Evaluation of the New ISGLS Definitions of Typical Posthepatectomy Complications.

BACKGROUND AND OBJECTIVES: The International Study Group of Liver Surgery established the first internationally standardized definitions and grading for posthepatectomy hemorrhage, posthepatectomy liver failure, and bile leakage. We aimed to correlate these definitions and grades of complications with objective parameters of the postoperative course, namely, mortality and length of stay, to assess the usefulness in clinical routine. METHODS: A total of 415 patients underwent hepatic surgery between 2004 and 2014. Uni- and multivariate analyses were made for correlations of posthepatectomy hemorrhage, posthepatectomy liver failure, and bile leakage with perioperative parameters and mortality. RESULTS: Of the total, 25 (6.1%) patients developed a posthepatectomy hemorrhage Grade A, 3 (0.7%) patients a posthepatectomy hemorrhage Grade B, and 1 (0.2%) patient a posthepatectomy hemorrhage Grade C; 23 (5.5%) patients had a posthepatectomy liver failure Grade A, 24 (5.8%) patients a posthepatectomy liver failure Grade B, and 7 patients (1.6%) a posthepatectomy liver failure Grade C. Bile leakage Grade A occurred in 10 (2.4%) patients, bile leakage Grade B in 24 (5.8%) patients, and bile leakage Grade C in 7 (1.6%) patients. Mortality was significantly increased in patients with posthepatectomy hemorrhage Grades B and C and in patients with posthepatectomy liver failure Grades A, B, and C. Three (42.9%) patients with bile leakage Grade C died. CONCLUSION: Our data indicate that the new definitions correlate well with mortality and duration of hospital stay.

International Study Group of Pancreatic Surgery Definitions for Postpancreatectomy Complications: Applicability at a High-Volume Center.

INTRODUCTION: The perioperative morbidity following pancreas surgery remains high due to various specific complications: postoperative pancreatic fistula, postpancreatectomy hemorrhage, and delayed gastric emptying. The International Study Group of Pancreatic Surgery has defined these complications. The aim of this study is to evaluate the clinical applicability, to validate the International Study Group of Pancreatic Surgery definition, and to evaluate the postoperative morbidity. METHODS: Between 2004 and 2014, 769 patients underwent resection. Data were collected in a prospective database. Univariate examination was performed using the χ2-test. Continuous data were tested with the Mann-Whitney U-test. Student's t-tests and Fisher's exact tests were performed. RESULTS: A total of 542 patients were included in this study. In all, 91 (16.8%) patients developed postoperative pancreatic fistula, 69 of them clinically relevant grades B and C postoperative pancreatic fistula. Grades B and C postoperative pancreatic fistulas were significantly associated with a longer hospital stay. The postoperative pancreatic fistula grade significantly correlated with re-operation. Totally, 32 (5.9%) patients developed postpancreatectomy hemorrhage. Postpancreatectomy hemorrhage grade was significantly associated with re-operation and 30-day mortality. In all, 14 of 19 patients with grade C postpancreatectomy hemorrhage (73.7%) were re-operated; 3 had a simultaneous postoperative pancreatic fistula C. Grade B postpancreatectomy hemorrhage significantly prolonged hospital stay. Grade C postpancreatectomy hemorrhage significantly prolonged intensive care unit stay. Grade C postpancreatectomy hemorrhage led to longer intensive care unit stay but a shorter hospital stay. Delayed gastric emptying occurred in 131 (24.2%) patients. The delayed gastric emptying grade was significantly associated with re-operation. Nine of the re-operated patients had a simultaneous postoperative pancreatic fistula C. Grades A, B, and C delayed gastric emptying were associated with prolonged hospital- and intensive care unit stay. CONCLUSION: Delayed gastric emptying is the most common specific complication after pancreas resection, followed by postoperative pancreatic fistula and postpancreatectomy hemorrhage. The International Study Group of Pancreatic Surgery definitions are well applicable in clinical routine and the different grades correlate well with severity of clinical condition, length of hospital or intensive care unit stay, and mortality. Their widespread use can contribute to a more reproducible and reliable comparison of surgical outcomes in pancreas surgery.

Hepatocyte-specific Smad7 deletion accelerates DEN-induced HCC via activation of STAT3 signaling in mice.

TGF-ß signaling in liver cells has variant roles in the dynamics of liver diseases, including hepatocellular carcinoma (HCC). We previously found a correlation of high levels of the important endogenous negative TGF-ß signaling regulator SMAD7 with better clinical outcome in HCC patients. However, the underlying tumor-suppressive molecular mechanisms are still unclear. Here, we show that conditional (TTR-Cre) hepatocyte-specific SMAD7 knockout (KO) mice develop more tumors than wild-type and corresponding SMAD7 transgenic mice 9 months after diethylnitrosamine (DEN) challenge, verifying SMAD7 as a tumor suppressor in HCC. In line with our findings in patients, Smad7 levels in both tumor tissue as well as surrounding tissue show a significant inverse correlation with tumor numbers. SMAD7 KO mice presented with increased pSMAD2/3 levels and decreased apoptosis in the tumor tissue. Higher tumor incidence was accompanied by reduced P21 and upregulated c-MYC expression in the tumors. Activation of signal transducer and activator of transcription factor 3 signaling was found in Smad7-deficient mouse tumors and in patients with low tumoral SMAD7 expression as compared with surrounding tissue. Together, our results provide new mechanistic insights into the tumor-suppressive functions of SMAD7 in hepatocarcinogenesis.

Inter-hospital transfer of ECMO-assisted patients with a portable miniaturized ECMO device: 4 years of experience.

