Faculty Bibliography

OBJECTIVE:The aim of the present study is to determine if CEACAM6 can be detected in the bile of patients with biliary cancer and can serve as a diagnostic biomarker for cholangiocarcinoma. SUMMARY BACKGROUND DATA/BACKGROUND:Distinguishing bile duct carcinoma from other diagnoses is often difficult using endoscopic or percutaneous techniques. The cell surface protein CEACAM6 is over-expressed in many gastrointestinal cancers and may be selectively elevated in biliary adenocarcinoma. METHODS:Bile from patients with benign biliary disease and cholangiocarcinoma (hilar, intrahepatic and distal) was collected at the time of index operation. The concentration of CEACAM6 was quantified by sandwich enzyme-linked immunosorbent assay (ELISA) and correlated to pathologic diagnosis. Diagnostic capability of CEACAM6 was evaluated by Wilcoxon rank-sum, linear regression, multiple regression, and receiver operating characteristic (ROC) curve analysis. RESULTS:Bile from 83 patients was analyzed: 42 with benign disease and 41 with cholangiocarcinoma. Patients in the benign cohort were younger, predominantly female, and had lower median biliary CEACAM6 levels than patients in the malignant cohort (7.5 ng/ml vs. 40 ng/ml; p = <.001). ROC curve analysis determined CEACAM6 to be a positive predictor cholangiocarcinoma with a CEACAM6 level >14 ng/ml associated with 87.5% sensitivity, 69.1% specificity, and a likelihood ratio of 2.8 (AUC 0.74). Multiple regression analysis suggested elevated alkaline phosphatase and the presence of biliary endoprostheses may influence CEACAM6 levels. CONCLUSION/CONCLUSIONS:Biliary CEACAM6 can identify patients with extrahepatic cholangiocarcinoma with a high degree of sensitivity and should be investigated further as a potential screening tool.

BACKGROUND:MicroRNAs (miRNAs) are potential biomarkers in various malignancies. We aim to characterize miRNA expression in intrahepatic cholangiocarcinoma (ICC) and identify circulating plasma miRNAs with potential diagnostic and prognostic utility. METHODS:Using deep-sequencing techniques, miRNA expression between tumor samples and non-neoplastic liver parenchyma were compared. Overexpressed miRNAs were measured in plasma from an independent cohort of patients with cholangiocarcinoma using RT-qPCR and compared with that healthy volunteers. The discriminatory ability of the evaluated plasma miRNAs between patients and controls was evaluated with receiving operating characteristic (ROC) curves. RESULTS:Small RNAs from 12 ICC and 11 tumor-free liver samples were evaluated. Unsupervised hierarchical clustering using the miRNA expression data showed clear grouping of ICC vs. non-neoplastic liver parenchyma. We identified 134 down-regulated and 128 upregulated miRNAs. Based on overexpression and high fold-change, miR21, miR200b, miR221, and miR34c were measured in plasma from an independent cohort of patients with ICC (n = 25) and healthy controls (n = 7). Significant overexpression of miR-21 and miR-221 was found in plasma from ICC patients. Furthermore, circulating miR-21 demonstrated a high discriminatory ability between patients with ICC and healthy controls (AUC: 0.94). CONCLUSION/CONCLUSIONS:Among the differentially expressed miRNAs in ICC, miR-21 and miR-221 are overexpressed and detectable in the circulation. Plasma expression levels of these miRNAs, particularly miR-21, accurately differentiates patients with ICC from healthy controls and could potentially serve as adjuncts in diagnosis. Prospective validation and comparison with other hepatobiliary malignancies is required to establish their potential role as diagnostic and prognostic biomarkers.

OBJECTIVE:To perform an unbiased assessment of first postoperative day (POD 1) drain amylase level and pancreatic fistula (PF) after pancreaticoduodenectomy (PD). BACKGROUND:Recent evidence demonstrated that drain abandonment in PD is unsafe. Early drain amylase levels have been proposed as predictors of PF after PD, allowing for selection of patients for early drain removal. METHODS:Daily drain amylase levels were correlated with the development of PF in 2 independent cohorts of patients undergoing PD: training cohort (n = 126; year 2008) and validation cohort (n = 369; years 2009-2012). RESULTS:POD 1 drain amylase level had the highest predictive ability (concordance index: 0.911) for PF in the training cohort. An amylase level of 612 U/L or higher showed the best accuracy (86%), sensitivity (93%), and specificity (79%). Thus, a cutoff value of 600 U/L was utilized. In the validation cohort, 229 (62.1%) patients had a POD 1 drain amylase level of lower than 600 U/L, and PF developed in only 2 (0.9%) cases; whereas in patients with POD 1 drain amylase level of 600 U/L or higher (n = 140) the PF rate was 31.4% (odds ratio [OR] = 52, P < 0.0001). On multivariate analysis, POD 1 drain amylase level of lower than 600 U/L (OR = 0.0192, P < 0.0001) was a stronger predictor of the absence of PF than pancreatic gland texture (OR = 0.193, P = 0.002) and duct diameter (OR = 0.861, P = 0.835). CONCLUSIONS:After PD, the risk of PF is less than 1% if POD 1 drain amylase level is lower than 600 U/L. We propose that in this group, which comprise more than 60% of patients, drains should be removed on POD 1.

