[Endoscopic management of surgical biliary complications]. / Endoskopisches Management postoperativer Gallengangskomplikationen.

Endoscopic-retrograde cholangiopancreaticography (ERCP) is the method of choice for the treatment of surgical complications of the biliary system. Biliary leaks most frequently occur after cholecystectomy and partial liver resection. The most frequent complications after liver transplantation include biliary leaks, strictures and obstructive cholestasis. They are associated with significant morbidity and mortality as well as the risk of failure of the transplanted organ. The chance for a long-term successful therapy via ERCP is dependent on three main factors: (i) type, localisation and extent of the biliary damage, (ii) the time-point of appearance after surgery and (iii) the consequent accomplishment of the endoscopic therapy. In case of altered anatomy, e. g., hepatico- or choledocho-jejunostomy, endoscopic therapy can often be accomplished via an enteroscopic approach.

Gemcitabine plus sorafenib versus gemcitabine alone in advanced biliary tract cancer: a double-blind placebo-controlled multicentre phase II AIO study with biomarker and serum programme.

BACKGROUND: Since sorafenib has shown activity in different tumour types and gemcitabine regimens improved the outcome for biliary tract cancer (BTC) patients, we evaluated first-line gemcitabine plus sorafenib in a double-blind phase II study. PATIENTS AND METHODS: 102 unresectable or metastatic BTC patients with histologically proven adenocarcinoma of gallbladder or intrahepatic bile ducts, Eastern Cooperative Oncology Group (ECOG) 0-2 were randomised to gemcitabine (1000 mg/m2 once weekly, first 7-weeks+1-week rest followed by once 3-weeks+1-week rest) plus sorafenib (400 mg twice daily) or placebo. Treatment continued until progression or unacceptable toxicity. Tumour samples were prospectively stained for sorafenib targets and potential biomarkers. Serum samples (first two cycles) were measured for vascular endothelial growth factors (VEGFs), vascular endothelial growth factor receptor 2 (VEGFR-2) and stromal cell-derived factor 1 (SDF1)α by enzyme-linked immunosorbent assay (ELISA). RESULTS: Gemcitabine plus sorafenib was generally well tolerated. Four and three patients achieved partial responses in the sorafenib and placebo groups, respectively. There was no difference in the primary end-point, median progression-free survival (PFS) for gemcitabine plus sorafenib versus gemcitabine plus placebo (3.0 versus 4.9 months, P=0.859), and no difference for median overall survival (OS) (8.4 versus 11.2 months, P=0.775). Patients with liver metastasis after resection of primary BTC survived longer with sorafenib (P=0.019) compared to placebo. Patients who developed hand-foot syndrome (HFS) showed longer PFS and OS than patients without HFS. Two sorafenib targets, VEGFR-2 and c-kit, were not expressed in BTC samples. VEGFR-3 and Hif1α were associated with lymph node metastases and T stage. Absence of PDGFRß expression correlated with longer PFS. CONCLUSION: The addition of sorafenib to gemcitabine did not demonstrate improved efficacy in advanced BTC patients. Biomarker subgroup analysis suggested that some patients might benefit from combined treatment.

[Diagnosis of and therapy for hepatocellular carcinoma]. / Diagnostik und Therapie des hepatozellulären Karzinoms.

The interdisciplinary guidelines at the S3 level on the diagnosis of and therapy for hepatocellular carcinoma (HCC) constitute an evidence- and consensus-based instrument that is aimed at improving the diagnosis of and therapy for HCC since these are very challenging tasks. The purpose of the guidelines is to offer the patient (with suspected or confirmed HCC) adequate, scientifically based and up-to-date procedures in diagnosis, therapy and rehabilitation. This holds not only for locally limited or focally advanced disease but also for the existence of recurrences or distant metastases. Besides making a contribution to an appropriate health-care service, the guidelines should also provide the foundation for an individually adapted, high-quality therapy. The explanatory background texts should also enable non-specialist but responsible colleagues to give sound advice to their patients concerning specialist procedures, side effects and results. In the medium and long-term this should reduce the morbidity and mortality of patients with HCC and improve their quality of life.

[Early detection of colorectal cancer: role of endoscopy and imaging]. / Früherkennung des kolorektalen Karzinoms: rolle der Endoskopie und bildgebenden Verfahren.

