Faculty Bibliography

BACKGROUND:The incidence of venous thromboembolism (VTE) among patients undergoing hepatic surgery is poorly defined, leading to varied use of VTE prophylaxis among surgeons. We sought to define the incidence of VTE after liver surgery and identify risk factors associated with VTE. METHODS:Incidence of VTE and associated risk factors within 90 days of hepatic resection between 2006 and 2012 at a major academic center was analyzed. Risk factors for VTE were identified using univariate and multivariate analyses. RESULTS:A total of 599 patients were included in the study cohort; 30 (5.0 %) had a prior history of VTE. The indications for surgery were malignant (90.8 %) and benign lesions (9.2 %). The majority of patients underwent a minor hepatectomy (<3 Couinaud segments; n = 402, 67.1 %) while 195 (32.6 %) patients underwent a major hepatectomy (≥3 Couinaud segments). Three hundred seven (51.3 %) patients were started on VTE chemoprophylaxis preoperatively with 407 (67.8 %) patients receiving VTE chemoprophylaxis within 24 h of surgery. Twenty-eight (4.7 %) patients developed VTE; 20 (3.3 %) had deep venous thrombosis (DVT), 11 (1.8 %) had pulmonary embolism (PE), and three (0.5 %) developed both DVT and PE. Among the VTE patients, 23 (82.1 %) had received VTE chemoprophylaxis. On multivariate analyses, history of VTE (odds ratio [OR] 4.51, 95 % confidence interval [CI] 1.81-17.22, P = 0.03), prolonged operative time (OR 1.17 per additional hour, 95 % CI 1.04-1.32, P = 0.009), and increased length of stay (LOS) (OR 1.07, 95 % CI 1.02-1.12, P = 0.01) were independent risk factors for VTE. CONCLUSION/CONCLUSIONS:VTE within 90 days of hepatic resection is common, occurring in nearly one in 20 patients. Most VTE events occurred among patients who received current best practice prophylaxis for VTE. More aggressive strategies to identify and reduce the risk of VTE in patients at highest risk of VTE, including those with a history of VTE, extended operative time, and prolonged LOS, are warranted.

BACKGROUND:Left ventricular assist devices (LVADs) have become common as a bridge to heart transplant as well as destination therapy. Acute care surgical (ACS) problems in this population are prevalent but remain ill-defined. Therefore, we reviewed our experience with ACS interventions in LVAD patients. METHODS:A total of 173 patients who received HeartMate(®) XVE or HeartMate(®) II (HMII) LVADs between December 2001 and March 2010 were studied. Patient demographics, presentation of ACS problem, operative intervention, co-morbidities, transplantation, complications, and survival were analyzed. RESULTS:A total of 47 (27 %) patients underwent 67 ACS procedures at a median of 38 days after device implant (interquartile range 15-110), with a peri-operative mortality rate of 5 % (N = 3). Demographics, device type, and acuity were comparable between the ACS and non-ACS groups. A total of 21 ACS procedures were performed emergently, eight were urgent, and 38 were elective. Of 29 urgent and emergent procedures, 28 were for abdominal pathology. In eight patients, the cause of the ACS problem was related to LVADs or anticoagulation. Cumulative survival estimates revealed no survival differences if patients underwent ACS procedures (p = 0.17). Among HMII patients, transplantation rates were unaffected by an ACS intervention (p = 0.2). CONCLUSIONS:ACS problems occur frequently in LVAD patients and are not associated with adverse outcomes in HMII patients. The acute care surgeon is an integral member of a comprehensive approach to effective LVAD management.

An association between diabetes mellitus and pancreatic ductal adenocarcinoma (PDA) has long been recognized. This article assesses the effect of the baseline hemoglobin-A1c (HbA1c) value on the clinical outcomes of patients with PDA. HbA1c values were prospectively collected on 656 consecutive patients presenting to a pancreas multidisciplinary cancer clinic from 2009 to 2012. Patients were diagnosed with benign pancreatic disease (BPD) or biopsy-confirmed resectable (R), borderline/locally advanced (BL), or metastatic (M) PDA. Excluded were those with prior treatment for PDA or a history of chronic diabetes mellitus (>1-year or unknown duration), resulting in a final cohort of 284 patients. Of 284 patients, 44 had benign disease, 62 had R-PDA, 115 had BL-PDA, and 63 had M-PDA. Patients with malignant disease (R-, BL-, and M-PDA) collectively had a higher average HbA1c value than patients with BPD (6.1% vs 5.6%; P<.001). Among patients with PDA (n=240), HbA1c values of 6.5% or greater were significantly associated with inferior overall survival (OS) compared with patients with HbA1c values less than 6.5% (hazard ratio [HR], 1.74; OS, 10.2 vs 13.0 months; P=.007), along with other known prognostic factors, such as age of 65 years or older, ECOG performance status of 1 or greater, carbohydrate antigen 19-9 level greater than 90, tumor size larger than 3 cm, and disease stage. HbA1c values of 6.5% or greater remained in the final predictive model using backward elimination (HR, 1.46; P=.097), indicating that HbA1c values of 6.5% or greater influence OS of patients with PDA even when accounting for other known prognostic factors. HbA1c level at presentation is significantly higher in patients with PDA than patients with BPD and seems to affect survival.

