International Validation of a Nomogram to Predict Recurrence after Resection of Grade 1 and 2 Nonfunctioning Pancreatic Neuroendocrine Tumors

Background: Despite the low recurrence rate of resected nonfunctional pancreatic neuroendocrine tumors (NF-pNETs), nearly all patients undergo long-term surveillance. A prediction model for recurrence may help select patients for less intensive surveillance or identify patients for adjuvant therapy. The objective of this study was to assess the external validity of a recently published model predicting recurrence within 5 years after surgery for NF-pNET in an international cohort. This prediction model includes tumor grade, lymph node status and perineural invasion as predictors. Methods: Retrospectively, data were collected from 7 international referral centers on patients who underwent resection for a grade 1-2 NF-pNET between 1992 and 2018. Model performance was evaluated by calibration statistics, Harrel's C-statistic, and area under the curve (AUC) of the receiver operating characteristic curve for 5-year recurrence-free survival (RFS). A sub-analysis was performed in pNETs >2 cm. The model was improved to stratify patients into 3 risk groups (low, medium, high) for recurrence. Results: Overall, 342 patients were included in the validation cohort with a 5-year RFS of 83% (95% confidence interval [CI]: 78-88%). Fifty-eight patients (17%) developed a recurrence. Calibration showed an intercept of 0 and a slope of 0.74. The C-statistic was 0.77 (95% CI: 0.70-0.83), and the AUC for the prediction of 5-year RFS was 0.74. The prediction model had a better performance in tumors >2 cm (C-statistic 0.80). Conclusions: External validity of this prediction model for recurrence after curative surgery for grade 1-2 NF-pNET showed accurate overall performance using 3 easily accessible parameters. This model is available via www.pancreascalculator.com

Textbook Outcome Nationwide Analysis of a Novel Quality Measure in Pancreatic Surgery:Nationwide Analysis of a Novel Quality Measure in Pancreatic Surgery

Background: Textbook outcome (TO) is a multidimensional measure for quality assurance, reflecting the ‘‘ideal’’ surgical outcome. Methods: Post-hoc analysis of patients who underwent pancreatoduodenectomy (PD) or distal pancreatectomy (DP) for all indications between 2014 and 2017, queried from the nationwide prospective Dutch Pancreatic Cancer Audit. An international survey was conducted among 24 experts from 10 countries to reach consensus on the requirements for TO in pancreatic surgery. Univariable and multivariable logistic regression was performed to identify TO predictors. Between-hospital variation in TO rates was compared using observed-versus-expected rates. Results: Based on the survey (92% response rate), TO was defined by the absence of postoperative pancreatic fistula, bile leak, postpancreatectomy hemorrhage (all ISGPS grade B/C), severe complications (Clavien–Dindo III), readmission, and in-hospital mortality. Overall, 3341 patients were included (2633 (79%) PD and 708 (21%) DP) of whom 60.3% achieved TO; 58.3% for PD and 67.4% for DP. On multivariable analysis, ASA class 3 predicted a worse TO rate after PD (ASA 3 OR 0.59 [0.44–0.80]), whereas a dilated pancreatic duct (>3 mm) and pancreatic ductal ade

Conditional Survival After Resection for Pancreatic Cancer: A Population-Based Study and Prediction Model

Background: Conditional survival is the survival probability after already surviving a predefined time period. This may be informative during follow-up, especially when adjusted for tumor characteristics. Such prediction models for patients with resected pancreatic cancer are lacking and therefore conditional survival was assessed and a nomogram predicting 5-year survival at a predefined period after resection of pancreatic cancer was developed. Methods: This population-based study included patients with resected pancreatic ductal adenocarcinoma from the Netherlands Cancer Registry (2005–2016). Conditional survival was calculated as the median, and the probability of surviving up to 8 years in patients who already survived 0–5 years after resection was calculated using the Kaplan–Meier method. A prediction model was constructed. Results: Overall, 3082 patients were included, with a median age of 67 years. Median overall survival was 18 months (95% confidence interval 17–18 months), with a 5-year survival of 15%. The 1-year conditional survival (i.e. probability of surviving the next year) increased from 55 to 74 to 86% at 1, 3, and 5 years after surgery, respectively, while the median overall survival increased from 15 to 40 to 64 months at 1, 3, and 5 years after surgery, respectively. The prediction model demonstrated that the probability of achieving 5-year survival at 1 year after surgery varied from 1 to 58% depending on patient and tumor characteristics. Conclusions: This population-based study showed that 1-year conditional survival was 55% 1 year after resection and 74% 3 years after resection in patients with pancreatic cancer. The prediction model is available via www.pancreascalculator.com to inform patients and caregivers

