The road to tailored adjuvant chemotherapy for all four non-pancreatic periampullary cancers: An international multimethod cohort study.

BACKGROUND: Despite differences in tumour behaviour and characteristics between duodenal adenocarcinoma (DAC), the intestinal (AmpIT) and pancreatobiliary (AmpPB) subtype of ampullary adenocarcinoma and distal cholangiocarcinoma (dCCA), the effect of adjuvant chemotherapy (ACT) on these cancers, as well as the optimal ACT regimen, has not been comprehensively assessed. This study aims to assess the influence of tailored ACT on DAC, dCCA, AmpIT, and AmpPB. PATIENTS AND METHODS: Patients after pancreatoduodenectomy for non-pancreatic periampullary adenocarcinoma were identified and collected from 36 tertiary centres between 2010 - 2021. Per non-pancreatic periampullary tumour type, the effect of adjuvant chemotherapy and the main relevant regimens of adjuvant chemotherapy were compared. The primary outcome was overall survival (OS). RESULTS: The study included a total of 2866 patients with DAC (n = 330), AmpIT (n = 765), AmpPB (n = 819), and dCCA (n = 952). Among them, 1329 received ACT, and 1537 did not. ACT was associated with significant improvement in OS for AmpPB (P = 0.004) and dCCA (P < 0.001). Moreover, for patients with dCCA, capecitabine mono ACT provided the greatest OS benefit compared to gemcitabine (P = 0.004) and gemcitabine - cisplatin (P = 0.001). For patients with AmpPB, no superior ACT regime was found (P > 0.226). ACT was not associated with improved OS for DAC and AmpIT (P = 0.113 and P = 0.445, respectively). DISCUSSION: Patients with resected AmpPB and dCCA appear to benefit from ACT. While the optimal ACT for AmpPB remains undetermined, it appears that dCCA shows the most favourable response to capecitabine monotherapy. Tailored adjuvant treatments are essential for enhancing prognosis across all four non-pancreatic periampullary adenocarcinomas.

Outcome of Minimally Invasive and Open Pancreatoduodenectomy in Patients with Intestinal- and Pancreatobiliary Subtype Ampullary Cancer: An International Multicenter Cohort Study.

OBJECTIVE: To compare minimally invasive and open pancreatoduodenectomy in different subtypes of ampullary adenocarcinoma. SUMMARY BACKGROUND DATA: Ampullary adenocarcinoma (AAC) is widely seen as the best indication for minimally invasive pancreatoduodenectomy (MIPD) due to the lack of vascular involvement and dilated bile and pancreatic duct. However, it is unknown whether outcomes of MIPD for AAC differ between the pancreatobiliary (AAC-PB) and intestinal (AAC-IT) subtypes as large studies are lacking. METHODS: This is an international cohort study, encompassing 27 centers from 12 countries. Outcome of MIPD and open pancreatoduodenectomy (OPD) were compared in patients with AAC-IT and AAC-PB. Primary end points were R1 rate, lymph node yield, and 5-year overall survival (5yOS). RESULTS: Overall, 1187 patients after MIPD for AAC were included, of whom 572 with AAC-IT (62 MIPD, 510 OPD) and 615 with AAC-PB (41 MIPD and 574 OPD). The rate of R1 resection was not significantly different between MIPD and OPD for both AAC-IT (3.4% vs 6.9%, P=0,425) and AAC-PB (9.8% vs 14.9%, P=0,625). AAC-IT, more lymph nodes were resected with MIPD group (19 vs 16, P=0.007), compared to OPD. The 5y-OS did not differ after MIPD and OPD for both AAC-IT (56.8% vs 59.5%, P=0.827 and AAC-PB (52.5% vs 44.4%, P=0.357). The rates of surgical complication between MIPD and OPD did not differ between AmpIT and AmpPB. DISCUSSION: This international multicenter study found no differences in outcomes between MIPD and OPD for AAC-IT and AAC-PB. MIPD and OPD demonstrated comparable outcomes in oncological resection, survival and surgical outcomes for both subtypes of AAC.

Differences in Lymph Node Metastases Patterns Among Non-pancreatic Periampullary Cancers and Histologic Subtypes: An International Multicenter Retrospective Cohort Study and Systematic Review.