Colorectal cancer is one of the leading causes of cancer-related morbidity and mortality. Colorectal cancer commonly develops slowly via adenomatous polyps, a process usually requiring ≥ 10 years. This allows for early detection. Endoscopic polypectomy and surgery of early disease can reduce the incidence and mortality of colorectal cancer. Both hemoccult testing and colonoscopy are the most widely used tests for colorectal cancer screening; however, colonoscopy has the highest sensitivity for colorectal neoplasia. Sigmoidoscopy is not commonly used for screening in Germany. Colon contrast enema is no longer recommended for screening. As colonoscopy serves as a diagnostic and therapeutic tool and is the reference method in hemoccult and sigmoidoscopy studies, it is viewed as the gold standard for the diagnosis of colonic disease. New methods including capsule colonoscopy and virtual colonoscopy have great potential but are currently not recommended for early detection of colonic neoplasia.

[Current therapy of hepatocellular carcinoma with special consideration of new and multimodal treatment concepts]. / Aktuelle Therapie des hepatozellulären Karzinoms unter besonderer Berücksichtigung neuer und multimodaler Therapiekonzepte.

The incidence of hepatocellular carcinoma (HCC) is increasing worldwide due to the growing number of hepatitis C related HCCs. In more than 80% of the patients, HCC arises in a cirrhotic liver. Furthermore, more than half of the patients have an advanced Child-Pugh score or an inoperable tumor stage at the initial diagnosis. Recommendations for the treatment of HCC by national and international guidelines rely on the BCLC ("Barcelona Clinic for Liver Cancer") algorithm. Depending on the stage of liver function and tumor disease it recommends resection, liver transplantation, radiofrequency thermal ablation (RFA), transarterial chemoembolisation (TACE), systemic therapy with sorafenib or best supportive care, but does neither take into consideration combination of therapies nor new therapy modalities. However, there is increasing evidence that combinations i. e. sorafenib with TACE or combination of locoregional techniques enhance effectivity and tumor control compared to monotherapies. TACE with drug-eluting beads, selective internal radiotherapy (SIRT) and new locoregional therapy procedures like microwave ablation (MWA) are further promising therapeutic approaches. Patients with HCC should be discussed in a local tumor board in order to provide the optimal and most individual way of treatment.

[Therapy of hepatocellular carcinoma before liver transplantation]. / Therapie des hepatozellulären Karzinoms vor Lebertransplantation.

Liver transplantation is the optimal therapy for patients with non-resectable early stage hepatocellular carcinoma (HCC) which is limited to the liver. During the sometimes long waiting period patients usually receive neoadjuvant bridging therapy to avoid tumor progression. The armamentarium of bridging therapies includes local ablative and systemic therapies as well as liver resection. The oncological benefit of neoadjuvant therapy for patients who receive a liver transplantation is unclear; however, bridging therapy keeps patients eligible for transplantation in the formal framework of current allocation rules. Moreover, response to therapy may serve as a surrogate marker for favorable tumor biology and may therefore help to guide the selection process for patients undergoing liver transplantation for HCC.

Multimodality treatment for early-stage hepatocellular carcinoma: a bridging therapy for liver transplantation.

PURPOSE: To evaluate the efficiency of a multimodality approach consisting of transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) as bridging therapy for patients with hepatocellular carcinoma (HCC) awaiting orthotopic liver transplantation (OLT) and to evaluate the histopathological response in explant specimens. MATERIALS AND METHODS: Between April 2001 and November 2011, 36 patients with 50 HCC nodules (1.4-5.0 cm, median 2.8 cm) on the waiting list for liver transplantation were treated by TACE and RFA. The drop-out rate during the follow-up period was recorded. The local efficacy was evaluated by histopathological examination of the explanted livers. RESULTS: During a median follow-up time of 29 (4.0-95.3) months the cumulative drop-out rate for the patients on the waiting list was 0, 2.8, 5.5, 11.0, 13.9 and 16.7% at 3, 6, 12, 24, 36 and 48 months, respectively. 16 patients (with 26 HCC lesions) out of 36 (44.4%) were transplanted by the end of study with a median waiting list time of 13.7 (2.5-37.8) months. The histopathological examination of the explanted specimens revealed a complete necrosis in 20 of 26 HCCs (76.9%), whereas 6 (23.1%) nodules showed viable residual tumor tissue. All transplanted patients are alive at a median time of 29.9 months. Imaging correlation showed 100% specificity and 66.7% sensitivity for the depiction of residual or recurrent tumor. CONCLUSION: We conclude that TACE combined with RFA could provide an effective treatment to decrease the drop-out rate from the OLT waiting list for HCC patients. Furthermore, this combination therapy results in high rates of complete tumor necrosis as evaluated in the histopathological analysis of the explanted livers. Further randomized trials are needed to demonstrate if there is a benefit in comparison with a single-treatment approach.

