The development of a hiPSC-based platform to identify tissue-dependencies of IDH1 R132H.

The application of patient-derived (PD) in vitro tumor models represents the classical strategy for clinical translational oncology research. Using these cellular heterogeneous cultures for the isolation of cancer stem cells (CSCs), suggested to be the main driver for disease malignancy, relies on the use of surrogate biomarkers or is based on CSC-enriching culture conditions. However, the ability of those strategies to exclusively and efficiently enrich for CSC pool has been questioned. Here we present an alternative in vitro CSC model based on the oncogenic transformation of single clone-derived human induced pluripotent stem cells (hiPSC). Hotspot mutations in the DNA encoding for the R132 codon of the enzyme isocitrate dehydrogenase 1 (IDH1) and codon R175 of p53 are commonly occurring molecular features of different tumors and were selected for our transformation strategy. By choosing p53 mutant glial tumors as our model disease, we show that in vitro therapy discovery tests on IDH1-engineered synthetic CSCs (sCSCs) can identify kinases-targeting chemotherapeutics that preferentially target tumor cells expressing corresponding genetic alteration. In contrast, neural stem cells (NSCs) derived from the IDH1R132H overexpressing hiPSCs increase their resistance to the tested interventions indicating glial-to-neural tissue-dependent differences of IDH1R132H. Taken together, we provide proof for the potential of our sCSC technology as a potent addition to biomarker-driven drug development projects or studies on tumor therapy resistance. Moreover, follow-up projects such as comparing in vitro drug sensitivity profiles of hiPSC-derived tissue progenitors of different lineages, might help to understand a variety of tissue-related functions of IDH1 mutations.

Manifestation of acute appendicitis as known but paradox visceral side effect of ulcerative colitis anti-inflammatory therapy with januskinase-inhibitor Tofacitinib (Xeljanz™).

BACKGROUND: The etiopathogenesis of accompanying inflammatory phenomena and consequences of immunomodulation constitute a challenging and innovative field in the medical treatment of patients with autoimmune diseases. AIM: Based on i) clinical management experience gained from this challenging clinical case and ii) selective references of reports published in the scientific medical literature, we present an unusual counterfactual scientific case report. A patient diagnosed with ulcerative colitis undergoing januskinase (JAK)-inhibitor therapy developed acuteappendicitis as an unusual complication or as a visceral side effect of immunosuppressive/anti-inflammatory therapy. METHOD: Scientific case report. RESULTS: (case description): Medical history: A 52-year-old male presented with spasmodic pain in the right lower abdomen lasting for two days (no fever, no bowel movement changes (no stool irregularities), no vomiting). MEDICATION USED TO DATE: Steroid-resistant ulcerative colitis treated with immunosuppressive therapy (Adalimumab administered for 10 months [next generation anti-TNFα mAb], Vendolizumab for 9 months [α4ß7 integrin antagonist], Tofacitinib for 6 months); fructose intolerance, no previous abdominal surgery; medication: XeljanzTM (Tofacitinib, 5 mg 2x1; JAK-inhibitor; PFIZER PHARMA GmbH, Berlin,Germany); MutaflorTM (1x1; Ardeypharm GmbH, Herdecke, Germany). CLINICAL FINDINGS: Pressure pain in the right lower abdomen with local muscular defense (Mc-Burney's/Lanz's point positive), no peritonism, Psoas-muscle sign positive. DIAGNOSTIC MEASURES: Laboratory parameters: standard value of white blood cell count, CrP: 25 mg/l.-Transabdominal ultrasound revealed hypertrophic 'appendix vermiformis' with detectable target-phenomenon and surrounding fluid. DECISION-MAKING: Indication for laparoscopic exploration. THERAPY: Under perioperative single-shot antibiotic administration with UnacidTM, the patient underwent emergency laparoscopic appendectomy due to confirmed acute appendicitis with additional lavage and placement of local drainage. CLINICAL COURSE: The postoperative phase was uneventful (sufficient analgetic therapy, removal of local drainage on the 2nd postoperative day). The patient was discharged four days after surgery. Histopathology confirmed ulcero-phlegmonous, acute purulent appendicitis with fibrinous purulent mesenteriolitis. FURTHER MEASURES: Immunosuppressive therapy was continued. CONCLUSION: Based on the paradoxon of an acute inflammatory disease (acute appendicitis) seen in the case of a patient undergoing immunosuppressive/anti-inflammatory treatment using a JAK-Inhibitor for ulcerative colitis, we consider this case worthy of publication although this side effect has previously been described in patients with rheumatoid arthritis. This might be the manifestation of i) an immunomodulatory effect that reduced or at least altered mucosal defense, including an increased risk of opportunistic infections, presenting as a specific visceral 'side effect' of the JAK-Inhibitor and/or as a consequence; ii) an induced alternative inflammatory mechanism/proinflammatory signal transduction and - theoretically - an intestinal drainage defect in the segment of right colic artery with consecutive collection of necrotic cells and activation of inflammatory mediators.

