Global Gene Expression Change Induced by Major Thoracoabdominal Surgery.

OBJECTIVE: To test the hypothesis that major thoracoabdominal surgery induces gene expression changes associated with adverse outcomes. BACKGROUND: Widely different traumatic injuries evoke surprisingly similar gene expression profiles, but there is limited information on whether the iatrogenic injury caused by major surgery is associated with similar patterns. METHODS: With informed consent, blood samples were obtained from 50 patients before and after open transhiatal esophagectomy or pancreaticoduodenectomy. Twelve cases with complicated recoveries (death, infection, venous thromboembolism) were matched with 12 cases with uneventful recoveries. Global gene expression was assayed using human microarray chips. A 2-fold change with a corrected P < 0.05 was considered differentially expressed. RESULTS: In these 24 patients, 522 genes were differentially expressed after surgery; 248 (48%) were upregulated (innate immunity and inflammation) and 274 (52%) were downregulated [adaptive immunity (antigen presentation, T-cell function)]. Hierarchical clustering of the profile reliably predicted pre- and postoperative status. The within-patient change was 3.08 ±â€Š0.91-fold. There was no measurable association with age, malignancy, procedure, surgery length, operative blood loss, or transfusion requirements, but was positively associated with postoperative infection (3.81 ±â€Š0.97 vs 2.79 ±â€Š0.73; P = 0.009) and hospital length of stay (r = 0.583, P = 0.003). Venous thromboembolism and mortality each occurred in one patient, thus no associations were possible. CONCLUSIONS: Major surgery induces a quantifiable pattern of gene expression change that is associated with adverse outcome. This could reflect early impaired adaptive immunity and suggests potential therapeutic targets to improve postoperative recovery.

Full dose neoadjuvant FOLFIRINOX is associated with prolonged survival in patients with locally advanced pancreatic adenocarcinoma.

BACKGROUND: The efficacy of FOLFIRINOX for metastatic pancreatic cancer has led to its use in patients with earlier stages of disease. This study retrospectively analyzed a cohort of patients with locally-advanced pancreatic cancer (LAPC) treated with FOLFIRINOX. METHODS: Between 2008 and 2013, 51 treatment-naïve patients with LAPC at a single institution received first-line FOLFIRINOX with neoadjuvant intent, at the full dose as described in the PRODIGE 4/ACCORD 11 study. Combined chemoradiation was administered for those who remained unresectable after maximum response to chemotherapy. The primary outcome measure was overall survival (OS), and secondary outcomes were progression-free survival (PFS) and margin-negative (R0) resection rate, and toxicity profile. RESULTS: A total of 429 cycles of FOLFIRINOX were given with a median of 8 cycles (range 2-29) per patient; 66% of cycles were full dose. After chemotherapy, 27 (53%) received chemoradiation. The median OS was 35.4 months (95% CI 25.8-45). Ten (4 borderline resectable and 6 unresectable) patients had successful R0 resections; those who had R0 resections had a significantly longer survival than those who did not (3-year OS rate 67% versus 21%, log rank p = 0.042). Increasing number of full-dose cycles was significantly associated with increased survival. The toxicity profile was similar to previous reports of this regimen. CONCLUSIONS: FOLFIRINOX is feasible as neoadjuvant therapy for LAPC. Although the R0 resection rate was only 20%, the median OS of almost 3 years appears promising. Dose intensity and duration were associated with increased survival in this study, arguing against dose attenuated versions of this regimen.

Biliary-colonic fistula caused by cholecystectomy bile duct injury.

Biliary-colonic fistula is a rare complication after laparoscopic cholecystectomy. We present a case of post-cholecystectomy iatrogenic biliary injury that resulted in a fistula between the common hepatic duct and large bowel. Magnetic resonance cholangiopancreatography provided good visualization of injury even with concurrent normal level of alkaline phosphatase. Radiologic findings and surgical management of this condition are discussed in detail.

A retrospective study of neoadjuvant FOLFIRINOX in unresectable or borderline-resectable locally advanced pancreatic adenocarcinoma.

