Laparoscopic Living donor liver transplantation in irresectable intrahepatic cholangiocarcinoma in primary sclerosing cholangitis associated liver cirrhosis.

Intrahepatic cholangiocarcinoma (iCCA) is the second most common primary liver tumor and usually associated with a poor oncological prognosis. The current gold standard is the surgical resection of the tumor with subsequent adjuvant therapy. However, in case of irresectability e.g. in case of liver cirrhosis, a palliative treatment regime is conducted.This report demonstrates the case of an irresectable iCCA in liver cirrhosis due to primary sclerosing cholangitis (PSC) treated by living-donor liver transplantation (LDLT) facilitated by minimal invasive donor hepatectomy. No postoperative complications were observed in the donor and the donor was released on the 6th postoperative day. Further, after a follow-up of 1.5 years, no disease recurrence was detected in the recipient.According to the recent international literature, liver transplantation can be evaluated in case of small solitary iCCA (< 3 cm) in cirrhosis. Less evidence is provided for transplantation in advanced tumors which are surgically not resectable due to advanced liver disease or infiltration of major vessels, however some reports display adequate long-term survival after strict patient selection. The selection criteria comprise the absence of distant metastases and locoregional lymph node metastases as well as partial remission or stable disease after neoadjuvant chemotherapy. Due to no established graft allocation for iCCA in Germany, LDLT is currently the best option to realize transplantation in these patients. Developments in the last decade indicate that LDLT should preferentially be performed in minimal invasive manner (laparoscopic or robotic) as this approach is associated with less overall complications and a shorter hospitalization. The presented case illustrates the possibilities of modern surgery and the introduction of transplant oncology in the modern therapy of patients combining systemic therapy, surgical resection and transplantation to achieve optimal long-term results in patients which were initially indicated for palliative treatment.

Value of prognostic scoring systems in the era of multimodal therapy for recurrent colorectal liver metastases.

BACKGROUND: Various predictive scoring systems have been developed to estimate outcomes of patients undergoing surgery for colorectal liver metastases (CRLM). However, data regarding their effectiveness in recurrent CRLM (recCRLM) are very limited. METHODS: Patients who underwent repeat hepatectomy for recCRLM at the University Hospital RWTH Aachen, Germany from 2010 to 2021 were included. Nine predictive scoring systems (Fong's, Nordlinger, Nagashima, RAS mutation, Tumor Burden, GAME, CERR, and Glasgow Prognostic score, Basingstoke Index) were evaluated by likelihood ratio (LR) χ2, linear trend (LT) χ2 and Akaike Information Criterion (AIC) for their predictive value regarding overall survival (OS) and recurrence free survival (RFS). RESULTS: Among 150 patients, median RFS was 9 (2-124) months with a 5-year RFS rate of 10%. Median OS was 39 (4-131) months with a 5-year OS rate of 32%. For RFS and OS, the Nagashima score showed the best prognostic ability (LT χ2 3.00, LR χ2 9.39, AIC 266.66 and LT χ2 2.91, LR χ2 20.91, 290.36). DISCUSSION: The Nagashima score showed the best prognostic stratification to predict recurrence as well as survival, and therefore might be considered when evaluating patients with recCRLM for repeat hepatectomy.

The role of re-resection in recurrent hepatocellular carcinoma.

