Richard D. Schulick

Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors

Poorly differentiated neuroendocrine carcinomas (NECs) of the pancreas are rare malignant neoplasms with a poor prognosis. The aim of this study was to determine the clinicopathologic and genetic features of poorly differentiated NECs and compare them with other types of pancreatic neoplasms. We investigated alterations of KRAS, CDKN2A/p16, TP53, SMAD4/DPC4, DAXX, ATRX, PTEN, Bcl2, and RB1 by immunohistochemistry and/or targeted exomic sequencing in surgically resected specimens of 9 small cell NECs, 10 large cell NECs, and 11 well-differentiated neuroendocrine tumors (PanNETs) of the pancreas. Abnormal immunolabeling patterns of p53 and Rb were frequent (p53, 18 of 19, 95%; Rb, 14 of 19, 74%) in both small cell and large cell NECs, whereas Smad4/Dpc4, DAXX, and ATRX labeling was intact in virtually all of these same carcinomas. Abnormal immunolabeling of p53 and Rb proteins correlated with intragenic mutations in the TP53 and RB1 genes. In contrast, DAXX and ATRX labeling was lost in 45% of PanNETs, whereas p53 and Rb immunolabeling was intact in these same cases. Overexpression of Bcl-2 protein was observed in all 9 small cell NECs (100%) and in 5 of 10 (50%) large cell NECs compared with only 2 of 11 (18%) PanNETs. Bcl-2 overexpression was significantly correlated with higher mitotic rate and Ki67 labeling index in neoplasms in which it was present. Small cell NECs are genetically similar to large cell NECs, and these genetic changes are distinct from those reported in PanNETs. The finding of Bcl-2 overexpression in poorly differentiated NECs, particularly small cell NEC, suggests that Bcl-2 antagonists/inhibitors may be a viable treatment option for these patients.

Sarcopenia negatively impacts short-term outcomes in patients undergoing hepatic resection for colorectal liver metastasis

BACKGROUNDnAs indications for liver resection expand, objective measures to assess the risk of peri-operative morbidity are needed. The impact of sarcopenia on patients undergoing liver resection for colorectal liver metastasis (CRLM) was investigated.nnnMETHODSnSarcopenia was assessed in 259 patients undergoing liver resection for CRLM by measuring total psoas area (TPA) on computed tomography (CT). The impact of sarcopenia was assessed after controlling for clinicopathological factors using multivariate modelling.nnnRESULTSnMedian patient age was 58 years and most patients (60%) were male. Forty-one (16%) patients had sarcopenia (TPA ≤ 500 mm(2) /m(2) ). Post-operatively, 60 patients had a complication for an overall morbidity of 23%; 26 patients (10%) had a major complication (Clavien grade ≥3). The presence of sarcopenia was strongly associated with an increased risk of major post-operative complications [odds ratio (OR) 3.33; P= 0.008]. Patients with sarcopenia had longer hospital stays (6.6 vs. 5.4 days; P= 0.03) and a higher chance of an extended intensive care unit (ICU) stay (>2 days; P= 0.004). On multivariate analysis, sarcopenia remained independently associated with an increased risk of post-operative complications (OR 3.12; P= 0.02). Sarcopenia was not significantly associated with recurrence-free [hazard ratio (HR) = 1.07] or overall (HR = 1.05) survival (both P > 0.05).nnnCONCLUSIONSnSarcopenia impacts short-, but not long-term outcomes after resection of CRLM. While patients with sarcopenia are at an increased risk of post-operative morbidity and longer hospital stay, long-term survival is not impacted by the presence of sarcopenia.

Patient Readmission and Mortality after Colorectal Surgery for Colon Cancer: Impact of Length of Stay Relative to Other Clinical Factors

