Pancreas-protocol imaging at a high-volume center leads to improved preoperative staging of pancreatic ductal adenocarcinoma.

BACKGROUND: High-quality preoperative cross-sectional imaging is vital to accurately stage patients with pancreatic ductal adenocarcinoma (PDAC). We hypothesized that imaging performed at a high-volume pancreatic cancer center with pancreatic imaging protocols more accurately stages patients compared with pre-referral imaging. METHODS: We retrospectively reviewed data from all patients with PDAC who presented to the surgical oncology clinic at our institution between June 2005 and August 2009. Detailed preoperative imaging, staging, and operative data were collected for each patient. RESULTS: A total of 230 patients with PDAC were identified, of which 169 had pre-referral imaging. Patients were selectively reimaged at our institution based on the quality and timing of imaging at the outside facility: 108 (47%) patients were deemed resectable, 54 (23.5%) were deemed borderline-resectable, and 68 (29.5%) were deemed unresectable. Of the resectable patients, 99 opted for resection. Eighty-two of those 99 patients underwent preoperative imaging at our institution, and of these 27% had unresectable disease at the time of surgery compared with 47% of patients who only had pre-referral imaging (p = 0.14). Reimaging altered staging and changed management in 56% of patients. Among that group were 55 patients, categorized as resectable on pre-referral imaging, who on repeat imaging were deemed to be borderline resectable (n = 27) or unresectable (n = 28). CONCLUSIONS: Pancreas-protocol imaging at a high-volume center improves preoperative staging and alters management in a significant proportion of patients with PDAC who undergo pre-referral imaging. Thus, repeat imaging with pancreas protocols and dedicated radiologists is justified at high-volume centers.

Preoperative capecitabine and concurrent radiation for borderline resectable pancreatic cancer.

BACKGROUND: Patients with borderline resectable pancreatic ductal adenocarcinoma (PDA) represent a high-risk group of patients due to tumor or patient-related characteristics. The optimal management of these patients has not been fully defined. MATERIALS AND METHODS: All patients undergoing evaluation for PDA between 2005 and 2008 were identified. Clinical, radiographic, and pathological data were retrospectively reviewed. Patients were staged as borderline resectable using the M.D. Anderson Cancer Center (MDACC) classification. RESULTS: A total of 170 patients with PDA were identified, 40 with borderline resectable disease. Of these, 34 borderline resectable patients (85%) completed neoadjuvant therapy and were restaged; pancreatic resection was completed in 16 patients (46%). Also, 8 patients completed 50 Gy of radiation in 28 fractions in 6 weeks, whereas 8 patients received 50 Gy in 20 fractions in 4 weeks plus chronomodulated capecitabine. An R0 resection was achieved in 12 of the 16 patients (75%). Also, 5 patients (63%) treated in 20 fractions had >90% pathologic response versus 1 (13%) treated in 28 fractions (P < .05). Borderline resectable patients completing surgery had similar survival to patients with resectable disease who underwent surgery. Patients receiving accelerated fractionation radiation had improved survival compared with patients treated with standard fractionation protocol. CONCLUSIONS: A neoadjuvant approach to borderline resectable PDA identifies patients who are most likely to benefit from pancreatic resection. Preoperative capecitabine-based chemoradiation is an effective, well-tolerated treatment for these patients. Neoadjuvant therapy for borderline resectable PDA warrants further investigation using treatment schedules that can safely intensify irradiation dose.

Surgery versus intra-arterial therapy for neuroendocrine liver metastasis: a multicenter international analysis.

BACKGROUND: Management of patients with neuroendocrine liver metastasis (NELM) remains controversial. We sought to examine the relative efficacy of surgical management versus intra-arterial therapy (IAT) for NELM and determine factors predictive of survival. METHODS: A total of 753 patients who had surgery (n = 339) or IAT (n = 414) for NELM from 1985 to 2010 were identified from nine hepatobiliary centers. Clinicopathologic data were assessed with regression modeling and propensity score matching. RESULTS: Most patients had a pancreatic (32%) or a small bowel (27%) primary tumor; 47% had a hormonally active tumor. There were statistically significant differences in characteristics between surgery versus IAT groups (hormonally active tumors: 28 vs. 48%; hepatic tumor burden >25%: 52% vs. 76%) (all P < 0.001). Among surgical patients, most underwent hepatic resection alone without ablation (78%). The median number of IAT treatments was 1 (range, 1-4). Median and 5-year survival of patients treated with surgery was 123 months and 74% vs. 34 months and 30% for IAT (P < 0.001). In the propensity-adjusted multivariate Cox model, asymptomatic disease (hazard ratio 2.6) was strongly associated with worse outcome (P = 0.001). Although surgical management provided a survival benefit over IAT among symptomatic patients with >25% hepatic tumor involvement, there was no difference in long-term outcome after surgery versus IAT among asymptomatic patients (P = 0.78). CONCLUSIONS: Asymptomatic patients with a large (>25%) burden of liver disease benefited least from surgical management and IAT may be a more appropriate treatment strategy. Surgical management of NELM should be reserved for patients with low-volume disease or for those patients with symptomatic high-volume disease.