BACKGROUND: Standard lymphadenectomy for pancreatoduodenectomy is defined for pancreatic ductal adenocarcinoma and adopted for patients with non-pancreatic periampullary cancer (NPPC), ampullary adenocarcinoma (AAC), distal cholangiocarcinoma (dCCA), or duodenal adenocarcinoma (DAC). This study aimed to compare the patterns of lymph node metastases among the different NPPCs in a large series and in a systematic review to guide the discussion on surgical lymphadenectomy and pathology assessment. METHODS: This retrospective cohort study included patients after pancreatoduodenectomy for NPPC with at least one lymph node metastasis (2010-2021) from 24 centers in nine countries. The primary outcome was identification of lymph node stations affected in case of a lymph node metastasis per NPPC. A separate systematic review included studies on lymph node metastases patterns of AAC, dCCA, and DAC. RESULTS: The study included 2367 patients, of whom 1535 had AAC, 616 had dCCA, and 216 had DAC. More patients with pancreatobiliary type AAC had one or more lymph node metastasis (67.2% vs 44.8%; P < 0.001) compared with intestinal-type, but no differences in metastasis pattern were observed. Stations 13 and 17 were most frequently involved (95%, 94%, and 90%). Whereas dCCA metastasized more frequently to station 12 (13.0% vs 6.4% and 7.0%, P = 0.005), DAC metastasized more frequently to stations 6 (5.0% vs 0% and 2.7%; P < 0.001) and 14 (17.0% vs 8.4% and 11.7%, P = 0.015). CONCLUSION: This study is the first to comprehensively demonstrate the differences and similarities in lymph node metastases spread among NPPCs, to identify the existing research gaps, and to underscore the importance of standardized lymphadenectomy and pathologic assessment for AAC, dCCA, and DAC.

The Five Periampullary Cancers, not Just Different Siblings but Different Families: An International Multicenter Cohort Study.

BACKGROUND: Cancer arising in the periampullary region can be anatomically classified in pancreatic ductal adenocarcinoma (PDAC), distal cholangiocarcinoma (dCCA), duodenal adenocarcinoma (DAC), and ampullary carcinoma. Based on histopathology, ampullary carcinoma is currently subdivided in intestinal (AmpIT), pancreatobiliary (AmpPB), and mixed subtypes. Despite close anatomical resemblance, it is unclear how ampullary subtypes relate to the remaining periampullary cancers in tumor characteristics and behavior. METHODS: This international cohort study included patients after curative intent resection for periampullary cancer retrieved from 44 centers (from Europe, United States, Asia, Australia, and Canada) between 2010 and 2021. Preoperative CA19-9, pathology outcomes and 8-year overall survival were compared between DAC, AmpIT, AmpPB, dCCA, and PDAC. RESULTS: Overall, 3809 patients were analyzed, including 348 DAC, 774 AmpIT, 848 AmpPB, 1,036 dCCA, and 803 PDAC. The highest 8-year overall survival was found in patients with AmpIT and DAC (49.8% and 47.9%), followed by AmpPB (34.9%, P < 0.001), dCCA (26.4%, P = 0.020), and finally PDAC (12.9%, P < 0.001). A better survival was correlated with lower CA19-9 levels but not with tumor size, as DAC lesions showed the largest size. CONCLUSIONS: Despite close anatomic relations of the five periampullary cancers, this study revealed differences in preoperative blood markers, pathology, and long-term survival. More tumor characteristics are shared between DAC and AmpIT and between AmpPB and dCCA than between the two ampullary subtypes. Instead of using collective definitions for "periampullary cancers" or anatomical classification, this study emphasizes the importance of individual evaluation of each histopathological subtype with the ampullary subtypes as individual entities in future studies.

Abdominal drainage after minimally invasive distal pancreatectomy: out of sight, out of mind?

BACKGROUNDS: The use of drains in pancreatic surgery remains controversial. The present study investigated postoperative outcomes in patients undergoing minimally invasive distal pancreatectomy (MIDP) without intraperitoneal drain placement. METHODS: Data of consecutive patients undergoing MIDP between 2013 and 2023 were prospectively collected. Patients were divided in drain group (DG), including patients with prophylactic abdominal drain placed, and no-drain group (NDG) including those without drain. The groups were compared in terms of postoperative outcomes, using a propensity score-matched analysis. RESULTS: 116 patients were selected. After matching, DG and NDG consisted of 29 patients each. The rates of POPF and abdominal collection were lower in NDG in comparison to DG (3.4% vs. 27.6%, p 0.025 and 3.4% vs. 31.0%, p 0.011, respectively). The length of stay was significantly shorter in the NDG (5 vs. 9 days, p < 0.001). No difference between the groups was found for other outcomes. CONCLUSION: Drain omission was associated with lower rates of POPF and abdominal collections, as well as shorter hospital stays, not affecting the rate of severe complication, reoperation and readmission.

Long-term Outcomes After Laparoscopic, Robotic, and Open Pancreatoduodenectomy for Distal Cholangiocarcinoma: An International Propensity Score-matched Cohort Study.

