Real-World Data for Lenvatinib in Hepatocellular Carcinoma (ELEVATOR): A Retrospective Multicenter Study.

Background: Lenvatinib is approved as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). The efficacy of lenvatinib in Caucasian real-world patients is insufficiently defined. The purpose of this study was to evaluate the efficacy of lenvatinib in a multi-center cohort (ELEVATOR) from Germany and Austria. Methods: A retrospective data analysis of 205 patients treated with first-line systemic lenvatinib at 14 different sites was conducted. Overall survival, progression free survival, overall response rate and adverse event rates were assessed and analyzed. Results: Patients receiving lenvatinib in the real-world setting reached a median overall survival of 12.8 months, which was comparable to the results reported from the REFLECT study. Median overall survival (mOS) and progression free survival (mPFS) was superior in those patients who met the inclusion criteria of the REFLECT study compared to patients who failed to meet the inclusion criteria (mOS 15.6 vs 10.2 months, HR 0.55, 95% CI 0.38-0.81, p=0.002; mPFS 8.1 vs 4.8 months HR 0.65, 95% CI 0.46-0.91, p=0.0015). For patients with an impaired liver function according to the Albumin-Bilirubin (ALBI) grade, or reduced ECOG performance status ≥2, survival was significantly shorter compared to patients with sustained liver function (ALBI grade 1) and good performance status (ECOG performance status 0), respectively (HR 1.69, 95% CI 1.07-2.66, p=0.023; HR 2.25, 95% CI 1.19-4.23, p=0.012). Additionally, macrovascular invasion (HR 1.55, 95% CI 1.02-2.37, p=0.041) and an AFP ≥200 ng/mL (HR 1.56, 95% CI 1.03-2.34, p=0.034) were confirmed as independent negative prognostic factors in our cohort of patients with advanced HCC. Conclusion: Overall, our data confirm the efficacy of lenvatinib as first-line treatment and did not reveal new or unexpected side effects in a large retrospective Caucasian real-world cohort, supporting the use of lenvatinib as meaningful alternative for patients that cannot be treated with IO-based combinations in first-line HCC.

Extensive intrathoracic and intraperitoneal splenosis mimicking mesothelioma: a case report.

BACKGROUND: Splenosis is the heterotopic autotransplantation of splenic tissue after severe splenic trauma and/or splenectomy. The epidemiology is elusive, but splenosis is frequently misdiagnosed as malignant tumors of gastrointestinal, gynecological, or hematological origin before the correct diagnosis is ultimately found. We herein report a rare case of combined, extensive intraabdominal and intrathoracic splenosis initially presenting as pleural mesothelioma. CASE PRESENTATION: A 63-year-old Caucasian male presented with dyspnea and recurring thoracic pain. Initial X-ray and computed tomography scans showed disseminated intrathoracic and intraabdominal lesions. Consequently, thoracoabdominal mesothelioma or a polytopically metastasized cancer of unknown origin was suspected. A thorough examination of the patient's medical history and contrast-enhanced ultrasound by a skilled examiner revealed the diagnosis of extensive abdominal and thoracic splenosis as a consequence of an abdominal gunshot wound with a ruptured diaphragm several decades earlier. Timely diagnosis by noninvasive measures prevented the patient from potential complications of harmful diagnostic procedures, including nuclear imaging and biopsies. The patient is currently treated for hepatitis C and chronic obstructive lung disease, whereas no specific treatment for splenosis is required. CONCLUSIONS: We present a case of rare intrathoracic and intraperitoneal splenosis mimicking mesothelioma. Contrast-enhanced ultrasound and thorough patient history were used for diagnosis and prevented this patient from having to undergo potentially harmful diagnostics. Splenosis can occur after splenic trauma and, consequently, needs to be considered as a rare differential diagnosis to malignant tumors of various origins when a matching patient history is obtained.

Indication of Liver Transplantation for Hepatocellular Carcinoma Should Be Reconsidered in Case of Microvascular Invasion and Multilocular Tumor Occurrence.

