Inter-patient heterogeneity in the hepatic ischemia-reperfusion injury transcriptome: Implications for research and diagnostics.

Cellular responses induced by surgical procedure or ischemia-reperfusion injury (IRI) may severely alter transcriptome profiles and complicate molecular diagnostics. To investigate this effect, we characterized such pre-analytical effects in 143 non-malignant liver samples obtained from 30 patients at different time points of ischemia during surgery from two individual cohorts treated either with the Pringle manoeuvre or total vascular exclusion. Transcriptomics profiles were analyzed by Affymetrix microarrays and expression of selected mRNAs was validated by RT-PCR. We found 179 mutually deregulated genes which point to elevated cytokine signaling with NFκB as a dominant pathway in ischemia responses. In contrast to ischemia, reperfusion induced pro-apoptotic and pro-inflammatory cascades involving TNF, NFκB and MAPK pathways. FOS and JUN were down-regulated in steatosis compared to their up-regulation in normal livers. Surprisingly, molecular signatures of underlying primary and secondary cancers were present in non-tumor tissue. The reported inter-patient variability might reflect differences in individual stress responses and impact of underlying disease conditions. Furthermore, we provide a set of 230 pre-analytically highly robust genes identified from histologically normal livers (<2% covariation across both cohorts) that might serve as reference genes and could be particularly suited for future diagnostic applications.

Platelet to Lymphocyte Ratio Correlates With Carcinoma Progression in Pancreatic Intra Epithelial Neoplasia.

BACKGROUND/AIM: Pancreatic intraepithelial neoplasia (PanIN) is the most common precursor lesion to pancreatic adenocarcinoma (PDAC). Yet no criteria to quantify patients at risk for progression to PDAC with PanIN exist. Platelet to lymphocyte ratio is an inflammatory marker that has been associated with overall survival in patients with invasive malignancies including pancreatic cancer. Preoperative sarcopenia has been linked to more aggressive diseases in pancreatic neoplasms. We aimed to assess a relation between PLR and sarcopenia as predictors for tumor progression in patients undergoing pancreatic resection for IPMN. PATIENTS AND METHODS: We retrospectively reviewed 102 patients (46 females, 56 males) who underwent pancreatic resection for PanIn. PLR was calculated and quantified using a cutoff of 110, sarcopenia was quantified using the skeletal muscle index (SMI) on preoperative abdominal imaging. Both were co-evaluated with additional demographic, clinical, pathological, and imaging data for possible correlation with PanIN associated PDAC. RESULTS: PLR was significantly elevated in patients with PanIN - associated PDAC (p=0.006). In the multivariate analysis, invasive carcinomas were significantly more prevalent in patients with PLR above 110 (OR=4.06, 95%CI=3.91-4.12, p=0.04). Patients with elevated PLR had a two-times higher risk to die in the postoperative period (HR=2.26, 95%CI=1.04-2.21, p=0.001). Patients with elevated PLR, preoperative jaundice and sarcopenia were the most likely to have PanIN-associated PDAC (OR=3.48, 95%CI=2.98-8.41, p=0.02). CONCLUSION: PLR is an independent predictive marker for the presence of PanIN associated invasive carcinoma.

The Predictive Value of the CRP-to-Albumin Ratio for Patients With Pancreatic Cancer After Curative Resection: A Retrospective Single Center Study.

BACKGROUND/AIM: Prognostic factors like the CRP-to-albumin ratio (CAR) represent potential predictors for survival of pancreatic cancer patients. We aimed to investigate the prognostic strength of the CAR for overall survival of patients with pancreatic cancer undergoing pancreatic resection. PATIENTS AND METHODS: Data from a total of 202 patients with pancreatic adenocarcinoma who had undergone curative pancreatic resection were subjected to a retrospective review. Overall survival was calculated according to the Kaplan-Meier method, and multivariate Cox regression analysis was used for calculating the prognostic strength of CAR. RESULTS: CAR was an independent prognostic factor of overall survival in univariate and multivariate Cox regression analysis. Elevated CAR was associated with a higher median value of Charlson Index, higher Union for International Cancer Control (UICC) classification and increased carcinoembryonic antigen (CEA) levels. CONCLUSION: CAR is a useful prognostic factor for the prediction of overall survival for patients undergoing pancreatic surgery. The impact of CAR in individual risk assessment should be evaluated in further studies.