OBJECTIVE: This study aimed to compare surgical and oncological outcomes after minimally invasive pancreatoduodenectomy (MIPD) versus open pancreatoduodenectomy (OPD) for distal cholangiocarcinoma (dCCA). BACKGROUND: A dCCA might be a good indication for MIPD, as it is often diagnosed as primary resectable disease. However, multicenter series on MIPD for dCCA are lacking. METHODS: This is an international multicenter propensity score-matched cohort study including patients after MIPD or OPD for dCCA in 8 centers from 5 countries (2010-2021). Primary outcomes included overall survival (OS) and disease-free interval (DFI). Secondary outcomes included perioperative and postoperative complications and predictors for OS or DFI. Subgroup analyses included robotic pancreatoduodenectomy (RPD) and laparoscopic pancreatoduodenectomy (LPD). RESULTS: Overall, 478 patients after pancreatoduodenectomy for dCCA were included of which 97 after MIPD (37 RPD, 60 LPD) and 381 after OPD. MIPD was associated with less blood loss (300 vs 420 mL, P =0.025), longer operation time (453 vs 340 min; P <0.001), and less surgical site infections (7.8% vs 19.3%; P =0.042) compared with OPD. The median OS (30 vs 25 mo) and DFI (29 vs 18) for MIPD did not differ significantly between MIPD and OPD. Tumor stage (Hazard ratio: 2.939, P <0.001) and administration of adjuvant chemotherapy (Hazard ratio: 0.640, P =0.033) were individual predictors for OS. RPD was associated with a higher lymph node yield (18.0 vs 13.5; P =0.008) and less major morbidity (Clavien-Dindo 3b-5; 8.1% vs 32.1%; P =0.005) compared with LPD. DISCUSSION: Both surgical and oncological outcomes of MIPD for dCCA are acceptable as compared with OPD. Surgical outcomes seem to favor RPD as compared with LPD but more data are needed. Randomized controlled trials should be performed to confirm these findings.

Outcomes After Minimally Invasive Versus Open Total Pancreatectomy: A Pan-European Propensity Score Matched Study.

OBJECTIVE: To assess postoperative 90-day outcomes after minimally invasive (laparoscopic/robot-assisted) total pancreatectomy (MITP) in selected patients versus open total pancreatectomy (OTP) among European centers. BACKGROUND: Minimally invasive pancreatic surgery is becoming increasingly popular but data on MITP are scarce and multicenter studies comparing outcomes versus OTP are lacking. It therefore remains unclear if MITP is a valid alternative. METHODS: Multicenter retrospective propensity-score matched study including consecutive adult patients undergoing MITP or OTP for all indications at 16 European centers in 7 countries (2008-2017). Patients after MITP were matched (1:1, caliper 0.02) to OTP controls. Missing data were imputed. The primary outcome was 90-day major morbidity (Clavien-Dindo ≥3a). Secondary outcomes included 90-day mortality, length of hospital stay, and survival. RESULTS: Of 361 patients (99MITP/262 OTP), 70 MITP procedures (50 laparoscopic, 15 robotic, 5 hybrid) could be matched to 70 OTP controls. After matching, MITP was associated with a lower rate of major morbidity (17% MITP vs. 31% OTP, P = 0.022). The 90-day mortality (1.4% MITP vs. 7.1% OTP, P = 0.209) and median hospital stay (17 [IQR 11-24] MITP vs. 12 [10-23] days OTP, P = 0.876) did not differ significantly. Among 81 patients with PDAC, overall survival was 3.7 (IQR 1.7-N/A) versus 0.9 (IQR 0.5-N/ A) years, for MITP versus OTP, which was nonsignificant after stratification by T-stage. CONCLUSION: This international propensity score matched study showed that MITP may be a valuable alternative to OTP in selected patients, given the associated lower rate of major morbidity.

Standardized right artery first approach during laparoscopic pancreaticoduodenectomy for periampullary neoplasms: technical aspects and perioperative outcomes.

BACKGROUND: The most debated aspects of laparoscopic pancreaticoduodenectomy (LPD) concern the dissection of the pancreas from the surrounding vessels and the achievement of adequate resection margins, especially in patients with pancreatic cancer. METHODS: Data of consecutive patients undergoing LPD with right artery first approach from September 2020 to September 2021 for periampullary neoplasms (pancreatic, ampullary, duodenal, distal common biliary duct) were prospectively collected and retrospectively analyzed. The overall cohort was divided into two groups: patients affected by pancreatic carcinoma (PC) and patients affected by other periampullary neoplasms (OP). Surgical and postoperative outcomes between PC and OP were compared. RESULTS: Thirty-one patients (15 PC and 16 OP) were selected. No difference was found between PC and OP in terms of baseline characteristics. Median resection time and overall surgical time of the entire cohort were 275 min and 530 min, respectively, without difference between the groups (p = 0.599 and 0.052, respectively). Blood loss was similar between the groups, being 350 ml in PC and 325 ml in OP (p = 0.762). One patient (3.2%) was converted to laparotomy. No difference was found between the groups in terms of pathological outcomes. Median number of retrieved lymph nodes was 17. The majority of the patients (83.9%) received an R0 resection (73.3% and 93.7% in PC and OP, respectively; p = 0.172). Postoperative surgical outcomes did not differ between the groups, excepting for overall complication rate that was higher in the OP group (26.7% vs 68.7% in PC and OP, respectively; p = 0.032). CONCLUSION: Standardized right artery first approach during LPD was feasible and did not show worse surgical and postoperative outcomes in patients with pancreatic cancer as compared to those affected by other periampullary neoplasms, except for a higher rate of minor complications.