Liver transplantation (LT) is routinely performed for hepatocellular carcinoma (HCC) in cirrhosis without major vascular invasion. Although the adverse influence of microvascular invasion is recognized, its occurrence does not contraindicate LT. We retrospectively analyzed in our LT cohort the significance of microvascular invasion on survival and demonstrate bridging procedures. At our hospital, 346 patients were diagnosed with HCC, 171 patients were evaluated for LT, and 153 were listed at Eurotransplant during a period of 11 years. Among these, 112 patients received LT and were included in this study. Overall survival after 1, 3 and 5 years was 86.3%, 73.9%, and 67.9%, respectively. Microvascular invasion led to significantly reduced overall (p = 0.030) and disease-free survival (p = 0.002). Five-year disease-free survival with microvascular invasion was 10.5%. Multilocular tumor occurrence with simultaneous microvascular invasion revealed the worst prognosis. In our LT cohort, predominant bridging treatment was transarterial chemoembolization (TACE) and the number of TACE significantly correlated with poorer overall survival after LT (p = 0.028), which was confirmed in multiple Cox regression analysis for overall and disease-free survival (p = 0.015 and p = 0.011). Microvascular tumor invasion is significantly associated with reduced prognosis after LT, which is aggravated by simultaneous occurrence of multiple lesions. Therefore, indication strategies for LT should be reconsidered.

Lethal thrombosis of the iliac artery caused by Aspergillus fumigatus after liver transplantation: case report and review of the literature.

BACKGROUND: Aspergillus fumigatus infections frequently occur after solid organ transplantation. Yet, a fungal thrombosis after liver transplantation is an exceptional finding. CASE PRESENTATION: We report on a 44-year-old female with an aspergillosis after liver transplantation for autoimmune hepatitis. On postoperative day (pod) 7, seizures occurred and imaging diagnostics revealed an intracranial lesion. Anidulafungin was initiated in suspicion of mycosis and switched to voriconazole on suspicion of an Aspergillus spp. infection. Progression of the cerebral lesion prompted craniotomy (pod 48) and the aspergillosis was verified. The patient was discharged with oral voriconazole therapy. Re-admission was necessary with acute-on-chronic renal failure after a tacrolimus overdose on pod 130. The patient received a pelvic angiography due to a temperature difference in the legs. It showed a complete iliac artery thrombosis which was subsecutively surgically removed. The histopathological examination revealed an Aspergillus fumigatus conglomerate. The patient died on pod 210 due to systemic aspergillosis. CONCLUSION: The acute development of focal neurologic deficits is common in patients with an aspergillosis of the brain. Nevertheless, arterial thrombosis after Aspergillus fumigatus is less frequent and, to the best of our knowledge, its occurrence after liver transplantation has not yet been reported so far. Due to its rarity, we added a review of the literature to this manuscript.

Estimation of liver fibrosis by noncommercial serum markers in comparison with transient elastography in patients with chronic hepatitis C virus infection receiving direct-acting antiviral treatment.

Treatment decisions are based on extent of fibrosis in patients with chronic hepatitis C (HCV) infection. Noninvasive diagnostic tools may help to avoid liver biopsy. We investigated the diagnostic accuracy of noncommercial serum scores in comparison with transient elastography (TE). Data analysis was undertaken based on 2458 patients enrolled in the German Hepatitis C Registry, in a prospective, observational study. Aspartate aminotransferase-to-platelet ratio index (APRI), FORNS index and FIB-4 score were calculated and the diagnostic accuracy was compared to TE. As estimated by TE, 955 (38.9%) patients had absence of significant fibrosis (SF), 736 (29.9%) patients had SF, and 767 (31.2%) patients were shown to have cirrhosis. Patients with absence of SF had a sustained virological response (SVR) rate of 97.9%, whereas SVR was attained in 96.2% and 92.2% in those with SF and cirrhosis, respectively (P < 0.0001). The area under the receiver operator characteristic curve (AUROC), sensitivity and specificity in discriminating of SF were 0.789, 0.596 and 0.939 by APRI; 0.838, 0.852 and 0.748 by FORNS index; and 0.828, 0.658 and 0.946 by FIB-4 score. AUROCs for the prediction of cirrhosis, sensitivity and specificity were 0.881, 0.851 and 0.854 by APRI; 0.846, 0.948 and 0.628 by FORNS index; and 0.907, 0.907 and 0.848 by FIB-4 score. In conclusion, in the present multicentre real-world cohort, SF and cirrhosis were predicted with high accuracy with noncommercial serum markers using TE as reference. Further prospective long-term follow-up is necessary to compare biomarkers with TE concerning liver-related outcome and overall mortality.