BACKGROUND:The optimal perioperative fluid resuscitation strategy for liver resections remains undefined. Goal-directed therapy (GDT) embodies a number of physiologic strategies to achieve an ideal fluid balance and avoid the consequences of over- or under-resuscitation. STUDY DESIGN/METHODS:In a prospective randomized trial, patients undergoing liver resection were randomized to GDT using stroke volume variation as an end point or to standard perioperative resuscitation. Primary outcomes measure was 30-day morbidity. RESULTS:Between 2012 and 2014, one hundred and thirty-five patients were randomized (GDT: n = 69; standard perioperative resuscitation: n = 66). Median age was 57 years and 56% were male. Metastatic disease comprised 81% of patients. Overall (35% GDT vs 36% standard perioperative resuscitation; p = 0.86) and grade 3 morbidity (28% GDT vs 18% standard perioperative resuscitation; p = 0.22) were equivalent. Patients in the GDT arm received less intraoperative fluid (mean 2.0 L GDT vs 2.9 L standard perioperative resuscitation; p < 0.001). Perioperative transfusions were required in 4% (6% GDT vs 2% standard perioperative resuscitation; p = 0.37) and boluses in the postanesthesia care unit were administered to 24% (29% GDT vs 20% standard perioperative resuscitation; p = 0.23). Mortality rate was 1% (2 of 135 patients; both in GDT). On multivariable analysis, male sex, age, combined procedures, higher intraoperative fluid volume, and fluid boluses in the postanesthesia care unit were associated with higher 30-day morbidity. CONCLUSIONS:Stroke volume variation-guided GDT is safe in patients undergoing liver resection and led to less intraoperative fluid. Although the incidence of postoperative complications was similar in both arms, lower intraoperative resuscitation volume was independently associated with decreased postoperative morbidity in the entire cohort. Future studies should target extensive resections and identify patients receiving large resuscitation volumes, as this population is more likely to benefit from this technique.

BACKGROUND:The prognostic and predictive abilities of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) coupled with conventional computed tomography (CT) have not been studied in patients with unresectable colorectal liver metastases (uCRLM) treated with combined hepatic arterial infusion (HAI) and systemic chemotherapy. OBJECTIVES/OBJECTIVE:The ability of PET-CT metabolic response parameters to predict conversion to resectability and oncologic outcome in this setting was evaluated. METHODS:Thirty-eight patients undergoing serial PET-CT as part of a Phase II trial of HAI and systemic chemotherapy for uCRLM were included. Metabolic response was determined as the percentage change in standard uptake value (SUV) and total lesion glycolysis (TLG). Conversion to resection, overall survival (OS), progression-free survival (PFS) and recurrence-free survival were evaluated using standard statistics. RESULTS:Volumetric response sufficient to facilitate resection was seen in 53% of patients after a median of 5 months of therapy. Median follow-up was 38 months (range: 32-52 months). Median OS was not reached [95% confidence interval (CI) 32 months-unknown] and 3-year OS was 54% (range: 33-71%). Median PFS was 13 months (95% CI 6-21 months) and 3 year PFS was 10% (range: 3-20%). Neither baseline values nor the percentage change in any of the metabolic parameters evaluated correlated with conversion to resection, survival variables or hepatic recurrence on Cox regression analysis. CONCLUSIONS:Pre- and post-treatment PET-related metabolic parameters do not predict conversion to resection or oncologic outcome in patients with uCRLM treated with HAI and systemic chemotherapy. Metabolic parameters should not be used to monitor response or to determine prognosis in these patients.

