumor size >28 mm, higher grade and in case of PV located VHL exon 1. These data might help improving the management of these patients, who should be referred to an expert center.

Ampullary tumors: French Intergroup Clinical Practice Guidelines for diagnosis, treatments and follow-up (TNCD, SNFGE, FFCD, UNICANCER, GERCOR, SFCD, SFED, ACHBT, AFC, SFRO, RENAPE, SNFCP, AFEF, SFP, SFR).

BACKGROUND: Management of ampullary tumors (AT) is challenging because of a low level of scientific evidence. This document is a summary of the French intergroup guidelines regarding the management of AT, either adenoma (AA) or carcinoma (AC), published in July 2023, available on the website of the French Society of Gastroenterology (SNFGE) (www.tncd.org). METHODS: A collaborative work was conducted under the auspices of French medical, endoscopic, oncological and surgical societies involved in the management of AT. Recommendations are based on recent literature review and expert opinions and graded in three categories (A, B, C), according to quality of evidence. RESULTS: Accurate diagnosis of AT requires at least duodenoscopy and EUS. All patients should be discussed in multidisciplinary tumor board before treatment. Surveillance may only be proposed for small AA in familial adenomatous polyposis. For AA, endoscopic papillectomy is the preferred option only if R0 resection can be achieved. When not possible, surgical papillectomy should be considered. For AC beyond pT1a N0, pancreaticoduodenectomy is the procedure of choice. Adjuvant monochemotherapy (gemcitabine, 5FU) may be proposed. For aggressive tumors (pT3/T4, pN+, R1, poorly differentiated AC, pancreatobiliary differentiation) with high risk of recurrence, 6 months polychemotherapy (CAPOX/FOLFOX for the intestinal subtype and mFOLFIRINOX for the pancreatobiliary or the mixed subtype) may be a valid alternative. Clinical and radiological follow up is recommended for 5 years. CONCLUSIONS: These guidelines help to homogenize and highlight unmet needs in the management of AA and AC. Each individual case should be discussed by a multidisciplinary team.

Prospective observational study on biomarkers of response in pancreatic ductal adenocarcinoma.

Adjuvant chemotherapy benefits patients with resected pancreatic ductal adenocarcinoma (PDAC), but the compromised physical state of post-operative patients can hinder compliance. Biomarkers that identify candidates for prompt adjuvant therapy are needed. In this prospective observational study, 1,171 patients with PDAC who underwent pancreatectomy were enrolled and extensively followed-up. Proteomic profiling of 191 patient samples unveiled clinically relevant functional protein modules. A proteomics-level prognostic risk model was established for PDAC, with its utility further validated using a publicly available external cohort. More importantly, through an interaction effect regression analysis leveraging both clinical and proteomic datasets, we discovered two biomarkers (NDUFB8 and CEMIP2), indicative of the overall sensitivity of patients with PDAC to adjuvant chemotherapy. The biomarkers were validated through immunohistochemistry on an internal cohort of 386 patients. Rigorous validation extended to two external multicentic cohorts-a French multicentric cohort (230 patients) and a cohort from two grade-A tertiary hospitals in China (466 patients)-enhancing the robustness and generalizability of our findings. Moreover, experimental validation through functional assays was conducted on PDAC cell lines and patient-derived organoids. In summary, our cohort-scale integration of clinical and proteomic data demonstrates the potential of proteomics-guided prognosis and biomarker-aided adjuvant chemotherapy for PDAC.

Efecto de un debriefing (reunión informativa) combinado en los participantes en cursos de simulación interprofesional para la gestión de recursos de crisis: un estudio aleatorio, controlado y multicéntrico / Effect of combined individual–collective debriefing of participants in interprofessional simulation courses on crisis resource management: a randomized controlled multicenter trial

Objetivo: La simulación interprofesional (SIP) es eficaz para aprender gestión de recursos de crisis. La modalidad de debriefing utilizada en la SIP puede influir en el rendimiento de los participantes y en su integridad psicológica. Se evalúa y compara el rendimiento de un debriefing estándar (DE) –colectivo– con un debriefing combinado (DC) –individual y colectivo– en cursos de SIP en escenarios que simulan pacientes con patología aguda y grave. Método: Ensayo controlado, aleatorizado y multicéntrico. Se aleatorizó el tipo de debriefing realizado (DE o DC) en las sesiones de SIP. El rendimiento del debriefing se evaluó con la escala TEAM (Team Emergency Assessment Measure). La calidad de la SIP fue valorada por los participantes con la escala DASH (Debriefing Assessment for Simulation in Healthcare©). Resultados. Se aleatorizaron 40 cursos de SIP de los que se analizaron 30. Quince realizaron DE y 15 DC. Ambos grupos mejoraron entre la pre y la posprueba (p < 0,01), pero no hubo diferencias en el rendimiento global entre ambas modalidades de debriefing (p = 0,64). El DC obtuvo mejores resultados que el DE en la capacidad de liderazgo (p < 0,05), en la percepción de seguridad psicológica y en la experiencia de aprendizaje eficaz (p < 0,05). Conclusiones: Durante la SIP en situaciones de crisis, el debriefing mejora el rendimiento de los participantes, sin diferencias entre un DE y un DC. El DC podría ser más efectivo para mejorar la capacidad de liderazgo, la seguridad psicológica y la experiencia del aprendizaje

Objective: Interprofessional simulation (IPS) training is an effective way to learn crisis resource management. The type of debriefing used in IPS training may affect participants' performance and their level of psychological safety. We aimed to assess and compare performance after standard collective debriefing versus a combination of individual and collective debriefing ("combined" approach). Methods: Randomized, controlled multicenter trial. IPS sessions were randomized to have either standard or combined debriefing. Each team's performance in the IPS session was assessed with the Team Emergency Assessment Measure. The participants assessed the debriefing quality with the Debriefing Assessment for Simulation in Healthcare. Results: Forty IPS sessions were randomized, and 30 were analyzed, 15 using standard collective debriefing and 15 the combined individual–collective method. Teams' performance improved with both types of debriefing, based on pre-post testing (P<.01), and there were no significant differences in overall performance scores between the 2 types of debriefing (P=.64). However, the combined approach was associated with higher scores for leadership skills (P<.05) and psychological safety, and the participants' learning experience was better (P<.05). Conclusions: During IPS courses on crisis resource management, debriefing improves participants' performance, but similar overall results can be obtained with both debriefing methods. Combined debriefing might be more effective for improving participants' leadership skills and psychological safety and also provide a better learning experience