Faculty Bibliography

CONTEXT/BACKGROUND: Of the 200 million adults worldwide who undergo noncardiac surgery each year, more than 1 million will die within 30 days. OBJECTIVE:To determine the relationship between the peak fourth-generation troponin T (TnT) measurement in the first 3 days after noncardiac surgery and 30-day mortality. DESIGN, SETTING, AND PARTICIPANTS/METHODS: A prospective, international cohort study that enrolled patients from August 6, 2007, to January 11, 2011. Eligible patients were aged 45 years and older and required at least an overnight hospital admission after having noncardiac surgery. MAIN OUTCOME MEASURES/METHODS: Patients' TnT levels were measured 6 to 12 hours after surgery and on days 1, 2, and 3 after surgery. We undertook Cox regression analysis in which the dependent variable was mortality until 30 days after surgery, and the independent variables included 24 preoperative variables. We repeated this analysis, adding the peak TnT measurement during the first 3 postoperative days as an independent variable and used a minimum P value approach to determine if there were TnT thresholds that independently altered patients' risk of death. RESULTS: A total of 15 133 patients were included in this study. The 30-day mortality rate was 1.9% (95% CI, 1.7%-2.1%). Multivariable analysis demonstrated that peak TnT values of at least 0.02 ng/mL, occurring in 11.6% of patients, were associated with higher 30-day mortality compared with the reference group (peak TnT≤0.01 ng/mL): peak TnT of 0.02 ng/mL (adjusted hazard ratio [aHR], 2.41; 95% CI, 1.33-3.77); 0.03 to 0.29 ng/mL (aHR, 5.00; 95% CI, 3.72-6.76); and 0.30 ng/mL or greater (aHR, 10.48; 95% CI, 6.25-16.62). Patients with a peak TnT value of 0.01 ng/mL or less, 0.02, 0.03-0.29, and 0.30 or greater had 30-day mortality rates of 1.0%, 4.0%, 9.3%, and 16.9%, respectively. Peak TnT measurement added incremental prognostic value to discriminate those likely to die within 30 days for the model with peak TnT measurement vs without (C index = 0.85 vs 0.81; difference, 0.4; 95% CI, 0.2-0.5; P < .001 for difference between C index values). The net reclassification improvement with TnT was 25.0% (P < .001). CONCLUSIONS:Among patients undergoing noncardiac surgery, the peak postoperative TnT measurement during the first 3 days after surgery was significantly associated with 30-day mortality.

PURPOSE/OBJECTIVE:Genetic alterations of KRAS, CDKN2A, TP53, and SMAD4 are the most frequent events in pancreatic cancer. We determined the extent to which these 4 alterations are coexistent in the same carcinoma, and their impact on patient outcome. EXPERIMENTAL DESIGN/METHODS:Pancreatic cancer patients who underwent an autopsy were studied (n = 79). Matched primary and metastasis tissues were evaluated for intragenic mutations in KRAS, CDKN2A, and TP53 and immunolabeled for CDKN2A, TP53, and SMAD4 protein products. The number of altered driver genes in each carcinoma was correlated to clinicopathologic features. Kaplan-Meier estimates were used to determine median disease free and overall survival, and a Cox proportional hazards model used to compare risk factors. RESULTS:The number of genetically altered driver genes in a carcinoma was variable, with only 29 patients (37%) having an alteration in all 4 genes analyzed. The number of altered driver genes was significantly correlated with disease free survival (P = 0.008), overall survival (P = 0.041), and metastatic burden at autopsy (P = 0.002). On multivariate analysis, the number of driver gene alterations in a pancreatic carcinoma remained independently associated with overall survival (P = 0.046). Carcinomas with only 1 to 2 driver alterations were enriched for those patients with the longest survival (median 23 months, range 1 to 53). CONCLUSIONS:Determinations of the status of the 4 major driver genes in pancreatic cancer, and specifically the extent to which they are coexistent in an individual patients cancer, provides distinct information regarding disease progression and survival that is independent of clinical stage and treatment status.

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.