Learning curve of laparoscopic cholecystectomy: a risk-adjusted cumulative summation (RA-CUSUM) analysis of six general surgery residents.

BACKGROUND: Laparoscopic cholecystectomy (LapC) is one of the most frequently performed surgical procedures worldwide. Reaching technical competency in performing LapC is considered one essential task for young surgeons. Investigating the learning curve for LapC (LC-LapC) may provide important information regarding the learning process and guide the training pathway of residents, improving educational outcomes. The present study aimed to investigate LC-LapC among general surgery residents (GSRs). METHODS: Operative surgical reports of consecutive patients undergoing LapC performed by GSRs attending the General Surgery Residency Program at the University of Milan were analysed. Data on patient- and surgery-related variables were obtained from the ICD-9-CM diagnosis codes and gathered. A multidimensional assessment of the LC was performed through Cumulative Sum (CUSUM) and Risk-Adjusted (RA)-CUSUM analysis. RESULTS: 340 patients operated by 6 GSRs were collected. The CUSUM and RA-CUSUM graphs based on surgical failures allowed to distinguish two defined phases for all GSRs: an initial phase ending at the peak, so-called learning phase, followed by a phase in which there was a significant decrease in failure incidence, so-called proficiency phase. The learning phase was completed for all GSRs at most within 25 procedures, but the trend of the curves and the number of procedures needed to achieve technical competency varied among operators ranging between 7 and 25. CONCLUSIONS: The present study suggested that at most 25 procedures might be sufficient to acquire technical competency in LapC. The variability in the number of procedures needed to complete the LC, ranging between 7 and 25, could be due to the heterogeneous scenarios in which LapC was performed, and deserves to be investigated through a prospective study involving a larger number of GSRs and institutions.

The clinical implication of minimally invasive versus open pancreatoduodenectomy for non-pancreatic periampullary cancer: a systematic review and individual patient data meta-analysis.

BACKGROUND: Most studies on minimally invasive pancreatoduodenectomy (MIPD) combine patients with pancreatic and periampullary cancers even though there is substantial heterogeneity between these tumors. Therefore, this study aimed to evaluate the role of MIPD compared to open pancreatoduodenectomy (OPD) in patients with non-pancreatic periampullary cancer (NPPC). METHODS: A systematic review of Pubmed, Embase, and Cochrane databases was performed by two independent reviewers to identify studies comparing MIPD and OPD for NPPC (ampullary, distal cholangio, and duodenal adenocarcinoma) (01/2015-12/2021). Individual patient data were required from all identified studies. Primary outcomes were (90-day) mortality, and major morbidity (Clavien-Dindo 3a-5). Secondary outcomes were postoperative pancreatic fistula (POPF), delayed gastric emptying (DGE), postpancreatectomy hemorrhage (PPH), blood-loss, length of hospital stay (LOS), and overall survival (OS). RESULTS: Overall, 16 studies with 1949 patients were included, combining 928 patients with ampullary, 526 with distal cholangio, and 461 with duodenal cancer. In total, 902 (46.3%) patients underwent MIPD, and 1047 (53.7%) patients underwent OPD. The rates of 90-day mortality, major morbidity, POPF, DGE, PPH, blood-loss, and length of hospital stay did not differ between MIPD and OPD. Operation time was 67 min longer in the MIPD group (P = 0.009). A decrease in DFS for ampullary (HR 2.27, P = 0.019) and distal cholangio (HR 1.84, P = 0.025) cancer, as well as a decrease in OS for distal cholangio (HR 1.71, P = 0.045) and duodenal cancer (HR 4.59, P < 0.001) was found in the MIPD group. CONCLUSIONS: This individual patient data meta-analysis of MIPD versus OPD in patients with NPPC suggests that MIPD is not inferior in terms of short-term morbidity and mortality. Several major limitations in long-term data highlight a research gap that should be studied in prospective maintained international registries or randomized studies for ampullary, distal cholangio, and duodenum cancer separately. PROTOCOL REGISTRATION: PROSPERO (CRD42021277495) on the 25th of October 2021.