Intra-arterial PRRT with Lu-177 DOTATATE in Liver-dominant Metastatic Neuroendocrine Tumors: Early Assessment of Efficacy and Toxicity.

Purpose: We proposed to administer Lu-177-DOTATATE in intra-arterial (IA) mode for higher first-pass localization to somatostatin receptors, higher residence time in liver metastases, and more radiation to tumor. This study aimed at assessing early hematological, renal and hepatotoxicity; and objective response to IA peptide receptor radionuclide therapy (PRRT). Materials and Methods: Fourteen patients (4 females and 10 males) were prospectively assessed. 5/14 patients underwent 2 cycles, whereas 3/14 underwent 3 cycles, and 6/14 received 1 cycle of IA PRRT. 200 mCi of Lu-177-DOTATATE was administered in 15-20 min by IA route under angiographic guidance. Patients were asked to follow-up at 4 and 8 weeks with hematological, liver, and renal functional parameters, and Ga-68 DOTATATE positron emission tomography/computed tomography (PET/CT) after 8 weeks. Response was assessed using RECIST 1.1 and EORTC PET criteria. Results: Safety: 2/14 patients had high total and direct bilirubin, which reverted to normal after IA PRRT. Three patients had low albumin, which improved after 1 cycle. Nine patients showed no worsening of liver function. Two patients showed Grade 1 hematotoxicity which reverted to normal. Five patients showed high creatinine, but preserved glomerular filtration rate and EC clearance. On follow-up at 8 weeks, serum creatinine reverted to normal. Efficacy: In five patients who underwent 2 cycles of IA PRRT, 3 showed partial response (PR) on RECIST 1.1 and partial metabolic response (PMR) on EORTC criteria, whereas 2 showed stable disease (SD). In patients who underwent 3 cycles, 1 showed SD, whereas other patient showed PMR on DOTANOC PET/CT, with PR in size. Among the remaining seven patients, 5 showed PMR, whereas the other 2 showed SD. Thus 9/14 patients showed PR, whereas 5 showed SD on metabolic and size criteria. Conclusions: IA PRRT is a safe and efficacious approach for the treatment of liver dominant metastatic neuroendocrine tumors.

Differential impact of incrementally elevated CA 19-9 levels on prognosis of resected pancreatic ductal adenocarcinoma.

BACKGROUND: CA 19-9 is an extremely useful biomarker for pancreatic ductal adenocarcinomas (PDACs). However, the optimal cut-off and prognostic significance at higher cut-offs are yet to be determined. METHODS: Retrospective analysis included patients with PDAC who underwent curative resection from January 2010 to May 2020 at Tata Memorial Centre, Mumbai. The pretherapy CA 19-9 was dichotomized using various cut-off levels and analysed. RESULTS: In 244 included patients, the median overall survival (OS) for those with CA19-9 level (IU/ml) < or >78, 200, 500, 1000, and 2000 was 27, 24, 23, 22, 21 months versus 18, 16, 15, 14, 13 months; respectively, and was statistically significant (p-value- 0.002, 0.001, 0.002, 0.002 and 0.004, respectively). The number of recurrences and mortality had significant correlation with CA 19-9 cut-offs. On multivariate analysis, adjuvant treatment completion (p-0.004) and decreasing or stable CA19-9 after Neoadjuvant therapy (NAT) (p- 0.031) were associated with improved OS. CONCLUSION: The prognostic significance of CA 19-9 was observed at all the cut-off levels examined, beyond mere elevated value as per the standard cut-off level. In patients with high CA19-9 level, surgery should be offered if technically and conditionally feasible, only when a response in CA19-9 level to NAT is achieved.

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.

Neoadjuvant Therapy in Borderline Resectable Pancreatic Cancer.

In this perspective, we present our assessment of all of the known accumulated evidence on the role of neoadjuvant therapy in the management of borderline resectable pancreatic cancer highlighting the gaps in the data, the current regimens used and providing a brief insight into the way forward.

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.

Rescue from complications after pancreaticoduodenectomies at a low-volume Caribbean center: Value of tailored peri-pancreatectomy protocols.