PURPOSE: While liver resection is a well-established treatment for primary HCC, surgical treatment for recurrent HCC (rHCC) remains the topic of an ongoing debate. Thus, we investigated perioperative and long-term outcome in patients undergoing re-resection for rHCC in comparative analysis to patients with primary HCC treated by resection. METHODS: A monocentric cohort of 212 patients undergoing curative-intent liver resection for HCC between 2010 and 2020 in a large German hepatobiliary center were eligible for analysis. Patients with primary HCC (n = 189) were compared to individuals with rHCC (n = 23) regarding perioperative results by statistical group comparisons and oncological outcome using Kaplan-Meier analysis. RESULTS: Comparative analysis showed no statistical difference between the resection and re-resection group in terms of age (p = 0.204), gender (p = 0.180), ASA category (p = 0.346) as well as main preoperative tumor characteristics, liver function parameters, operative variables, and postoperative complications (p = 0.851). The perioperative morbidity (Clavien-Dindo ≥ 3a) and mortality were 21.7% (5/23) and 8.7% (2/23) in rHCC, while 25.4% (48/189) and 5.8% (11/189) in primary HCC, respectively (p = 0.851). The median overall survival (OS) and recurrence-free survival (RFS) in the resection group were 40 months and 26 months, while median OS and RFS were 41 months and 29 months in the re-resection group, respectively (p = 0.933; p = 0.607; log rank). CONCLUSION: Re-resection is technically feasible and safe in patients with rHCC. Further, comparative analysis displayed similar oncological outcome in patients with primary and rHCC treated by liver resection. Re-resection should therefore be considered in European patients diagnosed with rHCC.

Elevated Serum Levels of CCL23 Are Associated with Poor Outcome after Resection of Biliary Tract Cancer.

Background: Surgical tumor resection is the only potentially curative treatment option for patients with biliary tract cancer (BTC). However, 5-year survival rates are still below 50% mainly due to tumor recurrence. The preoperative identification of ideal surgical candidates has remained a major challenge and easily accessible algorithms including parameters of the individual tumor biology are missing. Chemokine (C-C motif) ligand 23 (CCl23) has been associated with tumor progression in hepatocellular carcinoma (HCC), but its role in the context of BTC is largely unknown. Here, we evaluated circulating levels of CCL23 as potential diagnostic and prognostic biomarker in patients with resectable BTC. Methods: CCl23 serum levels were analyzed by multiplex immunoassay in a cohort of 119 BTC patients receiving surgical tumor resection as well as 50 healthy control samples and 11 patients with primary sclerosing cholangitis (PSC). Results: Baseline serum CCL23 levels were significantly elevated in BTC patients compared to PSC patients as well as healthy controls. CCL23 increased the diagnostic sensitivity and specificity of established tumor markers including CA19-9 and correlated with patients' age and makers of systemic inflammation. Elevated preoperative CCL23 levels were associated with a significantly impaired postoperative outcome. BTC patients with a preoperative CCL23 level above the optimal prognostic cut-off value of 702.4 pg/ml showed a median OS of only 110 days compared to 501 days for patients with low initial CCL23 levels. The prognostic value of circulating CCL23 was confirmed in Cox-regression analysis. Conclusion: Serum levels of CCL23 are elevated in patients with BTC, and high preoperative CCL23 levels were associated with an impaired postoperative survival. CCL23 serum levels could help to identify the ideal surgical candidates for BTC resection in the future.

Role of Fibroblast Growth Factors in the Crosstalk of Hepatic Stellate Cells and Uveal Melanoma Cells in the Liver Metastatic Niche.

Hepatic metastasis is the critical factor determining tumor-associated mortality in different types of cancer. This is particularly true for uveal melanoma (UM), which almost exclusively metastasizes to the liver. Hepatic stellate cells (HSCs) are the precursors of tumor-associated fibroblasts and support the growth of metastases. However, the underlying mechanisms are widely unknown. Fibroblast growth factor (FGF) signaling is dysregulated in many types of cancer. The aim of this study was to analyze the pro-tumorigenic effects of HSCs on UM cells and the role of FGFs in this crosstalk. Conditioned medium (CM) from activated human HSCs significantly induced proliferation together with enhanced ERK and JNK activation in UM cells. An in silico database analysis revealed that there are almost no mutations of FGF receptors (FGFR) in UM. However, a high FGFR expression was found to be associated with poor survival for UM patients. In vitro, the pro-tumorigenic effects of HSC-CM on UM cells were abrogated by a pharmacological inhibitor (BGJ398) of FGFR1/2/3. The expression analysis revealed that the majority of paracrine FGFs are expressed by HSCs, but not by UM cells, including FGF9. Furthermore, the immunofluorescence analysis indicated HSCs as a cellular source of FGF9 in hepatic metastases of UM patients. Treatment with recombinant FGF9 significantly enhanced the proliferation of UM cells, and this effect was efficiently blocked by the FGFR1/2/3 inhibitor BGJ398. Our study indicates that FGF9 released by HSCs promotes the tumorigenicity of UM cells, and thus suggests FGF9 as a promising therapeutic target in hepatic metastasis.