Predicting overall survival and resection in patients with locally advanced pancreatic cancer treated with FOLFIRINOX:Development and internal validation of two nomograms

Background and Objectives Patients with locally advanced pancreatic cancer (LAPC) are increasingly treated with FOLFIRINOX, resulting in improved survival and resection of tumors that were initially unresectable. It remains unclear, however, which specific patients benefit from FOLFIRINOX. Two nomograms were developed predicting overall survival (OS) and resection at the start of FOLFIRINOX for LAPC. Methods From our multicenter, prospective LAPC registry in 14 Dutch hospitals, LAPC patients starting first-line FOLFIRINOX (April 2015-December 2017) were included. Stepwise backward selection according to the Akaike Information Criterion was used to identify independent baseline predictors for OS and resection. Two prognostic nomograms were generated. Results A total of 252 patients were included, with a median OS of 14 months. Thirty-two patients (13%) underwent resection, with a median OS of 23 months. Older age, female sex, Charlson Comorbidity Index 1, involvement of the superior mesenteric artery, celiac trunk, and superior mesenteric vein >= 270 degrees were independent factors decreasing the probability of resection (c-index: 0.79). Conclusions Two nomograms were developed to predict OS and resection in patients with LAPC before starting treatment with FOLFIRINOX. These nomograms could be beneficial in the shared decision-making process and counseling of these patients

Axial slicing versus bivalving in the pathological examination of pancreatoduodenectomy specimens (APOLLO): a multicentre randomized controlled trial

Background: In pancreatoduodenectomy specimens, dissection method may affect the assessment of primary tumour origin (i.e. pancreatic, distal bile duct or ampullary adenocarcinoma), which is primarily determined macroscopically. This is the first study to prospectively compare the two commonly used techniques, i.e. axial slicing and bivalving. Methods: In four centres, a randomized controlled trial was performed in specimens of patients with a suspected (pre)malignant tumour in the pancreatic head. Primary outcome measure was the level of certainty (scale 0–100) regarding tumour origin by four independent gastrointestinal pathologists based on macroscopic assessment. Secondary outcomes were inter-observer agreement and R1 rate. Results: In total, 128 pancreatoduodenectomy specimens were randomized. The level of certainty in determining the primary tumour origin did not differ between axial slicing and bivalving (mean score 72 [sd 13] vs. 68 [sd 16], p = 0.21), nor did inter-observer agreement, both being moderate (kappa 0.45 vs. 0.47). In pancreatic cancer specimens, R1 rate (60% vs. 55%, p = 0.71) and the number of harvested lymph nodes (median 16 vs. 17, p = 0.58) were similar. Conclusion: This study demonstrated no differences in determining the tumour origin between axial slicing and bivalving. Both techniques performed similarly regarding inter-observer agreement, R1 rate, and lymph node harvest

Pathological Complete Response in Patients With Resected Pancreatic Adenocarcinoma After Preoperative Chemotherapy