[Consultations by senior physicians in general and abdominal surgery for other medical disciplines over 10 years at a tertiary center-Is a fast time-consuming processing necessary? : Spectrum of clinical findings, diagnoses and treatment decision making]. / Allgemein- und viszeralchirurgische Oberarztkonsile für andere medizinische Disziplinen über 10 Jahre an einem tertiären Zentrum ­ ist eine schnelle, zeitaufwendige Abarbeitung notwendig? : Klinisches Befund­, Diagnose- und therapeutisches Entscheidungsspektrum.

BACKGROUND: The challenges of an adequate, efficient and rational medical treatment and care of patients are always associated with an interprofessional activity of several specialist disciplines. AIM: The spectrum of variable diagnoses and the profile of surgical decision-making with further surgical measures within the framework of senior physician consultation in general and visceral surgery for neighboring medical disciplines were analyzed on a representative patient cohort over a defined observational time period. PATIENTS AND METHODS: All consecutive patients (n = 549 cases) were documented as part of a clinical systematic prospective single center observational study at a tertiary center using a computer-based patient registry over 10 years (1 October 2006-30 September 2016). The data were analyzed with respect to the spectrum of clinical findings, diagnoses, treatment decisions and the influencing factors as well as gender and age differences and time-dependent developmental trends using χ2-tests and U­tests. RESULTS (KEY POINTS): The predominant discipline for requests for surgical consultation was cardiology (19.9%) followed by surgical disciplines (11.8%) and gastroenterology (11.3%). Disorders of wound healing (7.1%) and acute abdomen (7.1%) were predominant in the diagnostic profile. In 11.7% of the patients the indications for immediate surgery were derived, whereas in 12.9% elective surgery was recommended. The conformity rate of suspected and definitive diagnoses was only 58.4%. CONCLUSION: The surgical consultation work is an important mainstay of a sufficient and especially timely clarification of surgically relevant questions in nearly all medical institutions and especially in a center. This serves i) the quality assurance of surgery in the clinical care of patients with need of additional interdisciplinary needs for surgical treatment in the daily practice of general and abdominal surgery in research on clinical care, ii) clinical marketing and monetary aspects in the sense of patient recruitment and iii) last but not least to provide emergency care of patients. Due to the high proportion of 12% of subsequent emergency operations, which were derived from requests for general and visceral surgical consultations, such requests must be processed promptly during working hours.

Robotic and laparoscopic liver resection-comparative experiences at a high-volume German academic center.

PURPOSE: Minimally invasive liver surgery (MILS) is a feasible and safe procedure for benign and malignant tumors. There has been an ongoing debate on whether conventional laparoscopic liver resection (LLR) or robotic liver resection (RLR) is superior and if one approach should be favored over the other. We started using LLR in 2010, and introduced RLR in 2013. In the present paper, we report on our experiences with these two techniques as early adopters in Germany. METHODS: The data of patients who underwent MILS between 2010 and 2020 were collected prospectively in the Magdeburg Registry for Minimally Invasive Liver Surgery (MD-MILS). A retrospective analysis was performed regarding patient demographics, tumor characteristics, and perioperative parameters. RESULTS: We identified 155 patients fulfilling the inclusion criteria. Of these, 111 (71.6%) underwent LLR and 44 (29.4%) received RLR. After excluding cystic lesions, 113 cases were used for the analysis of perioperative parameters. Resected specimens were significantly bigger in the RLR vs. the LLR group (405 g vs. 169 g, p = 0.002); in addition, the tumor diameter was significantly larger in the RLR vs. the LLR group (5.6 cm vs. 3.7 cm, p = 0.001). Hence, the amount of major liver resections (three or more segments) was significantly higher in the RLR vs. the LLR group (39.0% vs. 16.7%, p = 0.005). The mean operative time was significantly longer in the RLR vs. the LLR group (331 min vs. 181 min, p = 0.0001). The postoperative hospital stay was significantly longer in the RLR vs. the LLR group (13.4 vs. LLR 8.7 days, p = 0.03). The R0 resection rate for solid tumors was higher in the RLR vs. the LLR group but without statistical significance (93.8% vs. 87.9%, p = 0.48). The postoperative morbidity ≥ Clavien-Dindo grade 3 was 5.6% in the LLR vs. 17.1% in the RLR group (p = 0.1). No patient died in the RLR but two patients (2.8%) died in the LLR group, 30 and 90 days after surgery (p = 0.53). CONCLUSION: Minimally invasive liver surgery is safe and feasible. Robotic and laparoscopic liver surgery shows similar and adequate perioperative oncological results for selected patients. RLR might be advantageous for more advanced and technically challenging procedures.

