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New principles of pancreatic cancer surgery
Abstracts / Pancreatology 16 (2016) S1eS192
reduction in tumor burden. Similar studies using human tumor xenografts implanted and propagated in mice also showed a dramatic decrease in tumor volume when treated with Minnelide. Our studies also showed that prolonged Minnelide treatment did not result in any obvious toxicity in the animals and the tumors did not recur even when treatment was stopped. Though Minnelide has been extremely efficient in inducing pancreatic cancer cell death, the signaling pathways leading to this are still unclear. Previous studies have demonstrated that Minnelide downregulates the pro-survival protein HSP70. We have now unraveled the relationship between several pro-proliferation pathways that are targeted by triptolide leading to downregulation of HSP70, eventually leading to cell death. Monotherapy with any agent leads to selection of resistant clones so current dictum is to use multiple anticancer agents. Minnelide™ at a dose of 0.42mg/kg has already been shown to be very effective against pancreatic cancer in preclinical models. We are currently evaluating the efficacy of Minnelide at a lower dose in combination with other standards of care drugs. This comprehensive study on Minnelide is of great usefulness in as it is undergoing Phase 1 clinical trials since August 2013.
SA-2. NET of the pancreas: Surgical treatment Thilo Hackert, Oliver Strobel, Markus W. Büchler Department of Surgery, University of Heidelberg, Germany Background: Pancreatic neuroendocrine tumors (pNET) are managed surgically in the majority of patients. However, there have been distinct changes in classification and guideline recommendations with regard to asymptomatic small pNET and metastases management in the recent years and the paradigm of surgery as the first-line treatment for this tumor entity has been challenged. Methods: The keynote lecture gives an overview of the current definitions, recommendations, management practice and outcomes in pNET. Results: Two classification of pNET are routinely used, defined by the ENETS and the UICC/AJCC/WHO with differences regarding TNM and clinical stages. Besides grading, the ENETS staging reflects patients' prognosis more accurately, especially with regard to clinical stages II and III. Recent studies have demonstrated that even G1 pNET are associated with perineural invasion and metastatic spread and should therefore be treated with an ocological resection and limited surgery can be considered in small pNET (<20mm) as they harbor a small risk of lymph node metastases or recurrence. Furthermore, literature data support the concept of primary tumor resection in metastatic pNET as this may offer a survival benefit. Conclusion: Management of pNET should be primarily surgical. A “watch-and-wait” strategy does not seem to be recommendable. Basically, oncological resections are the standard of care. Limited resections can be considered in small pNET. Even in metastatic pNET, surgical therapy should be considered.
SA-3. New principles of pancreatic cancer surgery Matthew H.G. Katz Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, USA As systemic therapies have improved, and as the efficacy of preoperative treatment regimens has increased, the role of surgery for patients with advanced pancreatic cancers has expanded. However, although these therapies may reduce the burden of micrometastatic disease and select patients with localized cancer who are most likely to benefit from surgery, they often do not reduce the size or anatomic extent of the primary cancer. Techniques of vascular resection and reconstruction are therefore often
S3
necessary to remove advanced tumors. In this presentation, we will illustrate and review technical principles involved in the resection of cancers that involve the major mesenteric vasculature, and provide a strategy for their safe and expeditious management in the operating room.
IC1-1. Autoimmune pancreatitis-a European perspective Markus M. Lerch, Georg Beyer, Julia Mayerle Department of Medicine A, University Medicine, Ernst-Moritz-ArndtUniversity of Greifswald, Germany Although the term ‘autoimmune pancreatitis’ was termed by the German pathologist Hans Peter Putzke in 1979 (Z Gesamte Inn Med. 1979 May 15; 34 (10): 266-71), the disease entity remained literally unknown in Europe until large Japanese cohorts have demonstrated their relevance. It complicated matter that two subtypes have merged which have very different distribution throughout the world. Type 1 autoimmune pancreatitis is now regarded as the pancreatic manifestation of the systemic IgG4associated syndrome which involves other organs. About one third of these patients can only be diagnosed by histology or a successful steroid trial but the majority is identified by testing for circulating IgG4 levels. This subtype is highly abundant in Japan, Korea and other Asian Countries. Type 2 presents as (circulating) IgG4-negative disease with the histological picture of an idiopathic duct centric pancreatitis and is to a higher degree associated with inflammatory bowel disease. A definitive diagnosis can only be made by EUS-guided or open biopsy. Usually both forms show respond to steroid treatment, but in type 1 up to 50% of the patients develop a relapse and this relaps is much less common (if existent at all) in type 2 AIP. Type 2 AIP is much more common among European patients than in Asia, accounting at least in part for the lower detection rates than in Japan since no serum parameter is yet available. Other than the need for diagnostic biopsies European preferences in comparison to Japan include a greater reluctance to employ ERCP for diagnostic purposes, a greater reluctance to use long term, low dose steroids for relapse prevention and higher initial steroid doses (1mg/kg/bodyweight). The discussion about alternative therapies such as azathioprine, rituximab and mTOR inhibitors remains undecided also in Europe.
