Factors Predicting Prognosis in Metastatic Grade 1 Gastro-entero-pancreatic Neuroendocrine Tumors.

INTRODUCTION: The incidence of gastroenteropancreatic neuroendocrine tumors (GEP-NET) has steadily increased. These tumors are considered relatively indolent even when metastatic. What determines survival outcomes in such situations is understudied. MATERIALS AND METHODS: Retrospective analysis of a prospectively maintained NET clinic database, to include patients of metastatic grade 1 GEP-NET, from January 2018 to December 2021, to assess factors affecting progression-free survival (PFS). RESULTS: Of the 589 patients of GEP-NET treated during the study period, 100 were grade 1, with radiological evidence of distant metastasis. The median age was 50 years, with 67% being men. Of these, 15 patients were observed, while 85 patients received treatment in the form of surgery (n = 32), peptide receptor radionuclide therapy (n = 50), octreotide LAR (n = 22), and/or chemotherapy (n = 4), either as a single modality or multi-modality treatment. The median (PFS) was 54.5 months. The estimated 3-year PFS and 3-year overall survival rates were 72.3% (SE 0.048) and 93.4% (SE 0.026), respectively. On Cox regression, a high liver tumor burden was the only independent predictor of PFS (OR 3.443, p = 0.014). The 5-year OS of patients with concomitant extra-hepatic disease was significantly lower than that of patients with liver-limited disease (70.7% vs. 100%, p = 0.017). CONCLUSION: A higher burden of liver disease is associated with shorter PFS in patients with metastatic grade I GEP-NETs. The OS is significantly lower in patients with associated extrahepatic involvement. These parameters may justify a more aggressive treatment approach in metastatic grade 1 GEP-NETs.

CA 19-9 Surveillance Detects Recurrences Early and Contributes to Improvement in Survival in Resected Ampullary Cancers: Analysis of 572 cases.

OBJECTIVE: To determine the clinical utility of serum CA 19-9 surveillance for detecting recurrences in resected ampullary carcinomas (ACs). INTRODUCTION: Although an established prognostic marker for pancreatic ductal adenocarcinoma, the value of CA 19-9 in resected ACs during follow-up is unknown. METHODS: Retrospective analysis of ACs undergoing pancreaticoduodenectomy at Tata Memorial Centre-Mumbai, from January 2012 to January 2020 was performed. Survival, recurrence patterns, factors associated with recurrences and the utility of CA 19-9 surveillance were assessed. RESULTS: The 5-year OS of 572 included patients with ACs, was 56.4%. There were 251(43.88%) recurrences, majority being distant (n=223). Higher 'T' & 'N' stage, margin involvement, perineural invasion, poor tumour differentiation and pancreatobiliary subtype were associated with poor outcomes. Optimal CA 19-9 level to predict recurrence was 77.85 U/mL (sensitivity-61.22%, specificity-76.67%, AUC-0.711); however, a serial rise was a more accurate predictor (sensitivity-71.05%, specificity-91.67%). The median duration between the first rise in CA 19-9 (>37 U/mL) and radiological evidence of recurrence was 4.04 months. The optimal level of relative rise in CA 19-9 in diagnosing a recurrence was established at 2.79x (sensitivity-46.26%, specificity-83.33%, AUC-0.614). A serial rise and absolute value of >200 U/mL was associated with recurrence in 87% & 92.9% of cases. Recurrence detection & treatment after serum CA 19-9 elevation was associated with superior median survival as compared to recurrence detection without elevation (12.8 mo vs. 7.6 mo, P=0.005). CONCLUSION: Serum CA 19-9 testing during follow-up evaluation detects recurrences early and improves survival in resected ACs, and therefore should be recommended as a routine surveillance test.

Impact of pCR after neoadjuvant chemotherapy and radical D2 dissection in locally advanced gastric cancers: Analysis of 1001 cases.