PURPOSE/OBJECTIVE:To determine how often loss of ataxia-telangiectasia-mutated (ATM) protein expression occurs in primary pancreatic ductal adenocarcinomas and to determine its prognostic significance. EXPERIMENTAL DESIGN/METHODS:The expression of ATM and TP53 was determined by immunohistochemistry in 397 surgically resected pancreatic ductal adenocarcinomas (Hopkins; Johns Hopkins Medical Institutions, Baltimore, MD), a second set of 159 cases (Emory; Emory University Hospital, Atlanta, GA), and 21 cancers after neoadjuvant chemoradiotherapy. Expression was correlated with the clinicopathologic parameters, including survival. RESULTS:Tumoral ATM loss was observed in one cancer known to have biallelic inactivation of ATM and 50 of the first 396 (12.8%) cases, significantly more often in patients with a family history of pancreatic cancer (12/49; 24.5%) than in those without (38/347; 11.0%; P = 0.019). In the Hopkins series, ATM loss was associated with a significantly decreased overall survival in patients whose cancers had normal TP53 expression (P = 0.019) and was a significant independent predictor of decreased overall survival (P = 0.014). Seventeen (10.7%) of 159 Emory cases had tumoral ATM loss and tumoral ATM loss/normal TP53 was associated with poorer overall survival (P = 0.1). Multivariate analysis of the combined Hopkins/Emory cases found that tumoral ATM loss/normal TP53 was an independent predictor of decreased overall survival [HR = 2.61; confidence interval (CI), 1.27-5.37; P = 0.009]. Of 21 cancers examined after neoadjuvant chemoradiotherapy, one had tumoral loss of ATM; it had no histologic evidence of tumor response. CONCLUSIONS:Tumoral loss of ATM protein was detected more often in patients with a family history of pancreatic cancer than in those without. Patients whose pancreatic cancers had loss of ATM but normal TP53 had worse overall survival after pancreatic resection.

BACKGROUND:In the pancreas, poorly differentiated neuroendocrine carcinomas include small cell carcinoma and large cell neuroendocrine carcinoma and are rare; data regarding their pathologic and clinical features are very limited. DESIGN/METHODS:A total of 107 pancreatic resections originally diagnosed as poorly differentiated neuroendocrine carcinomas were reassessed using the classification and grading (mitotic rate/Ki67 index) criteria put forth by the World Health Organization in 2010 for the gastroenteropancreatic system. Immunohistochemical labeling for neuroendocrine and acinar differentiation markers was performed. Sixty-three cases were reclassified, mostly as well-differentiated neuroendocrine tumor (NET) or acinar cell carcinoma, and eliminated. The clinicopathologic features and survival of the remaining 44 poorly differentiated neuroendocrine carcinomas were further assessed. RESULTS:The mean patient age was 59 years (range, 21 to 82 y), and the male/female ratio was 1.4. Twenty-seven tumors were located in the head of the pancreas, 3 in the body, and 11 in the tail. The median tumor size was 4 cm (range, 2 to 18 cm). Twenty-seven tumors were large cell neuroendocrine carcinomas, and 17 were small cell carcinomas (mean mitotic rate, 37/10 and 51/10 HPF; mean Ki67 index, 66% and 75%, respectively). Eight tumors had combined components, mostly adenocarcinomas. In addition, 2 tumors had components of well-differentiated NET. Eighty-eight percent of the patients had nodal or distant metastatic disease at presentation, and an additional 7% developed metastases subsequently. Follow-up information was available for 43 patients; 33 died of disease, with a median survival of 11 months (range, 0 to 104 mo); 8 were alive with disease, with a median follow-up of 19.5 months (range, 0 to 71 mo). The 2- and 5-year survival rates were 22.5% and 16.1%, respectively. CONCLUSIONS:Poorly differentiated neuroendocrine carcinoma of the pancreas is a highly aggressive neoplasm, with frequent metastases and poor survival. Most patients die within less than a year. Most (61%) are large cell neuroendocrine carcinomas. Well-differentiated NET and acinar cell carcinoma are often misdiagnosed as poorly differentiated neuroendocrine carcinoma, emphasizing that diagnostic criteria need to be clearly followed to ensure accurate diagnosis.

