The Role of Visceral Obesity, Sarcopenia and Sarcopenic Obesity on Surgical Outcomes After Liver Resections for Colorectal Metastases.

BACKGROUND: The impact of body compositions on surgical results is controversially discussed. This study examined whether visceral obesity, sarcopenia or sarcopenic obesity influence the outcome after hepatic resections of synchronous colorectal liver metastases. METHODS: Ninety-four consecutive patients with primary hepatic resections of synchronous colorectal metastases were identified from a single center database between January 2013 and August 2018. Patient characteristics and 30-day morbidity were retrospectively analyzed. Body fat and skeletal muscle were calculated by planimetry from single-slice CT images at the level of L3. RESULTS: Fifty-nine patients (62.8%) underwent minor hepatectomies, and 35 patients underwent major resections (37.2%). Postoperative complications occurred in 60 patients (62.8%) including 35 patients with major complications (Clavien-Dindo grade III-V). The mortality was nil at 30 days and 2.1% at 90 days. The body mass index showed no influence on postoperative outcomes (p = 1.0). Visceral obesity was found in 66 patients (70.2%) and was significantly associated with overall and major complication rates (p = .002, p = .012, respectively). Sarcopenia was observed in 34 patients (36.2%) without a significant impact on morbidity (p = .461), however, with longer hospital stay. Sarcopenic obesity was found in 18 patients (19.1%) and was significantly associated with postoperative complications (p = .014). Visceral obesity, sarcopenia and sarcopenic obesity were all identified as significant risk factors for overall postoperative complications. CONCLUSION: Visceral obesity, sarcopenic obesity and sarcopenia are independent risk factors for overall complications after resections of CRLM. Early recognition of extremes in body compositions could prompt to perioperative interventions and thus improve postoperative outcomes.

[Intrahepatic cholangiocarcinoma : Results after 84 resections]. / Das intrahepatische Cholangiokarzinom : Ergebnisse nach 84 Resektionen.

BACKGROUND: The incidence of intrahepatic cholangiocarcinoma (ICC) is increasing worldwide. Surgical resection is the only curative treatment option. AIM OF THE STUDY: This study analyzed the prognostic factors after resection of ICC. MATERIAL AND METHODS: A total of 84 patients were surgically treated under potentially curative intent. Perihilar and distal cholangiocarcinomas were excluded. The 5­year survival was analyzed with respect to tumor stage (TNM), number of lesions, complete surgical resection (R0), peritoneal carcinosis and postoperative complications. RESULTS: The 5­year survival was 27% and 77% of patients underwent R0 resections. In the univariate analysis a T stage >2, an N+ situation or an R+ resection as well as peritoneal and multilocular intrahepatic spread were associated with a poorer prognosis. Postoperative complications also negatively influenced survival. On multivariate analysis the absence of peritoneal spread, node-negative tumor stages, singular hepatic lesions and a low T stage as well as the absence of complications were associated with improved survival. DISCUSSION: The prognosis of ICC is poor even after successful surgical resection. Well-known tumor characteristics such as TNM are relevant prognostic factors. Surgical resection is accompanied by postoperative complications (most frequently biliary), which negatively influence survival. Adjuvant strategies are urgently needed to improve long-term survival even after complete surgical resection.

Cyclosporine A Inhibits the T-bet-Dependent Antitumor Response of CD8(+) T Cells.

Transplant recipients face an increased risk of cancer compared with the healthy population. Although several studies have examined the direct effects of immunosuppressive drugs on cancer cells, little is known about the interactions between pharmacological immunosuppression and cancer immunosurveillance. We investigated the different effects of rapamycin (Rapa) versus cyclosporine A (CsA) on tumor-reactive CD8(+) T cells. After adoptive transfer of CD8(+) T cell receptor-transgenic OTI T cells, recipient mice received either skin grafts expressing ovalbumin (OVA) or OVA-expressing B16F10 melanoma cells. Animals were treated daily with Rapa or CsA. Skin graft rejection and tumor growth as well as molecular and cellular analyses of skin- and tumor-infiltrating lymphocytes were performed. Both Rapa and CsA were equally efficient in prolonging skin graft survival when applied at clinically relevant doses. In contrast to Rapa-treated animals, CsA led to accelerated tumor growth in the presence of adoptively transferred tumor-reactive CD8(+) OTI T cells. Further analyses showed that T-bet was downregulated by CsA (but not Rapa) in CD8(+) T cells and that cancer cytotoxicity was profoundly inhibited in the absence of T-bet. CsA reduces T-bet-dependent cancer immunosurveillance by CD8(+) T cells. This may contribute to the increased cancer risk in transplant recipients receiving calcineurin inhibitors.

mTOR inhibition improves fibroblast growth factor receptor targeting in hepatocellular carcinoma.