BACKGROUND: Advances in perioperative chemotherapy have improved outcomes in patients with gastric cancers (GC). This strategy leads to tumour downstaging and may result in a pathologic complete response (pCR). The study aimed to evaluate the predictors of pCR and determine the impact of pCR on long-term survival. METHODS: At the Department of Gastrointestinal and HPB Oncology at the Tata Memorial Centre, Mumbai, 1001 consecutive patients with locally advanced GCs undergoing radical resection following neoadjuvant chemotherapy from January 2005 to June 2022 were included. RESULTS: At a median follow-up of 61 months, the median OS was 53 months with a 5-year OS of 46.8 %. Ninety-five patients (9.49 %) realized pCR. Non-signet and well-differentiated histology were associated with pCR. pCR was significantly associated with improved OS, 5-year OS 79.2 % vs 43.2 % (HR 0.30, p < 0.001). On multivariable analysis, the realization of pCR and completion of adjuvant chemotherapy had superior OS. Whereas, signet-ring histology, linitis-like tumours, and high lymph node ratio had adverse outcomes. CONCLUSION: Tumour grade and signet-ring histology predict achievement of pCR in locally advanced GCs after neoadjuvant chemotherapy. Patients with pCR have significantly improved survival. Future neoadjuvant strategies should focus on enhancing pCR rates to improve overall outcomes.

Robotic Pancreaticoduodenectomy with 'SMA-First Approach (Posterior and Right Medial)' and 'Triangle Operation'.

BACKGROUND: Notable improvements in pancreatic cancer surgery have been due to utilization of the superior mesenteric artery (SMA)-first approach1 and triangle operation (clearance of triangle tissue between origin of SMA and celiac artery).2 The SMA-first approach was originally defined to assess resectability before taking the irreversible surgical steps. However, in the present era, resectability is judged by the preoperative radiology, and the benefit of the SMA-first approach is by improving the R0 resection rate and reducing blood loss. The basic principle is to identify the SMA at its origin and in the distal part, to guide the plane of uncinate dissection. This video demonstrates the combination of the posterior and right medial SMA-first approach along with triangle clearance during robotic pancreaticoduodenectomy (RPD). METHODS: The technique consisted of early dissection of SMA from the posterior aspect, by performing a Kocher maneuver using the 'posterior SMA-first approach'. The origin of the celiac artery, along with the SMA, was defined early in the surgery. During uncinate process dissection, the 'right/medial uncinate approach' was used to approach the SMA. 'Level 3 systematic mesopancreatic dissection' was performed along the SMA,3 culminating in the 'triangle operation'.2 RESULTS: The procedure was performed within 600 min, with a blood loss of 150 mL and no intraoperative or postoperative complications. The final histopathology report showed a moderately differentiated adenocarcinoma (pT2, pN2), with all resection margins free. CONCLUSION: The standardized technique of the SMA-first approach and triangle clearance during RPD is demonstrated in the video. Prospective studies should further evaluate the benefits of this procedure.

Central versus distal pancreatectomy for low-grade and benign pancreatic neck-body tumours.

PURPOSE: Central pancreatectomy (CP) offers parenchymal preservation compared to conventional distal pancreato-splenectomy for pancreatic neck and body tumours. However, it is associated with more morbidity. This study is aimed at evaluating the peri-operative and long-term functional outcomes, comparing central and distal pancreatectomies (DPs). METHODS: Retrospective analysis of patients undergoing pancreatic resections for low-grade malignant or benign tumours in pancreatic neck and body was performed (from January 2007 to December 2022). Preoperative imaging was reviewed for all cases, and only patients with uninvolved pancreatic tail, whereby a CP was feasible, were included. Peri-operative outcomes and long-term functional outcomes were compared between CP and DP. RESULTS: One hundred twenty-two (5.2%) patients, amongst the total of 2304 pancreatic resections, underwent central or distal pancreatectomy for low-grade malignant or benign tumours. CP was feasible in 55 cases, of which 23 (42%) actually underwent CP and the remaining 32 (58%) underwent DP. CP group had a significantly longer operative time [370 min (IQR 300-480) versus 300 min (IQR 240-360); p = 0.002]; however, the major morbidity (43.5% versus 37.5%; p = 0.655) and median hospital stay (10 versus 11 days; p = 0.312) were comparable. The long-term endocrine functional outcome was favourable for the CP group [endocrine insufficiency rate was 13.6% in central versus 42.8% in distal (p = 0.046)]. CONCLUSION: Central pancreatectomy offers better long-term endocrine function without any increased morbidity in low malignant potential or benign pancreatic tumours of neck and body region.