Cognitive Evaluation in Liver Transplant Patients Under Calcineurin Inhibitor Maintenance Therapy.

BACKGROUND: Neurological disorders due to calcineurin inhibitor (CNI) treatment pose a well-known problem after liver transplantation (LTx). In this study, the impact of CNIs on cognitive functioning during maintenance therapy was analyzed. A possible improvement of cognitive functioning, compliance and health-related quality of life (HRQoL) after conversion to a once-daily tacrolimus formulation was prospectively assessed. METHODS: In a cross-section analysis cognitive functioning of living donors (LD), waiting list patients and LTx patients was tested using a 4 times trail making test (4-TTMT). In a further investigator-initiated trial a possible improvement of cognitive functioning, HRQoL and compliance after conversion to the once-daily tacrolimus formulation was prospectively assessed over 1 year. HRQoL was assessed using an EORTC-QLQ C30 questionnaire and patient's compliance was assessed by the Basel Assessment of Compliance with Immunosuppressive Medication Scales questionnaire. Correlated data were sex, age, time after surgery, liver disease, model of end-stage liver disease score, creatinine, CNI type, and CNI trough levels. RESULTS: Two hundred eleven patients were included in this cross-section analysis. Twenty-seven patients agreed to participate in the investigator-initiated trial. LTx patients completed the 4-TTMT slower than living donor patients and faster than waiting list patients. Patients with twice daily cyclosporine A (CSA) formulation needed longer to finish the 4-TTMT than patients with the once-daily tacrolimus formulation. After drug conversion of a twice-daily CNI formulation to a once-daily tacrolimus formulation, CSA-treated patients needed longer to improve their cognitive functioning. HRQoL and compliance did not improve after drug conversion. CONCLUSIONS: Patients with once-daily tacrolimus formulation had a better psychomotor speed than CSA-treated patients. The conversion to once-daily tacrolimus formulation significantly improved cognitive functioning, but had no impact on HRQoL or compliance.

Hepatitis B virus-induced lipid alterations contribute to natural killer T cell-dependent protective immunity.

In most adult humans, hepatitis B is a self-limiting disease leading to life-long protective immunity, which is the consequence of a robust adaptive immune response occurring weeks after hepatitis B virus (HBV) infection. Notably, HBV-specific T cells can be detected shortly after infection, but the mechanisms underlying this early immune priming and its consequences for subsequent control of viral replication are poorly understood. Using primary human and mouse hepatocytes and mouse models of transgenic and adenoviral HBV expression, we show that HBV-expressing hepatocytes produce endoplasmic reticulum (ER)-associated endogenous antigenic lipids including lysophospholipids that are generated by HBV-induced secretory phospholipases and that lead to activation of natural killer T (NKT) cells. The absence of NKT cells or CD1d or a defect in ER-associated transfer of lipids onto CD1d results in diminished HBV-specific T and B cell responses and delayed viral control in mice. NKT cells may therefore contribute to control of HBV infection through sensing of HBV-induced modified self-lipids.

Three ulcerative colitis susceptibility loci are associated with primary sclerosing cholangitis and indicate a role for IL2, REL, and CARD9.