BACKGROUND:Liver resection is used to treat primary and secondary malignancies. Historically, these procedures were associated with significant complications, which may affect cancer-specific outcomes. This study analyzed the changes in morbidity and mortality after hepatic resection over time. STUDY DESIGN/METHODS:Records of all patients undergoing liver resection for a malignant diagnosis from 1993 to 2012 at Memorial Sloan Kettering were analyzed. Patients were divided into early (1993 to 1999), middle (2000 to 2006), and recent (2007 to 2012) eras. Major hepatectomy was defined as resection of 3 or more segments. Univariate and multivariate analyses were made with t-tests or Mann-Whitney tests. RESULTS:There were 3,875 patients who underwent 4,152 resections for malignancy. The most common diagnosis was metastatic colorectal cancer (n = 2,476, 64% of patients). Over the study period, 90-day mortality rate decreased from 5% to 1.6% (p < 0.001). Perioperative morbidity decreased from 53% to 20% (p < 0.001). The percentage of major hepatectomies decreased from 66% to 36% (p < 0.001). The rate of perioperative transfusion decreased from 51% to 21% (p < 0.001). The spectrum of perioperative morbidity changed markedly over time, with abdominal infections (43% of complications) overtaking cardiopulmonary complications (22% of complications). Peak postoperative bilirubin (odds ratio [OR] 1.1, p < 0.001), blood loss (OR 1.5, p = 0.001), major hepatectomy (OR 1.3, p = 0.031), and concurrent partial colectomy (OR 2.4, p < 0.001) were independent predictors of perioperative morbidity. The mortality associated with trisectionectomy (6%) and right hepatectomy (3%) remained unchanged over time. CONCLUSIONS:Morbidity and mortality rates after partial hepatectomy for cancer have decreased substantially as the major hepatectomy rate has dropped. Encouraging parenchymal preservation and preventing abdominal infections are vital for continued improvement of liver resection outcomes.

OBJECTIVES/OBJECTIVE:Low central venous pressure (LCVP)-assisted hepatectomy is associated with decreased blood loss and lower transfusion rates. Concerns about its impact on renal function have prevented widespread application. This study was conducted to review the dynamics of renal function after LCVP-assisted hepatectomy. METHODS:A retrospective analysis of a prospective surgical database was carried out. Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) equation. The RIFLE (risk-injury-failure-loss-end-stage) criteria were used to define postoperative biochemical acute kidney injury (bAKI). Occurrences of clinically relevant AKI (cAKI) were identified in the study center postoperative database. RESULTS:During the period 2003-2012, 2116 LCVP-assisted hepatectomies were performed. The median patient age was 61 years [interquartile range (IQR): 51-70 years] and 51% of patients were male. The median number of resected segments was two; resections involved from one to four segments. Median estimated blood loss was 300 ml (IQR: 200-600 ml). Rates of morbidity and 90-day mortality were 21% and 2%, respectively. Low baseline eGFR (<90 ml/min) was seen in 84% of patients; 29% of patients had eGFR of <30 ml/min. Postoperative bAKI was seen in 17% (n = 350) of patients. Biochemical AKI with low eGFR was seen in 336 patients, representing 16% of the whole cohort; 13% of patients had been at risk, 2% experienced injury and 1% experienced failure. Kidney function had normalized at discharge in 159 of these patients. Nine patients (<1%) developed postoperative cAKI. CONCLUSIONS:The majority of patients in the study cohort had low baseline eGFR. Biochemical alterations in eGFR are transient in the vast majority of patients after LCVP-assisted hepatectomy and their clinical impact is limited. The present data suggest that clinically relevant renal dysfunction is a very uncommon event in patients undergoing LCVP-assisted liver resection.

OBJECTIVE:The prognosis of ampullary adenocarcinoma (AA) usually is favorable; however, a subset of AA have poor biology and outcomes similar to pancreatic cancer. Patients in this subset will have early recurrence and death usually within 2 years. To date, there are no genetic markers to identify these patients. This study identifies the high-risk subset of AA and evaluates the mutational status of KRAS in predicting poor outcome. METHODS:The tumor registry of an academic center was reviewed for data on patients managed operatively with AA. KRAS genotypes were determined for these patients using a polymerase chain reaction-based assay on clinical specimens. Analysis of variance and χ(2) tests was used to categorize continuous and categorical variables. Univariate and multivariate survival analyses were performed using Kaplan-Meier and Cox methods, respectively. RESULTS:A total of 146 patients were identified with AA between 1982 and 2008. After stringent pathologic review, 97 patients were confirmed with AA, of whom 75 had tissue specimens available for analysis. Genotyping revealed 67% were wild-type (KRAS(WT)), and 33% were mutant for KRAS. Patients with KRAS(G12D) (n = 9), the most common mutational genotype, had poorer median survival (62 months) compared with those with KRAS(non-G12D) mutants (median survival not reached, mean 145 months) and KRAS(WT) patients (155 months, P = .05). Patients with survival ≤30 months were labeled "high-risk." Of the 9 patients with KRAS(G12D), 56% were in this high-risk subset, compared with 18% of KRAS(WT) (P = .02) and 31% of KRAS(non-G12D) (P > .05) populations. Patients with KRAS(G12D) also were more likely to present with advanced T stage. CONCLUSION/CONCLUSIONS:The KRAS(G12D) mutation identifies a subset of AA patients with poor prognoses and may be used to identify patients at risk of early recurrence and poorer survival who may benefit from adjuvant therapy.