Marking Disappearing Colorectal Liver Metastases After Complete Response to Neoadjuvant Chemotherapy via CT - A Pilot Study.

BACKGROUND/AIM: The liver is a frequent site for metastases of colorectal cancer. Approximately 15% of patients have hepatic metastases at the time of diagnosis and another 50% develop them over the course of their disease. Only 10-25% of patients are candidates for liver resection. The aim of this study was to assess the benefit of preoperative computed tomography (CT)-guided wire marking of disappearing colorectal liver metastases (CRLMs) (radiological disappearance of metastases) before surgical resection. PATIENTS AND METHODS: Between January 2011 and January 2014, 20 patients with potentially disappearing CRLMs were selected for CT-guided wire marking. Following treatment with neoadjuvant chemotherapy, disappearing CRLMs were marked via CT guidance. Afterwards, the marked sites were resected. RESULTS: Complete histological response to neoadjuvant chemotherapy was only in 10 resected sites (18%), and 46 (82%) resected liver metastases showed metastatic tissue present. Both overall survival and the disease-free rates in patients after using our method were 55%. CONCLUSION: This study demonstrated the usefulness of CT-guided wire marking to mark disappearing CRLMs in order to improve long-term effectiveness of surgical treatment.

Diethylnitrosamine (DENA) recapitulates formation of hepatic angiosarcoma in pigs.

BACKGROUND & AIM: Primary hepatic angiosarcoma is a rare tumor with poor prognosis. The aim of this study was to generate a new angiosarcoma model to improve research on hepatic angiosarcoma. METHODS: Pigs sus scrofa were treated with different regimens of diethylnitrosamine (DENA). Tissues were analyzed by histology and immunohistochemistry. Serum parameters were determined. Angiosarcoma tissue was investigated for chromosomal aberrations by aCGH analysis. RESULTS: Animals of almost all different treatment regimens developed a multitude of variable liver lesions. Different tumor types such as granulation tissue type, cellular-like, hyalinization necrosis-like, angiosarcoma-like, dysplastic nodule-like, hepatocellular-like, glandular structure-like, and leiomyoma-like lesions were observed. Weekly treatment with 15 mg/kg for up to 52 weeks or a single shot of 200 mg/kg DENA led to the development of hepatic angiosarcomas. aCGH analysis of angiosarcoma tissue revealed increased alterations in tumors compared to non-tumorous tissue. Most of the chromosomal alterations were found on chromosomes 6, 7, 12, and 14. CONCLUSION: In this preliminary study treatment of sus scrofa with weekly injections of 15 mg/kg DENA results in a new model for primary hepatic angiosarcoma. This model may help to shed light on the pathomechanisms of primary hepatic angiosarcoma and might therefore open new treatment options.

Operative R0 resection of diffuse large B-cell lymphoma of the pelvis: a case report.

BACKGROUND: Diffuse large B-cell lymphoma is the most common subtype of non-Hodgkin lymphoma with or without involvement of extranodal sites. Rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) therapy represents the current standard therapy, achieving a rather dissatisfying outcome in approximately 30-40% of all cases. CASE PRESENTATION: We present the case of a 43-year-old Austrian woman with an incidentally detected large pelvic mass which was diagnosed as diffuse large B-cell lymphoma. Initially, the lymphoma intraoperatively appeared to be an inoperable conglomerate tumor. Soon, intestinal perforation induced by tumor infiltration occurred, which initiated a closure of the small intestine and application of a jejunal probe and a percutaneous endoscopic gastrotomy tube. Treatment utilizing the gold standard rituximab in combination with cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) was performed, partly resulting in remission according to radiological follow-up. In view of diagnosis and primary treatment development, the predictive outcome appeared unsound. However, within the procedure of the latest surgical intervention, which was intended to at least reconstruct the intestinal passage in order to improve quality of life, a surgical R0 resection of the residual tumor mass was achieved. CONCLUSIONS: The case presented here reports an unanticipated process of diffuse large B-cell lymphoma, underlining the importance of interdisciplinary cooperation and surgical intervention within the realms of state-of-the-art treatment.