BACKGROUND: 5-fluorouracil, leucovorin, irinotecan and oxaliplatin (FOLFIRINOX) is superior to gemcitabine in patients with metastatic pancreatic cancer who have a good performance status. We investigated this combination as neoadjuvant therapy for locally advanced pancreatic cancer (LAPC). METHODS: In this retrospective series, we included patients with unresectable LAPC who received neoadjuvant FOLFIRINOX with growth factor support. The primary analysis endpoint was R0 resection rate. RESULTS: Eighteen treatment-naïve patients with unresectable or borderline resectable LAPC were treated with neoadjuvant FOLFIRINOX. The median age was 57.5 years and all had ECOG PS of 0 or 1. Eleven (61 %) had tumors in the head of the pancreas and 9 (50 %) had biliary stents placed prior to chemotherapy. A total of 146 cycles were administered with a median of 8 cycles (range 3-17) per patient. At maximum response or tolerability, 7 (39 %) were converted to resectability by radiological criteria; 5 had R0 resections, 1 had an R1 resection, and 1 had unresectable disease. Among the 11 patients who remained unresectable after FOLFIRINOX, 3 went on to have R0 resections after combined chemoradiotherapy, giving an overall R0 resection rate of 44 % (95 % CI 22-69 %). After a median follow-up of 13.4 months, the 1-year progression-free survival was 83 % (95 % CI 59-96 %) and the 1-year overall survival was 100 % (95 % CI 85-100 %). Grade 3/4 chemotherapy-related toxicities were neutropenia (22 %), neutropenic fever (17 %), thrombocytopenia (11 %), fatigue (11 %), and diarrhea (11 %). Common grade 1/2 toxicities were neutropenia (33 %), anemia (72 %), thrombocytopenia (44 %), fatigue (78 %), nausea (50 %), diarrhea (33 %) and neuropathy (33 %). CONCLUSIONS: FOLFIRINOX followed by chemoradiotherapy is feasible as neoadjuvant therapy in patients with unresectable LAPC. The R0 resection rate of 44 % in this population is promising. Further studies are warranted.

EUS visualization and direct celiac ganglia neurolysis predicts better pain relief in patients with pancreatic malignancy (with video).

BACKGROUND: EUS-guided celiac plexus neurolysis (EUS-CPN) improves pain control in patients with pancreatic cancer. EUS allows visualization of the celiac ganglion. OBJECTIVE: To determine predictors of response to EUS-CPN in a cohort of 64 patients with pancreatic malignancy. DESIGN: Retrospective analysis of prospective database. SETTING: Academic medical center. PATIENTS: Sixty-four patients with pancreatic cancer referred for EUS between March 2008 and January 2010. INTERVENTIONS: EUS-CPN injected directly into celiac ganglia when visible by linear EUS or bilateral injection at the celiac vascular trunk. MAIN OUTCOME MEASUREMENTS: Predictors of pain improvement at week 1 by univariate and multivariate analysis. RESULTS: At week 1, 32 patients (50%) had a symptomatic response. In a multivariate model with 8 potential predictors, visualization of the ganglia was the best predictor of response; patients with visible ganglia were >15 times more likely to respond (odds ratio 15.7; P<.001). Tumors located outside the head of the pancreas and patients with a higher baseline pain level were weakly associated with a good response. LIMITATIONS: Retrospective design and lack of blinding. CONCLUSIONS: Visualization of celiac ganglia with direct injection is the best predictor of response to EUS-CPN in patients with pancreatic malignancy.

EUS-FNA with rescue fluorescence in situ hybridization for the diagnosis of pancreatic carcinoma in patients with inconclusive on-site cytopathology results.