Primary Pancreatic GIST - A-Single Centre Case Series and Systematic Review of Literature.

PURPOSE: GISTs arising from organs outside GI tract are defined as extragastrointestinal GISTs (EGIST). The majority of EGISTs arise from small intestinal mesentry, mesocolon, omentum, retroperitoneum, abdominal wall, liver and pancreas with pancreas comprising less than 5% of it. Due to limited data, it is unknown if the results of GIST can be generalised for EGISTs. We thereby present the largest single-centre case series of primary pancreatic GIST so far with review of existing literature. METHODS: A total of 9 patients of primary pancreatic GIST were treated at our institute from September 2016 to February 2023. After literature search for all studies published before February 2023, 51 articles including 57 patients were identified. Their clinicopathological data and survival analysis were assessed. RESULTS: The median age of patients treated at our centre was 53 years with a female predominance. The most common epicentre was pancreatic head with abdominal pain as the most common presenting symptom. All 57 patients documented in literature belonged to a similar age group with similar gender predilection. The factors impacting DFS were histologic type, mitotic index, NIH risk category and adjuvant therapy. The median DFS was 74 months with a 5-year DFS being 71.9%, while the 5-year OS was 90.4%. CONCLUSION: Pancreatic GIST is a rare entity. Due to limited evidence and evolving literature, results cannot be generalised to a larger population. Larger case series with longer follow-up data are required to further understand the disease biology and long-term outcomes of pancreatic GIST.

Gastric salvage after venous congestion during major pancreatic resections: A series of three cases.

Pancreatic resections, depending on the location of the tumor, usually require division of the vasculature of either the distal or proximal part of the stomach. In certain situations, such as total pancreatectomy and/or with splenic vein occlusion, viability of the stomach may be threatened due to inadequate venous drainage. We discuss three cases of complex pancreatic surgeries performed for carcinoma of the pancreas at a tertiary care center in India, wherein the stomach was salvaged by reimplanting the veins in two patients and preserving the only draining collateral in one case after the gastric venous drainage was compromised. The perioperative and postoperative course in these patients and the complications were analyzed. None of these 3 patients developed any complication related to gastric venous congestion, and additional gastrectomy was avoided in all these patients. Re-establishment of the Gastric venous outflow after extensive pancreatic resections helps to avoid additional gastric resection secondary to venous congestive changes.

Big data and RCT's in surgical oncology: Impact on improving hepatopancreatobiliary cancer surgical care on the global stage.

Randomized controlled clinical trials (RCTs) are at the heart of "evidence-based" medicine. Conducting well-designed RCTs for surgical procedures is often challenged by inadequate recruitment accrual, blinding, or standardization of the surgical procedure, as well as lack of funding and evolution of the treatment strategy during the many years over which such trials are conducted. In addition, most clinical trials are performed in academic high-volume centers with highly selected patients, which may not necessarily reflect a "real-world" practice setting. Large databases provide easy and inexpensive access to data on a large and diverse patient population at a variety of treatment centers. Furthermore, large database studies provide the opportunity to answer questions that would be impossible or very arduous to answer using RCTs, including questions regarding health policy efficacy, trends in surgical practice, access to health care, the impact of hospital volume, and adherence to practice guidelines, as well as research questions regarding rare disease, infrequent surgical outcomes, and specific subpopulations. Prospective data registries may also allow for quality benchmarking and auditing. There are several high-quality RCTs providing evidence to support current practices in hepatopancreatobiliary (HPB) oncology. Evidence from big data bridges the gap in several instances where RCTs are lacking. In this article, we review the evidence from RCTs and big data in HPB oncology identify the existing lacunae, and discuss the future directions of research in HPB oncology.