Surgical management of hepatic neuroendocrine tumor metastasis: results from an international multi-institutional analysis.

BACKGROUND: Management of neuroendocrine tumor liver metastasis (NELM) remains controversial, with some advocating an aggressive surgical approach while others have adopted a more conservative strategy. We sought to define the efficacy of the surgical management of NELM in a large multicenter international cohort of patients. METHODS: We identified 339 patients who underwent surgical management for NELM from 1985 to 2009 from an international database of eight major hepatobiliary centers. Relevant clinicopathologic data were assessed using Kaplan-Meier and Cox regression models. RESULTS: Most patients had a pancreatic (40%) or small bowel (25%) neuroendocrine tumor (NET) primary. The majority of patients (60%) had bilateral liver disease. At surgery, 78% of patients underwent hepatic resection, 3% ablation alone, and 19% resection + ablation. Major hepatectomy was performed in 45% of patients, and 14% underwent a second liver operation. Carcinoid was the most common NET histological subtype (53%). Median survival was 125 months, with overall 5- and 10-year survival of 74%, and 51%, respectively. Disease recurred in 94% of patients at 5 years. Patients with hormonally functional NET who had R0/R1 resection benefited the most from surgery (P = 0.01). On multivariate analyses, synchronous disease [hazard ratio (HR) = 1.9], nonfunctional NET hormonal status (HR = 2.0), and extrahepatic disease (HR = 3.0) remained predictive of worse survival (all P < 0.05). CONCLUSIONS: Liver-directed surgery for NELM is associated with prolonged survival; however, the majority of patients will develop recurrent disease. Patients with hormonally functional hepatic metastasis without prior extrahepatic or synchronous disease derive the greatest survival benefit from surgical management.

Adrenalectomy for adrenal-mediated hypertension: National Surgical Quality Improvement Program analysis of an institutional experience.

Adrenal-mediated hypertension (AMH) has been increasingly treated by laparoscopic adrenalectomy (LA). Metabolic derangements in patients with AMH could result in perioperative complications and mortality. Long-term operative and clinical outcomes after laparoscopic treatment of AMH have not been evaluated using large clinical databases. The institutional National Surgical Quality Improvement Program (NSQIP) data for patients undergoing adrenalectomy for AMH between 2002 and 2012 were reviewed. Patient demographics, perioperative variables, and outcomes were analyzed and compared with national NSQIP adrenalectomy data. Improvement in AMH was recorded when discontinuation or reduction of antihypertensive medication occurred or with a decrease of blood pressure on the preoperative antihypertensive regimen. Ninety-four patients underwent adrenalectomy. There were 48 patients with pheochromocytoma (PHE) and 46 patients with aldosterone-producing adenoma (APA). Eighty-five patients (90%) were taking antihypertensive medications preoperatively compared with 36 patients (38%) postoperatively (P < 0.0001). Patients with PHE were more likely to discontinue all medications compared with the patients with APA (80 vs 20%, respectively, P < 0.0001). Patients with PHE and APA, respectively, took an average of 2.0 and 3.2 antihypertensive medications preoperatively compared with 0.3 and 1.2 postoperatively. There were no conversions to open procedures or 30-day mortality. Our results were 0 per cent for cerebral vascular accident, 0 per cent for myocardial infarction, and 0.5 per cent for transfusions compared with the national NSQIP data of 0.2, 0, and 6.7 per cent, respectively. Patients presenting with significant AMH including PHE and APA can be effectively and safely treated with LA with minimal complications and with a significant number of patients eliminating or decreasing their need for antihypertensive medications.