BACKGROUND: Detection of chromosomal abnormalities by fluorescence in situ hybridization (FISH) analysis has not been well-studied in FNA samples of pancreatic masses. Selective use of FISH in patients with inconclusive on-site cytopathology results may improve the sensitivity of EUS for malignancy. OBJECTIVE: To determine the sensitivity and specificity of FISH analysis in patients with inconclusive on-site cytopathology results. DESIGN: Consecutive patients with suspected pancreatic malignancy, nonrandomized cohort study. Final diagnosis was based on either surgical biopsy or disease progression on extended follow-up or death. SETTING: Academic center, tertiary-care referral cancer center. PATIENTS: A total of 212 EUS examinations were performed in 206 patients for solid pancreatic lesions over a 24-month period (January 2009-December 2010). FISH analysis was done for 69 patients with inconclusive or nonavailable on-site cytology results. INTERVENTION: EUS-guided FNA (EUS-FNA) of solid pancreatic masses with cytology and FISH analysis for polysomy of chromosomes 3, 7, and 17 and deletion of 9p21. MAIN OUTCOME MEASUREMENTS: Sensitivity/specificity of cytology, FISH, and a composite of cytology and FISH. RESULTS: Patients with positive on-site cytology (110), neuroendocrine tumors (22), insufficient follow-up (1), FISH not obtained (3), and renal cancer with pancreatic metastasis (1) were excluded. Sixty-nine patients comprised the study cohort, 54 with malignancy and 15 with benign disease. Sensitivity for malignancy of cytology, FISH analysis, and the combination were 61%, 74%, and 85%, respectively (P = .009). FISH detected an additional 13 cases of pancreatic adenocarcinoma missed by cytology. There was no false-positive FISH analysis in 15 patients with benign disease. No major complications occurred from EUS-FNA. LIMITATIONS: Single center, selected patients underwent FISH analysis, limited number of patients with benign disease. CONCLUSION: In patients with suspected pancreatic cancer, FISH analysis can detect additional cases missed by cytology without compromising specificity. FISH analysis to detect polysomy of chromosomes 3, 7, and 17 and deletion of 9p21 should be considered when cytology is negative for malignancy in patients with a known pancreatic mass.

Single-session endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography for evaluation of pancreaticobiliary disorders.

BACKGROUND: Endoscopic ultrasonography (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) often are required in the evaluation and treatment of patients with pancreaticobiliary disorders. Few reports of single-session EUS-ERCP have raised questions regarding its safety and accuracy or about which procedure should be performed first. METHODS: Data from 2005 to 2009 were reviewed from a prospectively maintained EUS-ERCP database at a single tertiary care cancer center. Sensitivity and specificity of EUS and fine-needle aspiration (FNA), bile duct cannulation rate, duration of procedure, and complications were evaluated. RESULTS: Of the 35 patients (15 men and 20 women) studied, 28 had a final diagnosis of malignancy, and 7 had benign disorders. All the patients underwent ERCP and EUS, with FNA performed for 28 patients (80%). For 22 of the 35 patients (62.8%), EUS was the first procedure performed. The sensitivity of EUS-FNA for malignancy was 96.4%. The bile duct cannulation rate during ERCP was 97.1%. Five patients required a precut sphincterotomy for bile duct access, and one patient with chronic pancreatitis had a failed cannulation despite a EUS-guided rendezvous. A stent was successfully placed in 29 patients (96%). No major complications occurred, and no contrast leak was seen when FNA was performed before the cholangiogram. One patient had periduodenal bleeding after FNA, which was managed conservatively. The mean duration of the procedure was 83.7 min. CONCLUSION: Single-session EUS-ERCP can be performed safely and with efficacy similar to that of the procedures performed separately.

EUS-guided fine needle aspiration with and without trucut biopsy of pancreatic masses.