UNLABELLED: Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts. Both environmental and genetic factors contribute to its pathogenesis. To further clarify its genetic background, we investigated susceptibility loci recently identified for ulcerative colitis (UC) in a large cohort of 1,186 PSC patients and 1,748 controls. Single nucleotide polymorphisms (SNPs) tagging 13 UC susceptibility loci were initially genotyped in 854 PSC patients and 1,491 controls from Benelux (331 cases, 735 controls), Germany (265 cases, 368 controls), and Scandinavia (258 cases, 388 controls). Subsequently, a joint analysis was performed with an independent second Scandinavian cohort (332 cases, 257 controls). SNPs at chromosomes 2p16 (P-value 4.12 × 10(-4) ), 4q27 (P-value 4.10 × 10(-5) ), and 9q34 (P-value 8.41 × 10(-4) ) were associated with PSC in the joint analysis after correcting for multiple testing. In PSC patients without inflammatory bowel disease (IBD), SNPs at 4q27 and 9q34 were nominally associated (P < 0.05). We applied additional in silico analyses to identify likely candidate genes at PSC susceptibility loci. To identify nonrandom, evidence-based links we used GRAIL (Gene Relationships Across Implicated Loci) analysis showing interconnectivity between genes in six out of in total nine PSC-associated regions. Expression quantitative trait analysis from 1,469 Dutch and UK individuals demonstrated that five out of nine SNPs had an effect on cis-gene expression. These analyses prioritized IL2, CARD9, and REL as novel candidates. CONCLUSION: We have identified three UC susceptibility loci to be associated with PSC, harboring the putative candidate genes REL, IL2, and CARD9. These results add to the scarce knowledge on the genetic background of PSC and imply an important role for both innate and adaptive immunological factors.

Chronic portal vein thrombosis: transcapsular hepatic collateral vessels and communicating ectopic varices.

PURPOSE: To assess patients with chronic portal vein thrombosis (PVT) with respect to transcapsular collateral veins, the communication between these veins and ectopic varices, and the cause of PVT. MATERIALS AND METHODS: This study was approved by the institutional review committees, and written informed consent was obtained. From November 2003 to March 2008, 145 consecutive patients with chronic PVT due to a variety of causes were assessed for transcapsular collaterals and ectopic varices with ultrasonography (US). Analysis of contingency tables was performed with the Fisher exact test. RESULTS: Transcapsular collaterals were detected in 15 (10.3%) of 145 patients with chronic PVT. They were restricted to patients with a history of hepatobilary surgery, severe pancreatitis, or abdominal surgery (n = 21) and were not detected in patients with liver cirrhosis, systemic coagulopathy, extrahepatic malignancy, idiopathic PVT, chronic pancreatitis, or infectious or inflammatory diseases (n = 124) (P < .001). Ectopic varices were infrequent in 70 patients with liver cirrhosis (n = 2, 3%) but were common in 14 patients with PVT after hepatobiliary surgery (n = 9, 64%) (P < .001, odds ratio = 21.4). Direct communication between transcapsular collaterals and ectopic varices was visible in all nine patients in this cohort. In eight of these patients, ectopic varices were found to be the bleeding source in gastrointestinal hemorrhage. CONCLUSION: Transcapsular collaterals frequently occur in patients with chronic PVT due to hepatobilary surgery or necrotizing pancreatitis. They are associated with ectopic varices; therefore, awareness of transcapsular collaterals in this patient subgroup will help to localize ectopic varices as potential bleeding source.

The radiation of microhylid frogs (Amphibia: Anura) on New Guinea: a mitochondrial phylogeny reveals parallel evolution of morphological and life history traits and disproves the current morphology-based classification.

Microhylidae account for the majority of frog species on New Guinea and have evolved an extraordinarily wide range of ecological, behavioural, and morphological traits. Several species are known for their unique paternal care behaviour, which includes guarding of clutches in some and additional froglet transport in other species. We sampled 48 out of 215 New Guinean microhylid species and all but two (Mantophryne and Pherohapsis) of 18 New Guinean genera and analysed a concatenated data set of partial sequences of the mitochondrial genes 12S and 16S, which comprises 1220 aligned nucleotide positions, in order to infer the phylogenetic relationships within this diverse group of frogs. The trees do provide resolution at shallow, but not at deep branches. Monophyly is rejected for the genera Callulops, Liophryne, Austrochaperina, Copiula, and Cophixalus as currently recognized. Six clades are well supported: (1) Hylophorbus and Callulops cf. robustus, (2) its sister taxon comprising Xenorhina, Asterophrys turpicola, and Callulops except for C. cf. robustus, (3) Liophryne rhododactyla, L. dentata, Oxydactyla crassa, and Sphenophryne cornuta, (4) Copiula and Austrochaperina, (5) Barygenys exsul, Cophixalus spp., and Oreophryne, (6) Cophixalus sphagnicola, Albericus laurini, and Choerophryne. The phylogenies provide evidence for the parallel evolution of parental care modes, life styles, and morphological traits that have thus far been emphasized in recent classifications.