BACKGROUND: Pancreaticoduodenectomy (PD) is a technically complex operation, with a relatively high risk for complications. The ability to rescue patients from post-PD complications is as a recognized quality measure. Tailored protocols were instituted at our low volume facility in the year 2013. AIM: To document the rate of rescue from post-PD complications with tailored protocols in place as a measure of quality. METHODS: A retrospective audit was performed to collect data from patients who experienced major post-PD complications at a low volume pancreatic surgery unit in Trinidad and Tobago between January 1, 2013 and June 30, 2023. Standardized definitions from the International Study Group of Pancreatic Surgery were used to define post-PD complications, and the modified Clavien-Dindo classification was used to classify post-PD complications. RESULTS: Over the study period, 113 patients at a mean age of 57.5 years (standard deviation [SD] ± 9.23; range: 30-90; median: 56) underwent PDs at this facility. Major complications were recorded in 33 (29.2%) patients at a mean age of 53.8 years (SD: ± 7.9). Twenty-nine (87.9%) patients who experienced major morbidity were salvaged after aggressive treatment of their complication. Four (3.5%) died from bleeding pseudoaneurysm (1), septic shock secondary to a bile leak (1), anastomotic leak (1), and myocardial infarction (1). There was a significantly greater salvage rate in patients with American Society of Anesthesiologists scores ≤ 2 (93.3% vs 25%; P = 0.0024). CONCLUSION: This paper adds to the growing body of evidence that volume alone should not be used as a marker of quality for patients requiring PD. Despite low volumes at our facility, we demonstrated that 87.9% of patients were rescued from major complications. We attributed this to several factors including development of rescue protocols, the competence of the pancreatic surgery teams and continuous, and adaptive learning by the entire institution, culminating in the development of tailored peri-pancreatectomy protocols.

REDISCOVER guidelines for borderline-resectable and locally advanced pancreatic cancer: management algorithm, unanswered questions, and future perspectives.

The REDISCOVER guidelines present 34 recommendations for the selection and perioperative care of borderline-resectable (BR-PDAC) and locally advanced ductal adenocarcinoma of the pancreas (LA-PDAC). These guidelines represent a significant shift from previous approaches, prioritizing tumor biology over anatomical features as the primary indication for resection. Condensed herein, they provide a practical management algorithm for clinical practice. However, the guidelines also highlight the need to redefine LA-PDAC to align with modern treatment strategies and to solve some contradictions within the current definition, such as grouping "difficult" and "impossible" to resect tumors together. Furthermore, the REDISCOVER guidelines highlight several areas requiring urgent research. These include the resection of the superior mesenteric artery, the management strategies for patients with LA-PDAC who are fit for surgery but unable to receive multi-agent neoadjuvant chemotherapy, the approach to patients with LA-PDAC who are fit for surgery but demonstrate high serum Ca 19.9 levels even after neoadjuvant treatment, and the optimal timing and number of chemotherapy cycles prior to surgery. Additionally, the role of primary chemoradiotherapy versus chemotherapy alone in LA-PDAC, the timing of surgical resection post-neoadjuvant/primary chemoradiotherapy, the efficacy of ablation therapies, and the management of oligometastasis in patients with LA-PDAC warrant investigation. Given the limited evidence for many issues, refining existing management strategies is imperative. The establishment of the REDISCOVER registry ( https://rediscover.unipi.it/ ) offers promise of a unified research platform to advance understanding and improve the management of BR-PDAC and LA-PDAC.

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.

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.

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.

REDISCOVER International Guidelines on the Perioperative Care of Surgical Patients With Borderline-resectable and Locally Advanced Pancreatic Cancer.

OBJECTIVE: The REDISCOVER consensus conference aimed at developing and validating guidelines on the perioperative care of patients with borderline-resectable (BR-) and locally advanced (LA) pancreatic ductal adenocarcinoma (PDAC). BACKGROUND: Coupled with improvements in chemotherapy and radiation, the contemporary approach to pancreatic surgery supports the resection of BR-PDAC and, to a lesser extent, LA-PDAC. Guidelines outlining the selection and perioperative care for these patients are lacking. METHODS: The Scottish Intercollegiate Guidelines Network (SIGN) methodology was used to develop the REDISCOVER guidelines and create recommendations. The Delphi approach was used to reach a consensus (agreement ≥80%) among experts. Recommendations were approved after a debate and vote among international experts in pancreatic surgery and pancreatic cancer management. A Validation Committee used the AGREE II-GRS tool to assess the methodological quality of the guidelines. Moreover, an independent multidisciplinary advisory group revised the statements to ensure adherence to nonsurgical guidelines. RESULTS: Overall, 34 recommendations were created targeting centralization, training, staging, patient selection for surgery, possibility of surgery in uncommon scenarios, timing of surgery, avoidance of vascular reconstruction, details of vascular resection/reconstruction, arterial divestment, frozen section histology of perivascular tissue, extent of lymphadenectomy, anticoagulation prophylaxis, and role of minimally invasive surgery. The level of evidence was however low for 29 of 34 clinical questions. Participants agreed that the most conducive means to promptly advance our understanding in this field is to establish an international registry addressing this patient population ( https://rediscover.unipi.it/ ). CONCLUSIONS: The REDISCOVER guidelines provide clinical recommendations pertaining to pancreatectomy with vascular resection for patients with BR-PDAC and LA-PDAC, and serve as the basis of a new international registry for this patient population.