CONTEXT: Endoscopic ultrasound-guided trucut biopsy (EUS TCB) has a lower yield than fine needle aspiration (FNA) in pancreatic masses but the additional use of TCB to FNA may improve the diagnostic accuracy over FNA alone. OBJECTIVE: To compare the yield of EUS FNA alone or combined with EUS TCB for diagnosis of pancreatic masses. DESIGN: Single center retrospective case control study conducted at academic tertiary center. Study conducted between March 2004 and April 2007. PARTICIPANTS: A total of 126 consecutive patients referred for EUS guided biopsy of pancreatic mass; three patients excluded from analysis, final cohort comprised 123 patients (108 malignant and 15 benign). EUS FNA was performed in 72 patients and EUS FNA+TCB was performed in 51 patients. MAIN OUTCOME MEASURES: The diagnostic performance of EUS FNA versus EUS FNA+TCB was compared. RESULTS: The sensitivity, specificity and frequency of cases correctly identified for malignancy of FNA alone were 87.1% (54/62), 100% (10/10) and 88.8% (64/72), while for the combination of FNA+TCB they were: 95.7% (44/46), 100% (5/5) and 96.0% (49/51), respectively (P=0.184, 1.000, and 0.193 FNA versus FNA+TCB). No major complication occurred in either group. CONCLUSION: FNA+TCB can be safely performed in selected lesions but sensitivity is not statistically improved over FNA alone (95.7% versus 87.1%).

Enzyme-Driven Chemo-and Radiation-Therapy with 12 Pyrimidine Nucleoside Analogs Not Yet in the Clinic.

Enzymatic activity from tumor and adjacent normal tissue of 200 patients involving deoxycytidine kinase (dCK), uridine/cytidine kinase (U/CK), cytidine deaminase (CD) and deoxycytidylate deaminase (dCMPD) was quantified. Patients with brain (17), colon (24), and breast (30) tumors, 53, 67, and 73%, respectively, had an elevated T/N value (Specific Activity of tumor/ Specific Activity of normal tissue) involving dCK and dCMPD suggesting chemotherapy with 5-fluorodeoxycytidine (5-FdC) alone or in combination with thymidine plus deoxytetrahydrouridine, or with the radiosensitizer, 5-chlorodeoxycytidine (5-CldC) plus tetrahydrouridine (H4U). Among patients with colon (19) and pancreatic tumors (40), 53 and 68 %, respectively, displayed T/N values >4 for CD suggesting chemotherapy with 5-FdC, 4-N-methylamino-5-FdC, 5-trifluoromethyldeoxycytidine and radiosensitization with 5- CldC, 4-N-methylamino-5-CldC, 5-iododeoxycytidine and 5-bromodeoxycytidine. The percent of patients with tumors with a T/N value >4 for U/CK in lung (72), colon (23) and breast (28) was 47, 61 and 68, respectively, suggesting zebularine (plus thymidine) treatment for tumors involving gene silencing. Evidence is presented that the 4-N-alkylamino-dC substituted nucleosides and those with large 5-substitutions are activated only via CD to thymidine kinase (TK) using end-points of cytotoxicity and/or radiosensitization: H4U, the inhibitor of CD is an antagonist, cells with low CD or no TK are resistant to the analogs, the end points are indifferent to the dCK status of cells, they are poor substrates for dCK and good substrates for CD, whereas 5-FdC and 5-CldC are good substrates for both enzymes. The analogs present opportunities for Collateral Sensitivity for 5-azacytidine and gemcitabine resistant tumors.

Hepatectomy enables prolonged survival in select patients with isolated noncolorectal liver metastasis.

OBJECTIVE: This study was done to determine the benefit of undergoing liver resection for noncolorectal metastasis. METHODS: A single-institution retrospective review of all patients (n = 95) who underwent hepatic resection for a noncolorectal liver metastasis from 1990 to 2005 was performed. Primary outcomes measure was months of patient survival after liver resection. RESULTS: Median patient age was 58 years (range 19 to 83 years). There were 37 men (38.9%) and 58 women (61.1%). The 30-day postoperative mortality rate was 2.1%, and postoperative complications developed in 15.8% of patients. Mean hospital stay was 7 days (range 4 to 25 days). Median time of survival from date of liver resection was 36 months, and 5-year survival rate was 34.9%. Primary tumor sites were identified as foregut or gastrointestinal in 16.8% and nongastrointestinal in 83.2%. Patients with a nonforegut primary tumor had a median survival time twice as long as those with foregut primaries (49 months versus 20 months, p < 0.001). Multiple liver metastases were an independent prognostic factor for worse outcomes with a hazard ratio of 3.3 (p = 0.007). No treatment-dependent variables (initial treatment modality, extent of liver resection, margins, complications) were found on multivariable analysis to be important prognostic factors. CONCLUSIONS: In select patients with any of a variety of malignancies metastatic to the liver, prolonged survival can result from liver resection, especially in those with a single, resectable tumor from a nongastrointestinal primary site.