Importance: Preoperative chemo(radio)therapy is increasingly used in patients with localized pancreatic adenocarcinoma, leading to pathological complete response (pCR) in a small subset of patients. However, multicenter studies with in-depth data about pCR are lacking. Objective: To investigate the incidence, outcome, and risk factors of pCR after preoperative chemo(radio)therapy. Design, Setting, and Participants: This observational, international, multicenter cohort study assessed all consecutive patients with pathology-proven localized pancreatic adenocarcinoma who underwent resection after 2 or more cycles of chemotherapy (with or without radiotherapy) in 19 centers from 8 countries (January 1, 2010, to December 31, 2018). Data collection was performed from February 1, 2020, to April 30, 2022, and analyses from January 1, 2022, to December 31, 2023. Median follow-up was 19 months. Exposures: Preoperative chemotherapy (with or without radiotherapy) followed by resection. Main Outcomes and Measures: The incidence of pCR (defined as absence of vital tumor cells in the sampled pancreas specimen after resection), its association with OS from surgery, and factors associated with pCR. Factors associated with overall survival (OS) and pCR were investigated with Cox proportional hazards and logistic regression models, respectively. Results: Overall, 1758 patients (mean [SD] age, 64 [9] years; 879 [50.0%] male) were studied. The rate of pCR was 4.8% (n = 85), and pCR was associated with OS (hazard ratio, 0.46; 95% CI, 0.26-0.83). The 1-, 3-, and 5-year OS rates were 95%, 82%, and 63% in patients with pCR vs 80%, 46%, and 30% in patients without pCR, respectively (P &lt; .001). Factors associated with pCR included preoperative multiagent chemotherapy other than (m)FOLFIRINOX ([modified] leucovorin calcium [folinic acid], fluorouracil, irinotecan hydrochloride, and oxaliplatin) (odds ratio [OR], 0.48; 95% CI, 0.26-0.87), preoperative conventional radiotherapy (OR, 2.03; 95% CI, 1.00-4.10), preoperative stereotactic body radiotherapy (OR, 8.91; 95% CI, 4.17-19.05), radiologic response (OR, 13.00; 95% CI, 7.02-24.08), and normal(ized) serum carbohydrate antigen 19-9 after preoperative therapy (OR, 3.76; 95% CI, 1.79-7.89). Conclusions and Relevance: This international, retrospective cohort study found that pCR occurred in 4.8% of patients with resected localized pancreatic adenocarcinoma after preoperative chemo(radio)therapy. Although pCR does not reflect cure, it is associated with improved OS, with a doubled 5-year OS of 63% compared with 30% in patients without pCR. Factors associated with pCR related to preoperative chemo(radio)therapy regimens and anatomical and biological disease response features may have implications for treatment strategies that require validation in prospective studies because they may not universally apply to all patients with pancreatic adenocarcinoma.</p

Pathological Complete Response in Patients With Resected Pancreatic Adenocarcinoma After Preoperative Chemotherapy

Importance: Preoperative chemo(radio)therapy is increasingly used in patients with localized pancreatic adenocarcinoma, leading to pathological complete response (pCR) in a small subset of patients. However, multicenter studies with in-depth data about pCR are lacking. Objective: To investigate the incidence, outcome, and risk factors of pCR after preoperative chemo(radio)therapy. Design, Setting, and Participants: This observational, international, multicenter cohort study assessed all consecutive patients with pathology-proven localized pancreatic adenocarcinoma who underwent resection after 2 or more cycles of chemotherapy (with or without radiotherapy) in 19 centers from 8 countries (January 1, 2010, to December 31, 2018). Data collection was performed from February 1, 2020, to April 30, 2022, and analyses from January 1, 2022, to December 31, 2023. Median follow-up was 19 months. Exposures: Preoperative chemotherapy (with or without radiotherapy) followed by resection. Main Outcomes and Measures: The incidence of pCR (defined as absence of vital tumor cells in the sampled pancreas specimen after resection), its association with OS from surgery, and factors associated with pCR. Factors associated with overall survival (OS) and pCR were investigated with Cox proportional hazards and logistic regression models, respectively. Results: Overall, 1758 patients (mean [SD] age, 64 [9] years; 879 [50.0%] male) were studied. The rate of pCR was 4.8% (n = 85), and pCR was associated with OS (hazard ratio, 0.46; 95% CI, 0.26-0.83). The 1-, 3-, and 5-year OS rates were 95%, 82%, and 63% in patients with pCR vs 80%, 46%, and 30% in patients without pCR, respectively (P &lt; .001). Factors associated with pCR included preoperative multiagent chemotherapy other than (m)FOLFIRINOX ([modified] leucovorin calcium [folinic acid], fluorouracil, irinotecan hydrochloride, and oxaliplatin) (odds ratio [OR], 0.48; 95% CI, 0.26-0.87), preoperative conventional radiotherapy (OR, 2.03; 95% CI, 1.00-4.10), preoperative stereotactic body radiotherapy (OR, 8.91; 95% CI, 4.17-19.05), radiologic response (OR, 13.00; 95% CI, 7.02-24.08), and normal(ized) serum carbohydrate antigen 19-9 after preoperative therapy (OR, 3.76; 95% CI, 1.79-7.89). Conclusions and Relevance: This international, retrospective cohort study found that pCR occurred in 4.8% of patients with resected localized pancreatic adenocarcinoma after preoperative chemo(radio)therapy. Although pCR does not reflect cure, it is associated with improved OS, with a doubled 5-year OS of 63% compared with 30% in patients without pCR. Factors associated with pCR related to preoperative chemo(radio)therapy regimens and anatomical and biological disease response features may have implications for treatment strategies that require validation in prospective studies because they may not universally apply to all patients with pancreatic adenocarcinoma.</p