Perioperative and long-term outcome of en-bloc arterial resection in pancreatic surgery.

BACKGROUND: Pancreatic tumors are frequently diagnosed in a locally advanced stage with poor prognosis if untreated. This study assesses the safety and oncological outcomes of pancreatic surgery with arterial en-bloc resection. METHODS: We retrospectively reviewed a prospectively maintained database of patients who underwent a pancreatic resection with arterial resection between 2011 and 2020. Univariable analyses were used to assess prognostic factors for survival. RESULTS: Forty consecutive patients (22 female; 18 male) undergoing arterial resections were included. Surgical procedures consisted of 19 pancreatoduodenectomies (PD, 48%), 16 distal splenopancreatectomy (DSP, 40%), and 5 total pancreatectomies (TP, 12%). Arterial resection included hepatic arteries (HA, N = 23), coeliac trunk (TC, N = 15) and superior mesenteric artery (SMA, N = 2). Neoadjuvant therapy was applied in 22 patients (58%). Major complications after surgery were observed in 15% of cases. 90-day mortality was 5%. Median disease-free survival and median overall survival were for the R0/CRM- group 22.8 months and 27.9 months, 9.5 and 19.8 months for the R0/CRM+ group, and 10.1 and 13.1 months for the R1 group, respectively. CONCLUSION: In highly selected patients, arterial en-bloc resection can be performed with acceptable mortality and morbidity rates and beneficial oncological outcome.

The rate of cholangiocarcinoma in Caroli Disease A German multicenter study.

BACKGROUND: Caroli Disease (CD) and Caroli Syndrome (CS) are rare disorders presenting with dilation of the intrahepatic bile ducts. CD/CS are associated with cholangiocarcinoma (CCA). However, the true incidence of CCA is still unclear, although it may serve as an indication for surgery. In this paper, we analyzed (I) the incidence of CCA in German centers, (II) reviewed our single center population together with its clinical presentation and (III) performed a thorough literature review. METHODS: 17 large HPB-centers across Germany were contacted and their patients after surgical treatment due to CD/CS with histopathology were included. Medline search for all studies published in English or German literature was performed. Patients who underwent surgery at our department between 2012 and 2020 due to CD or CS were analyzed. RESULTS: In the multicenter study, 79 patients suffered from CD and 119 patients from CS, with a total number of 198 patients. In 14 patients, CCA was found (Overall: 7,1%; CD: 6,3%, CS 7,6%). Between 2012 and 2020, 1661 liver resections were performed at our department. 14 patients underwent surgery due to CD or CS. Histological examination showed synchronous cholangiocarcinoma in one patient. The literature review revealed a CCA-rate of 7,3% in large series, whereas in case reports a rate of 6,8% was found. CONCLUSION: There is risk of malignant transformation and patients with CD might also benefit from resection due to improvement of symptoms. Therefore, resection is strongly advised. As certain patients with CS require transplantation, treatment should not be guided by the relatively low rate of CCA but by the concomitant diseases that come along with hepatic failure.

The prognostic role of tumor-associated unilateral portal vein occlusion in perihilar cholangiocarcinoma.