R0 resection following chemo (radio)therapy improves survival of primary inoperable pancreatic cancer patients. Interim results of the German randomized CONKO-007± trial.

PURPOSE: Chemotherapy with or without radiotherapy is the standard in patients with initially nonmetastatic unresectable pancreatic cancer. Additional surgery is in discussion. The CONKO-007 multicenter randomized trial examines the value of radiotherapy. Our interim analysis showed a significant effect of surgery, which may be relevant to clinical practice. METHODS: One hundred eighty patients received induction chemotherapy (gemcitabine or FOLFIRINOX). Patients without tumor progression were randomized to either chemotherapy alone or to concurrent chemoradiotherapy. At the end of therapy, a panel of five independent pancreatic surgeons judged the resectability of the tumor. RESULTS: Following induction chemotherapy, 126/180 patients (70.0%) were randomized to further treatment. Following study treatment, 36/126 patients (28.5%) underwent surgery; (R0: 25/126 [19.8%]; R1/R2/Rx [n = 11/126; 6.1%]). Disease-free survival (DFS) and overall survival (OS) were significantly better for patients with R0 resected tumors (median DFS and OS: 16.6 months and 26.5 months, respectively) than for nonoperated patients (median DFS and OS: 11.9 months and 16.5 months, respectively; p = 0.003). In the 25 patients with R0 resected tumors before treatment, only 6/113 (5.3%) of the recommendations of the panel surgeons recommended R0 resectability, compared with 17/48 (35.4%) after treatment (p < 0.001). CONCLUSION: Tumor resectability of pancreatic cancer staged as unresectable at primary diagnosis should be reassessed after neoadjuvant treatment. The patient should undergo surgery if a resectability is reached, as this significantly improves their prognosis.

Oncological outcome after hyperthermic isolated limb perfusion for primarily unresectable versus locally recurrent soft tissue sarcoma of extremities.

INTRODUCTION: The management of locally advanced extremity soft tissue sarcomas, particularly in terms of a limb salvage strategy, represents a challenge, especially in recurrent tumors. In the context of a patient-tailored multimodal therapy, hyperthermic isolated limb perfusion (ILP) is a promising limb-saving treatment option. We report the outcome of patients with primarily irresectable and locally recurrent soft tissue sarcoma (STS) treated by ILP. PATIENTS AND METHODS: Data about patient demographics, clinical und histopathological characteristics, tumor response, morbidity and oncological outcome of all patients with STS, who underwent an ILP at our institution in a 10-year period, were retrospectively detected and analyzed. RESULTS: The cohort comprised 30 patients. Two patients were treated with ILP for palliative tumor control, 13 patients because of a local recurrent soft tissue sarcoma (rSTS) and 15 patients because of primarily unresectable soft tissue sarcoma (puSTS). 25 of the 28 patients with curative intention received surgery after ILP (11 pts with rSTS and 14 pts with puSTS). Histopathologically we observed complete response in 6 patients (24%) and partial responses in 19 patients (76%) with a significant better remission in patients with puSTS (p = 0,043). Limb salvage rate was 75%. Mean follow-up was 69 months [range 13-142 months]. Seven (7/11; 64%) patients with rSTS and one (1/14; 7%) patient with puSTS developed local recurrence after ILP and surgery, whereas eight (8/13; 62%) rSTS patients and seven (7/15; 47%) puSTS patients developed distant metastasis. During follow-up, eight patients (28.5%) died of disease (5/13; 38%) rSTS and 3/15 (20%) puSTS. ILP in the group of previously irradiated sarcoma patients (n = 13) resulted in a limb salvage rate of 69% and was not associated in an increased risk for adverse events. DISCUSSION: ILP for advanced extremity STS is a treatment option for both puSTS and rSTS resulting in good local control and should be considered in multimodal management. ILP is also a good option for patients after radiation history.

A falciform ligament flap surface sealing technique for laparoscopic and robotic-assisted liver surgery.