Austrian consensus guidelines on imaging requirements prior to hepatic surgery and during follow-up in patients with malignant hepatic lesions.

Rapid advances in imaging technology have improved the detection, characterization and staging of colorectal liver metastases, hepatocellular carcinoma and cholangiocarcinoma. A variety of imaging modalities are available and play a pivotal role in the work-up of patients, particularly as imaging findings determine resectability. Surgery often represents the only measure that can render long-term survival possible. Imaging is also indispensable for the assessment of responses to neoadjuvant treatment and for the detection of recurrence. At a consensus meeting held in June 2017 in Vienna, Austria, Austrian experts in the fields of surgery and radiology discussed imaging requirements prior to and after hepatic surgery for malignant liver lesions. This consensus was refined by online voting on a total of 47 items. Generally, the degree of consensus was high. The recommendations relate to the type of preferred preoperative imaging modalities, technical settings with respect to computed tomography and magnetic resonance imaging, use of contrast agents, reporting, postoperative follow-up, and long-term follow-up. Taking local resources into account, these consensus recommendations can be implemented in daily clinical practice at specialized centers as well as outpatient diagnostic institutes in Austria.

Rarity among benign gastric tumors: Plexiform fibromyxoma - Report of two cases.

Plexiform fibromyxoma is a very rare mesenchymal tumor of the stomach, found almost exclusively in the antrum/pylorus region. The most common presenting symptoms are anemia, hematemesis, nausea and unintentional weight loss, without sex or age predilection. We describe here two cases of plexiform fibromyxoma, involving a 16-year-old female and a 34-year-old male. Both patients underwent complete resection (R0) by distal gastrectomy and retrocolic gastrojejunostomy (according to Billroth 2); for both, the postoperative course was uneventful. Histology showed multiple intramural and subserosal nodules with characteristic plexiform growth, featuring bland spindle cells situated in an abundant myxoid stroma with low mitotic activity. Immunohistochemistry showed α-smooth muscle actin-positive spindle cells, focal positivity for CD10, and negative staining for KIT, DOG1, CD34, S100, ß-catenin, STAT-6 and anaplastic lymphoma kinase. One of the cases showed focal positivity for h-caldesmon and desmin. Upon follow-up, no sign of disease was found. In the differential diagnosis of plexiform fibromyxoma, it is important to exclude the more common gastrointestinal stromal tumors as they have greater potential for aggressive behavior. Other lesions, like neuronal and vascular tumors, inflammatory fibroid polyps, abdominal desmoid-type fibromatosis, solitary fibrous tumors and smooth muscle tumors, must also be excluded.

Metachronous gallbladder metastasis from renal cell carcinoma-a rare clinical manifestation.

Renal cell carcinoma (RCC) represents a rare tumor entity accounting for approximately 3 % of all malignancies in the adult population. Approximately 30 % of all patients suffering from RCC develop metastases after nephrectomy and another 30 % of patients suffer from synchronous metastases at the date of diagnosis. Gallbladder metastases represent an extremely rare clinical condition and up to date there are only 35 published cases of gallbladder metastasis from RCC. Surgical resection should be the treatment of choice in any case based on the reported data in literature. In spite of the small series of cases, survival can be improved even in patients suffering from additional sites of metastases.

The Value of Lymph Node Dissection in the Surgery of Colorectal Cancer Liver Metastases.