[Screening for colorectal cancer. Current evidence and novel developments]. / Screening auf kolorektale Neoplasien. Aktuelle Evidenz und neue Entwicklungen.

CLINICAL ISSUE: Colorectal cancer is one of the leading causes of cancer-related morbidity and mortality. Screening has been demonstrated to reduce both the incidence and mortality of colorectal cancer. In addition to the large group with a normal risk level, two further risk groups need to be distinguished: increased family risk and hereditary colorectal cancer syndromes. STANDARD METHODS FOR SCREENING: The highest evidence for all screening tests has been demonstrated for guaiac-based fecal occult blood testing. Colonoscopy is a diagnostic and therapeutic tool and it serves as the reference standard for other tests in clinical studies. INNOVATIONS: Fecal immunochemical tests have a higher sensitivity than guaiac-based tests. Several novel techniques are under development and could be adopted by screening programs in the future. Next to colonoscopy, computed tomography (CT) colonography and colon capsule endoscopy have the highest sensitivity for colorectal neoplasia. Molecular tests which are based on the detection of genetic and epigenetic changes of DNA released by the tumor into feces or blood have a high potential and could potentially replace occult blood tests in the future. PRACTICAL RECOMMENDATIONS: Colonoscopy is the primary instrument for screening for colorectal neoplasia. Fecal occult blood testing should only be performed if colonoscopy is denied and CT colonography has not yet been approved for screening in Germany.

Dickkopf 4 (DKK4) acts on Wnt/ß-catenin pathway by influencing ß-catenin in hepatocellular carcinoma.

Deregulation of Wnt/ß-catenin pathway is a hallmark of major gastrointestinal cancers including hepatocellular carcinoma (HCC). The oncogenic role of ß-catenin is well defined but reasons for its accumulation in HCC remain unclear. Dickkopf 4 (DKK4) acts as a negative regulator of Wnt/ß-catenin pathway but its functional role in liver carcinogenesis has not been studied. We investigated the role of DKK4 in ß-catenin regulation in HCC. Reduced expression of DKK4 was found in 47% (38/81) of HCC, as measured by quantitative real time PCR. Ectopic expression of DKK4 in two HCC cell lines, PLC/PRF/5 (PLC) and MHCC97L (97L), attenuated ß-catenin responsive luciferase activity, and decreased both ß-catenin and cyclin D1 protein levels. To study the effect of DKK4 on cell growth and tumourigenicity, two stable HCC cell lines were established from PLC and 97L cells. Functional assays demonstrated that overexpression of DKK4 hampered cell proliferation, reduced colony formation and retarded cell migration. When DKK4-expressing 97L stable cells were used to induce tumour xenografts in nude mice (n=8), reduction in tumour sizes was observed (P=0.027). Furthermore, immunohistochemical studies showed that decreased expression of DKK4 was associated with ß-catenin accumulation in HCC tissues. Additionally, inhibition of the proteasome using specific inhibitor in DKK4-expressing 97L stable cells masked the effect of ß-catenin. Our findings suggest a potential tumour suppressive role of DKK4 as well as that of an important regulator of HCC.

Multimodality treatment with conventional transcatheter arterial chemoembolization and radiofrequency ablation for unresectable hepatocellular carcinoma.

BACKGROUND/AIMS: To evaluate the efficacy of multimodality treatment consisting of conventional transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) in patients with non-resectable and non-ablatable hepatocellular carcinoma (HCC). METHODS: In this retrospective study, 85 consecutive patients with HCC (59 solitary, 29 multifocal HCC) received TACE followed by RFA between 2001 and 2010. The mean number of tumors per patient was 1.6 ± 0.7 with a mean size of 3.0 ± 0.9 cm. Both local efficacy and patient survival were evaluated. RESULTS: Of 120 treated HCCs, 99 (82.5%) showed a complete response (CR), while in 21 HCCs (17.5%) a partial response was depicted. Patients with solitary HCC revealed CR in 91% (51/56); in patients with multifocal HCC (n = 29) CR was achieved in 75% (48 of 64 HCCs). The median survival for all patients was 25.5 months. The 1-, 2-, 3- and 5-year survival rates were 84.6, 58.7, 37.6 and 14.6%, respectively. Statistical analysis revealed a significant difference in survival between Barcelona Clinic Liver Cancer (BCLC) A (73.4 months) and B (50.3 months) patients, while analyses failed to show a difference for Child-Pugh score, Cancer of Liver Italian Program (CLIP) score and tumor distribution pattern. CONCLUSION: TACE combined with RFA provides an effective treatment approach with high local tumor control rates and promising survival data, especially for BCLC A patients. Randomized trials are needed to compare this multimodality approach with a single modality approach for early-stage HCC.

