The Prognostic Impact of Primary Tumor Site Differs According to the KRAS Mutational Status: A Study By the International Genetic Consortium for Colorectal Liver Metastasis.

OBJECTIVE: To examine the prognostic impact of tumor laterality in colon cancer liver metastases (CLM) after stratifying by Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutational status. BACKGROUND: Although some studies have demonstrated that patients with CLM from a right sided (RS) primary cancer fare worse, others have found equivocal outcomes of patients with CLM with RS versus left-sided (LS) primary tumors. Importantly, recent evidence from unresectable metastatic CRC suggests that tumor laterality impacts prognosis only in those with wild-type tumors. METHODS: Patients with rectal or transverse colon tumors and those with unknown KRAS mutational status were excluded from analysis. The prognostic impact of RS versus LS primary CRC was determined after stratifying by KRAS mutational status. RESULTS: 277 patients had a RS (38.6%) and 441 (61.4%) had a LS tumor. Approximately one-third of tumors (28.1%) harbored KRAS mutations. In the entire cohort, RS was associated with worse 5-year overall survival (OS) compared with LS (39.4% vs 50.8%, P = 0.03) and remained significantly associated with worse OS in the multivariable analysis (hazard ratio 1.45, P = 0.04). In wild-type patients, a worse 5-year OS associated with a RS tumor was evident in univariable analysis (43.7% vs 55.5%, P = 0.02) and persisted in multivariable analysis (hazard ratio 1.49, P = 0.01). In contrast, among patients with KRAS mutated tumors, tumor laterality had no impact on 5-year OS, even in the univariable analysis (32.8% vs 34.0%, P = 0.38). CONCLUSIONS: This study demonstrated, for the first time, that the prognostic impact of primary tumor side differs according to KRAS mutational status. RS tumors were associated with worse survival only in patients with wild-type tumors.

Gastrointestinal complications following on-pump cardiac surgery-A propensity matched analysis.

BACKGROUND: Gastrointestinal complications following on-pump cardiac surgery are orphan but serious risk factors for postoperative morbidity and mortality. We aimed to assess incidence, perioperative risk factors, treatment modalities and outcomes. MATERIAL AND METHODS: A university medical center audit comprised 4883 consecutive patients (median age 69 [interquartile range IQR 60-76] years, 33% female, median logistic EuroScore 5 [IQR 3-11]) undergoing all types of cardiac surgery including surgery on the thoracic aorta; patients undergoing repair of congenital heart disease, implantation of assist devices or cardiac transplantation were excluded. Coronary artery disease was the leading indication for on-pump cardiac surgery (60%), patients undergoing cardiac surgery under urgency or emergency setting were included in analysis. We identified a total of 142 patients with gastrointestinal complications. To identify intra- and postoperative predictors for gastrointestinal complications, we applied a 1:1 propensity score matching procedure based on a logistic regression model. RESULTS: Overall, 30-day mortality for the entire cohort was 5.4%; the incidence of gastrointestinal complications was 2.9% and median time to complication 8 days (IQR 4-12). Acute pancreatitis (n = 41), paralytic ileus (n = 14) and acute cholecystitis (n = 18) were the leading pathologies. Mesenteric ischemia and gastrointestinal bleeding accounted for 16 vs. 18 cases, respectively. While 72 patients (51%) could be managed conservatively, 27 patients required endoscopic/radiological (19%) or surgical intervention (43/142 patients, 30%); overall 30-day mortality was 12.1% (p<0.001). Propensity score matching identified prolonged skin-to-skin times (p = 0.026; Odds Ratio OR 1.003, 95% Confidence Interval CI 1.000-1.007) and extended on-pump periods (p = 0.010; OR 1.006, 95%CI 1.001-1.011) as significant perioperative risk factors. COMMENT: Prolonged skin-to-skin times and extended on-pump periods are important perioperative risk factors regardless of preoperative risk factors.

Prognostic Factors Change Over Time After Hepatectomy for Colorectal Liver Metastases: A Multi-institutional, International Analysis of 1099 Patients.