International Hepato-Pancreato-Billiary Association (IHPBA) registry study on COVID-19 infections in HPB surgery patients.

BACKGROUND: In response to the pandemic, the International Hepato-Pancreato-Biliary Association (IHPBA) developed the IHPBA-COVID Registry to capture data on HPB surgery outcomes in COVID-positive patients prior to mass vaccination programs. The aim was to provide a tool to help members gain a better understanding of the impact of COVID-19 on patient outcomes following HPB surgery worldwide. METHODS: An online registry updated in real time was disseminated to all IHPBA, E-AHPBA, A-HPBA and A-PHPBA members to assess the effects of the pandemic on the outcomes of HPB procedures, perioperative COVID-19 management and other aspects of surgical care. RESULTS: One hundred twenty-five patients from 35 centres in 18 countries were included. Seventy-three (58%) patients were diagnosed with COVID-19 preoperatively. Operative mortality after pancreaticoduodenectomy and major hepatectomy was 28% and 15%, respectively, and 2.5% after cholecystectomy. Postoperative complication rates of pancreatic procedures, hepatic interventions and biliary interventions were respectively 80%, 50% and 37%. Respiratory complication rates were 37%, 31% and 10%, respectively. CONCLUSION: This study reveals a high risk of mortality and complication after HPB surgeries in patient infected with COVID-19. The more extensive the procedure, the higher the risk. Nonetheless, an increased risk was observed across all types of interventions, suggesting that elective HPB surgery should be avoided in COVID positive patients, delaying it at distance from the viral infection.

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.

Global Perceptions on ERAS® in Pancreatoduodenectomy.

BACKGROUND: Uptake of ERAS® pathways for pancreatic surgery have been slow and impacted by low compliance. OBJECTIVE: To explore global awareness, perceptions and practice of ERAS® peri-pancreatoduodenectomy (PD). METHODS: A structured, web-based survey (EPSILON) was administered through the ERAS® society and IHPBA membership. RESULTS: The 140 respondents included predominantly males (86.4%), from Europe (45%), practicing surgery (95%) at academic/teaching hospitals (63.6%) over a period of 10-20 years (38.6%). Most respondents identified themselves as general surgeons (68.6%) with 40.7% reporting an annual PD volume of 20-50 cases, practicing post-PD clinical pathways (37.9%), with 31.4% of respondents auditing their outcomes annually. Reduced medical complications, cost and hospital length of stay, and improved patient satisfaction were perceived benefits of compliance to enhancing-recovery. Multidisciplinary co-ordination was considered the most important factor in the implementation and sustainability of peri-PD ERAS® pathways, while reluctance to change among health care practitioners, difficulties in data collection and audit, lack of administrative support, and recruitment of an ERAS® dedicated nurse were reported to be important barriers. CONCLUSIONS: The EPSILON survey highlighted global clinician perceptions regarding the benefits of compliance to peri-PD ERAS®, the importance of individual components, perceived facilitators and barriers, to the implementation and sustainability of these pathways.

IgG4-related disorders of the gastrointestinal tract: Experience from a tertiary care centre with systematic review of Indian literature.

INTRODUCTION: IgG4-related disease (IgG4-RD) is a rare disease entity in India. We aimed at studying the clinical profile of IgG4-RD of gastrointestinal tract (GIT) from our centre, while systematically reviewing data from India. METHODS: Retrospective review of IgG4-RD of GIT was done using electronic medical records between January 2013 and July 2022. Literature search was done for studies of IgG4-RD of the GIT reported from India from 2000 till January 2023. Case series, case reports of IgG4-RD of GIT and case reports describing GIT with multi-organ involvement were included in the review. Primary outcome measure was response to treatment. Secondary outcome measure was relapse after remission. RESULTS: Thirty-one patients were included with 71% (22/31) having autoimmune pancreatitis. The diagnosis was achieved on surgical specimen in 35% (11/31) patients. Steroid was given to 64% (20/31) patients with remission achieved in 70% (14/20) patients. Four patients exhibitted response to prolonged course of steroids with maintenance azathioprine. Relapse was seen in four (20%) patients who achieved remission. Of 731 articles screened, 48 studies (four case series and 44 case reports) were included in the literature review. Of 95 patients described, steroids were given to 65.2% (62/95), while surgery was done in 33.6% (32/95). Remission was seen in 96.6% (85/88) with relapse occurring in 11.4% (10/88) patients on follow-up. CONCLUSION: One-third patients of IgG4-RD of GIT are diagnosed after surgery. Response to steroids is good with relapse occurring in up to 12% patients.