BACKGROUND: While a certain degree of tumor infiltration of the portal vein is common in patients with perihilar cholangiocarcinoma (pCCA) scheduled for surgery, complete tumor-associated portal vein occlusion (PVO) is less frequently observed. Here, we analyzed the impact of PVO on perioperative and oncological outcomes in pCCA patients. METHODS: Between 2010 and 2019, 127 patients with pCCA underwent surgery in curative intent at our department of which 17.3% (22/127) presented with PVO. Extensive group comparisons were conducted and the association of cancer-specific (CSS) and disease-free survival (DFS) with PVO and other clinico-pathological characteristics were assessed using Cox regression models. RESULTS: Patients without PVO showed a median CSS of 65 months (3-year-CSS = 64%, 5-year-CSS = 53%) compared to 31 months (3-year-CSS = 43%, 5-year-CSS = 17%) in patients with PVO (p = 0.025 log rank). Patients with PVO did also display significant perioperative mortality (22.7%, 5/22) compared to patients without PVO (14.3%, 15/105, p = 0.323). Further, PVO (CSS: HR = 5.25, p = 0.001; DFS: HR = 5.53, p = 0.001) was identified as independent predictors of oncological outcome. CONCLUSIONS: PVO has been identified as an important prognostic marker playing a role in inferior oncological outcome in patients with pCCA. As PVO is also associated with notable perioperative mortality, surgical therapy should be considered carefully in pCCA patients.

Neoadjuvant chemotherapy with gemcitabine plus cisplatin followed by radical liver resection versus immediate radical liver resection alone with or without adjuvant chemotherapy in incidentally detected gallbladder carcinoma after simple cholecystectomy or in front of radical resection of BTC (ICC/ECC) - a phase III study of the German registry of incidental gallbladder carcinoma platform (GR)- the AIO/ CALGP/ ACO- GAIN-trial.

BACKGROUND: Currently, complete surgical resection represents the only potentially curative treatment option for Biliary Tract Cancer (BTC) including Gallbladder Cancer (GBC). Even after curative resection, 5-year OS is only 20-40%. Gallbladder carcinoma is relatively rare, but still the fifth most common neoplasm of the digestive tract and even the most frequent cancer of the biliary system. Gallbladder carcinoma is suspected preoperatively in only 30% of all pts., while the majority of cases are discovered incidentally by the pathologist after cholecystectomy for a benign indication. For improving curative rates in BTC and GBC, early systemic therapy combined with radical resection seems to be a promising approach. The earliest moment to apply chemotherapy would be in front of radical surgery. The encouraging results of neoadjuvant/perioperative concepts in other malignancies provide an additional rationale to use this treatment in the early phase of GBC management and even ICC/ECC. Especially because data regarding pure adjuvant chemotherapy in BTC's are conflicting. METHODS: This is a multicenter, randomized, controlled, open-label phase III study including pts. with incidentally discovered GBCs after simple cholecystectomy in front of radical liver resection and pts. with resectable/ borderline resectable cholangiocarcinomas (ICC/ ECC) scheduled to receive perioperative chemotherapy (Gemcitabine + Cisplatin 3 cycles pre- and post-surgery) or surgery alone followed by a therapy of investigator's choice. Primary endpoint is OS; secondary endpoints are PFS, R0-resection rate, toxicity, perioperative morbidity, mortality and QoL. A total of N = 333 patients with GBC or BTC will be included. Recruitment has started in August 2019. DISCUSSION: The current proposed phase III GAIN study investigates whether induction chemotherapy followed by radical resection in ICC/ECC and re-resection in IGBC (and - if possible - postoperative chemotherapy) prolongs overall survival compared to radical surgery alone for incidental gallbladder carcinoma and primary resectable or borderline resectable cholangiocarcinoma. Utilizing a neoadjuvant approach including a second radical surgery will help to raise awareness for the necessity of radical surgery, especially second radical completion surgery in IGBC and improve the adherence to the guidelines. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03673072 from 17.09.2018. EudraCT number: 2017-004444-38 from 02.11.2017.

Pharmacological Inhibition of mTORC2 Reduces Migration and Metastasis in Melanoma.

