Charles M. Vollmer

Predominant Bcl-XL Knockdown Disables Antiapoptotic Mechanisms: Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand–Based Triple Chemotherapy Overcomes Chemoresistance in Pancreatic Cancer Cells In vitro

Pancreatic cancer is lethal because of its invasiveness, rapid progression, and profound resistance to chemotherapy and radiation therapy. To identify the molecular mechanisms underlying this, we have examined the expression and potency of three major death receptors: tumor necrosis factor receptor (TNF-R), TNF-related apoptosis-inducing ligand receptor (TRAIL-R), and Fas in mediating cytotoxicity in four invasive pancreatic cancer cell lines. We have analyzed the expression of major antiapoptotic factors, cell cycle regulators and death receptor decoys (DcR) in comparison with normal pancreas tissues and five other human malignant tumor cell lines. We have found that different pancreatic cancer cell lines coexpress high-level TRAIL-R, Fas, and TNF-R1 but are strongly resistant to apoptosis triggered by the death receptors. DcR2 and DcR3 overexpression may partly contribute to the resistance of pancreatic cancer cells to TRAIL-R- and Fas-mediated cytotoxicity. Bcl-XL and Bcl-2 are predominantly overexpressed in pancreatic cancer cell lines, respectively. Bcl-XL is also predominantly overexpressed in prostate, colorectal, and intestinal cancer cells. The knockdown of the predominant Bcl-XL overexpression significantly reduces the viability of pancreatic cancer cells to TNFalpha- and TRAIL-mediated apoptosis by sublethal-dose single and combined antitumor drugs, including geldanamycin, PS-341, Trichostatin A, and doxorubicine. Geldanamyin and PS-341 synergistically block NFkappaB activation, suppress Akt/PKB pathway, and down-regulate Bcl-XL, Bcl-2, cIAP-1, and cyclin D1 expression. This combined regimen dramatically enhances TRAIL cytotoxic effects and breaks through chemoresistance. Bcl-XL plays a vital role in pancreatic cancer chemoresistance. Geldanamycin, PS-341, and TRAIL triple combination may be a novel therapeutic strategy for pancreatic cancer.

A root-cause analysis of mortality following major pancreatectomy

IntroductionAlthough mortality rates from pancreatectomy have decreased worldwide, death remains an infrequent but profound event at an individual practice level. Root-cause analysis is a retrospective method commonly employed to understand adverse events. We evaluate whether emerging mortality risk assessment tools sufficiently predict and account for actual clinical events that are often identified by root-cause analysis.MethodsWe assembled a Pancreatic Surgery Mortality Study Group comprised of 36 pancreatic surgeons from 15 institutions in 4 countries. Mortalities after pancreatectomy (30 and 90xa0days) were accrued from 2000 to 2010. For root-cause analysis, each surgeon “deconstructed” the clinical events preceding a death to determine cause. We next tested whether mortality risk assessment tools (ASA, POSSUM, Charlson, SOAR, and NSQIP) could predict those patients who would die (nu2009=u2009218) and compared their prognostic accuracy against a cohort of resections in which no patient died (nu2009=u20091,177).ResultsTwo hundred eighteen deaths (184 Whipple’s resection, 18 distal pancreatectomies, and 16 total pancreatectomies) were identified from 11,559 pancreatectomies performed by surgeons whose experience averaged 14.5xa0years. Overall 30- and 90-day mortalities were 0.96% and 1.89%, respectively. Individual surgeon rates ranged from 0% to 4.7%. Only 5 patients died intraoperatively, while the other 213 succumbed at a median of 29xa0days. Mean patient age was 70xa0years old (38% were >75xa0years old). Malignancy was the indication in 90% of cases, mostly pancreatic cancer (57%). Median operative time was 365xa0min and estimated blood loss was 700xa0cc (range, 100–16,000xa0cc). Vascular repair or multivisceral resections were required for 19.7% and 15.1%, respectively. Seventy-seven percent had a variety of major complications before death. Eighty-seven percent required intensive care unit care, 55% were transfused, and 35% were reoperated upon. Fifty percent died during the index admission, while another 11% died after a readmission. Almost half (nu2009=u2009107) expired between 31 and 90xa0days. Only 11% had autopsies. Operation-related complications contributed to 40% of deaths, with pancreatic fistula being the most evident (14%). Technical errors (21%) and poor patient selection (15%) were cited by surgeons. Of deaths, 5.5% had associated cancer progression—all occurring between 31 and 90xa0days. Even after root-cause scrutiny, the ultimate cause of death could not be determined for a quarter of the patients—most often between 31 and 90xa0days. While assorted risk models predicted mortality with variable discrimination from nonmortalities, they consistently underestimated the actual mortality events we report.ConclusionRoot-cause analysis suggests that risk prediction should include, if not emphasize, operative factors related to pancreatectomy. While risk models can distinguish between mortalities and nonmortalities in a collective fashion, they vastly miscalculate the actual chance of death on an individual basis. This study reveals the contributions of both comorbidities and aggressive surgical decisions to mortality.