BACKGROUND: Systemic therapy has proven only marginal effects in hepatocellular carcinoma (HCC) so far. The aim of this study was to evaluate the effect of targeting fibroblast growth factor receptor (FGFR) on tumour and stromal cells in HCC models. METHODS: Human and murine HCC cells, endothelial cells (ECs), vascular smooth muscle cells (VSMCs), hepatic stellate cells (HSCs), human HCC samples, FGFR inhibitor BGJ398 and mammalian target of rapamycin (mTOR) inhibitor rapamycin were used. Effects on growth, motility, signalling and angiogenic markers were determined. In vivo subcutaneous and syngeneic orthotopic tumour models were used. RESULTS: In tumour cells and ECs, targeting FGFR showed significant inhibitory effects on signalling and motility. Minor effects of FGFR inhibition were observed on VSMCs and HSCs, which were significantly enhanced by combining FGFR and mTOR blockade. In vivo daily (5 mg kg(-1)) treatment with BGJ398 led to a significant growth inhibition in subcutaneous tumour models, but only a combination of FGFR and mTOR blockade impaired tumour growth in the orthotopic model. This was paralleled by reduced tumour cell proliferation, vascularisation, pericytes and increased apoptosis. CONCLUSIONS: Targeting FGFR with BGJ398 affects tumour cells and ECs, whereas only a combination with mTOR inhibition impairs recruitment of VSMCs and HSCs. Therefore, this study provides evidence for combined FGFR/mTOR inhibition in HCC.

["In-situ split" (ISS) liver resection: new aspects of technique and indication]. / "In-situ-Split"- (ISS) Leberresektion: Neue Aspekte zu Technik und Indikation.

The combination of right portal vein ligation with complete parenchyma dissection ("in-situ split", ISS) for rapid hypertrophy induction of the left-lateral liver lobe is a novel strategy to convert primarily irresectable liver tumours into a resectable stage. Available data so far show a 60-80 % growth induction of the remnant liver within 7(- 9) days. Certainly, a novel concept that comprises two operations within a very short time period raises questions. Based on the very few literature reports that have been published so far, as well as our own experience, we here discuss technical issues such as the use of a plastic sheet on the resection margin, the possibility of laparoscopic dissection and the timing of the second operation. Moreover, aspects of the preoperative diagnostic work-up that is necessary are assessed. Finally, open questions, e.g., concerning the influence of preoperative chemotherapy and the use of ISS in patients with cirrhosis are evaluated. In summary, the assessment of chances and risks of this novel concept with regard to indication and technical issues helps to provide the potentially curative option of the "in-situ split" procedure to more patients with marginal or even irresectable liver tumours.

[Biliodigestive anastomosis: indications, complications and interdisciplinary management]. / Biliodigestive Anastomosen: Indikationen, Komplikationen und interdisziplinäres Management.

Techniques for biliodigestive anastomoses are a frequent indication in primary surgical interventions. Moreover, they are required to manage secondary complications of hepatobiliary surgery. Evidence for the management of complications following biliodigestive anastomoses is low. Biliodigestive anastomoses can be performed as hepaticojejunostomy, hepatojejunostomy/portoenterostomy and hepaticoduodenostomy using running or single stitch suture techniques. Complication management in the hands of experienced hepatopancreatobiliary surgeons should consider a time delay to the primary operation and an interdisciplinary surgical and/or endoscopic or radiologic interventional approach. The therapy may be protracted and requires repeated critical reflection of the particular complication.

TdTomato and EGFP identification in histological sections: insight and alternatives.

Tandem dimer Tomato (tdTomato) provides a useful alternative to enhanced green fluorescent protein (eGFP) for performing simultaneous detection of fluorescent protein in histological sections together with fluorescence immunohistochemistry (IHC). eGFP has many properties that make it useful for cell labeling; however, during simultaneous fluorescence IHC, the usefulness of eGFP may be limited. This limitation results from a fixation step required to identify eGFP in histological tissue sections that can mask antibody epitopes and adversely affect staining intensity. An alternative fluorescent protein, tdTomato, may assist concurrent detection of fluorescent protein within tissue sections and fluorescence IHC, because detection of tdTomato does not require tissue fixation. Tissue sections were obtained from various organs of mice ubiquitously expressing eGFP or tdTomato that were either unfixed or fixed with 4% paraformaldehyde. These tissues later were combined with fluorescence IHC. Both eGFP and tdTomato displayed robust signals in fixed frozen sections. Only tdTomato fluorescence, however, was detected in unfixed frozen sections. Simultaneous detection of fluorescence IHC and fluorescent protein in histological sections was observed only in unfixed frozen tdTomato tissue. For this reason, tdTomato is a useful substitute for eGFP for cell labeling when simultaneous fluorescence IHC is required.