Despite recent advances in therapy, liver metastasis from melanoma is still associated with poor prognosis. Although targeting the mTOR signaling pathway exerts potent anti-tumor activity, little is known about specific mTORC2 inhibition regarding liver metastasis. Using the novel mTORC2 specific inhibitor JR-AB2-011, we show significantly reduced migration and invasion capacity by impaired activation of MMP2 in melanoma cells. In addition, blockade of mTORC2 induces cell death by non-apoptotic pathways and reduces tumor cell proliferation rate dose-dependently. Furthermore, a significant reduction of liver metastasis was detected in a syngeneic murine metastasis model upon therapy with JR-AB2-011 as determined by in vivo imaging and necropsy. Hence, our study for the first time highlights the impact of the pharmacological blockade of mTORC2 as a potent novel anti-cancer approach for liver metastasis from melanoma.

ALPPS (associating liver partition and portal vein ligation for staged hepatectomy) does not affect proliferation, apoptosis, or angiogenesis as compared to standard liver resection for colorectal liver metastases.

BACKGROUND: ALPPS (associating liver partition and portal vein ligation for staged hepatectomy) is a novel two-stage strategy to induce rapid hypertrophy of the future liver remnant (FLR) when patients are in danger of postoperative liver failure due to insufficient FLR. However, the effects of ALPPS on colorectal liver metastases (CRLM) are not clear so far. The aim of our study was to determine whether ALPPS induces proliferation, apoptosis, or vascularization compared to standard (one-stage) liver resection. METHODS: Six patients who underwent ALPPS were matched with 12 patients undergoing standard liver resection regarding characteristics of the metastases (size, number), time of appearance (syn-/metachronous), preoperative chemotherapy, primary tumor (localization, TNM stage, grading), and patient variables (gender, age). The largest resected metastasis was used for the analyses. Tissue was stained for tumor cell proliferation (Ki67), apoptosis (TUNEL, caspase-3), vascularization (CD31), and pericytes (αSMA). RESULTS: Vascularization (CD31; p = 0.149), proliferation (Mib-1; p = 0.244), and αSMA expression (p = 0.205) did not significantly differ between the two groups, although a trend towards less proliferation and αSMA expression was observed in patients undergoing ALPPS. Concerning apoptosis, caspase-3 staining showed significantly fewer apoptotic cells upon ALPPS (p < 0.0001), but this was not confirmed by TUNEL staining (p = 0.7344). CONCLUSIONS: ALPPS does not induce proliferation, apoptosis, or vascularization of CRLM when compared to standard liver resection.

Receptor tyrosine kinase inhibitors: Are they real tumor killers?

Inhibiting tumor growth by targeting the tumor vasculature was first proposed by Judah Folkman almost 40 years ago. Since then, different approaches and numerous drugs and agents have been developed to achieve this goal, either with the aim of inhibiting tumor neoangiogenesis or normalizing the tumor vasculature. Among the most promising therapeutic targets are receptor tyrosine kinases (RTKs), some of which are predominantly expressed on tumor endothelial cells, although they are sometimes also present on tumor cells. The majority of RTK inhibitors investigated over the past two decades competes with ATP at the active site of the kinase and therefore block the phosphorylation of intracellular targets. Some of these drugs have been approved for therapy, whereas others are still in clinical trials. Here, we discuss the scientific basis, current status, problems and future prospects of RTK inhibition in anti-tumor therapy.

Bile Duct Injury after Irreversible Electroporation of Hepatic Malignancies: Evaluation of MR Imaging Findings and Laboratory Values.