CpG island methylator phenotype (CIMP) has been found in multiple precancerous and cancerous lesions, including colorectal adenomas, colorectal cancers, and duodenal adenocarcinomas. There are no reports in the literature of a relationship between CIMP status and clinicopathologic features of sporadic duodenal adenomas. This study sought to elucidate the role of methylation in duodenal adenomas and correlate it with KRAS and BRAF mutations. CIMP+ (with more than 2 markers methylated) was seen in 33.3% of duodenal adenomas; 61% of these CIMP+ adenomas were CIMP-high (with more than 3 markers methylated). Furthermore, CIMP+ status significantly correlated with older age of patients, larger size and villous type of tumor, coexistent dysplasia and periampullary location. MLH1 methylation was seen in 11.1% of duodenal adenomas and was significantly associated with CIMP+ tumors, while p16 methylation was an infrequent event. KRAS mutations were frequent and seen in 26.3% of adenomas; however, no BRAF mutations were detected. Furthermore, CIMP-high status was associated with larger size and villous type of tumor and race (non-white). These results suggest that CIMP+ duodenal adenomas may have a higher risk for developing malignancy and may require more aggressive management and surveillance.

Incipient intraductal papillary mucinous neoplasms (IPMNs) are poorly described subcentimeter pancreatic cysts with papillae and mucin similar to IPMNs. They are larger than pancreatic intraepithelial neoplasia but do not meet the cutoff size for IPMNs (≥ 1 cm). GNAS codon 201 mutations are hallmark genetic alterations of IPMNs. Hence, we sought to determine the GNAS status of incipient IPMNs to better classify these lesions. Incipient IPMNs from 3 institutions were histologically reassessed, manually microdissected, and the genomic DNA was extracted. Using a sensitive digital ligation technique, the mutational status of KRAS at codon 12 and GNAS at codon 201 was determined. We included 21 incipient IPMNs from 7 male and 12 female patients with a median age of 63 years (range, 40 to 76 y). Most patients underwent surgery for pancreatic ductal adenocarcinoma (N = 8) or ampullary adenocarcinoma (N = 3). The median incipient IPMN size was 4 mm (range, 2 to 7 mm), and a majority had gastric-foveolar (N = 11) or intestinal (N = 5) differentiation. The maximum dysplasia observed was intermediate, and most of the lesions had intermediate-grade dysplasia. Mutational analysis revealed KRAS codon 12 mutations in all 21 incipient IPMNs, whereas 7 lesions (33%) in 7 individual patients harbored GNAS codon 201 mutations. The presence of GNAS 201 mutations in incipient IPMNs suggests that a fraction of these cysts are in fact small IPMNs. Morphologically, incipient IPMNs do not appear to be high-risk lesions. Additional studies in a larger cohort are needed to define the relationship of incipient IPMNs to larger IPMNs and, more importantly, to determine their clinical significance.

The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.

Many patients with pancreas cancer present with locally advanced pancreatic cancer (LAPC). The principle tools used for diagnosis and staging of LAPC include endoscopic ultrasound, axial imaging with computed tomography and magnetic resonance imaging, and diagnostic laparoscopy. The definition of resectability has historically been vague, as there is considerable debate and controversy as to the definition of LAPC. For the patient with LAPC, there is some level of involvement of the surrounding vascular structures, which include the superior mesenteric artery, celiac axis, hepatic artery, superior mesenteric vein, or portal vein. When feasible, most surgeons would recommend possible surgical resection for patients with borderline LAPC, with the goal of an R0 resection. For initially unresectable LAPC, neoadjuvant should be strongly considered. Specifically, these patients should be offered neoadjuvant therapy, and the tumor should be assessed for possible response and eventual resection. The efficacy of neoadjuvant therapy with this approach as a bridge to potential curative resection is broad, ranging from 3%-79%. The different modalities of neoadjuvant therapy include single or multi-agent chemotherapy combined with radiation, chemotherapy alone, and chemotherapy followed by chemotherapy with radiation. This review focuses on patients with LAPC and addresses recent advances and controversies in the field.

OBJECTIVE:The aim of the study was to determine if there had been any change in the number of solid-pseudopapillary neoplasm (SPN) cases detected and their evaluation or management over time. METHODS:A systematic review of SPN was performed of all articles published in English in PubMed and Scopus. RESULTS:A total of 2744 patients with SPN were identified in 484 studies published between 1961 and 2012; 87.8% of the cases were reported between 2000 and 2012. A total of 2408 (87.8%) were females, and the mean age was 28.5 (SD, 13.7) years. The most common symptom was abdominal pain in 63.6% of the cases and incidentally detected in 38.1% of the cases. There were 2285 patients who underwent pancreatic resection. The mean tumor size was 8.6 (SD, 4.3) cm. Follow-up was reported for 1952 (90.5%) patients, with a mean follow-up of 36.1 (SD, 32.8) months. Disease-free survival was documented in 1866 (95.6%) patients with recurrence in 86 (4.4%) patients; the median time to recurrence was 50.5 months. CONCLUSIONS:The number of SPNs reported in the literature has seen a 7-fold increase in the number of cases reported since 2000 compared with before. Solid-pseudopapillary neoplasms continue to be primarily found in young women and present with nonspecific symptoms. Surgery remains the mainstay of treatment with an excellent long-term prognosis.