Whether sealing the hepatic resection surface after liver surgery decreases morbidity is still unclear. Nevertheless, various methods and materials are currently in use for this procedure. Here, we describe our experience with a simple technique using a mobilized falciform ligament flap in minimally invasive liver surgery (MILS). We retrospectively analyzed the charts from 46 patients who received minor MILS between 2011 and 2019 from the same surgical team in a university hospital setting in Germany. Twenty-four patients underwent laparoscopic liver resection, and 22 patients received robotic-assisted liver resection. Sixteen patients in the laparoscopic group and fourteen in the robotic group received a falciform ligament flap (FLF) to cover the resection surface after liver surgery. Our cohort was thus divided into two groups: laparoscopic and robotic patients with (MILS + FLF) and without an FLF (MILS-FLF). Twenty-eight patients (60.9%) in our cohort were male. The overall mean age was 56.8 years (SD 16.8). The mean operating time was 249 min in the MILS + FLF group vs. 235 min in the MILS-FLF group (p = 0.682). The mean blood loss was 301 ml in the MILS + FLF group vs. 318 ml in the MILS-FLF group (p = 0.859). Overall morbidity was 3.3% in the MILS + FLF group vs. 18.8% in the MILS-FLF group (p = 0.114). One patient in the MILS-FLF group (overall 2.2%), who underwent robotic liver surgery, developed bile leakage, but this did not occur in the MILS + FLF group. Covering the resection surface of the liver after minor minimally invasive liver resection with an FLF is a simple and cost-effective technique that does not prolong surgical time or negatively affect other perioperative parameters. In fact, it is a safe add-on step during MILS that may reduce postoperative morbidity. Further studies with larger cohorts will be needed to substantiate our proof of concept and results.

Consensus in determining the resectability of locally progressed pancreatic ductal adenocarcinoma - results of the Conko-007 multicenter trial.

BACKGROUND: One critical step in the therapy of patients with localized pancreatic cancer is the determination of local resectability. The decision between primary surgery versus upfront local or systemic cancer therapy seems especially to differ between pancreatic cancer centers. In our cohort study, we analyzed the independent judgement of resectability of five experienced high volume pancreatic surgeons in 200 consecutive patients with borderline resectable or locally advanced pancreatic cancer. METHODS: Pretherapeutic CT or MRI scans of 200 consecutive patients with borderline resectable or locally advanced pancreatic cancer were evaluated by 5 independent pancreatic surgeons. Resectability and the degree of abutment of the tumor to the venous and arterial structures adjacent to the pancreas were reported. Interrater reliability and dispersion indices were compared. RESULTS: One hundred ninety-four CT scans and 6 MRI scans were evaluated and all parameters were evaluated by all surgeons in 133 (66.5%) cases. Low agreement was observed for tumor infiltration of venous structures (κ = 0.265 and κ = 0.285) while good agreement was achieved for the abutment of the tumor to arterial structures (interrater reliability celiac trunk κ = 0.708 P < 0.001). In patients with vascular tumor contact indicating locally advanced disease, surgeons highly agreed on unresectability, but in patients with vascular tumor abutment consistent with borderline resectable disease, the judgement of resectability was less uniform (dispersion index locally advanced vs. borderline resectable p < 0.05). CONCLUSION: Excellent agreement between surgeons exists in determining the presence of arterial abutment and locally advanced pancreatic cancer. The determination of resectability in borderline resectable patients is influenced by additional subjective factors. TRIAL REGISTRATION: EudraCT:2009-014476-21 (2013-02-22) and NCT01827553 (2013-04-09).

Predictive value of PD-L1 based on mRNA level in the treatment of stage IV melanoma with ipilimumab.

INTRODUCTION: PD-L1 is established as a predictive marker for therapy of non-small cell lung cancer with pembrolizumab. Furthermore, PD-L1 positive melanoma has shown more favorable outcomes when treated with anti-PD1 antibodies and dacarbazine compared to PD-L1 negative melanoma. However, the role of PD-L1 expression with regard to response to checkpoint inhibition with anti-CTLA-4 is not clear, yet. In addition, the lack of standardization in the immunohistochemical assessment of PD-L1 makes the comparison of results difficult. In this study, we investigated the PD-L1 gene expression with a new fully automated technique via RT-PCR and correlated the findings with the response to the anti-CTLA-4 antibody ipilimumab. MATERIALS AND METHODS: Within a retrospective multi-center trial, PD-L1 gene expression was evaluated in 78 melanoma patients in a total of 111 pre-treatment tumor samples from 6 skin cancer centers and analyzed with regard to response to ipilimumab. For meaningful statistical analysis, the cohort was enriched for responders with 30 responders and 48 non-responders. Gene expression was assessed by quantitative RT-PCR after extracting mRNA from formalin-fixed paraffin embedded tumor tissue and correlated with results from immunohistochemical (IHC) stainings. RESULTS AND DISCUSSION: The evaluation of PD-L1 expression based on mRNA level is feasible. Correlation between PD-L1 expression as assessed by IHC and RT-PCR showed varying levels of concordance depending on the antibody employed. RT-PCR should be further investigated to measure PD-L1 expression, since it is a semi-quantitative method with observer-independent evaluation. With this approach, there was no statistical significant difference in the PD-L1 expression between responders and non-responders to the therapy with ipilimumab. The evaluation of PD-L1 expression based on mRNA level is feasible. Correlation between PD-L1 expression as assessed by IHC and RT-PCR showed varying levels of concordance depending on the antibody employed. RT-PCR should be further investigated to measure PD-L1 expression, since it is a semi-quantitative method with observer-independent evaluation. With this approach, there was no statistical significant difference in the PD-L1 expression between responders and non-responders to the therapy with ipilimumab.