Evolving Treatment Strategies for Gallbladder Cancer

Gallbladder cancer is an uncommon cancer that has traditionally been associated with a poor prognosis. In the era of laparoscopic cholecystectomy, incidental gallbladder cancer has dramatically increased and now constitutes the major way patients present with gallbladder cancer. While patients with incidental gallbladder cancer have a better survival than patients with nonincidental gallbladder cancer, incidental gallbladder cancer can be associated with a varied prognosis. Imaging with computed tomography (CT), magnetic resonance imaging (MRI), and [18]F-fluorodeoxyglucose (FDG) positron emission tomography (PET), as well as diagnostic laparoscopy, all have varying roles in the workup of patients with incidental gallbladder cancer. For patients with T1b, T2, and T3 incidental gallbladder cancer re-resection is generally recommended. At re-exploration, many patients with incidental gallbladder cancer will have residual disease. Definitive oncologic management requires re-resection of the liver, portal lymphadenectomy, and attention to the common bile duct. The extent of the hepatic resection should be dictated by the ability to achieve a microscopically negative (R0) margin. Routine resection of the common bile duct is unnecessary but should be undertaken in the setting of a positive cystic duct margin. If an incidental gallbladder cancer is discovered at the time of surgery, whether the surgeon should directly proceed with a more definitive oncologic operation should depend on the surgeon’s skill-set and experience. Gallbladder cancer has a propensity to recur. Although data for adjuvant therapy following resection are limited, some data do suggest a survival benefit for adjuvant chemoradiation therapy. Management of patients with gallbladder cancer requires a multidisciplinary approach with input from a surgeon skilled in hepatobiliary surgery.

Prevention and Management of Pancreatic Fistula

Despite significant improvements in the safety and efficacy of pancreatic surgery, post-operative pancreatic fistulae remain an unsolved dilemma. These occur when the transected pancreatic gland, pancreatic-enteric anastomosis, or both, leak rendering the patient at significant risk. They are especially important today since indications for resection (IPMN, carcinoma) continue to increase. This review considers definitions and classifications of pancreatic fistulae, risk factors, preventative approaches and offers management strategies for when they do occur. Key citations from the past seventeen years have been scrutinized, and together with personal experience, provide the basis for this review.