BACKGROUND:Criteria for resectability of colon cancer liver metastases (CLM) are evolving, yet little is known about how physicians choose a therapeutic strategy for potentially resectable CLM. METHODS:Physicians completed a national Web-based survey that consisted of varied CLM conjoint tasks. Respondents chose among three treatment strategies: immediate liver resection (LR), preoperative chemotherapy followed by surgery (C → LR), or palliative chemotherapy (PC). Data were analyzed by multinomial logistic regression, yielding odds ratios (OR). RESULTS:Of 219 respondents, 79 % practiced at academic centers and 63 % were in practice ≥10 years. Median number of cases evaluated was four per month. Surgical training varied: 51 % surgical oncology, 44 % hepato-pancreato-biliary/transplantation, 5 % no fellowship. Although each factor affected the choice of CLM therapy, the relative effect differed. Hilar lymph node disease predicted a strong aversion to LR with surgeons more likely to choose C → LR (OR 8.92) or PC (OR 49.9). Solitary lung metastasis also deterred choice of LR, with respondents favoring C → LR (OR 4.43) or PC (OR 6.97). After controlling for clinical factors, surgeons with more years in practice were more likely to choose PC over C → LR (OR 1.94) (P = 0.005). Surgical oncology-trained surgeons were more likely than hepatobiliary/transplant-trained surgeons to choose C → LR (OR 2.53) or PC (OR 4.15) (P < 0.001). CONCLUSIONS:This is the first nationwide study to define the relative impact of key clinical factors on choice of therapy for CLM. Although clinical factors influence choice of therapy, surgical subspeciality and physician experience are also important determinants of care.

BACKGROUND:The incidence and associated risk factors for readmission after hepato-pancreato-biliary surgery are poorly characterized. The objective of the current study was to compare readmission after pancreatic vs hepatobiliary surgical procedures, as well as to identify potential factors associated with higher readmission within 30 days of discharge. STUDY DESIGN/METHODS:Using Surveillance, Epidemiology and End Results-Medicare linked data from 1986-2005, we identified 9,957 individuals aged 66 years and older who underwent complex hepatic, biliary, or pancreatic procedures for cancer treatment and were eligible for analysis. In-hospital morbidity, mortality, and 30-day readmission were examined. RESULTS:Primary surgical treatment consisted of a pancreatic (46.7%), hepatic (50.0%), or biliary (3.4%) procedure. Mean patient age was 72.6 years and most patients were male (53.2%). The number of patients with multiple preoperative comorbidities increased over time (patients with Elixhauser's comorbidity score >13: 1986-1990, 47.0% vs 2001-2005, 62.9%; p < 0.001). Pancreatic operations had higher inpatient mortality vs hepatobiliary procedures (9.2% vs 7.3%; p < 0.001). Mean length of stay after pancreatic procedures was longer compared with hepatobiliary procedures (19.7 vs 10.3 days; p < 0.001). The proportion of patients readmitted after a pancreatic (1986-1990, 17.7%; 1991-1995, 16.1%; 1996-2000, 18.6%; 2001-2005, 19.6%; p = 0.15) or hepatobiliary (1986-1990, 14.3%; 1991-1995, 14.1%; 1996-2000, 15.2%; 2001-2005, 15.5%; p = 0.69) procedure did not change over time. Factors associated with increased risk of readmission included preoperative Elixhauser comorbidities >13 (odds ratio = 1.90) and prolonged index hospital stay ≥10 days (odds ratio = 1.54; both p < 0.05). During the readmission, additional morbidity and mortality were 46.5% and 8.0%, respectively. CONCLUSIONS:Although the incidence of readmission did not change across the time periods examined, readmission was higher among patients undergoing a pancreatic procedure vs a hepatobiliary procedure. Other factors associated with risk of readmission included number of patient comorbidities and prolonged hospital stay. Readmission was associated with additional short-term morbidity and mortality.