Acute tumor lysis syndrome after proximal splenic artery embolization.

Preoperative splenic artery embolization for massive splenomegaly has been shown to reduce intraoperative hemorrhage during splenectomy. We describe a case of tumor lysis syndrome after proximal splenic artery embolization in a patient with advanced mantle cell lymphoma and splenic involvement. The patient presented initially with hyperkalemia two days after embolization that worsened during splenectomy. He was stabilized, but developed laboratory tumor lysis syndrome with renal failure and expired. High clinical suspicion of tumor lysis syndrome in this setting is advised. Treatment must be started early to avoid serious renal injury and death. Lastly, same day splenectomy and embolization should be considered to decrease the likelihood of developing tumor lysis syndrome.

Risk of postoperative infection in patients with bactibilia undergoing surgery for obstructive jaundice.

BACKGROUND: This study was performed to investigate the relationship between bactibilia and postoperative infection in patients undergoing surgery for obstructive jaundice. METHODS: With IRB approval, we prospectively examined 76 patients undergoing surgery for obstructive jaundice. It was the routine practice of the surgeons performing the operations to culture the common bile duct bile (CBDB). Rates of postoperative infection were analyzed with regard to the effect of positive bile cultures and biliary instrumentation preoperatively. RESULTS: Seventy-one patients had CBDB cultures, 16 of whom had bactibilia. Bactibilia was present in 15 of 47 (33%) who had preoperative ERCP versus one of 24 (4%) of those without preoperative ERCP (p = 0.0075). Postoperative infection, including pneumonia, bloodstream, central venous catheter, surgical site, intraabdominal, and urinary tract infection, occurred in six of 16 (38%) of those with bactibilia versus four of 55 (7%) of those without bactibilia (p = 0.0071). CONCLUSIONS: Preoperative ERCP was associated with an approximately eightfold increase in the likelihood of having culture-positive bile at the time of surgery for obstructive jaundice. Additionally, culture-positive bile at the time of surgery was associated with a greater than fivefold incidence of postoperative infection.

Rapid insulin assay for intraoperative confirmation of complete resection of insulinomas.

BACKGROUND: Solitary insulinomas are usually the cause of organic hypoglycemia, whereas 13% to 24% of patients with hyperinsulinemia have multiple tumors or nesidioblastosis. Intraoperative glucose levels confirming complete excision have variable accuracy. Intraoperative insulin levels have been shown to predict operative outcome. The purpose of this study was to establish criteria for predicting operative success by using a new, rapid insulin assay as an intraoperative adjunct. METHODS: Eight consecutive patients with organic hypoglycemia underwent pancreatic exploration. With an 8-minute immunochemiluminescent insulin assay, peripheral blood levels were obtained preoperatively, during resection, and at 5-minute intervals after surgical excisions. Operative findings and outcome were compared with intraoperative insulin/glucose ratios (I/G), glucose, and insulin levels. RESULTS: By using the return of insulin levels to normal range and I/G ratios < or = 0.4 15 minutes after tumor(s) resection as criteria to predict operative success, 6 patients had their outcomes correctly predicted (5 true-positive and 1 true-negative). One patient with nesidioblastosis had a false-negative result. One could not be evaluated because of diazoxide medication. These criteria predicted postoperative absence of hypoglycemia with specificity of 100% and accuracy of 89%. CONCLUSIONS: These 8-minute insulin assay and criteria can be a useful adjunct for intraoperative assurance of complete insulinoma resection and prediction of postoperative outcome.

The value of cholangiography through Jackson-Pratt drains in the management of postoperative biliary injuries.