BACKGROUNDnData on readmission as well as the potential impact of length of stay (LOS) after colectomy for colon cancer remain poorly defined. The objective of the current study was to evaluate risk factors associated with readmission among a nationwide cohort of patients after colorectal surgery.nnnSTUDY DESIGNnWe identified 149,622 unique individuals from the Surveillance, Epidemiology, and End Results-Medicare dataset with a diagnosis of primary colorectal cancer who underwent colectomy between 1986 and 2005. In-hospital morbidity, mortality, LOS, and 30-day readmission were examined using univariate and multivariate logistic regression models.nnnRESULTSnPrimary surgical treatment consisted of right (37.4%), transverse (4.9%), left (10.5%), sigmoid (22.8%), abdominoperineal resection (7.3%), low anterior resection (5.6%), total colectomy (1.2%), or other/unspecified (10.3%). Mean patient age was 76.5 years and more patients were female (52.9%). The number of patients with multiple preoperative comorbidities increased over time (Charlson comorbidity score ≥3: 1986 to 1990, 52.5% vs 2001 to 2005, 63.1%; p < 0.001). Mean LOS was 11.7 days and morbidity and mortality were 36.5% and 4.2%, respectively. LOS decreased over time (1986 to 1990, 14.0 days; 1991 to 1995, 12.0 days; 1996 to 2000, 10.4 days; 2001 to 2005, 10.6 days; p < 0.001). In contrast, 30-day readmission rates increased (1986 to 1990, 10.2%; 1991 to 1995, 10.9%; 1996 to 2000, 12.4%; 2001 to 2005, 13.7%; p < 0.001). Factors associated with increased risk of readmission included LOS (odds ratio = 1.02), Charlson comorbidities ≥3 (odds ratio = 1.27), and postoperative complications (odds ratio = 1.17) (all p < 0.01).nnnCONCLUSIONSnReadmission rates after colectomies have increased during the past 2 decades and mean LOS after this operation has declined. More research is needed to understand the balance and possible trade off between these hospital performance measures for all surgical procedures.

Gallbladder Cancer: The Role of Laparoscopy and Radical Resection

Objectives:We assess how laparoscopy has altered the presentation of patients with gallbladder cancer and determine whether radical resection in patients with gallbladder cancer is beneficial. Summary Background Data:The widespread adoption of laparoscopic cholecystectomy has led to an increased frequency of incidentally discovered gallbladder carcinoma. Little data exist to guide surgeons in the optimum management of patients with gallbladder cancer, particularly with respect to the potential advantages of radical resection. Methods:Records of 107 patients with gallbladder cancer admitted to a tertiary academic medical center between 1995 and 2004 were reviewed. Gallbladder cancer was found incidentally in 53 patients (50%). Fifty-two of these patients underwent a routine laparoscopic cholecystectomy and were found to have gallbladder cancer intraoperatively or following the operation by subsequent pathologic evaluation of the specimen. Gallbladder cancer had been diagnosed preoperatively by radiology in the other 54 patients (50%). These patients did not undergo laparoscopic cholecystectomy and were explored electively. Results:The median age at presentation was 67 years and 66% were female. Patients who were found to have gallbladder carcinoma incidentally at laparoscopic cholecystectomy had a significant increase in survival when compared with those who were admitted electively with a known diagnosis (P < 0.001). All patients who presented with a known diagnosis had stage II or greater disease, and 36% of these were stage IV carcinomas. However, 82% of those patients who were found incidentally were stage I or II. The overall 5-year survival for all patients was 15%; those discovered incidentally at laparoscopic cholecystectomy had a 5-year survival of 33%. This difference was significant among patients with stage II carcinomas. In the laparoscopic group, there was no difference in survival between the patients who were immediately converted to an open resection when identified to have gallbladder cancer intraoperatively (n = 6) and those who had a completed laparoscopic cholecystectomy and were re-explored at a later point when found to have gallbladder cancer by subsequent pathology (n = 33). There was a significant improvement in survival in 50 patients (47%) who underwent some form of radical resection (P < 0.001). Stage for stage comparison showed that this was significant in stage II disease. Patients who underwent hepatic resection along with lymphadenectomy and extra hepatic biliary resection had similar survival compared with those who had hepatic resection and lymphadenectomy alone. Conclusions:Laparoscopic cholecystectomy appears to have resulted in the earlier discovery of gallbladder cancer in some patients, resulting in increased probability of survival. Patients discovered with gallbladder carcinoma during a laparoscopic cholecystectomy do not have to be converted immediately to an open resection and should be referred to a tertiary care center for further exploration. Adjunctive radical surgical resection, either at the time of cholecystectomy or subsequently, increases survival significantly in early stage disease.