OBJECTIVES: Extracorporeal membrane oxygenation (ECMO) in patients with severe pulmonary failure is able to keep patients alive until organ regeneration, until shunting out for further diagnostic and therapeutic options or until transportation to specialized centers. Nonetheless, extracorporeal techniques require a high degree of expertise, so that a confinement to specialized centers is meaningful. Following from this requirement, the need for inter-hospital transfer of patients with severely compromised pulmonary function is rising. METHODS: We report about our experience with a portable ECMO system during inter-hospital air or ground transfer of patients with cardiopulmonary failure. RESULTS: The portable ECMO system was used for transportation to the center and in-hospital treatment in 36 patients with an average age of 53 years suffering from respiratory failure. Accordingly, the ECMO system was implanted as a veno-venous extracorporeal system. Pre-ECMO ventilation time was 5.2 (2-9) days. Twelve patients were transported to our institution by ground and 24 patients by air ambulance over a median distance of 46 km. With the assistance of the ECMO device, prompt stabilization of cardiopulmonary function could be achieved in all patients without any technical complications. Post-ECMO ventilation was 9.8 days. Weaning from the ECMO system was successful in 61% of all patients after a median device working period of 12.7 days; median ICU stay was 34 days and a survival rate of 64% of patients was achieved. Technical (8%) and device-associated bleeding (11%)/thromboembolic (8%) complication rates showed very acceptable levels. CONCLUSION: Our experience demonstrates that miniaturized, portable ECMO therapy allows location-independent, out-of-center stabilization of pulmonary compromised patients with consecutive inter-hospital transfer and further in-house treatment, so that sophisticated ECMO therapy can be offered to every patient, even in hospitals with primary healthcare.

Co-expression of KLK6 and KLK10 as prognostic factors for survival in pancreatic ductal adenocarcinoma.

Kallikreins play an important role in tumour microenvironment and as cancer biomarkers in different cancer entities. Previous studies suggested an upregulation of KLK10 and KLK6 in pancreatic ductal adenocarcinoma (PDAC). Therefore, we evaluated the clinicopathological role of these kallikreins and their value as biomarkers in PDAC.Differential expression was validated by DNA-microarrays and immunohistochemistry in normal and malignant pancreatic tissues. Sera concentrations of both kallikreins were evaluated using ELISA. In silico analysis of possible protein interactions and gene silencing of KLK10 in vitro using siRNAs gave further insights in the pathomechanisms.Gene expression analysis and immunohistochemistry demonstrated a strong expression for KLK10 and KLK6 in PDAC. Statistical analysis showed that co-expression of these kallikreins correlated with an R1-resection status (P=0.017) and worse outcome for overall survival (P=0.031). Multivariate analysis proofed that co-expression is an independent prognostic factor for survival (P=0.043). Importantly, KLK10 knockdown in AsPC-1 cells significantly reduced cell migration, whereas computational analysis suggested interaction of KLK6 with angiogenetic factors as an important mechanism.Co-expression of KLK10 and KLK6 plays an unfavourable role in PDAC. Our results suggest that this effect is likely mediated by an interaction with the factors of the extracellular matrix and enhancement of cancer cell motility.

Serum parathyroid hormone-related protein levels and response to bisphosphonate treatment in hypercalcemia of malignancy.

The pathogenesis of hypercalcemia of malignancy comprises increased net bone resorption and enhanced renal tubular reabsorption of calcium (Ca). To evaluate the prevalence of an increased renal tubular reabsorption of Ca index [tubular reabsorption of calcium index (TRCaI)] in cancer patients with hypercalcemia and of elevated circulating levels of PTH-related protein (PTHrP), which is recognized as a major mediator of this syndrome, we investigated 315 well rehydrated patients, aged 58.1 +/- 0.7 yr (mean +/- SEM), with hypercalcemia [albumin-corrected plasma Ca (pCa), >2.7 mmol/L] secondary to histologically proven malignancy. Changes in pCa and, therefore, various Ca filtered loads were obtained by different degrees of bone resorption inhibition achieved with a single infusion of the bisphosphonate ibandronate, given at various doses on a randomized, double blind basis. PTHrP was determined at baseline in 147 of the patients and 7 days after bisphosphonate therapy in 73. Before ibandronate therapy, pCa was 3.36 +/- 0.02 mmol/L, mean TRCaI was increased at 3.09 +/- 0.03 mmol/L glomerular filtration rate (GFR; normal, 2.40-2.90), and 65% of patients had TRCaI above 2.90 mmol/L GFR. Mean serum PTHrP levels were 4.9 +/- 0.5 pmol/L (normal, <2.5) and values above the normal range were found in 53% of the patients (76% in lung and upper respiratory tract malignancies). By 7 days after the infusion of ibandronate, a decrease in pCa of 0.69 +/- 0.03 mmol/L (20.0 +/- 0.7%; P < 0.001) and in bone resorption [mean change in fasting urinary Ca, 0.09 +/- 0.04 mmol/L GFR (47.6 +/- 8.6%; P < 0.001) and 14.4 +/- 1.7 nmol/mmol (27.6 +/- 10.6%; P < 0.01) in deoxypyridinoline] was observed. TRCaI was slightly lowered by 0.30 +/- 0.09 mmol/L GFR. Mean changes in PTHrP, 1,25-dihydroxyvitamin D3, and PTH were +0.7 +/- 0.4 (P = NS), +27.6 +/- 3.0 (P < 0.001), and +2.9 +/- 0.8 (P < 0.005) pmol/L, respectively. After ibandronate treatment, the relative risk of relapsing hypercalcemia was particularly increased (3.43-fold) in lung and upper respiratory tract malignancies. These results obtained in a large cohort of patients indicate a significant prevalence of an increased renal tubular reabsorption of calcium index in hypercalcemia of malignancy and a substantial proportion of patients with detectable PTHrP.