Iatrogenic biliary injury is the most significant complication after laparoscopic cholecystectomy. We present our experience with an alternative diagnostic approach using transcatheter cholangiography (TCC) through a Jackson-Pratt (JP) drain and discuss potential benefits and limitations of the technique. From March 2002 to February 2012, 40 patients with major postoperative biliary injury underwent biliary reconstruction at our institution. Mean age was 51.7 ± 18.1 years (range, 19 to 86 years) with 30 (75%) females. Seventeen (42.5%) injuries were detected intraoperatively and in 13 (32.5%) cases, JP drains were placed for biliary drainage. Lesions were classified according to Bismuth grade: I (10 patients [25%]), II (10 patients [25%]), III (six patients [15%]), IV (10 patients [25%]), and V (four patients [10%]). TCC was performed in seven patients with JP drains (53.8%). It fully defined the injury site in three cases of limited magnetic resonance cholangiopancreatography (MRCP) such as common hepatic duct and common bile duct leaks and in four cases (57.1%) that endoscopic retrograde cholangiopancreatography (ERCP) was limited as a result of clipping of the distal common bile duct. TCC showed promising results in cases of limited MRCP and ERCP such as fistulous orifices or leakage. It may represent an alternative adjunct in the diagnostic armamentarium of complex biliary injuries.

Pre-existing hypercoagulability in patients undergoing potentially curative cancer resection.

BACKGROUND: Rotational thromboelastometry (ROTEM) is a new point-of-care test that allows a rapid and comprehensive evaluation of coagulation. We were among the first to show that ROTEM identifies baseline hypercoagulability in 40% of patients with intra-abdominal malignancies and that hypercoagulability persists for ≥1 month after resection. The purpose of this follow-up study was to confirm and extend these observations to a larger population in outpatient preoperative clinics. The hypothesis is that pre-existing hypercoagulability is present in patients undergoing surgery for malignant disease and that coagulation status varies by tumor type. METHODS: After informed consent, preoperative blood samples were drawn from patients undergoing exploratory laparotomies for intra-abdominal malignancies and analyzed with ROTEM. RESULTS: Eighty-two patients were enrolled, including 72 with a confirmed pathologic diagnosis and 10 age-matched controls with benign disease. The most common cancers involved the pancreas (n = 23; 32%), esophagus (n = 19; 26%), liver (n = 12; 17%), stomach (n = 7; 10%), and bile ducts (n = 5; 7%). Preoperative hypercoagulability was detected in 31% (n = 22); these patients were more likely to have lymphovascular invasion (88% vs 50%; P = .011), perineural invasion (77% vs 36%; P = .007), and stage III/IV disease (80% vs 62%; P = .039). More patients with pancreatic tumors (9/23, 39%) were hypercoagulable than with esophageal (3/19, 16%) or liver (2/13, 15%, P = .034) tumors. When only resectable malignancies were considered, clot formation was more rapid (low clot formation time, high alpha) with enhanced maximum clot strength (high maximum clot firmness) in pancreatic versus esophageal or liver cancers and in all cancers versus those with benign disease. CONCLUSION: Preoperative hypercoagulability can be identified with ROTEM and is associated with lymphovascular/perineural invasion and advanced-staged disease in cancer. Compared with other tumor types, pancreatic adenocarcinomas have the greatest risk for hypercoagulability.

A phase II study of capecitabine plus docetaxel in gemcitabine-pretreated metastatic pancreatic cancer patients: CapTere.