Surgical treatment of resectable and borderline resectable pancreas cancer: Expert consensus statement

Margins in pancreatic cancer resection procedures occur at planes where the specimen is separated from surrounding structures or where the pancreas or bowel are divided. These include duodenal/gastric, common bile duct, proximal jejunal, and pancreatic neck transection margins, as well as margins measured “radially” or “tangentially” (anterior and posterior pancreatic surfaces).42 The most important margin is the plane of abutment of the uncinate process with the SMA. Unlike other margins such as the posterior margin where a buffer of fat and areolar tissue lie between the pancreas and the margin, the uncinate process of the pancreas directly contacts the SMA as well as the neural and lymphatic plexus associated with the celiac trunk.26,44 This margin is variously referred to as the uncinate, posterior pancreatic, mesenteric, or retroperitoneal margin. It should be referred to by the more appropriately descriptive term “SMA margin.” n nMargins can be described clinically and pathologically by R status, where R represents the degree of residual disease.42 R0 means there is neither gross, nor microscopic evidence of cancer at the margin. R1 indicates grossly negative, but microscopically positive disease at the margin. Finally, R2 indicates that gross tumor remains. There is a paucity of detailed literature regarding margins and their influence on survival following pancreatic resections.45,46 Most papers indicate total numbers or percentage of positive margin cases, yet do not provide R status by margin site.47 Nor is the influence of the distance of the margin from edge of the tumor well understood. n nAccordingly, some investigators have proposed standardization of the process of margin evaluation. This begins in the preoperative period with expert evaluation of the relationship between the tumor and with critical vasculature using high-quality imaging such as dual-phase CT with three-dimensional (3D) reconstruction. A major goal of this evaluation is to eliminate R2 resections prior to surgery. Next, the margins of resected specimens need to be properly oriented by the surgeon and the specimen inked by the pathologist or by the surgeon in the presence of a pathologist. Most importantly, the SMA margin should be evaluated using perpendicular, rather than en face, sampling which should lead to greater specificity, but possibly less sensitivity. It is critical that the surgeon and pathologist reconcile the R status collaboratively in the postoperative period. These principles have been nicely delineated in the current AJCC cancer staging manual (Sixth Edition).42 nClinical Impact of Positive Margins n nOverall, positive margin rates are reported to range between 15% and 85% and, when present, these are regularly predictive of decreased survival.26,46,48 Unfortunately, in many papers R2 and R1 margin results are lumped, making determination of the individual effect on survival of each of these outcomes is difficult. The SMA margin is most frequently involved (up to 85% of all positive margins). Increased blood loss and large tumor size are predictive of positive margins.26 Outcomes of these historical series indicate that any positive margin will have a survival equivalent to patients with palliative procedures alone.46 However, the most contemporary series (in the setting of regular multimodality therapy, and no R2 resections) shows R1 resection median survival as high as 22 months. This differed significantly from 28 months for R0 resections, but R status did not predict survival on multivariate analysis.26 n n nSurgical Technique n nThe effect of surgical technique on margin positivity has not been rigorously studied. Meticulous dissection of the pancreatic parenchyma off the adventitia of the SMA is advocated, but is not always practically possible.26,44 Procedures have been proposed to minimize positive margins in body and tail tumors (RAMPS), and en bloc resection of adjacent organs to achieve positive margins is also appropriate.49,50 Numerous devices are available to help the surgeon with transection of the pancreas, but none have been rigorously evaluated and none show superiority over the conventional clamp-and-ligate technique. Many surgeons perform frozen section analysis intraoperatively routinely; however, the utility of this practice is undefined in the literature, except in the specific circumstance of intraductal papillary mucinous neoplasm (IPMN).51,52 Obtaining such analysis at the neck and bile duct transection points would seem appropriate in that further tissue may be resected to achieve a clean margin, if positive. However, this is practically not possible on the SMA margin where the artery provides the absolute boundary. n nCases with concomitant vein resection may have higher rates of positive margins, especially at the SMA margin, if the patients are not carefully selected. Venous wall invasion occurs up to two-thirds of the time when a decision is made to resect vein. However, despite these findings, on multivariate analysis survival is driven not by the positive margin, but rather by the larger tumor size encountered in these cases.25 It is quite possible that vein resection may, in fact, decrease margin positivity, by facilitating a more controlled tumor resection off of the veins. Pylorus-preserving resection has been shown to have equivalent rates of margin positivity when compared to classical Whipple’s resections, and extended lymphadenectomy procedures, likewise, are not superior in achieving clean margins.17,53 On the other hand, a surgeon’s experience appears to improve performance in this metric, with a threshold of >60 cases executed showing superior outcomes.54 n n nEffect of Multimodality Oncologic Therapy n nIt is possible that combined multimodality (chemo/radiation) therapy may have a positive biologic effect on a positive margin.26,55 The use of preoperative “neoadjuvant” chemoradiation therapy has been studied in this regard and appears to provide lower rates of positive margins, although this does not necessarily equate to improved survival.47 Similarly, focal “boosts” of adjuvant radiation to the positive resection margin may be beneficial. n n nConsensus Statement n n n n1. n nNomenclature regarding margins in pancreaticoduodenectomy should be should be standardized. Currently it is vague, confusing, and imprecise. The margin of the pancreas with the SMA should be termed “the SMA margin.” n n n n n2. n nPathologic assessment of margins is poorly standardized and inconsistently reported. n n n n n3. n nWhipple specimens should be inked, examined, and reported by techniques in conformity with CAP or AJCC guidelines. Manuscripts that assess vascular (usually venous) resection as a prognostic factor for survival must include a system for the assessment of R status. This would include a clear description by the surgeon (in the operative report) of the presence or absence of gross residual disease, and a pathology report that conforms to CAP or AJCC guidelines. n n n n n4. n nThe utility of routine intraoperative frozen-section analysis should be determined by carefully planned studies. n n n n n5. n nSafe achievement of an R0 margin is the main surgical objectives of pancreaticoduodenectomy as it is great importance for extended survival. The SMA margin is the most important driver of this outcome. n n n n n6. n nThe impact of a microscopically positive (R1) resection on ultimate clinical outcome is uncertain. Multimodality therapy may “recover” a R1 margin and improve survival to that similar to R0 resections.