Distant metastases in colorectal carcinoma: A proposal for a new M1 subclassification.

INTRODUCTION: In 2010, the seventh Tumour-Node-Metastasis (TNM) cancer staging system of the International Union for Cancer Control (UICC) and the American Joint Committee of Cancer (AJCC) introduced a subdivision of M1 in the TNM classification of colorectal carcinomas. For the eighth TNM edition which will be released in the autumn of 2016 and will become effective in January 2017 new proposals are appreciated. The aim of our study was to define a new and better proposal for M1 subclassification. METHODS: In a total of 814 patients with stage IV colorectal carcinoma treated between 1995 and 2013 prognostic factors were analysed in univariate and multivariate analyses. RESULTS: Advanced age, treatment in the earlier period 1995-2003, involvement of multiple metastatic sites, and non-curative resection were found to be independent prognostic factors. In patients with only one metastatic site, survival was good in patients with liver or lung metastasis, moderate in patients with metastasis of the peritoneum or non-regional lymph nodes and poor in patients with other rarely metastatic involved organs. The new proposal defines M1a, Metastasis confined to one organ: liver or lung (2-year survival 51.6%); M1b, Metastasis confined to one organ: peritoneum or non-regional lymph nodes, or Metastasis confined to liver plus lung (2-year survival 39.4%); and M1c, Metastasis confined to one organ: all other sites, or Metastasis in more than one organ, except liver plus lung (2-year survival 21.6%). CONCLUSION: The new proposal can identify three prognostic groups in stage IV colorectal carcinomas with significant differences in survival.

[Surgery for metastases, anatomical and ethical limits. Special aspect: oligometastases]. / Metastasenchirurgie - anatomische und ethische Grenzen. Besonderer Aspekt: Oligometastasierung.

The surgical resection of metastases is nowadays feasible in selected patients with multifocal metastatic disease due to the implementation of interdisciplinary multimodal therapeutic options. Anatomical limitations do not seem to represent obstacles which cannot be overcome because of the development of new surgical techniques. The cornerstone of the selection of patients is the correct staging diagnosis achieved through modern diagnostic tools; however, surgery alone does not always offer acceptable survival and recurrence-free rates. Furthermore, in every complex surgical procedure there is the risk of morbidity and mortality; therefore, parameters such as alternative therapeutic modalities, the individual situation of the patient and tumor biology have to be considered in order to make the correct selection of patients. This is one of the major future challenges and should never be driven by unfounded hopes and expectations of the patients. The same principle also applies for brain metastases, which represent the most common brain tumors. Approximately 70 % of patients with brain metastases have 1-3 lesions (oligometastases). Treatment is now individualized and the goal of therapy has shifted towards long-term survival (≥ 24 months) and improved quality of life. Under this aspect surgery is one of the important treatment options, particularly in patients with a single metastasis or oligometastases. Furthermore, approximately 20 % of patients who have recurrent brain metastases, successfully undergo a complete resection of tumors and with a Karnofsky performance status (KPS) score > 70 show a long-term survival of ≥ 24 months.

[Avoidance of complications in oncological surgery of the pelvic region : combined oncosurgical and plastic reconstruction measures]. / Komplikationsvermeidung in der onkologischen Chirurgie der Becken-/Leistenregion : Kombiniert onkochirurgische und plastisch-rekonstruktive Maßnahmen.