PURPOSE: Docetaxel and capecitabine combination is synergistic in preclinical models. We investigated the efficacy and toxicity of this combination as second-line chemotherapy in patients with metastatic pancreatic adenocarcinoma (mPC), pretreated with gemcitabine-based chemotherapy. METHODS: Eligible patients were treated with capecitabine 800 mg/m(2) orally PO bid on days 1-14 in combination with intravenous docetaxel 30 mg/m(2) on days 1 and 8 of each 21-day cycle. The primary end point was overall response rate. Using a three-stage sequential design, two interim analyses for early stopping due to lack of efficacy were planned and conducted after 13 and 26 patients were accrued. Secondary end points included time to treatment failure, progression-free survival (PFS), overall survival (OS) and 50 % drop in CA19-9 levels. RESULTS: Forty-three patients were evaluable for toxicity and 42 evaluable for response, at a median age of 64 years. The majority of patients (74 %) had ECOG PS 0-1. Six patients (14 %) achieved a partial tumor response, and stable disease for ≥2 cycles was observed in 59 % of patients (n = 25). Thirty-five percent (n = 11/31) of patients had a ≥50 % decrease in CA19-9 levels. The median PFS was 3.7 months (95 % CI 2.1-4.3 months), and the median OS was 5.3 months (95 % CI 4.3-8.6 months). Treatment was generally well tolerated. Grade 3 toxicity and grade 4 toxicity were seen in 45 and 5 % of patients, respectively. One patient had a potential treatment-related mortality. CONCLUSIONS: The combination of capecitabine and docetaxel is active and well tolerated in mPC patients pretreated with gemcitabine-based therapy.

Long-term coagulation changes after resection of thoracoabdominal malignancies.

BACKGROUND: The purpose of this study was to evaluate the long-term coagulation status of patients undergoing malignancy resection. STUDY DESIGN: A prospective observational trial was conducted with informed consent in 52 patients (age 66 ± 10 years and 60% male) with thoracoabdominal tumors (pancreas [n = 18, 35%], esophagus [n = 13, 25%], liver [n = 7, 14%], stomach [n = 6, 12%], bile duct [n = 3, 6%], retroperitoneal [n = 3, 6%], and duodenum [n = 2, 4%]) with 6- to 12-month follow-up. Coagulation was evaluated with rotational thromboelastography (ROTEM) on whole blood and with a panel of hemostatic markers on stored plasma. RESULTS: Maximum clot firmness (MCF) in the intrinsic, extrinsic, and fibrinogen pathways increased immediately postoperatively and then decreased by 9.2 ± 4.1 months (p < 0.05). Markers of thrombin generation (prothrombin fragment 1 + 2, fibrinolysis [D-dimer], and endothelial activation [coagulation factor VIII]) were elevated at all time points. The ROTEM pattern depended on histologic type and cancer location. All esophageal tumors were adenocarcinoma and demonstrated similar patterns to the overall population, with MCF differences over time in all 3 pathways (all p < 0.05). Regarding tumors of the pancreas or liver, there were no statistically significant differences when comparing all 3 time periods, but there were time-related differences when evaluating only primary adenocarcinomas of the liver (all p < 0.05). Three patients (6%) developed venous thromboembolism (VTE) and had decreased clot formation time, increased angle, and increased MCF (all p < 0.05). CONCLUSIONS: Cancer patients at risk for VTE can be identified with a point-of-care ROTEM test and may benefit from additional anticoagulation. Biomarkers reflecting different functional hemostasis activity groups (fibrinolysis, thrombin generation, and endothelial activation) confirm the ongoing prothrombotic state. The ROTEM demonstrated increased hypercoagulability postoperatively, which returned to baseline in long-term follow-up. Reversal of cancer-induced hypercoagulability occurred in some patients and varied with tumor histology and location.

Mucoepidermoid carcinoma of the intrapancreatic common bile duct: immunohistochemical profile, prognosis, and review of the literature.

Mucoepidermoid carcinoma of the bile duct is a rare entity. Only one mucoepidermoid carcinoma from the common bile duct has been reported in the Korean literature. Herein, we present the first in the English literature. The tumor arose in the intrapancreatic (distal) common bile duct in an 83-year-old woman who presented with obstructive jaundice and elevated liver enzymes. The tumor invaded the underlying pancreas and peripancreatic adipose tissue and showed pagetoid spread into the extrapancreatic common bile duct and cystic duct. The tumor exhibited nests of malignant cells with diffuse CK7 and MUC1 positivity. The basal cells were p63 and CK5/6 positive. The luminal cells were stained with carcinoembryonic antigen, MUC5, and mucicarmine and were focally positive for CK20. There was focal MUC4 staining on the apical luminal border. The neoplastic cells were negative for MUC2 and HER2-neu. We discuss the clinical presentation, diagnostic features, immunohistochemical profile, and prognosis of mucoepidermoid carcinoma of the common bile duct. The features of this neoplasm are further compared with mucoepidermoid carcinoma of the hepatobiliary system, adenosquamous carcinoma, and mucoepidermoid carcinoma of other organs.