Donor risk index predicts graft failure reliably but not post-transplant infections.

BACKGROUND: The Donor Risk Index (DRI) is used to predict graft survival following liver transplantation, but has not been used to predict post-operative infections in graft recipients. We hypothesized that lower-quality grafts would result in more frequent infectious complications. METHODS: Using a prospectively collected infection data set, we matched liver transplant recipients (and the respective allograft DRI scores) with their specific post-transplant infectious complications. All transplant recipients were organized by DRI score and divided into groups with low-DRI and high-DRI scores. RESULTS: We identified 378 liver transplants, with 189 recipients each in the low-DRI and high-DRI groups. The mean DRI scores for the low- and high-DRI-score groups were 1.14±0.01 and 1.74±0.02, respectively (p<0.0001 for the difference). The mean Model for End-Stage Liver Disease (MELD) scores were 26.25±0.53 and 24.76±0.55, respectively (p=0.052), and the mean number of infectious complications per patient were 1.60±0.19 and 1.94±0.24, respectively (p=0.26). Logistic regression showed only length of hospital stay and a history of vascular disease as being associated independently with infection, with a trend toward significance for MELD score (p=0.13). CONCLUSION: We conclude that although DRI score predicts graft-liver survival, infectious complications depend more heavily on recipient factors.

Minimally invasive surgery fellowship does not adversely affect general surgery resident case volume: a decade of experience.

BACKGROUND: With the advent of clinical fellowships in general surgery, there has been a continual debate over the effect on general surgical resident training. Will a fellowship interfere with a chief resident's experience or case volume? The aim of this study was to test the hypothesis that the presence of an advanced laparoscopic fellow in a tertiary care hospital and residency has had no deleterious effect on chief resident laparoscopic case volume. METHODS: The operative case logs of graduating residents and fellows from 2001 to 2011 were reviewed, focusing on laparoscopic basic and complex cases and comparing between those 2 groups and comparing residents' case numbers with the national average published by the Accreditation Council for Graduate Medical Education. RESULTS: Residents graduating from 2001 to 2011 (4-6 chief residents per year) performed an average of 989 ± 76.2 laparoscopic cases per graduating chief class, with each chief averaging 207.7 ± 10.7. The average number of laparoscopic basic cases per graduating chief year was 555.3 ± 42.1, with each chief averaging 116.2 ± 4.9. The average number of laparoscopic complex cases per graduating chief year was 434.4 ± 39.2, with each chief averaging 91.5 ± 7.2. Over the same period of time (1 or 2 fellows per year), fellows performed an average of 336 ± 23.3 cases per year. When comparing residents' total average cases with the national data, the residents performed a similar number of cases (209.9 ± 11.9 vs 195.0 ± 19.5, P = .53). When comparing years when there were 2 clinical fellows vs years with 1 fellow, there was no change in the total number of laparoscopic cases per chief (224.2 vs 195.6, P = .26) and no change in the number of complex laparoscopic cases (97.1 vs 88.7, P = .63). There was a significant difference for basic laparoscopic cases, with a slight decrease when there were 2 fellows (127.8 vs 106.9, P = .04). CONCLUSIONS: A laparoscopic fellowship has not had an adverse impact on the complex or basic laparoscopic case experience of surgical residents. In a busy academic practice, laparoscopic fellowships and general surgical residency can coexist.

Inhibition of the growth of patient-derived pancreatic cancer xenografts with the MEK inhibitor trametinib is augmented by combined treatment with the epidermal growth factor receptor/HER2 inhibitor lapatinib.