[The techniques of peritonectomy and hyperthermic intraperitoneal chemotherapy]. / Technik der Peritonektomie sowie der hyperthermen intraperitonealen Chemotherapie.

The treatment of peritoneal carcinomatosis represents a challenge in the therapy for gastrointestinal cancer. A multimodal approach with complete surgical cytoreduction and hyperthermic intraperitoneal chemotherapy can improve the prognosis in selected patients. Complete surgical cytoreduction, consisting of parietal and visceral peritonectomy, is a sophisticated procedure, frequently requiring multivisceral resections and should only be performed by experienced visceral surgeons. In addition, hyperthermic intraperitoneal chemotherapy is of some complexity. Furthermore, regarding the learning curve for this procedure, combined treatment should only be performed in specialised centres. Under optimal conditions, the therapy can be carried out with reasonable morbidity and mortality rates. Patients with peritoneal carcinomatosis should be evaluated by an interdisciplinary team concerning this multimodal therapy option and, if applicable, they should be referred to therapy within the framework of clinical studies.

Mesenchymal stem cells can induce long-term acceptance of solid organ allografts in synergy with low-dose mycophenolate.

The induction of tolerance towards allogeneic solid organ grafts is one of the major goals in transplantation medicine. Mesenchymal stem cells (MSC) inhibit the immune response in vitro, and thus are promising candidate cells to promote acceptance of transplanted organs in vivo. Such novel approaches of tolerance induction are needed since, to date, graft acceptance can only be maintained through life-long treatment with unspecific immunosuppressants that are associated with toxic injury, opportunistic infections and malignancies. We demonstrate that donor-derived MSC induce long-term allograft acceptance in a rat heart transplantation model, when concurrently applied with a short course of low-dose mycophenolate. This tolerogenic effect of MSC is at least partially mediated by the expression of indoleamine 2,3-dioxygenase (IDO), demonstrated by the fact that blocking of IDO with 1-methyl tryptophan (1-MT) abrogates graft acceptance. Moreover we hypothesize that MSC interact with dendritic cells (DC) in vivo, because allogeneic MSC are rejected in the long-term but DC acquire a tolerogenic phenotype after applying MSC. In summary, we demonstrate that MSC constitute a promising tool for induction of non-responsiveness in solid organ transplantation that warrants further investigation in clinical trials.

Mesenteric ischemia--outcome after surgical therapy in 83 patients.

BACKGROUND: Intestinal ischemia is the prime vascular emergency for the visceral surgeon. However, the diagnosis of mesenteric ischemia is difficult, the surgical options are often limited and the overall outcome is generally poor. METHODS: We report on a single center series of 83 patients undergoing surgery for mesenteric ischemia during a 3-year period. Risk factors, clinical presentation, type and timing of imaging studies and their implications for surgical therapy and outcome are analyzed. RESULTS: Hypertension and diabetes were the most common risk factors (68/64% of all patients). Abdominal pain was the most general symptom upon presentation to the surgical unit (73%). Two-phase, contrast-enhanced computed tomography was applied as the standard preoperative imaging modality (correct diagnosis in 69%). Bowel resections were necessary in most patients; approaches to restore blood flow by vascular surgery interventions were applied in 17 patients (20%). The overall morbidity and mortality rate in our study cohort was expectedly high (59% 1 month mortality). CONCLUSION: The diagnosis and surgical treatment of mesenteric ischemia remains a major difficulty. We recommend preoperative CT analysis followed by an aggressive indication for early surgical exploration and bowel resection. An attempt of revascularization is justified for selected patients with limited macrovascular disease.

[Peritoneal carcinomatosis. Surgical treatment, including hyperthermal intraperitoneal chemotherapy]. / Peritonealkarzinose. Chirurgische Behandlungsmöglichkeiten einschliesslich hyperthermer intraperitonealer Chemotherapie.