BACKGROUND/AIM: Liver resection is the best treatment for metastatic colorectal cancer (CRC). Hepatic lymph node metastases are considered as extrahepatic disease and represent an unfavorable prognostic factor. However, extrahepatic disease, when resectable, provides no contraindication for surgical therapy. The aim of this study was to evaluate the prevalence of hepatic lymph node involvement in our patients' cohort. PATIENTS AND METHODS: Twenty patients submitted to resection for colorectal liver metastases were studied prospectively. Three areas for lymph node dissection were defined and analyzed separately. Lymph nodes were examined by hematoxylin and eosin staining and immunohistochemistry for Pan-Keratin. RESULTS: In average, 5 lymph nodes were harvested per patient. Macroscopic enlargement was not a definite sign for metastatic involvement. No morbidity or mortality was associated with lymphadenectomy. In our patients' collective, no cases of lymph node metastases occurred. CONCLUSION: There is no evidence of a survival benefit after lymph node dissection in patients with CRC liver metastases in the literature. Systematic lymphadenectomy can, however, provide a prognostic tool to better plan further treatment.

Surgical Management of Duodenal Gastrointestinal Stromal Tumors: A Case Report.

Gastrointestinal stromal tumors (GISTs) represent the most common mesenchymal tumor entity of the gastrointestinal tract. In fewer than 5% of cases, primary GISTs are located in the duodenum. Surgery represents the treatment of choice for localized tumor disease and remains challenging in GISTs located at the duodenum. The optimal surgical approach is currently discussed controversially in the literature due to the fact that extended resections in terms of pancreaticoduodenectomy may cause significant postoperative morbidity and mortality compared to limited resection. We report on a rare case of GIST located in the upper part of the duodenum treated by limited surgical resection. Avoidance of postoperative complications may lead to optimal oncological outcome in selected patients.

A Case of Focal Small-cell Neuroendocrine Carcinoma in the Vicinity of the Extrahepatic Bile Duct, Adjacent to an Extensive Biliary Intraepithelial Neoplasm: A Diagnostic Challenge with Major Clinical Implications.

Gastroenteropancreatic neuroendocrine tumors are known for their aggressiveness. Diagnosis of various bile duct pathologies, like biliar intraepithelial neoplasm, mixed adenoneuroendocrine carcinomas or small cell carcinomas, is challenging. This case report focuses on a rare case of a focal primary minute small cell carcinoma in the vicinity of the extrahepatic bile duct, presenting itself next to an extensive biliar intraepithelial neoplasm. This finding led to adjuvant chemotherapy, followed by major surgery. Therapeutic approach was based on CT and MRI scans but most importantly on immunohistochemistry and histological evaluation. Initially CR seemed achievable, but metastases were to be found rapidly. The authors want to underline the fact that major clinical decisions are based on sometimes tiny specimens; as literature shows it is absolutely advisable to use markers to differentiate the dignity of investigated areas. The authors call for keeping collision of tumors in mind and adding KOC staining and using it in a routine manner examining biliary duct lesions.

Preparing for prospective clinical trials: a national initiative of an excellence registry for consecutive pancreatic cancer resections.