PURPOSE: To evaluate biliary complications after irreversible electroporation (IRE) of hepatic malignancies. MATERIALS AND METHODS: In 24 patients (17 men; mean age, 59.3 y), bile ducts were located within a 1.0-cm radius of the ablation zone at subacute follow-up (ie, 1­3 d) after percutaneous IRE of 53 hepatic tumors (primary hepatic tumors, n = 14). MR imaging, conducted with a hepatocyte-specific contrast agent before and after treatment, was examined for evidence of bile duct injury. Serum bilirubin and alkaline phosphatase levels measured at subacute and short-term follow-up (ie, 1­2 mo after IRE) were analyzed for evidence of biliary injury. Correlations between bile duct injury and characteristics of patients, lesions, and ablation procedures were assessed by generalized linear models. RESULTS: Fifty-five bile ducts were located within 1.0 cm of an ablation defect. Locations relative to the ablation area were as follows: 33 were encased, 14 were abutting, and 8 were located within a radius of 0.1­1.0 cm of the ablation zone. Subacute follow-up MR images showed 15 bile duct injuries (narrowing, n = 8; dilation, n = 7). At subacute follow-up, three patients showed transient abnormalities of laboratory values (bilirubin, 1.6­5.2 mg/dL). Short-term laboratory values were abnormal in one patient (increase in alkaline phosphatase of 533 U/L vs baseline) as a result of local tumor recurrence. Patient age (continuous, P = .026; < 65 y vs ≥ 65 y, P = .001) was independently associated with post-IRE bile duct injury. CONCLUSIONS: Bile ducts adjacent to an IRE ablation area remain largely unaffected by this procedure.

KLRG1+ NK cells protect T-bet-deficient mice from pulmonary metastatic colorectal carcinoma.

We studied the developmental and functional mechanisms behind NK cell-mediated antitumor responses against metastatic colorectal carcinoma (CRC) in mice. In particular, we focused on investigating the significance of T-box transcription factors and the immunotherapeutic relevance of IL-15 in the development and function of tumor-reactive NK cells. Pulmonary CRC metastases were experimentally seeded via an adoptive i.v. transfer of luciferase-expressing CT26 CRC cells that form viewable masses via an in vivo imaging device; genetically deficient mice were used to dissect the antitumor effects of developmentally different NK cell subsets. IL-15 precomplexed to IL-15 receptor-α was used in immunotherapy experiments. We found that mice deficient for the T-box transcription factor T-bet lack terminally differentiated antitumor CD27(low)KLRG1(+) NK cells, leading to a terminal course of rapid-onset pulmonary CRC metastases. The importance of this NK cell subset for effective antitumor immunity was shown by adoptively transferring purified CD27(low)KLRG1(+) NK cells into T-bet-deficient mice and, thereby, restoring immunity against lung metastasis formation. Importantly, immunity to metastasis formation could also be restored in T-bet-deficient recipients by treating mice with IL-15 precomplexed to IL-15 receptor-α, which induced the development of eomesodermin(+)KLRG1(+) NK cells from existing NK cell populations. Thus, contingent upon their T-bet-dependent development and activation status, NK cells can control metastatic CRC in mice, which is highly relevant for the development of immunotherapeutic approaches in the clinic.

Morbidity of hepatic resection for intermediate and advanced hepatocellular carcinoma.

PURPOSE: According to current treatment guidelines, surgical resection of hepatocellular carcinoma (HCC) is mostly restricted to a limited subgroup of patients. Due to improved surgical techniques and perioperative management, liver resections may also be performed more extendedly and also in cirrhotic livers with clinical signs of portal hypertension in selected patients. In this study, the clinical and long-term outcomes of liver resection in HCC patients with or without liver cirrhosis were evaluated. METHODS: One hundred fifty-eight patients undergoing liver resection for primary HCC at our institution were identified. Logistic and Cox regression analyses were used to identify prognostic parameters for postoperative complications and survival. RESULTS: In our cohort of patients, there was no association between clinical parameters or extent of surgical resection and postoperative morbidity. Only Barcelona Clinic Liver Cancer (BCLC) stage C patients were at significantly higher risk for major complications (OR 5.27, P = 0.009). Risk factors influencing long-term survival were patient age (HR 1.026, P = 0.027) and BCLC stage C (HR 3.47, P = 0.002). Compared to patients without liver cirrhosis, BCLC stage A and B patients undergoing resection were at similar risk for the development of severe complications and long-term mortality. CONCLUSION: Liver resection as potentially curative therapy can be performed in selected patients in BCLC stage B, as well as in patients with clinical signs of portal hypertension. The resection of HCC-classified BCLC stage C is feasible but associated with significant morbidity and mortality.