Pancreaticoduodenectomy in the Portal Annular Pancreas-Mesopancreas Triangle Approach (with Video).

BACKGROUND: Portal Annular Pancreas (PAP) is a relatively uncommon entity with 4% reported incidence. Pancreaticoduodenectomy is challenging in cases with PAP and is associated with higher postoperative pancreatic fistula rate and overall morbidity. PAP is classified according to the pattern and location of fusion around the portal vein as-supra-splenic, infra-splenic & mixed fusion type. Also, the ductal anatomy can vary as pancreatic duct present only in the ante-portal portion or only in the retro-portal portion or ducts in both ante and retro-portal portion. At present, ideal surgical strategy is not defined as per the PAP types. METHODS: The case demonstrated in the video presented with a localized, large duodenal mass with type IIA PAP (supra-splenic fusion with both ante and retro-portal ducts) detected on the preoperative triphasic CT scan. To achieve a single pancreatic cut surface with a single pancreatic duct for anastomosis, an extended pancreatic resection was performed using meso-pancreas triangle approach. RESULTS: Patient had a smooth intraoperative course & the postoperative recovery was also uneventful. Pathology reported pT3 duodenal cancer with negative margins and uninvolved lymph nodes. CONCLUSION: A preoperative knowledge of PAP and its various types is extremely important in order to tailor intraoperative management, specially of the retro-portal portion. In patients with retro-portal duct or both ante and retro-portal ducts (as the case presented in the video), an extended resection is recommended to mitigate postoperative pancreatic fistula.

Practice Patterns and Survival in Patients with Resected Pancreatic Ductal Adenocarcinomas (PDAC) - Results from the Multicentre Indian Pancreatic & Periampullary Adenocarcinoma Project (MIPPAP) Study.

BACKGROUND: There is limited data from India with regard to presentation, practice patterns and survivals in resected pancreatic ductal adenocarcinomas (PDACs). METHODS: The Multicentre Indian Pancreatic & Periampullary Adenocarcinoma Project (MIPPAP) included data from 8 major academic institutions across India and presents the outcomes in upfront resected PDACs from January 2015 to June 2019. RESULTS: Of 288 patients, R0 resection was achieved in 81% and adjuvant therapy was administered in 75% of patients. With a median follow-up of 42 months (95% CI: 39-45), median DFS for the entire cohort was 39 months (95% CI: 25.4-52.5), and median overall survival (OS) was 45 months (95% CI: 32.3-57.7). A separate analysis was done in which patients were divided into 3 groups: (a) those with stage I and absent PNI (SI&PNI-), (b) those with either stage II/III OR presence of PNI (SII/III/PNI+), and (c) those with stage II/III AND presence of PNI (SII/III&PNI+). The DFS was significantly lesser in patients with SII/III&PNI+ (median 25, 95% CI: 14.1-35.9 months), compared to SII/III/PNI + (median 40, 95% CI: 24-55 months) and SI&PNI- (median, not reached) (p = 0.036)). CONCLUSIONS: The MIPPAP study shows that resectable PDACs in India have survivals at par with previously published data. Adjuvant therapy was administered in 75% patients. Adjuvant radiotherapy does not seem to add to survival after R0 resection.

Rapid on-site evaluation (ROSE) versus macroscopic on-site evaluation (MOSE) for endoscopic ultrasound-guided sampling of solid pancreatic lesions: a paired comparative analysis using newer-generation fine needle biopsy needles.