Colorectal cancer is a common malignant disease with increasing incidence and a significant cause of death in cancer patients. More than 10% of patients with colorectal cancer show peritoneal carcinomatosis at initial diagnosis. Moreover, peritoneal metastasis is a common sign of recurrence. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are a new treatment strategy for highly selected patients with peritoneal carcinomatosis. Numerous studies show prolonged survival after CRS and HIPEC with acceptable morbidity and mortality rates. Accurate preoperative diagnostics and patient selection play a pivotal role in postoperative patient outcome. This promising treatment strategy is discussed regarding surgical technique, intraperitoneal chemotherapy, and patient outcome.

Multimodality treatment of peritoneal carcinomatosis from colorectal cancer: first results of a new German centre for peritoneal surface malignancies.

BACKGROUND: The presence of peritoneal carcinomatosis arising from colorectal cancer is associated with a poor prognosis. It was the purpose of this study to analyze morbidity, mortality, and survival after major cytoreductive surgery and intraperitoneal chemotherapy. MATERIALS AND METHODS: Thirty-two patients with peritoneal carcinomatosis were operated between April 2004 and June 2006 with the aim of complete macroscopical cytoreduction. All had a primary colorectal carcinoma. Surgery in these patients was followed by hyperthermic intraperitoneal chemotherapy (HIPEC) consisting of mitomycin C and doxorubicin. Data were analyzed retrospectively. RESULTS: Of all patients, 16 had appendix and 16 non-appendiceal colorectal carcinoma. A macroscopically complete cytoreduction was achieved in 24 patients by parietal and visceral peritonectomy procedures. All resections were combined with HIPEC. Overall morbidity was 34%. Most frequent surgical complications were intestinal obstruction (4/32), enteric fistula (2/32), pancreatitis (2/32), and bile leakage (2/32). One patient presented grade 4 renal toxicity. There was no hospital mortality. The median follow-up was 12 months. The 1-year overall survival rate is 96%. All patients after complete cytoreduction are still alive. CONCLUSIONS: Cytoreductive surgery combined with HIPEC is associated with an acceptable morbidity and low mortality. Complete cytoreduction may improve survival, particularly in well-selected patients having a low tumor volume and no extra-abdominal metastases.

Who is willing to take the risk? Assessing the readiness for living liver donation in the general German population.

BACKGROUND: Shortage of donor organs is one of the major problems for liver transplant programmes. Living liver donation is a possible alternative, which could increase the amount of donor organs available in the short term. OBJECTIVE: To assess the attitude towards living organ donation in the general population to have an overview of the overall attitude within Germany. METHODS: A representative quota of people was evaluated by a mail questionnaire (n = 250). This questionnaire had 24 questions assessing the willingness to be a living liver donor for different potential recipients. Factors for and against living liver donation were assessed. RESULTS: Donating a part of the liver was almost as accepted as donating a kidney. The readiness to donate was highest when participants were asked to donate for children. In an urgent life-threatening situation the will to donate was especially high, whereas it was lower in the case of recipient substance misuse. More women than men expressed a higher disposition to donate for their children. Sex, religion, state of health and age of the donor, however, did not influence other questions on the readiness to consider living organ donation. The will for postmortem organ donation positively correlated with the will to be a living organ donor. CONCLUSIONS: The motivation in different demographic subgroups to participate in living liver transplantation is described. Differences in donation readiness resulting from the situation of every donor and recipient are thoroughly outlined. The acceptance for a living liver donation was found to be high - and comparable to that of living kidney donation.

Inhibition of influenza A virus replication by compounds interfering with the fusogenic function of the viral hemagglutinin.

Several compounds that specifically inhibited replication of the H1 and H2 subtypes of influenza virus type A were identified by screening a chemical library for antiviral activity. In single-cycle infections, the compounds inhibited virus-specific protein synthesis when added before or immediately after infection but were ineffective when added 30 min later, suggesting that an uncoating step was blocked. Sequencing of hemagglutinin (HA) genes of several independent mutant viruses resistant to the compounds revealed single amino acid changes that clustered in the stem region of the HA trimer in and near the HA2 fusion peptide. One of the compounds, an N-substituted piperidine, could be docked in a pocket in this region by computer-assisted molecular modeling. This compound blocked the fusogenic activity of HA, as evidenced by its inhibition of low-pH-induced cell-cell fusion in infected cell monolayers. An analog which was more effective than the parent compound in inhibiting virus replication was synthesized. It was also more effective in blocking other manifestations of the low-pH-induced conformational change in HA, including virus inactivation, virus-induced hemolysis of erythrocytes, and susceptibility of the HA to proteolytic degradation. Both compounds inhibited viral protein synthesis and replication more effectively in cells infected with a virus mutated in its M2 protein than with wild-type virus. The possible functional relationship between M2 and HA suggested by these results is discussed.