Persistence of hypercoagulable state after resection of intra-abdominal malignancies.

BACKGROUND: The hypercoagulable state associated with cancer imparts considerable risk for venous thromboembolism. Surgical resection of malignancies should theoretically reverse tumor-induced hypercoagulability. However, coagulation changes in cancer patients postresection have not been described thoroughly. Conventional coagulation tests are unable to detect hypercoagulable states. In contrast, rotational thromboelastography (ROTEM) can detect hypo- or hypercoagulable conditions. We hypothesized that the cancer-induced hypercoagulable state would improve after surgical resection. METHODS: After informed consent, blood samples of patients undergoing surgical resection for curative intent were analyzed with serial ROTEM. RESULTS: Thirty-five patients (mean ± SD age 66 ± 17 years; 67% male) had cancers involving the pancreas (n = 12 [34%]), esophagus (n = 10 [29%]), stomach (n = 7 [20%]), bile ducts (n = 3 [9%]), and duodenum (n = 3 [9%]). Preoperative ROTEM identified 14 (40%) who were hypercoagulable. After surgical resection, patients became progressively hypercoagulable with more rapid clot formation time (low clot formation time, high alpha) and higher maximum clot firmness. By week one, 86% (n = 30) had abnormal ROTEM values, including 17 of 21 (81%) who had normal coagulation profiles preoperatively. Most (n = 30 [86%]) remained hypercoagulable at 3 to 4 weeks. CONCLUSIONS: Rotational thromboelastography identifies baseline hypercoagulability in more than one third of patients with intra-abdominal malignancies. This is among the first studies to demonstrate progressive hypercoagulability that persists for at least 1 month after resection. These data support postdischarge thromboprophylaxis regimens in high-risk cancer patients.

Phase II study of gemcitabine, oxaliplatin, and cetuximab in advanced pancreatic cancer.

OBJECTIVE: Little progress has been made in the treatment of pancreatic cancer (PC). This study evaluated the clinical activity of gemcitabine, oxaliplatin, and cetuximab (GOC) in patients with locally advanced or metastatic PC. METHODS: The study primary endpoint was progression-free survival (PFS). Eligible, chemotherapy-naive PC patients were treated with gemcitabine (1000 mg/m(2) over 100 min) on day 1, oxaliplatin (100 mg/m(2)) on day 2, every 2 weeks, and weekly cetuximab, (loading dose of 400 mg/m(2) on cycle 1 day 1 and 250 mg/m(2) thereafter). It was expected that GOC treatment would extend the median PFS from 5.8 to 7.54 months, a relative increase of 30%, compared with gemcitabine and oxaliplatin (historical control). RESULTS: A total of 41 evaluable patients were enrolled. The overall response rate was 24%. Median PFS time was 6.9 months and median overall survival (OS) was 11.3 months. Patients with locally advanced disease had longer median PFS (12.4 vs. 4.7 mo) and OS (15.7 vs. 6.4 mo) compared with patients with metastatic disease. The most common grade 3 to 4 toxicities included neutropenia (32%), infection (with normal or grade 1 to 2 neutropenia, in 24%), neuropathy (17%), fatigue (15%), and rash (7%). Five patients (12%) discontinued study treatment without evidence of progression. Rash was not a significant prognostic factor affecting PFS or OS. CONCLUSIONS: GOC is a feasible combination with an acceptable toxicity profile. However, GOC did not significantly extend PFS in the overall patient population to consider it for further development.