Trends in Survival after Surgery for Cholangiocarcinoma: A 30-Year Population-Based SEER Database Analysis

The prognosis of patients with cholangiocarcinoma historically has been poor, even after surgical resection. Although data from some single-institution series indicate improvement over historical results, survival after surgical therapy for cholangiocarcinoma has not been investigated in a population-based study. We used the Surveillance, Epidemiology, and End Results database to identify patients who underwent surgery for cholangiocarcinoma from 1973 through 2002. Multivariate modeling of survival after surgery for intrahepatic cholangiocarcinoma showed an improvement in survival only within the last decade studied, resulting in a cumulative 34.4% improvement in survival from 1992 through 2002. In contrast, multivariate modeling of survival after surgery for extrahepatic cholangiocarcinoma revealed a 23.3% increase in adjusted survival per each decade studied, resulting in a cumulative 53.7% improvement from 1973 through 2002. We conclude that survival after surgery for extrahepatic cholangiocarcinoma has dramatically improved since 1973. Patients with intrahepatic cholangiocarcinoma, however, have achieved an improvement in survival largely confined to more recent years. We suggest that these trends are largely caused by developments in imaging technology, improvements in patient selection, and advances in surgical techniques.

New markers of pancreatic cancer identified through differential gene expression analyses: claudin 18 and annexin A8.

Background New markers to distinguish benign reactive glands from infiltrating ductal adenocarcinoma of the pancreas are needed. Design The gene expression patterns of 24 surgically resected primary infiltrating ductal adenocarcinomas of the pancreas were compared with 18 non-neoplastic samples using the Affymetrix U133 Plus 2.0 Arrays and the Gene Logic GeneExpress Software System. Gene fragments from 4 genes (annexin A8, claudin 18, CXCL5, and S100 A2) were selected from the fragments found to be highly expressed in infiltrating adenocarcinomas when compared with normal tissues. The protein expression of these genes was examined using immunohistochemical labeling of tissue microarrays. Results Claudin 18 labeled infiltrating carcinomas in a membranous pattern. When compared with normal and reactive ducts, claudin 18 was overexpressed, at least focally, in 159 of 166 evaluable carcinomas (96%). Strong and diffuse claudin 18 overexpression was most often seen in well-differentiated carcinomas (P=0.02). Claudin 18 was overexpressed in 51 of 52 cases (98%) of pancreatic intraepithelial neoplasia. Annexin A8 was at least focally overexpressed in 149 of 154 evaluable infiltrating carcinomas (97%). S100 A2 was at least focally overexpressed in 118 of 154 evaluable infiltrating carcinomas (77%). Non-neoplastic glands also frequently expressed S100 A2 diminishing its potential diagnostic utility. Immunolabeling with antibodies directed against CXCL5 did not reveal any significant differences in protein expression between infiltrating adenocarcinomas and normal pancreatic ducts. Conclusions Claudin 18 and annexin A8 are frequently highly overexpressed in infiltrating ductal adenocarcinomas when compared with normal reactive ducts, suggesting a role for these molecules in pancreatic ductal adenocarcinomas. Furthermore, these may serve as diagnostic markers, as screening tests and as therapeutic targets.