Prevention of perioperative and postoperative complications resulting from surgical oncology in the pelvic region remains a major interdisciplinary challenge. With modern interdisciplinary concepts joining forces of various surgical specialties, tumor resection can be sufficiently carried out with wide margins and the patients benefit from reduced morbidity even in complex situations. As an example chronic fistulation and secretion from the presacral cavity and sinus may result as potential sequelae from intra-abdominal and intrapelvic tumor resection, especially when neoadjuvant multimodal therapies have been applied. This can be prevented by simultaneous transplantation of for example transpelvic vertical rectus abdominis myocutaneous (VRAM) flap transfer, while extensive perineal skin and soft tissue defects may also be simultaneously reconstructed. In cases of malignant soft tissue tumors in the pelvic region a staged surgical procedure can be performed with a period of time between tumor resection and reconstruction. Thus, a histological R0 status can be secured prior to plastic reconstruction surgery in order to increase oncological safety. In cases of postresectional exposition of e. g. pelvic or femoral vessels or intrapelvic and intra-abdominal organs simultaneous flap procedure is mandatory.The reconstructive armamentarium of the plastic surgeon should contain not only pedicled but also free microsurgical flaps so that no compromise in terms of the extent of the oncological resection has to be accepted. At the same time perioperative and postoperative complications may be avoided and the patient quality of life can be preserved even in more complex cases.

Molecular staging of lymph node-negative colon carcinomas by one-step nucleic acid amplification (OSNA) results in upstaging of a quarter of patients in a prospective, European, multicentre study.

BACKGROUND: Current histopathological staging procedures in colon carcinomas depend on midline division of the lymph nodes with one section of haematoxylin & eosin (H&E) staining only. By this method, tumour deposits outside this transection line may be missed and could lead to understaging of a high-risk group of stage UICC II cases, which recurs in ∼20% of cases. A new diagnostic semiautomated system, one-step nucleic acid amplification (OSNA), detects cytokeratin (CK) 19 mRNA in lymph node metastases and enables the investigation of the whole lymph node. The objective of this study was to assess whether histopathological pN0 patients can be upstaged to stage UICC III by OSNA. METHODS: Lymph nodes from patients who were classified as lymph node negative after standard histopathology (single (H&E) slice) were subjected to OSNA. A result revealing a CK19 mRNA copy number >250, which makes sure to detect mainly macrometastases and not isolated tumour cells (ITC) or micrometastases only, was regarded as positive for lymph node metastases based on previous threshold investigations. RESULTS: In total, 1594 pN0 lymph nodes from 103 colon carcinomas (median number of lymph nodes per patient: 14, range: 1-46) were analysed with OSNA. Out of 103 pN0 patients, 26 had OSNA-positive lymph nodes, resulting in an upstaging rate of 25.2%. Among these were 6/37 (16.2%) stage UICC I and 20/66 (30.3%) stage UICC II patients. Overall, 38 lymph nodes were OSNA positive: 19 patients had one, 3 had two, 3 had three, and 1 patient had four OSNA-positive lymph nodes. CONCLUSIONS: OSNA resulted in an upstaging of over 25% of initially histopathologically lymph node-negative patients. OSNA is a standardised, observer-independent technique, allowing the analysis of the whole lymph node. Therefore, sampling bias due to missing investigation of certain lymph node tissue can be avoided, which may lead to a more accurate staging.

Liver transplantation for hepatitis B-induced liver disease: long-term outcome and effectiveness of antiviral therapy for prevention of recurrent hepatitis B infection.

OBJECTIVE: The aim of this study was to examine the efficacy of preoperative, perioperative, and long-term treatment in liver transplant (OLT) patients suffering hepatitis B (HBV)-induced liver disease, in terms of graft and survivals as well as disease recurrence. MATERIALS AND METHODS: We reviewed the medical records of 19 HBV-infected patients who underwent OLT between 2000 and 2010 using antiviral treatment with either lamivudine (LAM, n = 14) and/or adefovir/entecavir/tenofovir (n = 8) before OLT. Fifteen subjects showed a HBV DNA-negative status prior to OLT. All patients were administered HBIG (antiHBs immunoglobulin) perioperatively: 10,000 international units (IU) in the anhepatic phase and 2.000 IU/d until day 7 after OLT. The preoperative antiviral regimen was continued as maintenance prophylaxis from day 1 after OLT. In cases of the YMMD mutation the antiviral treatment was switched to combination therapy with entecavir and tenofovir. RESULTS: Patient follow-up as of December 2011 or till time of death ranged from 6 to 129 months (median = 47). All patients were prescribed tacrolimus. None of them experienced HBV-related graft dysfunction or graft loss. All subjects were HBV DNA negative at 6 months after OLT. HBV recurrence in the post-OLT phase was discovered in 3 patients, 2 of whom had undergone OLT because of acute liver failure due to hepatitis B. They showed LAM-resistant mutations at the time of recurrence and underwent entecavir/tenofovir therapy to achieve HBV DNA negative status. CONCLUSIONS: Our study demonstrated excellent long-term outcomes among patients after successful preoperative antiviral treatment for HBV. Patients should be given a high dosage of HBIG during the first week after OLT in combination with the preoperatively established antiviral treatment. In presence of a LAM-resistance mutation, antiviral treatment should be adapted individually to achieve HBV recurrence freedom and graft survival.