OBJECTIVE: To evaluate the changing impact of genetic and clinicopathologic factors on conditional overall survival (CS) over time in patients with resectable colorectal liver metastasis. BACKGROUND: CS estimates account for the changing likelihood of survival over time and may reveal the changing impact of prognostic factors as time accrues from the date of surgery. METHODS: CS analysis was performed in 1099 patients of an international, multi-institutional cohort. Three-year CS (CS3) estimates at the "xth" year after surgery were calculated as follows: CS3 = CS (x + 3)/CS (x). The standardized difference (d) between CS3 rates was used to estimate the changing prognostic power of selected variables over time. A d < 0.1 indicated very small differences between groups, 0.1 ≤ d < 0.3 indicated small differences, 0.3 ≤ d < 0.5 indicated moderate differences, and d ≥ 0.5 indicated strong differences. RESULTS: According to OS estimates calculated at the time of surgery, the presence of BRAF and KRAS mutations, R1 margin status, resected extrahepatic disease, patient age, primary tumor lymph node metastasis, tumor number, and carcinoembryonic antigen levels independently predicted worse survival. However, when temporal changes in the prognostic impact of these variables were considered using CS3 estimates, BRAF mutation dominated prognosis during the first year (d = 0.48), whereas surgeon-related variables (ie, surgical margin and resected extrahepatic disease) determined prognosis thereafter (d ≥ 0.5). Traditional clinicopathologic factors affected survival constantly, but only to a moderate degree (0.3 ≤ d < 0.5). CONCLUSIONS: The impact of genetic, surgery-related, and clinicopathologic factors on OS and CS3 changed dramatically over time. Specifically, BRAF mutation status dominated prognosis in the first year, whereas positive surgical margins and resected extrahepatic disease determined prognosis thereafter.

Should heart failure patients be left to fate? Temporary implementation of veno-arterial extracorporeal membrane oxygenation for haemodynamic support during excision of rectal carcinoma in an end-stage biventricular heart failure patient.

Management of end-stage heart failure patients requiring major general surgery is not well defined. Due to poor cardiorespiratory reserve, perioperative morbidity and mortality are excessively high. We report a case of temporary implementation of veno-arterial extracorporeal membrane oxygenation for haemodynamic support during excision of rectal carcinoma in an end-stage heart failure patient and describe perioperative management.

Double KRAS and BRAF Mutations in Surgically Treated Colorectal Cancer Liver Metastases: An International, Multi-institutional Case Series.

BACKGROUND: While previously believed to be mutually exclusive, concomitant mutation of Kirsten rat sarcoma viral oncogene homolog (KRAS)- and V-raf murine sarcoma b-viral oncogene homolog B1 (BRAF)-mutated colorectal carcinoma (CRC), has been described in rare instances and been associated with advanced-stage disease. The present case series is the first to report on the implications of concurrent KRAS/BRAF mutations among surgically treated patients, and the largest set of patients with surgically treated colorectal liver metastasis (CRLM) and data on KRAS/BRAF mutational status thus far described. CASE SERIES: We present cases from an international, multi-institutional cohort of patients that underwent hepatic resection for CRLM between 2000-2015 at seven tertiary centers. The incidence of KRAS/BRAF mutation in patients with CRLM was 0.5% (4/820). Of these cases, patient 1 (T2N1 primary, G13D/V600E), patient 2 (T3N1 primary, G12V/V600E) and patient 3 (T4N2 primary, G13D/D594N) succumbed to their disease within 485, 236 and 79 days respectively, post-hepatic resection. Patient 4 (T4 primary, G12S/G469S) was alive 416 days after hepatic resection. CONCLUSION: The present case series suggests that the incidence of concomitant KRAS/BRAF mutations in surgical cohorts may be higher than previously hypothesized, and associated with more variable survival outcomes than expected.

Pancreatic resection for intraductal papillary mucinous neoplasm- a thirteen-year single center experience.