Background: Rapid on-site examination (ROSE) during endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) has been a subject of debate. We compared the yield of EUS-FNB with adequacy assessed using macroscopic on-site evaluation (MOSE), and smear cytology with adequacy confirmed by ROSE, acquired using the same needle. Methods: Consecutive patients with solid pancreatic lesions (SPLs) who underwent EUS-FNB of pancreatic solid lesions between January 2021 and July 2022 were included. Demographic details, site and size of lesion, number of passes, and the diagnosis by cytology and histopathology of core tissue were noted. The first pass was used for ROSE adequacy assessment and was subsequently sent for cytological assessment. Additional passes were taken subsequently to acquire core tissue. Adequacy was confirmed by MOSE (whitish core of more than 4 mm). Final cytology and histopathology (HPE) were compared for diagnostic accuracy. Results: One hundred fifty-five patients were included in the analysis during the study period (mean age 55.1+12.9 years; 60% male; 77% in pancreatic head; median size 3.7 cm). The final diagnosis was malignancy in 129, while 26 were negative for malignancy. Sensitivity and specificity for ROSE with cytology in detecting malignant SPLs were 96.9% and 100%, respectively. HPE with MOSE had sensitivity and specificity of 96.1% and 100%, respectively. A comparison of diagnostic accuracy showed no significant difference (P>0.99) between HPE with MOSE and ROSE with cytology, using an FNB needle. Conclusion: MOSE is as good as ROSE in terms of diagnostic yield for solid pancreatic lesions sampled using newer-generation EUS biopsy needles.

Prognostic predictors for recurrence following curative resection in grade I/II pancreatic neuroendocrine tumours.

INTRODUCTION: Pancreatic neuroendocrine tumours (pNETs) have an excellent long-term survival after resection, but are associated with a high recurrence rate. Identification of prognostic factors affecting recurrences would enable identifying subgroup of patients at higher risk of recurrences, who may benefit from more aggressive treatment. METHODS: A retrospective analysis of prospectively maintained database of patients undergoing pancreatectomy with curative intent for grade I and II pNETs between July 2007 and June 2021 was performed. Perioperative and long-term outcomes were analysed. RESULTS: A total of 68 resected patients of pNETs were included in this analysis. Fifty-two patients (76.47%) underwent pancreaticoduodenectomy, 10 (14.7%) patients had distal pancreatectomy, and 2 (2.9%) patients underwent median pancreatectomy, while enucleation was performed in 4 patients (5.8%). The overall major morbidity (Clavien-Dindo III/IV) and mortality rates were 33.82% and 2.94%, respectively. At a median follow-up period of 48 months, 22 (32.35%) patients had disease recurrence. The 5-year overall survival and 5-year recurrence-free survival (RFS) rates were 90.2% and 60.8%, respectively. While OS was unaffected by different prognostic factors, multivariate analysis showed that lymph node involvement, Ki-67 index ≥5%, and presence of perineural invasion (PNI) were independently associated with recurrence. CONCLUSIONS: While surgical resection gives excellent overall survival in grade I/II pNETs, lymph node positivity, higher Ki-67 index, and PNI are associated with a high risk for recurrence. Patients with these characteristics should be stratified as high risk and evaluated for more intensive follow-up and aggressive treatment strategies in future prospective studies.

Splenectomy and Distal Pancreaticosplenectomy: Surgical Anatomy and Technique Specific to Advanced Ovarian Cancer.

Ovarian cancer is one of the most aggressive malignancies in women and usually presents at an advanced stage. Complete tumor debulking and platinum sensitivity are the two important determinants of survival in ovarian cancer. Upper abdominal surgery with bowel resections and peritonectomy are usually needed to achieve optimal cytoreduction. Splenic disease in the form of diaphragmatic peritoneal disease or omental caking at the splenic hilum is not infrequent. Around 1-2% of these require distal pancreaticosplenectomy (DPS) and the decision to perform DPS versus splenectomy should be made early in the intraoperative period to prevent unnecessary hilar dissection and bleeding. We hereby describe the surgical anatomy of the spleen and pancreas and point of technique of splenectomy and DPS specific to advanced ovarian cancers.