Pancreatic neuroendocrine tumors (PanNETs) are typically solid neoplasms but in rare instances may present as cystic lesions. This unusual presentation can make clinical diagnosis challenging. In addition, the clinical and histopathologic characteristics of cystic PanNETs are poorly defined. We identified 53 cystic PanNETs in our single-institution experience of 491 surgically resected PanNETs. Similar to solid PanNETs, cystic PanNETs developed with an equal sex distribution and over a wide age range (23 to 91 y; mean, 52 y). The unusual cystic appearance made radiologic differentiation from other cystic pancreatic neoplasms difficult with a misdiagnosis in 23 of 53 (43%) cases. An association between cystic PanNETs and multiple endocrine neoplasia type 1 or multifocal disease [5 of 53 (9%) and 7 of 53 (13%), respectively] was not observed as compared with solid PanNETs (P=0.34 and P=0.31, respectively). Grossly, cystic PanNETs were predominantly located in the tail of the pancreas (n=28, 53%) and were similar in size (mean, 3.3 cm) to solid PanNETs (mean, 4.1 cm; P=0.12). All cysts were unilocular (n=53, 100%) and filled with clear to straw-colored fluid. Larger cysts were sometimes noted to be hemorrhagic. Histologically, the cysts were lined by a thin fibrous band that separated the cyst from the neoplastic cells. In comparison with their solid counterparts, cystic PanNETs were less likely to demonstrate tumor necrosis (6%; P=0.04), perineural invasion (8%; P<0.001), vascular invasion (4%; P<0.001), regional lymph node metastasis (13%; P<0.001), and synchronous distant metastasis (4%; P=0.015). The neoplastic cells of the cystic PanNETs were well differentiated (n=53, 100%) with a low mitotic rate and low Ki-67 proliferation index (range, 0.2% to 11%; mean, 1.8%). On the basis of both the American Joint Cancer Committee and European Neuroendocrine Tumor Society staging systems, the majority of cystic PanNETs presented at a lower pathologic stage as compared with solid PanNETs. In summary, cystic PanNETs are a distinctive subgroup of PanNETs with unique clinical, radiographic, and pathologic features.

BACKGROUND:Duodenal gastrointestinal stromal tumors (GISTs) are a small subset of GISTs, and their management is poorly defined. We evaluated surgical management and outcomes of patients with duodenal GISTs treated with pancreaticoduodenectomy (PD) versus local resection (LR) and defined factors associated with prognosis. METHODS:Between January 1994 and January 2011, 96 patients with duodenal GISTs were identified from five major surgical centers. Perioperative and long-term outcomes were compared based on surgical approach (PD vs LR). RESULTS:A total of 58 patients (60.4%) underwent LR, while 38 (39.6%) underwent PD. Patients presented with gross bleeding (n = 25; 26.0%), pain (n = 23; 24.0%), occult bleeding (n = 19; 19.8%), or obstruction (n = 3; 3.1%). GIST lesions were located in first (n = 8, 8.4%), second (n = 47; 49%), or third/fourth (n = 41; 42.7%) portion of duodenum. Most patients (n = 86; 89.6%) had negative surgical margins (R0) (PD, 92.1 vs LR, 87.9%) (P = 0.34). Median length of stay was longer for PD (11 days) versus LR (7 days) (P = 0.001). PD also had more complications (PD, 57.9 vs LR, 29.3%) (P = 0.005). The 1-, 2-, and 3-year actuarial recurrence-free survival was 94.2, 82.3, and 67.3%, respectively. Factors associated with a worse recurrence-free survival included tumor size [hazard ratio (HR) = 1.09], mitotic count >10 mitosis/50 HPF (HR = 6.89), AJCC stage III disease (HR = 4.85), and NIH high risk classification (HR = 4.31) (all P < 0.05). The 1-, 3-, and 5-year actuarial survival was 98.3, 87.4, and 82.0%, respectively. PD versus LR was not associated with overall survival. CONCLUSIONS:Recurrence of duodenal GIST is dependent on tumor biology rather than surgical approach. PD was associated with longer hospital stays and higher risk of perioperative complications. When feasible, LR is appropriate for duodenal GIST and PD should be reserved for lesions not amenable to LR.