Epidural Analgesia for Pancreatoduodenectomy: A Critical Appraisal

IntroductionEpidural analgesia has emerged as a commonly applied method to improve pain management and reduce perioperative complications in major abdominal surgery. However, there is no detailed analysis of its efficacy for pancreatic operations. This study compares clinical and economic outcomes after epidural and intravenous analgesia for pancreatoduodenectomy.Material and methodsData for 233 consecutive patients, who underwent pancreatoduodenectomy, were prospectively acquired and retrospectively reviewed at a single institution, pancreato-biliary specialty practice. From October 2001 to February 2007, all patients were offered thoracic epidural analgesia, and those who declined received intravenous analgesia. Perioperative pain management was dictated as an element of a standardized clinical pathway for pancreatic resections. Clinical and economic outcomes were analyzed and compared for epidural analgesia and intravenous analgesia groups.ResultsOne hundred eighty-five patients received epidural analgesia, and 48 received intravenous analgesia, with equivalent baseline patient demographics between the groups. Patients administered epidural analgesia had lower pain scores but significantly higher rates of major complications. Pancreatic fistulae and postoperative ileus occurred more frequently, and patients with epidural analgesia more often required discharge to rehabilitation facilities. A trend towards longer hospitalizations was observed among epidural analgesia patients, but total costs were statistically equivalent between the groups. Further analysis demonstrates that 31% of epidural infusions were aborted before anticipated (fourth postoperative day) because of hemodynamic compromise and/or inadequate analgesia. These select patients required more transfusions, aggressive fluid resuscitation, and subsequently suffered even higher rates of gastrointestinal and respiratory complications, all attributing to higher costs. Multivariate analysis demonstrates that preoperative hematocrit concentration less than 36%, elderly age (>75xa0years), and chronic pancreatitis predict failure of epidural infusions.ConclusionThoracic epidural analgesia after pancreatic resections is associated with hemodynamic instability, which may compromise enteric anastomoses, gastrointestinal recovery, and respiratory function. These outcomes are exacerbated in poorly functioning epidurals and suggest that epidural analgesia may not be the optimal method for perioperative pain control when pancreatoduodenectomy is performed.

Impact of Regional Lymph Node Evaluation in Staging Patients With Periampullary Tumors

BackgroundTwo distinct lymph nodes reproducibly assessed by computed tomography for the evaluation of periampullary tumors are the common bile duct (CBD) node and the gastroduodenal artery (GDA) node. We examined whether radiographical enlargement of either lymph node predicts tumor resectability, nodal metastasis, or patient survival.MethodsNinety-four consecutive patients underwent attempted curative resection of periampullary tumors between September 2001 and June 2003. A single radiologist recorded in a retrospective, blinded fashion the short- and long-axis measurements of the CBD and GDA nodes.ResultsSixty-one percent (n = 57) of tumors were resectable by pancreaticoduodenectomy. Overall, actual 6-, 12-, and 18-month survival was 87%, 68%, and 63%, respectively. Enlarged radiographical nodal size by either axis was not associated with the presence of metastasis to these lymph nodes or with reduced overall patient survival. Only a CBD node short-axis size >10 mm predicted unresectability (odds ratio, 3.2; P = .036). Liver metastasis and/or carcinomatosis were present in 43% of unresectable patients, and this was associated with decreased survival at both 1 year (25% vs. 77%; P < .001) and 18 months (19% vs. 72%; P <.001). A pathologic diagnosis of metastasis to the GDA node, but not the CBD node, was associated with a similarly decreased survival (1 year: 33% vs. 78%, P = .028; 18 months: 22% vs. 70%, P = .023).ConclusionsFor presumed periampullary malignancy, a CBD node short-axis size >10 mm predicts tumor unresectability. Metastatic disease to the GDA node, particularly for pancreatic adenocarcinoma, portends a poor prognosis equivalent to that of hepatic or peritoneal spread. Given these findings, radiographical CBD lymph node measurements may guide selection for performing laparoscopic staging with or without ultrasonography in conjunction with GDA nodal biopsy in patients with periampullary malignancy.

Clinical implications of mucinous nonneoplastic cysts of the pancreas.

Objectives An undercharacterized subclass of pancreatic mucinous cysts without histologic characteristics of neoplasia is emerging. This article aimed to highlight the clinical characteristics and implications of this new subset of pancreatic cystic lesions. Methods The clinical, radiologic, and pathologic features of all cysts that underwent operative resection at a tertiary referral pancreatic disease center from February 2005 to June 2009 were reviewed. Immunohistochemistry for mucinous peptide antigens was selectively performed. Results Of 104 operations, a pathologic examination revealed 52 intraductal papillary mucinous neoplasms, 9 mucinous cystadenomas, 17 serous cystadenomas, 9 pseudocysts, 5 solid pseudopapillary tumors, 2 carcinomas, 1 cystic pancreatic endocrine tumor, and 2 other cystic lesions. Seven mucinous cysts without neoplastic features were identified, representing 2% of all pancreatic resections, 6.7% of all resected cysts, and 10.3% of the 68 mucinous cysts. There was no evidence of cytologic atypia, papillary growth, or ovarian-type stroma in any of the cases. MUC1, MUC2, and MUC5AC were expressed in 83%, 0%, and 100%, respectively. There has been no recurrence with a mean follow-up of 44 months. Conclusions This underappreciated entity belongs to the family of mucinous pancreatic cysts. However, unifying clinical characteristics that would prevent unnecessary resections in patients harboring these seemingly benign lesions are currently lacking.