[How physicians inform about colorectal cancer and screening]. / Arztliche Aufklärung über Darmkrebs und Darmkrebsvorsorge.

Screening colonoscopy is an efficient and safe instrument for the early detection of colonic neoplasia. The cumulative participation rate in Germany remains low with 15.5% of eligible men and 17.2% of eligible women. Reasons for this are not well understood. Especially physicians have an important role. The aim of this study was to analyse information and recommendations of primary care physicians, urologists and gynaecologists on colorectal cancer screening. A survey of 239 primary care physicians, urologists and gynaecologists by a structured questionnaire on information concerning colorectal cancer and colorectal cancer prevention was carried out. Statistical analysis was performed by pair-wise comparison of the three groups. There were only small differences between primary care physicians, urologists and gynaecologists. Primary care physicians offer patients more consulting time for this information than the other two groups. In the majority of cases colonoscopy is recommended. Gynaecologists less often recommend the classical guaiac-based faecal occult blood test, but more frequently immunochemical tests. The complication rate of colonoscopy is overestimated at 1.25% (0 - 40%). The majority of physicians have previously participated in colorectal cancer screening. Information about the risk of colorectal cancer and screening has a high priority. The level of knowledge of physicians may be improved.

[Hepatitis A - combined prolonged biphasic and cholestatic course of disease]. / Hepatitis A - kombinierte protrahierte zweigipflige und cholestatische Verlaufsform.

HISTORY AND ADMISSION FINDINGS: One month after a first manifestation of a hepatitis A infection and transaminases had become normal, a 44-year-old woman again became jaundiced with accompanied by weakness, nausea and nocturnal sweating. INVESTIGATIONS: Laboratory tests again showed features of hepatitis with decreased synthetic liver function and hyperbilirubinemia, changes which persisted for 12 weeks. Serological and virological studies revealed a positive test for anti-hepatitis A virus (HAV) IgM and HAV-RNA was detected in the stool. DIAGNOSIS, TREATMENT AND COURSE: These tests demonstrated two rare features of hepatitis A, namely a prolonged biphasic course combined with cholestasis form. In addition a hemolytic anaemia developed. CONCLUSION: The severity of a relapse of hepatitis A varies: in this case it was more severe than the initial manifestation. The reasons for the different courses of hepatitis A infection remain unclear.

[Diagnosis and multimodal therapy for hepatocellular carcinoma]. / Diagnose und multimodale Therapie des hepatozellulären Karzinoms.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death in the world. The majority of HCCs develops on the basis of a chronic liver disease. This often complicates diagnosis and therapy. Non-invasive diagnostic criteria are based on dynamic imaging techniques and the serum level of AFP (alpha-fetoprotein). When evaluating HCC patients for therapy, besides tumor burden and localisation, the therapeutic evaluation must also consider the general condition of the patient and his/her liver function. For this purpose, the BCLC algorithm of the Barcelona Clinic for Liver Disease has proven helpful. Only one-third of the patients can be cured by resection, transplantation or local tumour ablation. In locally advanced cases transarterial procedures including transarterial chemoembolisation and radioembolisation are applied. HCC is a chemo-resistant tumour and chemotherapy is not accepted as standard of care in HCC. Sorafenib is the first systemic treatment with proven efficacy approved for the treatment of advanced and metastatic HCC. Interdisciplinary management of HCC patients is essential in order to provide every patient with the optimal therapy at his specific stage of disease.

[Acute exacerbation of a chronic esophagitis]. / Akute Exazerbation einer chronischen Osophagitis.

HISTORY AND ADMISSION FINDINGS: A 50-year-old woman presented with progressive dysphagia and chest pain. Clinical and laboratory findings revealed a moderate epigastric pain and moderately elevated D-dimers. She had previously been diagnosed with esophagitis. Current oral medication included risedonate and clindamycin. INVESTIGATIONS: The electrocardiogram was appropriate for age, with a SIQIII-sign and sinus tachycardia. Echocardiography, abdominal sonography and chest X-ray were unremarkable. Gastroscopy demonstrated severe inflammatory lesions in the middle part of the esophagus. The biopsies revealed crystalline material microscopically. TREATMENT AND COURSE: The findings supported the diagnosis of an acute exacerbation of a chronic risedronat-induced esophagitis caused by clindamycin. After discontinuing the oral medication and giving intermittent parenteral nutrition the lesions healed completely. CONCLUSION: Drug-induced esophagitis is often not recognized. Because of the high number of patients on bisphosphonate medication, often in combination with other potentially ulcerogenic drugs, the differential diagnosis should include drug-induced esophagitis.