Unconventional RORγt+ T cells drive hepatic ischemia reperfusion injury.

An emerging body of evidence suggests a pivotal role of CD3(+) T cells in mediating early ischemia reperfusion injury (IRI). However, the precise phenotype of T cells involved and the mechanisms underlying such T cell-mediated immune responses in IRI, as well as their clinical relevance, are poorly understood. In this study, we investigated early immunological events in a model of partial warm hepatic IRI in genetically targeted mice to study the precise pathomechanistic role of RORγt(+) T cells. We found that unconventional CD27(-)γδTCR(+) and CD4(-)CD8(-) double-negative T cells are the major RORγt-expressing effector cells in hepatic IRI that play a mechanistic role by being the main source of IRI-mediating IL-17A. We further show that unconventional IRI-mediating T cells are contingent on RORγt, as highlighted by the fact that a genetic deficiency for RORγt, or its therapeutic antagonization via digoxin, is protective against hepatic IRI. Therefore, identification of CD27(-)γδTCR(+) and CD4(-)CD8(-) double-negative T cells as the major source of IL-17A via RORγt in hepatic IRI opens new therapeutic options to improve liver transplantation outcomes.

Long-term results after in-situ split (ISS) liver resection.

PURPOSE: In-situ split (ISS) liver resection is a novel method to induce rapid hypertrophy of the contralateral liver lobe in patients at risk for postoperative liver failure due to insufficient liver remnant. So far, no data about oncological long-term survival after ISS liver resection is available. METHODS: We retrospectively analyzed our patients treated with ISS liver resection at the Department of Surgery of the University of Regensburg, the first center worldwide to perform ISS. RESULTS: Between 2007 and 2014, ISS liver resection was performed in 16 patients. Two patients (12.5 %) were lost in early postoperative phase (90 days) and one was lost to follow-up. Thirteen patients with a follow-up period of more than 3 months were included into oncologically focused analyses. Median follow-up was 26.4 months (range 3.2-54.6). Seven patients had suffered from colorectal liver metastases (CRLM) and six from various other liver malignancies (non-CRLM). The ISS procedure had led to a median increase of 86.3 % of the left lateral liver lobe after a median of 9 days (range 4-28 days). Median disease-free survival (DFS) was 14.6 months and median overall survival (OS) was 41.7 months (26.4 months when including 90-days mortality). Three-year survival was calculated with 56.4 and 48.9 % when including perioperative mortality, respectively (CRLM 64.3 % vs. non-CRLM 50 %). CONCLUSION: ISS liver resection can provide long-term survival of selected patients with advanced liver malignancies that otherwise are not eligible for liver resection due to insufficient liver remnant.

Continuous water infusion enhances atmospheric pressure chemical ionization of methyl chloroformate derivatives in gas chromatography coupled to time-of-flight mass spectrometry-based metabolomics.

The effects of continuous water infusion on efficiency and repeatability of atmospheric pressure chemical ionization of both methyl chloroformate (MCF) and methoxime-trimethylsilyl (MO-TMS) derivatives of metabolites were evaluated using gas chromatography-time-of-flight mass spectrometry. Water infusion at a flow-rate of 0.4 mL/h yielded not only an average 16.6-fold increase in intensity of the quasimolecular ion for 20 MCF-derivatized metabolite standards through suppression of in-source fragmentation but also the most repeatable peak area integrals. The impact of water infusion was the greatest for dicarboxylic acids and the least for (hetero-) aromatic compounds. Water infusion also improved the ability to detect reliably fold changes as small as 1.33-fold for the same 20 MCF-derivatized metabolite standards spiked into a human serum extract. On the other hand, MO-TMS derivatives were not significantly affected by water infusion, neither in their fragmentation patterns nor with regard to the detection of differentially regulated compounds. As a proof of principle, we applied MCF derivatization and GC-APCI-TOFMS to the detection of changes in abundance of metabolites in pancreatic cancer cells upon treatment with 17-DMAG. Water infusion increased not only the number of metabolites identified via their quasimolecular ion but also the reproducibility of peak areas, thereby almost doubling the number of significantly regulated metabolites (false discovery rate < 0.05) to a total of 23.