An unusual variant of anomalous pancreaticobiliary junction in a patient with pancreas divisum diagnosed with secretin-magnetic resonance cholangiopancreatography.

Anomalous pancreaticobiliary junction is an unusual variant of pancreaticobiliary anatomy of clinical importance because it is associated with increased risk of pancreatitis and, also, for the development of cholangiocarcinoma. We report an unusual variant of anomalous pancreaticobiliary junction, occurring in a patient with pancreas divisum, with an anomalous communication between the dorsal pancreatic and the common bile duct. The patient presented with a distal biliary stricture. This variant anatomy was occult on magnetic resonance cholangiopancreatography but was diagnosed on magnetic resonance cholangiopancreatography that was performed with intravenous secretin administration and further delineated by endoscopic retrograde cholangiopancreatography. The features that allowed the diagnosis to be made and the implications of this diagnosis are described in this report.

BRAZILIAN CONSENSUS FOR MULTIMODAL TREATMENT OF COLORECTAL LIVER METASTASES. MODULE 3: CONTROVERSIES AND UNRESECTABLE METASTASES

ABSTRACT In the last module of this consensus, controversial topics were discussed. Management of the disease after progression during first line chemotherapy was the first discussion. Next, the benefits of liver resection in the presence of extra-hepatic disease were debated, as soon as, the best sequence of treatment. Conversion chemotherapy in the presence of unresectable liver disease was also discussed in this module. Lastly, the approach to the unresectable disease was also discussed, focusing in the best chemotherapy regimens and hole of chemo-embolization.

The obstructed pancreatico-biliary drainage limb: presentation, management, and outcomes.

IntroductionObstruction of the pancreatico-biliary (PB) drainage limb following major PB operations creates unique diagnostic and management dilemmas. We describe the etiology and prevalence, as well as diagnostic and therapeutic approaches for this challenging problem.MethodsIndividuals with PB limb obstruction were identified from a cohort of 477 patients undergoing major PB resections or bypasses for benign and malignant (Nu2009=u2009265) diseases from September 2000 to January 2010. Their presentation, management, short-term outcomes, and survival were analyzed.ResultsThirteen patients developed eventual PB limb obstruction with a mean time to presentation of 18.4xa0months (range 0.5–41.9), representing an overall adjusted incidence of 4%. Presenting symptoms were reflective of limb obstruction (elevated LFTs, jaundice, cholangitis, and pancreatitis). CT scans demonstrated dilation of the PB drainage limb in all 13 patients and evidence of intrahepatic biliary dilation in eight. Endoscopy was not valuable for either diagnostic or therapeutic purposes in the five patients evaluated in this manner. Percutaneous transhepatic biliary drainage (PTC) was pursued in six patients and provided definitive palliation in two, while three were temporized by this modality prior to a definitive operation, and it was employed postoperatively in another. Operative management occurred in 11 of 13 patients. Causative lesions were not accurately predicted by preoperative imaging and included adhesions, limb volvulus, abscess, malignant local recurrence, solitary metastatic disease, and carcinomatosis. Surgical interventions varied (five enteric bypasses, three adhesiolyses, two explorations, and one external limb venting). There were two perioperative mortalities, but limited morbidity otherwise (one myocardial infarction, one wound dehiscence, and one empyema from PTC placement). The median duration of postoperative hospital stay was 9xa0days, and no patient required readmission for further surgical management. No patients suffered subsequent recurrence of PB obstruction. In follow-up, nine of the remaining 11 patients are deceased with a median survival of 2.3xa0months (0.6–9.4xa0months). The other two are alive at a mean follow-up of 48xa0months.ConclusionAlthough infrequent, PB limb obstruction occurs for a variety of reasons and most commonly in the setting of an original malignancy. Since numerous therapeutic modalities are available, an improved understanding of the condition is important in managing these complex patients. Decisive operative intervention accurately assesses the cause and extent of the problem and, for most presentations, provides definitive palliation with limited morbidity for this near-terminal event.