Perioperative Modified FLOT Versus EOX in Locally Advanced Resectable Gastric and Gastro-Oesophageal Junction Adenocarcinoma: Results of a Matched-Pair Analysis.

BACKGROUND AND OBJECTIVES: There is limited real-world data on the efficacy of 2-weekly cycles of docetaxel, oxaliplatin, leucovorin, and fluorouracil (FLOT) compared to epirubicin, oxaliplatin, and capecitabine (EOX) as perioperative therapy in esophagogastric adenocarcinomas (EGAC). METHODS: The data of 611 patients with EGAC treated with perioperative chemotherapy and planned for curative resection between January 2013 and December 2019 were retrieved. Patients receiving EOX and a dose-modified version of FLOT (mFLOT) were evaluated. A 1:1 matching, using age, tumour location, signet ring histology, and Eastern Cooperative Oncology Group performance status, without replacement was performed by using nearest neighbour matching method. The primary endpoint of the study was 3-year event-free survival (EFS). RESULTS: A total of 593 patients (261 with EOX and 332 with mFLOT) were matched. One hundred and nighty-eight patients (76%) and 285 patients (86%) in the EOX and mFLOT cohorts underwent curative resection, respectively (p = 0.002). With a median follow-up of 35 and 53 months, respectively, the primary outcome of 3-year EFS was statistically superior in patients receiving mFLOT as compared to the EOX regimen (60% vs. 39%; p < 0.001). There was a greater incidence of grade 3 and grade 4 neutropenia (neoadjuvant: 18% vs. 2%; p < 0.001, adjuvant: 18% vs. 1%; p = 0.001) and febrile neutropenia (neoadjuvant: 8% vs. 1.1%; p < 0.001, adjuvant: 6% vs. 0; p = 0.001) with mFLOT. INTERPRETATION AND CONCLUSION: mFLOT is associated with improved resection rates and survival in comparison to EOX as perioperative therapy in gastric adenocarcinomas in this large real-world cohort, with manageable increase in clinically relevant toxicities such as grade 3 and grade 4 febrile neutropenia and neutropenia.

An Analysis of Tolerance and Early Survival Outcomes with Perioperative Modified FLOT in Gastric Cancers.

Anant RamaswamyPurpose Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT) is a current standard of care for locoregionally advanced gastric adenocarcinomas. There is limited real world data with regard to the tolerance and efficacy of this regimen. Materials and Methods This is a retrospective analysis of gastric cancer patients who were offered neoadjuvant perioperative modified FLOT regimen between December 2016 and October 2018, at the Tata Memorial Hospital, Mumbai. Chemotherapy-related side-effects are reported along with overall survival (OS), as calculated by Kaplan-Meier method. Results Three hundred and forty-three consecutive patients were started on neoadjuvant chemotherapy (NACT) with mFLOT of which 298 patients (87%) completed the planned treatment. A total of 294 patients (86%) underwent curative resection of gastric cancer. Common grade 3 and grade 4 toxicities during NACT were diarrhea in 42 patients (12%) and febrile neutropenia in 27 patients (8%). Toxic death was seen in nine (2.6%) patients. A total of 264 patients (77%) completed planned adjuvant chemotherapy. Common grade 3 and grade 4 toxicities during adjuvant therapy were diarrhea in 42 patients (12%) and febrile neutropenia in 16 patients (6%). With a median follow-up of 19 months, the estimated 2-year median OS was 69.4%. Conclusion Administration of modified FLOT regimen in locoregionally advanced gastric cancers is feasible in clinical practice with high completion rates, though requiring dose modifications due to the incidence of clinically relevant grade 3 to 5 toxicities. Early outcomes with the regimen are on par with survivals from the FLOT-AIO study.