BACKGROUND: Despite significant improvements in perioperative mortality as well as response rates to multimodality treatment, results after surgical resection of pancreatic adenocarcinoma with respect to long-term outcomes remain disappointing. Patient recruitment for prospective international trials on adjuvant and neoadjuvant regimens is challenging for various reasons. We set out to assess the preconditions and potential to perform perioperative trials for pancreatic cancer within a well-established Austrian nationwide network of surgical and medical oncologists (Austrian Breast & Colorectal Cancer Study Group). METHODS: From 2005 to 2010 five high-volume centers and one medium-volume center completed standardized data entry forms with 33 parameters (history and patient related data, preoperative clinical staging and work-up, surgical details and intraoperative findings, postoperative complications, reinterventions, reoperations, 30-day mortality, histology, and timing of multimodality treatment). Outside of the study group, in Austria pancreatic resections are performed in three "high-volume" centers (>10 pancreatic resections per year), three "medium-volume" centers (5­10 pancreatic resections per year), and the rest in various low-volume centers (<5 pancreatic resections per year) in Austria. Nationwide data for prevalence of and surgical resections for pancreatic adenocarcinoma were contributed by the National Cancer Registry of Statistics of Austria and the Austrian Health Institute. RESULTS: In total, 492 consecutive patients underwent pancreatic resection for ductal adenocarcinoma. All postoperative complications leading to hospital readmission were treated at the primary surgical department and documented in the database. Overall morbidity and pancreatic fistula rate were 45.5 % and 10.1 %, respectively. Within the entire cohort there were 9.8 % radiological reinterventions and 10.4 % reoperations. Length of stay was 16 days in median (0­209); 12 of 492 patients died within 30 days after operation, resulting in a 30-day mortality rate of 2.4 %. Seven of the total 19 deaths (36.8 %) occurred after 30 days, during hospitalization at the surgical department, resulting in a hospital mortality rate of 3.9 % (19/492). With a standardized histopathological protocol, there were 70 % (21/30) R0 resections, 30 % (9/30) R1 resections, and no R2 resections in Vienna and 62.7 % (32/51) R0 resections, 35.3 % (18/51) R1 resections, and 2 % (1/51) R2 resections in Salzburg. Resection margin status with nonstandardized protocols was classified as R0 in 82 % (339/411), R1 in 16 % (16/411), and R2 in 1.2 % (5/411). Perioperative chemotherapy was administered in 81.1 % of patients (8.3 % neoadjuvant; 68.5 % adjuvant; 4.3 % palliative); chemoradiotherapy (1.6 % neoadjuvant; 3 % adjuvant; 0.2 % palliative), in 4.9 % of patients. The six centers that contributed to this registry initiative provided surgical treatment to 40 % of all Austrian patients, resulting in a median annual recruitment of 85 (51­104) patients for the entire ABCSG-group and a median of 11.8 (0­38) surgeries for each individual department. CONCLUSIONS: Surgical quality data of the ABCSG core pancreatic group are in line with international standards. With continuing centralization the essential potential to perform prospective clinical trials for pancreatic adenocarcinoma is given in Austria. Several protocol proposals aiming at surgical and multimodality research questions are currently being discussed

Health-related quality of life after TAPP repair for the sportsmen's groin.

BACKGROUND: Sportsmen's groin (SG) is a clinical diagnosis of chronic, painful musculotendinous injury to the medial inguinal floor in the absence of a groin hernia. Long-term results for laparoscopic inguinal hernia repair, especially data on health-related quality of life (HRQOL), are scant and there are no available data whatsoever on HRQOL after SG. The main goal of this study was to compare postoperative QOL data in the long term after transabdominal preperitoneal hernioplasty (TAPP) in groin hernia and SG patients with QOL data of a normal population. METHODS: This study included all patients (n = 559) who underwent TAPP repair between 2000 and 2005. Forty seven patients (8.4 %) were operated on for SG. We sent out the Short Form 36 Health Survey (SF-36) questionnaire for QOL evaluation. QOL data were compared with data from an age- and sex-matched normal population. RESULTS: Ultimately, 383 completed questionnaires were available for evaluation (69 % response rate). The mean follow-up time was 94 ± 20 months. In the SG group there were statistically significant differences in three subscales of the SF-36 and the mental component summary measure, showing better results for the SG group compared to the sex- and age-matched normal group data. There were no statistically significant differences between groin hernia patients and the sex- and age-matched normal population. CONCLUSION: TAPP repair for SG as well as groin hernia results in good HRQOL in the long term. Results for SG patients are comparable with QOL data of a normal population or even better.

Effects of intra- and post-operative ischemia on the metabolic profile of clinical liver tissue specimens monitored by NMR.