Long-term outcome of liver transplantation as treatment modality in patients with hepatocellular carcinoma in cirrhosis: a single-center experience.

BACKGROUND: Hepatocellular carcinoma (HCC) is among the most frequent malignant diseases worldwide. In the vast majority of cases, it is associated with liver cirrhosis. Liver transplantation (OLT) is potentially the gold standard treatment for patients suffering HCC in cirrhosis, because of synchronous eradication of HCC and of the underlying hepatic disease. The aim of this study was to evaluate long-term outcomes of OLT in HCC patients. MATERIAL AND METHODS: Between January 2000 and December 2011, 43 patients who were diagnosed with HCC in liver cirrhosis and underwent OLT in our department, were identified from a prospective database. All patients received their grafts from deceased donors. We analyzed demographic data, laboratory values, number and size of lesions, primary liver disease, diagnostic methods, bridging therapy modalities, and postoperative outcomes, including complications, recurrences, and their treatment. RESULTS: Patient follow-up as of January 2012 or to death ranged from 0 to 138 months (median, 59; mean, 63). None of the patients were lost to follow-up. The gender bias was 85%:15% (male:female) and the median age, 57.8 years (range, 44-69). The most common underlying diseases for cirrhosis and HCC were alcoholic (n = 12) and hepatitis C (n = 16). Thirty-one subjects underwent bridging therapy through transarterial chemoembolization (TACE), and/or radiofrequency ablation. All patients underwent OLT within the Milan criteria according to the preoperative evaluation and histopathologic examination of the explanted liver. Twenty-one of them suffered postoperative complications (48.8%). HCC recurrence, which occurred in 5 (10.4%), was treated by surgery (n = 3), systemic chemotherapy with sorafenib (n = 1), or TACE (n = 1). CONCLUSIONS: OLT for HCC in cirrhosis, displays a relatively high complication rate. It shows good survivals with and low recurrence.

The diagnostic value of systolic acceleration time and resistive index as noninvasive modality for detection of graft rejection after orthotopic liver transplantation.

BACKGROUND: Acute cellular and chronic graft rejection are major disorders in the postoperative setting after orthotopic liver transplantation (OLT). An immediate diagnosis and successful therapy are essential for graft survival. We sought to determine whether quantitative and qualitative analysis of Doppler sonography data was predictive and sensitive as noninvasive diagnostic tools for rejection episodes. MATERIALS AND METHODS: We prospectively recorded and retrospectively analyzed the medical records of patients who underwent OLT between January 2000 and November 2011, identifying patients with acute cellular (ACR) and chronic rejection (CR) and the grade classified the activity index according to BANFF criteria. Analyzed parameters included resistive index (R/I), systolic acceleration time (SAT) in the hepatic artery, laboratory values, histopathologic grade and therapy as well as graft and patient survival. RESULTS: Patient follow-up as of December 2011 or to the time of death ranged from 2 to 132 months (median follow- up: 79 months, mean = 83 months). We registered 29 rejection episodes (ACR n = 20 and CR n = 9) in 20 subjects. The majority of patients received a tacrolimus-based immunsuppressive regimen (n = 14, trough level: 7-12 ng/mL) in addition to high-dose corticosteroids, and sometimes a third drug. One patient displayed a corticosteroid-resistant ACR and 4 CR cases, graft loss followed by retransplantation. R/I was calculated for all patients and SA for those who underwent OLT since 2009. As a control group we used subjects with delayed SAT and high R/I without graft rejection. In all patients with a high R/I (>0.7, range: 0.71-0.91) and in all patients who suffered graft rejection since 2009 (n = 14), we observed a delayed SAT (>0.08, range: 0.08-0.18). The sensitivity and specificity for R/I were 82%, and 54.9%; for SAT 100% and 78%, respectively. CONCLUSION: Delayed SAT (>0.08) and high R/I (>0.7) were sensitive indices of graft rejection episode. The limitation of these diagnostic parameters is their specificity, especially in the immediate postoperative period, where early vascular disorders trigger similar sonographic results. Nevertheless SAT and R/I may be considered to be important diagnostic tools, in combination with elevated laboratory liver values they can provide an early diagnosis of graft rejection.

The value of pre-emptive therapy for cytomegalovirus after liver transplantation.