Liver resection for colorectal metastases in presence of extrahepatic disease: results from an international multi-institutional analysis

BackgroundHepatic resection for colorectal liver metastasis (CLM) with concomitant extrahepatic disease (EHD) is a controversial topic. We sought to evaluate the long-term outcome of patients undergoing liver resection for CLM in presence of EHD and identify factors associated with prognosis.MethodsFrom 1996 to 2007, a total of 1629 patients who underwent resection of CLM were identified from an international multi-institutional database. One hundred seventy-one patients (10.4%) underwent resection of EHD. Clinicopathologic and outcome data were collected and analyzed by univariate and multivariate analyses.ResultsMedian number of treated CLM was 2 (range, 1–18); most patients had solitary EHD (nxa0=xa0114; 66.6%) a single anatomic site of EHD (nxa0=xa0153; 89.4%). The 5-year survival for patients with EHD was 26% compared with 58% for those without EHD (Pxa0<xa00.001). Recurrence was common (84%). Among patients with EHD, R1 margin status, multiple EHD sites, and location of EHD were associated with worse survival (all Pxa0<xa00.05). Patients with multiple EHD sites or aortocaval lymph node metastasis had a 5-year survival of 14% and 7%, respectively. When survival was stratified by the total number of metastases treated, the presence of EHD still had a prognostic impact, but the relative impact of EHD diminished as the total number of metastases treated increased.ConclusionConcurrent resection of hepatic and EHD in well-selected patients may provide the possibility of long-term survival. The risk of recurrence, however, remains high, and a worse outcome is associated with both number of metastases and location of EHD.

Predicting resectability of periampullary cancer with three-dimensional computed tomography.

The radiographic assessment of extent of tumor burden and local vascular invasion appears to be enhanced with three-dimensional computed tomography (3D-CT). The purpose of this study was to evaluate the impact of preoperative 3D-CT in determining the resectability of patients with periampullary tumors. Intraoperative findings from exploratory laparotomy were gathered prospectively from 140 patients who were thought to have periampullary tumors and were deemed resectable after undergoing preoperative 3D-CT imaging. CT findings were compared to intraoperative findings, and the accuracy of 3D-CT in predicting tumor resectability and, ultimately, the likelihood of obtaining a margin-negative resection were assessed. Of the 140 patients who were thought to have resectable periampullary tumors after preoperative 3D-CT, 115 (82%) were subsequently determined to have periampullary cancer. The remaining 25 patients had benign disease. Among the patients with periampullary cancer, the extent of local tumor burden involving the pancreas and peripancreatic tissues was accurately depicted by 3D-CT in 93 % of the patients. 3D-CT was 95% accurate in determining cancer invasion of the superior mesenteric vessels. Preoperative 3D-CT accurately predicted periampullary cancer resectability and a margin-negative resection in 98% and 86% of patients, respectively. For patients with pancreatic adenocarcinoma (n=85), preoperative 3D-CT resulted in a resectability rate and a margin-negative resection rate of 79% and 73%, respectively. The ability of 3 D-CT to predict a margin-negative resection for periampullary cancer, including pancreatic adenocarcinoma, relies on its enhanced assessment of the extent of local tumor burden and involvement of the mesenteric vascular anatomy.

Cyclophosphamide resets dendritic cell homeostasis and enhances antitumor immunity through effects that extend beyond regulatory T cell elimination

Using a model of established malignancy, we found that cyclophosphamide (Cy), administered at a dose not requiring hematopoietic stem cell support, is superior to low-dose total body irradiation in augmenting antitumor immunity. We observed that Cy administration resulted in expansion of tumor antigen-specific T cells and transient depletion of CD4+Foxp3+ regulatory T cells (Tregs). The antitumor efficacy of Cy was not improved by administration of anti-CD25 monoclonal antibody given to induce more profound Treg depletion. We found that Cy, through its myelosuppressive action, induced rebound myelopoiesis and perturbed dendritic cell (DC) homeostasis. The resulting DC turnover led to the emergence of tumor-infiltrating DCs that secreted more IL-12 and less IL-10 compared to those from untreated tumor-bearing animals. These newly recruited DCs, originating from proliferating early DC progenitors, were fully capable of priming T cell responses and ineffective in inducing expansion of Tregs. Together, our results show that Cy-mediated antitumor effects extend beyond the well-documented cytotoxicity and lymphodepletion and include resetting the DC homeostasis, thus providing an excellent platform for integration with other immunotherapeutic strategies.