Oxaliplatin-based versus irinotecan-based hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal metastasis from appendiceal and colorectal cancer: a retrospective analysis.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) provide an effective treatment option for selected patients with colorectal peritoneal metastasis with encouraging survival results. Many different drug combinations and HIPEC regimens including bidirectional, i.e. synchronous intravenous and intraperitoneal, drug application have been used. However, there is still no standardization of the HIPEC regimen. METHODS: Between 05/2007 and 04/2010 190 patients underwent CRS and HIPEC at the University Hospital Regensburg. Thirty-two patients with peritoneal metastasis arising from colorectal or appendiceal cancer underwent complete macroscopic cytoreduction (CC-0/1) and bidirectional HIPEC and completed at least 3-year follow-up. Twenty patients received oxaliplatin-based (OX) and twelve patients received irinotecan-based HIPEC (IRI). Group-specific perioperative morbidity and 3-year survival has been determined. RESULTS: The grade 3/4 morbidity rate according to CTCAE v4 was 35.0% in the OX group vs. 33.3% in the IRI group (p = 1.000). There was no perioperative mortality in both groups. Median survival was 26.8 months (95% CI 15.7-33.1 months) in the IRI group and has not yet been reached in the OX group during a median follow-up of 39.4 months. Three-year survival rates were 65.0% in the OX group vs. 41.7% in the IRI group (p = 0.295). CONCLUSIONS: The morbidity and toxicity rates of bidirectional irinotecan-based and oxaliplatin-based HIPEC are comparable. Nevertheless, in the absence of contraindications oxaliplatin-based HIPEC might be preferred due to the positive trend regarding 3-year and median survival.

Inhibition of heat shock protein 90 with AUY922 represses tumor growth in a transgenic mouse model of islet cell neoplasms.

BACKGROUND: This study was designed to evaluate the role of heat shock protein 90 (HSP90) in tumor progression of murine islet cell tumors. Blockade of HSP90 has recently been proposed as a therapeutic target, but effects in models of islet cell tumors with AUY922, a newly developed HSP90 inhibitor, have not been examined. MATERIAL AND METHODS: The carcinoid cell line BON-1 and the HSP90 inhibitor AUY922 were used to determine effects on signaling and growth in vitro. In vivo transgenic RIP1-Tag2 mice, which develop islet cell neoplasms, were treated with vehicle or AUY922 (25 mg/kg/twice per week) from week 5 until death. The resected pancreata were evaluated macroscopically and microscopically by immunohistochemistry. Quantitative real-time PCR was performed for HSP90 targets with RNA from islets isolated from treated and untreated RIP1-Tag2 mice. RESULTS: HSP90 blockade impaired constitutive and growth factor-induced signaling in vitro. Moreover, HSP90 inhibition attenuated in vitro cell growth in a dose-dependent manner. In vivo, AUY922 significantly reduced tumor volume by 92% compared to untreated controls (p = 0.000), and median survival in the used transgenic mouse model was prolonged (110 vs. 119 days; p = 0.75). Quantitative real-time PCR for downstream target genes of HSP90 demonstrated significant downregulation in the islet cell tumors of RIP1-Tag2 mice treated with AUY922, confirming our ability to achieve effective pharmacologic levels of AUY922 within the desired tissue site in vivo. CONCLUSION: This is the first study to show that the HSP90 antagonist AUY922 may provide a new option for therapy of islet cell neoplasms.