Mutations of the oncogene KRAS are important drivers of pancreatic cancer progression. Activation of epidermal growth factor receptor (EGFR) and human EGFR2 (HER2) is observed frequent in pancreatic adenocarcinomas. Because of co-activation of these two signaling pathways, we assessed the efficacy of inhibition of EGFR/HER2 receptors and the downstream KRAS effector, mitogen-activated protein kinase/extracellular-signal regulated kinase (ERK) kinase 1 and 2 (MEK1/2), on pancreatic cancer proliferation in vitro and in a murine orthotopic xenograft model. Treatment of established and patient-derived pancreatic cancer cell lines with the MEK1/2 inhibitor trametinib (GSK1120212) inhibited proliferation, and addition of the EGFR/HER2 inhibitor lapatinib enhanced the inhibition elicited by trametinib in three of eight cell lines. Importantly, in the orthotopic xenograft model, treatment with lapatinib and trametinib resulted in significantly enhanced inhibition of tumor growth relative to trametinib treatment alone in four of five patient-derived tumors tested and was, in all cases, significantly more effective in reducing the size of established tumors than treatment with lapatinib or trametinib alone. Acute treatment of established tumors with trametinib resulted in an increase in AKT2 phosphorylation that was blunted in mice treated with both trametinib and lapatinib. These data indicate that inhibition of the EGFR family receptor signaling may contribute to the effectiveness of MEK1/2 inhibition of tumor growth possibly through the inhibition of feedback activation of receptor tyrosine kinases in response to inhibition of the RAS-RAF-MEK-ERK pathway. These studies provide a rationale for assessing the co-inhibition of these pathways in the treatment of pancreatic cancer patients.

Clinical, molecular and genetic validation of a murine orthotopic xenograft model of pancreatic adenocarcinoma using fresh human specimens.

BACKGROUND: Relevant preclinical models that recapitulate the key features of human pancreatic ductal adenocarcinoma (PDAC) are needed in order to provide biologically tractable models to probe disease progression and therapeutic responses and ultimately improve patient outcomes for this disease. Here, we describe the establishment and clinical, pathological, molecular and genetic validation of a murine, orthotopic xenograft model of PDAC. METHODS: Human PDACs were resected and orthotopically implanted and propagated in immunocompromised mice. Patient survival was correlated with xenograft growth and metastatic rate in mice. Human and mouse tumor pathology were compared. Tumors were analyzed for genetic mutations, gene expression, receptor tyrosine kinase activation, and cytokine expression. RESULTS: Fifteen human PDACs were propagated orthotopically in mice. Xenograft-bearing mice developed peritoneal and liver metastases. Time to tumor growth and metastatic efficiency in mice each correlated with patient survival. Tumor architecture, nuclear grade and stromal content were similar in patient and xenografted tumors. Propagated tumors closely exhibited the genetic and molecular features known to characterize pancreatic cancer (e.g. high rate of KRAS, P53, SMAD4 mutation and EGFR activation). The correlation coefficient of gene expression between patient tumors and xenografts propagated through multiple generations was 93 to 99%. Analysis of gene expression demonstrated distinct differences between xenografts from fresh patient tumors versus commercially available PDAC cell lines. CONCLUSIONS: The orthotopic xenograft model derived from fresh human PDACs closely recapitulates the clinical, pathologic, genetic and molecular aspects of human disease. This model has resulted in the identification of rational therapeutic strategies to be tested in clinical trials and will permit additional therapeutic approaches and identification of biomarkers of response to therapy.

Use of a falciform ligament pedicle flap to decrease pancreatic fistula after distal pancreatectomy.

OBJECTIVES: Postoperative pancreatic fistula (POPF) remains a significant source of morbidity after distal pancreatectomy (DP). We describe a technique for coverage of the pancreatic stump after DP using a pedicled falciform ligament flap with a low POPF rate. METHODS: A retrospective review of clinical, radiographic, and pathologic variables of patients undergoing open DP between November 2005 and August 2009 was performed. After standardized DP, the pancreatic stump was closed using a pedicled falciform ligament flap. Postoperative pancreatic fistula was defined using the International Study Group classification for pancreatic fistula definition. RESULTS: Twenty-three consecutive patients underwent open DP and splenectomy with closure of the pancreatic stump using a pedicled falciform ligament flap. Pancreatic transection and stump closure was performed in a uniform fashion in all patients. Eight patients (35%) had additional organs resected. Two patients (8.7%) developed grade C POPFs, which were successfully managed with percutaneous drain placement. No additional patients developed a POPF or abdominal abscess. The median length of stay was 5 days. There were no perioperative mortalities. CONCLUSIONS: We conclude that use of a pedicled falciform ligament flap for coverage of the pancreatic stump is associated with a low incidence of POPF. Continued investigation of this technique is warranted.

Inhibition of focal adhesion kinase by PF-562,271 inhibits the growth and metastasis of pancreatic cancer concomitant with altering the tumor microenvironment.