Malnutrition, steatorrhoea and pancreatic head tumour.

A 61-year-old female patient is described who presented with weight loss, steatorrhoea and enlargement of the pancreatic head. Surgical exploration for suspected pancreatic cancer revealed multiple peritoneal white spots, initially suggestive for peritoneal metastases or tuberculosis but finally identified as peritoneal sarcoidosis. Pancreatic insufficiency could not be proven in further studies. We found pancreas divisum as an additional cause for the pancreatic head mass, and steatorrhoea was due to late-onset oligosymptomatic coeliac disease. This case demonstrates diagnostic pitfalls when several rare disorders are manifest in a single patient. Coeliac disease and sarcoidosis might be sequels of similar immune responses to certain antigens.

Transient agonist-induced regulation of the cholecystokinin-A and cholecystokinin-B receptor mRNA levels in rat pancreatic acinar AR42J cells.

BACKGROUND: CCK-8 and gastrin exert multiple effects in the gastrointestinal tract and the nervous system. Their actions are mediated via the G-protein coupled CCK-A and CCK-B receptors. METHODS: Rat pancreatic acinar tumor AR42J cells express both CCK receptor subtypes. This cell line was used to characterize the agonist-dependent regulation of CCK-A and CCK-B receptor gene expression. RESULTS: CCK-8 (10 nM) or gastrin (10 nM) reduced CCK-A receptor mRNA expression to 56% and 53%, respectively 2 h after hormonal exposure. In contrast, the level of CCK-B receptor gene expression was upregulated to 157% and 153%, respectively. These effects are most probably linked to the CCK-B receptor in AR42J cells. The phorbolester PMA (100 nM), a protein kinase C activator, downregulated CCK-A receptor expression but did not affect CCK-B receptor gene transcription. Activation of protein kinase A by forskolin (10 microM) or Bt(2)cAMP (100 microM) is not involved in the transient regulation of CCK receptor mRNA expression. Both elevated CCK-B and decreased CCK-A receptor mRNA expression returned to basal levels 6 h after continuous stimulation. CONCLUSION: These results demonstrate that CCK-A and CCK-B receptor mRNA levels are differentially regulated by their agonists via distinct signal transduction mechanisms in AR42J cells.

[Erythema gyratum repens: drug reaction following azathioprine administration in a patient with type I autoimmune hepatitis]. / Erythema gyratum repens: Arzneimittelreaktion nach Azathioprin bei einer Patientin mit Autoimmunhepatitis Typ I.

BACKGROUND: Erythema gyratum repens is a rare, clinically specific, and distinctive paraneoplastic syndrome. CASE REPORT: A case of erythema gyratum repens in a 76-year-old woman with autoimmune hepatitis type I treated with glucocorticoids is reported. Within 3 weeks of supplementary azathioprine treatment, the patient reported gastrointestinal discomfort and developed an erythema gyratum repens confined to the abdomen, thighs and knees. Azathioprine medication was stopped and the dermatologic features resolved completely after a period of 1 week. Absence of any demonstrable underlying malignancy was confirmed by different tests. Molecular diagnosis detected heterozygous G460A and A719G transitions in the thiopurine methyltransferase (TPMT) gene. 18 month later, complete remission on maintenance therapy (prednisone 7.5 mg) was observed with further absence of malignancy. CONCLUSION: This is the first report of an erythema gyratum repens in association with azathioprine treatment in an autoimmune hepatitis type I patient with proven common polymorphism in the TPMT gene.