BACKGROUND: The purpose of this study is to review our results for pancreatic resection in patients with intraductal papillary mucinous neoplasm (IPMN) with and without associated carcinoma. METHODS: A total of 54 patients undergoing pancreatic resection for IPMN in a single university surgical center (Medical University of Graz) were reviewed retrospectively. Their survival rates were compared to those of patients with pancreatic ductal adenocarcinoma. RESULTS: Twenty-four patients exhibit non-invasive IPMN and thirty patients invasive IPMN with associated carcinoma. The mean age is 67 (+/-11) years, 43 % female. Surgical strategies include classical or pylorus-preserving Whipple procedure (n = 30), distal (n = 13) or total pancreatectomy (n = 11), and additional portal venous resection in three patients (n = 3). Median intensive care stay is three days (range 1 - 87), median in hospital stay is 23 days (range 7 - 87). Thirty-day mortality is 3.7 %. Median follow up is 42 months (range 0 - 127). One-, five- and ten-year overall actuarial survival is 87 %; 84 % and 51 % respectively. Median overall survival is 120 months. Patients with non-invasive IPMN have significantly better survival than patients with invasive IPMN and IPMN-associated carcinoma (p < 0.008). In the subgroup of invasive IPMN with associated carcinoma, a positive nodal state, perineural invasion as well as lymphovascular infiltration are associated with poor outcome (p < 0.0001; <0.0001 and =0.001, respectively). Elevated CA 19-9(>37 U/l) as well as elevated lipase (>60 U/l) serum levels are associated with unfavorable outcome (p = 0.009 and 0.018; respectively). Patients operated for pancreatic ductal adenocarcinoma show significantly shorter long-term survival than patients with IPMN associated carcinoma (p = 0.001). CONCLUSIONS: Long-term outcome after pancreatic resection for non-invasive IPMN is excellent. Outcome after resection for invasive IPMN with invasive carcinoma is significantly better than for pancreatic ductal adenocarcinoma. In low- and intermediate risk IPMN with no clear indication for immediate surgical resection, a watchful waiting strategy should be evaluated carefully against surgical treatment individually for each patient.

Pancreas Cancer Surgery in Octogenarians - Should We or Should We Not?

BACKGROUND/AIM: In this study we aimed to determine if advanced age represents a risk factor for negative perioperative and long-term outcome in patients undergoing curative surgery ductal pancreatic adenocarcinoma surgery. PATIENTS AND METHODS: Two-hundred-twenty-one consecutive patients, twelve (6%) patients ≥80 years were included in the study. We assessed perioperative and long-term outcome and independent predictors for in-hospital mortality with Cox regression analysis. RESULTS: Advanced age was not a predictor for in-hospital mortality (6.3% in non-octogenarian versus 8.3% in octogenarians; p=0.55) nor for morbidity (31% vs. 32%; p=0.69). An ASA score >II was the only predictor for in-hospital mortality (odds ratio (OR)=10.10, 95%CI=1.28-79.60; Hosmer-Lemeshow: p=0.86). No significant difference was observed in one- and five-year survival rates (68 and 58% vs. 16 and 14%; log-rank p=0.61). CONCLUSION: Advanced age is not a risk factor for negative outcome in curative pancreatic cancer surgery. Therefore, this single curative option should be considered in octogenarians at risk.

Variability of protein and phosphoprotein levels in clinical tissue specimens during the preanalytical phase.

The quality of human tissue specimens can have a significant impact on analytical data sets for biomarker research. The aim of this study was to characterize fluctuations of protein and phosphoprotein levels in human tissue samples during the preanalytical phase. Eleven intestine and 17 liver specimens were surgically resected, aliquoted, and either snap-frozen or fixed in formalin immediately or exposed to different ischemic conditions before preservation. Protein levels in the resultant samples were investigated by reverse phase protein array, Western blot analysis, and liquid chromatography-tandem mass spectrometry. Our data revealed that the degree of sensitivity of proteins and phosphoproteins to delayed preservation varied between different patients and tissue types. For example, up-regulation of phospho-p42/44 MAPK in intestine samples was seen in some patients but not in others. General trends toward up- or down-regulation of most proteins were not evident due to pronounced interpatient variability but signal intensities of only a few proteins, such as cytokeratin 18, were altered from baseline in postresection samples. In contrast, glyceraldehyde 3-phosphate dehydrogenase was found to be stable during periods of cold ischemia. Our study represents a proper approach for studying potential protein fluctuations in tissue specimens for future biomarker development programs.

Effect of somatostatin analogue octreotide on pain relief after major abdominal surgery.