BACKGROUND: Cytomegalovirus (CMV) infections are among the most common infections following liver transplantation. The main preventive methods for CMV infections are universal prophylaxis and pre-emptive therapy. In our study, we adopted a pre-emptive strategy in a higth-risk group of donor CMV-positive (D+)/recipient CMV-negative (R-) casses. We investigated whether this strategy was safe and effective to prevent CMV disease. METHODS: One hundred fifty-nine liver transplantation recipients who underwent over a 15-year period were retrospectively analyzed after follow-up for at least 6 months (mean, 63 months). Weekly quantitative polymerase chain reaction (PCR) measurements were performed to detect viral DNA. No CMV drug prophylaxis was given: antiviral CMV therapy was initiated when the PCR for CMV-DNA was >400 copies/mL. RESULTS: Fifty-one of 159 liver transplant recipients enrolled in the study received antiviral therapy. High-risk patients (D+/R-) developed CMV infections significantly more often than D-/R- serostatus (P = .005). CMV disease was diagnosed in 12% of CMV-positive patients. Independent of serostatus in 14 cases (27.5%) virological recurrence of CMV infection occurred after primary treatment. Survival analysis showed no significant difference between patients with versus without CMV infection (P = .950). No relationship could be found between transplant rejection and CMV infection (P = .349). CONCLUSION: Our results showed that a pre-emptive strategy to prevent CMV disease was possible, even among the serological high-risk group. Only 12% of cases with CMV infection went on to manifest CMV disease with organ involvement. Survival curves were similar among patients with versus without CMV infections.

Impact of the conversion of the immunosuppressive regimen from prograf to advagraf or to sirolimus in long-term stable liver transplant recipients: indications, safety, and outcome.

BACKGROUND: Compliance problems have arisen due to the twice a day administration of calcineurin inhibitors (CNI). We examined the safety, indications, and efficacy in terms of graft and patient survivals after conversion from tacrolimus to sirolimus or advagraf. PATIENTS AND METHODS: Between January 2006 and December 2009, 36 orthotopic liver transplantation patients underwent conversion of the immunosuppressive regimen from prograf to either sirolimus (group 1; n=10) or advagraf (group 2; n=26). A group of patients taking prograf was used as a control group (group 3; n=15). We identified 51 patients of mean age 57 years and male:female percentages of 57%:43% from a prospective database. Renal and liver graft functions, patient survival, as well as laboratory and clinical data over at least 12 months (mean, 38) were the investigated parameters. RESULTS: Patients converted to sirolimus did not show significantly improved renal function at 12 months as evidenced by creatinine levels (1.31 mg/dL+/-0.47 vs 1.34 mg/dL+/-0.78) and glomerular filtration rate (GFR, 57+/-16 vs 56+/-16 mL/min). However, there were significant antiproliferative effects. Patients with a hepatocellular carcinoma in the pretransplantation phase remained without a recurrence. The side effects including ankle edema, aphthae, and tachyarrhythmia absoluta, required reconversion to the CNI. Patients prescribed advagraf reported a better life quality because of the single administration and a slight, insignificant improvement in renal function. An acute rejection episode was evidenced under either immunosuppresant. CONCLUSION: Sirolimus is a safe immunosuppressive option in liver transplant recipients suffering from hepatocellular carcinoma. Advagraf showed a lower incidence of side effects than prograf and probably is not as harmful for renal function, offering better compliance and better life quality.

[Neoadjuvant radiochemotherapy for rectal cancer]. / Neoadjuvante Radiochemotherapie des Rektumkarzinoms.

Neoadjuvant radiochemotherapy has become established treatment for rectal cancer. It is indicated when primary R0 resection is not an option, in cases of higher risk of locoregional relapse following surgical treatment alone, and when initially impossible conservation of the anal sphincter becomes possible in conjunction with neoadjuvant radiochemotherapy. The indication for radiochemotherapy in the upper third of the rectum is still controversial. Reevaluation of the tumor situation following neoadjuvant treatment is necessary before decisions on operative strategy. Modern imaging techniques are limited in this respect, as they hardly allow differentiation between living tumor tissue and lesions. In case of doubt clarity is possible only through surgical exploration, taking R1 resection into account. Overall the recognition of lymph node metastasis is not a sufficient indicator of local relapse. The frequency of postoperative complications following neoadjuvant radiochemotherapy is independent of the operative method. The effect of neoadjuvant radiochemotherapy on long-term survival and formation of distant metastases is still not clarified. Current studies seek clarification through the use of new chemotherapies and modified treatment regimes. Further, the correct time interval between the end of neoadjuvant radiochemotherapy and the following surgical therapy has yet to be determined. This applies also to the management of patients following complete remission.