Metabolomic profiles of tissues could greatly contribute to advancements in personalized medicine but are influenced by differences in adopted preanalytical procedures; nonhomogeneous pre- and post-excision ischemia times are potential sources of variability. In this study, we monitored the impact of ischemia on the metabolic profiles, acquired with high-resolution magic-angle-spinning (1)H NMR, of 162 human liver samples collected during and up to 6 h after routine surgery. The profiles changed significantly as a function of intraoperative warm ischemia (WI) and postresection cold ischemia (CI) time, with significant variations in the concentration of the same 16 metabolites. Therefore, a tight control of the preanalytical phase is essential for reliable metabolomic analyses of liver diseases. The NMR profiles provide a reliable "fingerprint" of ischemia and have predictive value: the best-performing predictive models are found to discriminate extreme time points of CI (0' vs 360 ') in the training set with cross-validation accuracy of ~90%; samples in the validation cohort can discriminate short (≤60') from long (≥180') CI with an accuracy of ~80%. For WI, the corresponding figures are 95.6 and 92%, respectively. Therefore, ischemia NMR profiles might become a tool for tissue quality control in biobanks.

A case report of an intraabdominal microcystic and pseudopapillary spindle and round cell neoplasm and a comparison to other intraabdominal mesenchymal tumors.

AIM: We present a case of a new mesenchymal tumor entity named 'distinctive microcystic and pseudopapillary spindle and round cell neoplasm', of which only 30 cases have been reported worldwide. CASE REPORT: A fifty-two-year-old woman presented in January 2012 with epigastric pain of changing character and weight loss. Examinations revealed a tumor 10×6.8×9.8 cm in diameter showing infiltration in the surrounding organs. A Whipple procedure and a right hemicolectomy were necessary to achieve free resection margins. At the last follow-up in November 2012 the patient was well and there were no signs of recurrence or metastatic spread. Intra-abdominal mesenchymal tumors cause unspecific abdominal symptoms. Local recurrence and metastatic spread can occur. The main prognostic factors for survival are a free margin after resection and the histological subtype of the tumor. Behavioral prediction is not possible in every case and the treatment has to be individualized for every patient. CONCLUSION: This case represents a new entity of mesenchymal tumor. It was treated according to the guidelines for intra-abdominal sarcomas. Further investigation of this kind of tumor is necessary to define therapeutic guidelines.

Hepatobiliary transporter expression and post-operative jaundice in patients undergoing partial hepatectomy.

BACKGROUND AND AIMS: Post-operative hyperbilirubinaemia in patients undergoing liver resections is associated with high morbidity and mortality. Apart from different known factors responsible for the development of post-operative jaundice, little is known about the role of hepatobiliary transport systems in the pathogenesis of post-operative jaundice in humans after liver resection. METHODS: Two liver tissue samples were taken from 14 patients undergoing liver resection before and after Pringle manoeuvre. Patients were retrospectively divided into two groups according to post-operative bilirubin serum levels. The two groups were analysed comparing the results of hepatobiliary transporter [Na-taurocholate cotransporter (NTCP); multidrug resistance gene/phospholipid export pump(MDR3); bile salt export pump (BSEP); canalicular bile salt export pump (MRP2)], heat shock protein 70 (HSP70) expression as well as the results of routinely taken post-operative liver chemistry tests. RESULTS: Patients with low post-operative bilirubin had lower levels of NTCP, MDR3 and BSEP mRNA compared to those with high bilirubin after Pringle manoeuvre. HSP70 levels were significantly higher after ischaemia-reperfusion (IR) injury in both groups resulting in 4.5-fold median increase. Baseline median mRNA expression of all four transporters prior to Pringle manoeuvre tended to be lower in the low bilirubin group whereas expression of HSP70 was higher in the low bilirubin group compared to the high bilirubin group. DISCUSSION: Higher mRNA levels of HSP70 in the low bilirubin group could indicate a possible protective effect of high HSP70 levels against IR injury. Although the exact role of hepatobiliary transport systems in the development of post-operative hyper bilirubinemia is not yet completely understood, this study provides new insights into the molecular aspects of post-operative jaundice after liver surgery.