BACKGROUND: Octreotide acetate is an 8-amino-acids synthetic octapeptide analogue of somatostatin with much-enhanced duration of action and lower incidence of side effects. We assessed the utility of using intravenous octreotide as an adjuvant to opioid analgesia that might exert a post-operative opioid-sparing effect. METHODS: Forty-four patients were randomly allocated, to receive either a placebo or intraoperative octreotide 0.33 microg kg(-1)h(-1) intravenous infusion that was maintained in the post-operative period. Patients received for post-operative analgesia an intravenous piritramide patient controlled analgesia (PCA), set to deliver a piritramide 0.02 mgkg(-1) dose. RESULTS: Two-way ANOVA revealed significantly fewer (P=0.0003) mean+/-SD weighted piritramide dose requirements in the octreotide group (19.5+/-6.3 microg kg(-1)h(-1)) than in the control group (35.7+/-8.2 microg kg(-1)h(-1)). Dunnett's two-sided multiple-comparison post hoc test revealed a significant difference between the two groups during the first 22 post-operative hours, following which there were no differences between the two groups. There were no significant differences over time in the mean arterial pressure (P=0.722), heart rate (P=0.579) and respiratory rate (P=0.823) between the octreotide group (80+/-10mm Hg, 74+/-12, 14+/-2) and the control group (82+/-9 mm Hg, 76+/-11, 15+/-3), respectively. CONCLUSION: We demonstrated that perioperative octreotide intravenous infusion could be an adjuvant to opioid analgesia as it exerted a piritramide opioid-sparing effect. We encountered more systemic side effects such as nausea, abdominal discomfort, and diarrhea in the octreotide group than in the control group. Our findings could be beneficial to patients who cannot tolerate the adverse effects of opioids.

Surgical therapy options in polycystic liver disease.

INTRODUCTION: Polycystic liver disease (PLD) is a rare affliction frequently observed in association with polycystic kidney disease. Only symptomatic patients require treatment, which can be conservative or surgical, i.e. laparoscopic or conventional. We report the results of our experience in the surgical management of polycystic liver disease. METHODS: Between 1994 and 2003, 19 patients (16 female, 3 male) were referred to our center for the management of PLD. Their median age was 50 years (range 33-72). All were symptomatic and their cysts had a median diameter of 11 cm (range 5-22). RESULTS: Laparoscopic management was undertaken in eight patients, with one conversion to open technique because of bleeding from a superficial hepatic vein. An open procedure was performed in 11 patients: one left hemihepatectomy, deroofing in two patients, segment resection 2/3 plus deroofing in six patients, and segment resection 5/6 plus deroofing in two patients. Four patients had complications: one case of biliary leakage was managed conservatively; two patients had pneumothorax caused by the cava catheter inserted for anesthesia, and one patient's abdominal drain tore off and had to be removed by relaparotomy on the fourth postoperative day. Median follow-up of all patients was 49 months (range 7-98). In one patient there was symptomatic recurrence with hepatomegaly and compression of the inferior vena cava 84 months after the first operation. CONCLUSIONS: Careful selection of patients and meticulous surgical technique are recommended in the management of PLD. The treatment of choice for symptomatic Gigot or Morino type 1 PLD is laparoscopic surgery, and for advanced stage PLD combined hepatic resection and cyst fenestration.

Minimally invasive management of dysontogenetic hepatic cysts.

BACKGROUND: Liver cysts occur with a prevalence of 4%-7% in the general population. Laparoscopic surgery is effective for solitary cysts and in selected patients with polycystic liver disease (PLD). We present our experience in the laparoscopic management of dysontogenetic cysts. PATIENTS AND METHODS: Between 1994 and 2002, 36 patients were referred to our centre for the management of dysontogenetic cystic liver disease. Management was laparoscopic in 16 cases. Indications were solitary giant cysts (n=9) and PLD (n=7). RESULTS: Laparoscopic procedures were completed in 15 patients. Mean operating time was 90 min. There were no deaths. In one case there was an intraoperative complication: bleeding from a superficial hepatic vein necessitated conversion to an open procedure. There were two postoperative complications: one patient with biliary leakage, which was managed conservatively, and one patient with a pneumothorax caused by the cava catheter installed for anaesthesia. Median follow-up was 36 months. There was no symptomatic recurrence. CONCLUSION: Laparoscopy can be recommended as the procedure of choice for symptomatic solitary giant cysts and PLD Gigot type I.

Pyloric obstruction caused by prolapse of a hyperplastic gastric polyp.

Hyperplastic gastric polyps account for the majority of benign gastric polyps and are generally diagnosed by routine gastroscopy as they rarely become symptomatic. We report a 79-year-old woman who presented with intermittent attacks of bloating, belching, nausea and vomiting. Endoscopy showed a pedunculated polyp in the gastric antrum prolapsing through the pylorus, thus obstructing the gastric outlet. The polyp was repositioned with an endoscopic forceps and then removed at its pedicle by endoscopic snare excision. Histologic examination showed a hyperplastic polyp without dysplasia or malignancy. The significance of gastric polyps is discussed from the clinical point of view.