Faculty Bibliography

INTRODUCTION/BACKGROUND:Patient-specific factors impacting the need for possible perioperative blood transfusions have not been examined in patients undergoing hepatopancreatobiliary (HPB) procedures. We sought to define the overall utilization of blood transfusions for HPB surgery stratified by procedure type, as well as identify patient-level risk factors for transfusion. METHODS:Hepatic and pancreatic resections were selected from the 2005-2011 American College of Surgeons National Surgical Quality Improvement Program's public use files. Transfusion utilization, risk factors, temporal trends, and outcomes were assessed using regression models. Missing data were addressed using multiple imputation. RESULTS:Twenty-six thousand eight hundred twenty-seven patients met the inclusion criteria. There were 16,953 pancreas cases (distal pancreatectomy (31.2%), pancreaticoduodenectomy (65.8%), total pancreatectomy (3.0%)), and 9,874 liver cases (wedge resection (60.0%), hemi-hepatectomy (30.1%), trisegmentectomy (9.9%)). Overall, 25.7% patients received a perioperative transfusion. Transfusion rates varied by operation type (hepatic wedge resection 18.7%, lobectomy 31.3%, trisegmentectomy 39.8%, distal pancreatectomy 19.8%, Whipple 28.7%, total pancreatectomy 43.6%, p < 0.001). On multivariate analysis, several patient-level factors were strongly associated with the risk of transfusion: preoperative hematocrit <36% (risk ratios (RR) 1.99, 95% CI 1.91-2.08), preoperative albumin <3.0 g/dL (RR 1.25, 95% CI 1.19-1.31), American Society of Anesthesiologists (ASA) class IV (RR 1.24, 95% CI 1.16-1.33), and anticoagulation/bleeding disorder (RR 1.26, 95% CI 1.15-1.38) (all p < 0.001). Patients with any one of these high-risk factors had an over twofold increased risk of perioperative transfusion (RR 2.31, 95% CI 2.21-2.40, p < 0.001). CONCLUSION/CONCLUSIONS:There are large differences in the incidence of transfusion among patients undergoing HPB procedures. While the type of HPB procedure was associated with the risk of transfusion, patient-level factors-including preoperative hematocrit and albumin, ASA classification, and history of anticoagulation/bleeding disorder-were as important.

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.

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.

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.

BACKGROUND:The determination of the primary tumor origin in patients with neuroendocrine tumor liver metastases (NELM) can pose a considerable management challenge. Recent studies have shown that the alternative lengthening of telomeres (ALT) is prevalent in some human tumors, including pancreatic neuroendocrine tumors (PanNET), and can be useful in predicting tumor biology. In this study, we aimed to evaluate the use of ALT as a biomarker in patients with NELM, in particular to predict the site of origin of metastases. METHODS:Tissue microarrays (TMAs) were constructed using tumor tissue from NELM patients undergoing liver resection between 1998 and 2010. These included 43 PanNET and 47 gastrointestinal carcinoid tumors. The TMAs were tested for ALT using telomere-specific fluorescent in situ hybridization. The association between ALT positivity and clinicopathologic features and long-term outcomes was investigated. RESULTS:Alternative lengthening of telomeres was positive (ALT+) in 26 (29%) of the 90 tumors included in the TMAs. Pancreatic neuroendocrine tumors were ALT+ in 56% of patients, compared with only 4% ALT+ among gastrointestinal carcinoid tumors (p < 0.001). The specificity of ALT for detecting pancreatic origin was 96% and the positive predictive value was 92%, and sensitivity was 56% and the negative predictive value was 70%. Additionally, ALT was associated with the pattern of metastatic disease: ALT+ NELM were more likely to have oligometastases (p = 0.001) and less likely to be bilateral in distribution (p = 0.05) than were ALT tumors. In addition, ALT+ was associated with improved prognosis in the PanNET patient population. CONCLUSIONS:Alternative lengthening of telomeres was found to be a useful biomarker in patients with NELM. This marker can be helpful in guiding therapy by identifying the site of origin in patients in whom the primary site is unknown.

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.

Pancreatic carcinomas with acinar differentiation, including acinar cell carcinoma, pancreatoblastoma and carcinomas with mixed differentiation, are distinct pancreatic neoplasms with poor prognosis. Although recent whole-exome sequencing analyses have defined the somatic mutations that characterize the other major neoplasms of the pancreas, the molecular alterations underlying pancreatic carcinomas with acinar differentiation remain largely unknown. In the current study, we sequenced the exomes of 23 surgically resected pancreatic carcinomas with acinar differentiation. These analyses revealed a relatively large number of genetic alterations at both the individual base pair and chromosomal levels. There was an average of 119 somatic mutations/carcinoma. When three outliers were excluded, there was an average of 64 somatic mutations/tumour (range 12-189). The mean fractional allelic loss (FAL) was 0.27 (range 0-0.89) and heterogeneity at the chromosome level was confirmed in selected cases using fluorescence in situ hybridization (FISH). No gene was mutated in >30% of the cancers. Genes altered in other neoplasms of the pancreas were occasionally targeted in carcinomas with acinar differentiation; SMAD4 was mutated in six tumours (26%), TP53 in three (13%), GNAS in two (9%), RNF43 in one (4%) and MEN1 in one (4%). Somatic mutations were identified in genes in which constitutional alterations are associated with familial pancreatic ductal adenocarcinoma, such as ATM, BRCA2 and PALB2 (one tumour each), as well as in genes altered in extra-pancreatic neoplasms, such as JAK1 in four tumours (17%), BRAF in three (13%), RB1 in three (13%), APC in two (9%), PTEN in two (9%), ARID1A in two (9%), MLL3 in two (9%) and BAP1 in one (4%). Perhaps most importantly, we found that more than one-third of these carcinomas have potentially targetable genetic alterations, including mutations in BRCA2, PALB2, ATM, BAP1, BRAF and JAK1.

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.

High-dose-rate intraoperative radiation therapy (HDR-IORT) has historically provided effective local control (LC) for patients with unresectable and recurrent tumors. However, IORT is limited to only a few specialized institutions and it can be difficult to initiate an HDR-IORT program. Herein, we provide a brief overview on how to initiate and implement an HDR-IORT program for a selected group of patients with gastrointestinal and pelvic solid tumors using a multidisciplinary approach. Proper administration of HDR-IORT requires institutional support and a joint effort among physics staff, oncologists, surgeons, anesthesiologists, and nurses. In order to determine the true efficacy of IORT for various malignancies, collaboration among institutions with established IORT programs is needed.

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.