Comparison of CT colonography, colonoscopy, sigmoidoscopy and faecal occult blood tests for the detection of advanced adenoma in an average risk population.

BACKGROUND AND AIMS: This prospective trial was designed to compare the performance characteristics of five different screening tests in parallel for the detection of advanced colonic neoplasia: CT colonography (CTC), colonoscopy (OC), flexible sigmoidoscopy (FS), faecal immunochemical stool testing (FIT) and faecal occult blood testing (FOBT). METHODS: Average risk adults provided stool specimens for FOBT and FIT, and underwent same-day low-dose 64-multidetector row CTC and OC using segmentally unblinded OC as the standard of reference. Sensitivities and specificities were calculated for each single test, and for combinations of FS and stool tests. CTC radiation exposure was measured, and patient comfort levels and preferences were assessed by questionnaire. RESULTS: 221 adenomas were detected in 307 subjects who completed CTC (mean radiation dose, 4.5 mSv) and OC; 269 patients provided stool samples for both FOBT and FIT. Sensitivities of OC, CTC, FS, FIT and FOBT for advanced colonic neoplasia were 100% (95% CI 88.4% to 100%), 96.7% (82.8% to 99.9%), 83.3% (95% CI 65.3% to 94.4%), 32% (95% CI 14.9% to 53.5) and 20% (95% CI 6.8% to 40.7%), respectively. Combination of FS with FOBT or FIT led to no relevant increase in sensitivity. 12 of 45 advanced adenomas were smaller than 10 mm. 46% of patients preferred CTC and 37% preferred OC (p<0.001). CONCLUSIONS: High-resolution and low-dose CTC is feasible for colorectal cancer screening and reaches sensitivities comparable with OC for polyps >5 mm. For patients who refuse full bowel preparation and OC or CTC, FS should be preferred over stool tests. However, in cases where stool tests are performed, FIT should be recommended rather than FOBT.

JNK inhibition sensitises hepatocellular carcinoma cells but not normal hepatocytes to the TNF-related apoptosis-inducing ligand.

BACKGROUND: cJun terminal kinase (JNK) is constitutively activated in most hepatocellular carcinomas (HCCs), yet its exact role in carcinogenesis remains controversial. While tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is known as a major mediator of acquired immune tumour surveillance, and is currently being tested in clinical trials as a novel cancer therapy, the resistance of many tumours to TRAIL and concerns about its toxicity in vivo represent obstacles to its clinical application. In this study we investigated whether JNK activity in HCC could contribute to the resistance to apoptosis in these tumours. METHODS: The effect of JNK/Jun inhibition on receptor-mediated apoptosis was analysed by pharmacological inhibition or RNA interference in cancer cells and non-tumour cells isolated from human liver or transgenic mice lacking a phosphorylation site for Jun. RESULTS: JNK inhibition caused cell cycle arrest, enhanced caspase recruitment, and greatly sensitised HCC cells but not normal hepatocytes to TRAIL. TRAIL-induced activation of JNK could be effectively interrupted by administration of the JNK inhibitor SP600125. CONCLUSIONS: Expression and TRAIL-dependent feedback activation of JNK likely represent a mechanism by which cancer cells escape TRAIL-mediated tumour surveillance. JNK inhibition might represent a novel strategy for specifically sensitising HCC cells to TRAIL thus opening promising therapeutic perspectives for safe and effective use of TRAIL in cancer treatment.

A conserved domain in the transcription factor ITF-2B attenuates its activity.

The immunoglobulin transcription factor-2B (ITF-2B) belongs to the basic helix-loop-helix (bHLH) family of transcription factors. It is ubiquitously expressed and plays a prominent role in the regulation of differentiation processes. Protein sequence alignment of the closely related bHLH transcription factors ITF-2B, HeLa E box protein (HITF4), and the E2A proteins E12 and E47 revealed the presence of a highly conserved protein domain. Functional analysis of this domain demonstrated that it plays an important role in repressing the transcriptional activity of the ITF-2B protein. Moreover, this domain comprises a self-contained transcriptional repressor whose activity depends on specific amino acid residues.