IC1-2. Standard treatment of AIP in USA: Is biliary drainage needed in obstructive jaundice before treatment? Suresh T. Chari Mayo Clinic, USA Autoimmune pancreatitis is exquisitely sensitive to steroid therapy. In our practice we have observed that obstructive jaundice and liver test abnormalities rapidly resolve following initiation of steroid therapy. Therefore, we retrospectively reviewed our experience with treatment of AIP with steroids without stenting the bile duct in patients with obstructive jaundice. Fifteen AIP subjects (87% male, mean age 68.4 years) were treated with corticosteroids at initial presentation (n¼8), or at first (n¼5) or subsequent (n¼2) relapse. Mean values (upper limit of normal, ULN) of liver tests prior to corticosteroids were aspartate aminotransferase (AST) 203.5u/l (4xULN), alanine aminotransferase (ALT) 325.8u/l (6xULN), alkaline phosphatase (ALP) 567.4u/l (5xULN), and total bilirubin (TB) 5.9mg/dl (5.9xULN). At first follow-up (mean 4 days) the decrease was 54.9% for AST, 51.6% for ALT, 33% for ALP and 47.2% for TB (all p<0.05). After 15-45 days, all patients had normal AST, 3/15 had ALT＞1.5xULN, 1/15 had ALP＞1.5xULN, 1/ 15 had TB＞1.5xULN. No patient required biliary stent placement, or developed cholangitis or other infectious complications during steroid treatment. Based on review of our experience we believe that under the supervision of an experienced pancreatologist and with close monitoring of patients, obstructive jaundice secondary to definitive AIP can be safely and effectively managed with corticosteroids alone, without the need for biliary stenting.
reduction in tumor burden. Similar studies using human tumor xenografts implanted and propagated in mice also showed a dramatic decrease in tumor volume when treated with Minnelide. Our studies also showed that prolonged Minnelide treatment did not result in any obvious toxicity in the animals and the tumors did not recur even when treatment was stopped. Though Minnelide has been extremely efficient in inducing pancreatic cancer cell death, the signaling pathways leading to this are still unclear. Previous studies have demonstrated that Minnelide downregulates the pro-survival protein HSP70. We have now unraveled the relationship between several pro-proliferation pathways that are targeted by triptolide leading to downregulation of HSP70, eventually leading to cell death. Monotherapy with any agent leads to selection of resistant clones so current dictum is to use multiple anticancer agents. Minnelide™ at a dose of 0.42mg/kg has already been shown to be very effective against pancreatic cancer in preclinical models. We are currently evaluating the efficacy of Minnelide at a lower dose in combination with other standards of care drugs. This comprehensive study on Minnelide is of great usefulness in as it is undergoing Phase 1 clinical trials since August 2013.
SA-2. NET of the pancreas: Surgical treatment Thilo Hackert, Oliver Strobel, Markus W. Büchler Department of Surgery, University of Heidelberg, Germany Background: Pancreatic neuroendocrine tumors (pNET) are managed surgically in the majority of patients. However, there have been distinct changes in classification and guideline recommendations with regard to asymptomatic small pNET and metastases management in the recent years and the paradigm of surgery as the first-line treatment for this tumor entity has been challenged. Methods: The keynote lecture gives an overview of the current definitions, recommendations, management practice and outcomes in pNET. Results: Two classification of pNET are routinely used, defined by the ENETS and the UICC/AJCC/WHO with differences regarding TNM and clinical stages. Besides grading, the ENETS staging reflects patients' prognosis more accurately, especially with regard to clinical stages II and III. Recent studies have demonstrated that even G1 pNET are associated with perineural invasion and metastatic spread and should therefore be treated with an ocological resection and limited surgery can be considered in small pNET (<20mm) as they harbor a small risk of lymph node metastases or recurrence. Furthermore, literature data support the concept of primary tumor resection in metastatic pNET as this may offer a survival benefit. Conclusion: Management of pNET should be primarily surgical. A “watch-and-wait” strategy does not seem to be recommendable. Basically, oncological resections are the standard of care. Limited resections can be considered in small pNET. Even in metastatic pNET, surgical therapy should be considered.