Current therapies for pancreatic ductal adenocarcinoma (PDA) target individual tumor cells. Focal adhesion kinase (FAK) is activated in PDA, and levels are inversely associated with survival. We investigated the effects of PF-562,271 (a small-molecule inhibitor of FAK/PYK2) on (i) in vitro migration, invasion, and proliferation; (ii) tumor proliferation, invasion, and metastasis in a murine model; and (iii) stromal cell composition in the PDA microenvironment. Migration assays were conducted to assess tumor and stromal cell migration in response to cellular factors, collagen, and the effects of PF-562,271. An orthotopic murine model was used to assess the effects of PF-562,271 on tumor growth, invasion, and metastasis. Proliferation assays measured PF-562,271 effects on in vitro growth. Immunohistochemistry was used to examine the effects of FAK inhibition on the cellular composition of the tumor microenvironment. FAK and PYK2 were activated and expressed in patient-derived PDA tumors, stromal components, and human PDA cell lines. PF-562,271 blocked phosphorylation of FAK (phospho-FAK or Y397) in a dose-dependent manner. PF-562,271 inhibited migration of tumor cells, cancer-associated fibroblasts, and macrophages. Treatment of mice with PF-562,271 resulted in reduced tumor growth, invasion, and metastases. PF-562,271 had no effect on tumor necrosis, angiogenesis, or apoptosis, but it did decrease tumor cell proliferation and resulted in fewer tumor-associated macrophages and fibroblasts than control or gemcitabine. These data support a role for FAK in PDA and suggest that inhibitors of FAK may contribute to efficacious treatment of patients with PDA.

Patients with Merkel cell carcinoma tumors < or = 1.0 cm in diameter are unlikely to harbor regional lymph node metastasis.

PURPOSE: Merkel cell carcinoma (MCC) is a rare, aggressive neuroendocrine cutaneous malignancy. Current recommendations include offering regional lymph node evaluation by either sentinel lymph node biopsy (SLNB) or complete lymph node dissection (CLND) to all patients with MCC; however, we hypothesized a cohort of low-risk patients may exist for whom regional nodal metastasis would be unlikely. METHODS: A retrospective review of the Department of Veterans Affairs national health care database was performed. Patients undergoing resection of primary MCC were identified; and demographic, medical, and social history; tumor characteristics; nodal status; and recurrence events were recorded. RESULTS: Between 1995 and 2006, 346 patients were diagnosed with MCC. Of these, 213 underwent resection of the primary lesion and evaluation of the draining lymph node basin. Fifty-four patients (25%) had tumors < or = 1.0 cm in diameter. Average tumor diameter was 0.7 cm, and 63% were located on the head or neck. Only two patients (4%) with tumors < or = 1.0 cm had regional lymph node metastasis, compared with 51 (24%) of 213 patients with tumors more than 1.0 cm (P < .0001). Both patients had clinically evident nodal disease at presentation and underwent CLND. Both have remained recurrence-free for 40 months. Thirteen (25%) of 51 patients with nodal metastasis and tumors more than 1 cm had occult nodal metastasis. CONCLUSION: In this series, patients with MCC < or = 1.0 cm were unlikely to have regional lymph node metastasis, suggesting that regional nodal evaluation may reasonably be avoided in these patients. However, these data support SLNB for MCC more than 1 cm in diameter.

Proactive versus reactive: the effect of experience on performance in a critical care simulator.

BACKGROUND: We sought to study the cognitive performance of residents in a critical care patient simulator. METHODS: Residents in general surgery and emergency medicine were recruited to participate in the study. Subjects were read a morning report and presented with written data for 4 critical care patients. The subjects were evaluated on completing essential clinical tasks, cognitive errors, and directionality of reasoning. RESULTS: Nine residents completed the study. Months of clinical residency training did not significantly affect performance. Residents with more than 10 weeks of intensive care unit (ICU) experience (EXP) made significantly fewer cognitive errors than those with less than 10 weeks of ICU experience (N-I) (EXP: .75 +/- .96 vs N-I: 7 +/- 5.6 errors per subject, P < .05). An unexpected finding was that EXP performed far more proactive actions than N-I (EXP: 21.8 +/- 9.9/subject vs N-I: 5.7 +/- .6/subjects, P < .01). CONCLUSIONS: A unique finding was that residents with more than 10 weeks of ICU experience initiated a large number of proactive actions immediately following presentation of patient information, while N-I rarely performed these actions. In addition, residents with this degree of experience committed significantly fewer cognitive errors. These differences might play a role in efficiency, cost, and overall outcome in the care of ICU patients.