RET gene rearrangements occur in a subset of pancreatic acinar cell carcinomas.

Pancreatic acinar cell carcinoma is relatively rare (1 to 2% of pancreatic malignancies) but may be under-recognized. In contrast to pancreatic ductal adenocarcinoma, most acinar cell carcinomas lack mutations in KRAS, DPC, CDKN2A or TP53, but appear to have a high incidence of gene rearrangements, with up to 20% reported to be driven by BRAF fusions. With the development of a new class of RET-specific tyrosine kinase inhibitors, which appear to have particularly strong activity against RET gene rearranged tumours, there is now considerable interest in identifying RET gene rearrangements across a wide range of cancers. RET rearrangements have been reported to occur at a very low incidence (<1%) in all pancreatic carcinomas. We postulated that given its unique molecular profile, RET gene rearrangements may be common in acinar cell carcinomas. We performed fluorescent in-situ hybridization (FISH) studies on a cohort of 40 acinar cell spectrum tumours comprising 36 pure acinar cell carcinomas, three pancreatoblastomas and one mixed acinar-pancreatic neuroendocrine tumour. RET gene rearrangements were identified in 3 (7.5%) cases and BRAF gene rearrangements in 5 (12.5%). All gene rearranged tumours were pure acinar cell carcinomas. Our findings indicate that amongst all pancreatic carcinomas, acinar carcinomas are highly enriched for potentially actionable gene rearrangements in RET or BRAF. FISH testing is inexpensive and readily available in the routine clinical setting and may have a role in the assessment of all acinar cell carcinomas-at this stage to recruit patients for clinical trials of new targeted therapies, but perhaps in the near future as part of routine care

International Validation of a Nomogram to Predict Recurrence after Resection of Grade 1 and 2 Nonfunctioning Pancreatic Neuroendocrine Tumors

BACKGROUND: Despite the low recurrence rate of resected nonfunctional pancreatic neuroendocrine tumors (NF-pNETs), nearly all patients undergo long-term surveillance. A prediction model for recurrence may help select patients for less intensive surveillance or identify patients for adjuvant therapy. The objective of this study was to assess the external validity of a recently published model predicting recurrence within 5 years after surgery for NF-pNET in an international cohort. This prediction model includes tumor grade, lymph node status and perineural invasion as predictors. METHODS: Retrospectively, data were collected from 7 international referral centers on patients who underwent resection for a grade 1-2 NF-pNET between 1992 and 2018. Model performance was evaluated by calibration statistics, Harrel's C-statistic, and area under the curve (AUC) of the receiver operating characteristic curve for 5-year recurrence-free survival (RFS). A sub-analysis was performed in pNETs >2 cm. The model was improved to stratify patients into 3 risk groups (low, medium, high) for recurrence. RESULTS: Overall, 342 patients were included in the validation cohort with a 5-year RFS of 83% (95% confidence interval [CI]: 78-88%). Fifty-eight patients (17%) developed a recurrence. Calibration showed an intercept of 0 and a slope of 0.74. The C-statistic was 0.77 (95% CI: 0.70-0.83), and the AUC for the prediction of 5-year RFS was 0.74. The prediction model had a better performance in tumors >2 cm (C-statistic 0.80). CONCLUSIONS: External validity of this prediction model for recurrence after curative surgery for grade 1-2 NF-pNET showed accurate overall performance using 3 easily accessible parameters. This model is available via www.pancreascalculator.com