SA-3. New principles of pancreatic cancer surgery Matthew H.G. Katz Department of Surgical Oncology, Division of Surgery, The University of Texas MD Anderson Cancer Center, USA As systemic therapies have improved, and as the efficacy of preoperative treatment regimens has increased, the role of surgery for patients with advanced pancreatic cancers has expanded. However, although these therapies may reduce the burden of micrometastatic disease and select patients with localized cancer who are most likely to benefit from surgery, they often do not reduce the size or anatomic extent of the primary cancer. Techniques of vascular resection and reconstruction are therefore often
S3
necessary to remove advanced tumors. In this presentation, we will illustrate and review technical principles involved in the resection of cancers that involve the major mesenteric vasculature, and provide a strategy for their safe and expeditious management in the operating room.
IC1-1. Autoimmune pancreatitis-a European perspective Markus M. Lerch, Georg Beyer, Julia Mayerle Department of Medicine A, University Medicine, Ernst-Moritz-ArndtUniversity of Greifswald, Germany Although the term ‘autoimmune pancreatitis’ was termed by the German pathologist Hans Peter Putzke in 1979 (Z Gesamte Inn Med. 1979 May 15; 34 (10): 266-71), the disease entity remained literally unknown in Europe until large Japanese cohorts have demonstrated their relevance. It complicated matter that two subtypes have merged which have very different distribution throughout the world. Type 1 autoimmune pancreatitis is now regarded as the pancreatic manifestation of the systemic IgG4associated syndrome which involves other organs. About one third of these patients can only be diagnosed by histology or a successful steroid trial but the majority is identified by testing for circulating IgG4 levels. This subtype is highly abundant in Japan, Korea and other Asian Countries. Type 2 presents as (circulating) IgG4-negative disease with the histological picture of an idiopathic duct centric pancreatitis and is to a higher degree associated with inflammatory bowel disease. A definitive diagnosis can only be made by EUS-guided or open biopsy. Usually both forms show respond to steroid treatment, but in type 1 up to 50% of the patients develop a relapse and this relaps is much less common (if existent at all) in type 2 AIP. Type 2 AIP is much more common among European patients than in Asia, accounting at least in part for the lower detection rates than in Japan since no serum parameter is yet available. Other than the need for diagnostic biopsies European preferences in comparison to Japan include a greater reluctance to employ ERCP for diagnostic purposes, a greater reluctance to use long term, low dose steroids for relapse prevention and higher initial steroid doses (1mg/kg/bodyweight). The discussion about alternative therapies such as azathioprine, rituximab and mTOR inhibitors remains undecided also in Europe.
IC1-2. Standard treatment of AIP in USA: Is biliary drainage needed in obstructive jaundice before treatment? Suresh T. Chari Mayo Clinic, USA Autoimmune pancreatitis is exquisitely sensitive to steroid therapy. In our practice we have observed that obstructive jaundice and liver test abnormalities rapidly resolve following initiation of steroid therapy. Therefore, we retrospectively reviewed our experience with treatment of AIP with steroids without stenting the bile duct in patients with obstructive jaundice. Fifteen AIP subjects (87% male, mean age 68.4 years) were treated with corticosteroids at initial presentation (n¼8), or at first (n¼5) or subsequent (n¼2) relapse. Mean values (upper limit of normal, ULN) of liver tests prior to corticosteroids were aspartate aminotransferase (AST) 203.5u/l (4xULN), alanine aminotransferase (ALT) 325.8u/l (6xULN), alkaline phosphatase (ALP) 567.4u/l (5xULN), and total bilirubin (TB) 5.9mg/dl (5.9xULN). At first follow-up (mean 4 days) the decrease was 54.9% for AST, 51.6% for ALT, 33% for ALP and 47.2% for TB (all p<0.05). After 15-45 days, all patients had normal AST, 3/15 had ALT＞1.5xULN, 1/15 had ALP＞1.5xULN, 1/ 15 had TB＞1.5xULN. No patient required biliary stent placement, or developed cholangitis or other infectious complications during steroid treatment. Based on review of our experience we believe that under the supervision of an experienced pancreatologist and with close monitoring of patients, obstructive jaundice secondary to definitive AIP can be safely and effectively managed with corticosteroids alone, without the need for biliary stenting.