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. Copyright (C) 2011 S. Karger AG, Base

Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: subanalyses of a phase III trial

Background & AimsThe Sorafenib Hepatocellular Carcinoma (HCC) Assessment Randomized Protocol (SHARP) trial demonstrated that sorafenib improves overall survival and is safe for patients with advanced HCC. In this trial, 602 patients with well-preserved liver function (>95% Child–Pugh A) were randomized to receive either sorafenib 400mg or matching placebo orally b.i.d. on a continuous basis. Because HCC is a heterogeneous disease, baseline patient characteristics may affect individual responses to treatment. In a comprehensive series of exploratory subgroup analyses, data from the SHARP trial were analyzed to discern if baseline patient characteristics influenced the efficacy and safety of sorafenib.MethodsFive subgroup domains were assessed: disease etiology, tumor burden, performance status, tumor stage, and prior therapy. Overall survival (OS), time to progression (TTP), disease control rate (DCR), and safety were assessed for subgroups within each domain.ResultsSubgroup analyses showed that sorafenib consistently improved median OS compared with placebo, as reflected by hazard ratios (HRs) of 0.50–0.85, similar to the complete cohort (HR=0.69). Sorafenib also consistently improved median TTP (HR, 0.40–0.64), except in HBV-positive patients (HR, 1.03), and DCR. Results are limited by small patient numbers in some subsets. The most common grade 3/4 adverse events included diarrhea, hand-foot skin reaction, and fatigue; the incidence of which did not differ appreciably among subgroups.ConclusionsThese exploratory subgroup analyses showed that sorafenib consistently improved median OS and DCR compared with placebo in patients with advanced HCC, irrespective of disease etiology, baseline tumor burden, performance status, tumor stage, and prior therapy

Octreotide treatment of patients with hepatocellular carcinoma - a retrospective single centre controlled study

<p>Abstract</p> <p>Background</p> <p>Studies of treatment with octreotide of patients with hepatocellular carcinoma (HCC) gave conflicting results. We analyzed retrospectively the survival of our patients treated with octreotide monotherapy and compared it to stage-matched patients who received either TACE, multimodal therapy or palliative care.</p> <p>Methods</p> <p>95 patients seen at the department of Gastroenterology and Hepatology, Medical University of Vienna with HCC in BCLC stage A or B, who received either TACE, multimodal therapy, long-acting octreotide or palliative care were reviewed for this retrospective study.</p> <p>Results</p> <p>Survival rates of patients with BCLC stage B and any "active" treatment (long-acting octreotide, TACE or multimodal therapy) were significantly higher (22.4, 22.0, 35.5 months) compared to patients who received palliative care only (2.9 months). Survival rates of patients with BCLC stage A and "active" treatment (31.4, 37.3, 40.2 months) compared to patients who received only palliative care (15.1 months) did not show statistically significant differences. Octreotide monotherapy showed a similar outcome compared to patients who received TACE or multimodal therapy.</p> <p>Conclusion</p> <p>Survival under octreotide treatment was not different compared to TACE or multimodal therapy and might be a therapeutic option for patients with HCC.</p

DNA Resection at Chromosome Breaks Promotes Genome Stability by Constraining Non-Allelic Homologous Recombination

DNA double-strand breaks impact genome stability by triggering many of the large-scale genome rearrangements associated with evolution and cancer. One of the first steps in repairing this damage is 5′→3′ resection beginning at the break site. Recently, tools have become available to study the consequences of not extensively resecting double-strand breaks. Here we examine the role of Sgs1- and Exo1-dependent resection on genome stability using a non-selective assay that we previously developed using diploid yeast. We find that Saccharomyces cerevisiae lacking Sgs1 and Exo1 retains a very efficient repair process that is highly mutagenic to genome structure. Specifically, 51% of cells lacking Sgs1 and Exo1 repair a double-strand break using repetitive sequences 12–48 kb distal from the initial break site, thereby generating a genome rearrangement. These Sgs1- and Exo1-independent rearrangements depend partially upon a Rad51-mediated homologous recombination pathway. Furthermore, without resection a robust cell cycle arrest is not activated, allowing a cell with a single double-strand break to divide before repair, potentially yielding multiple progeny each with a different rearrangement. This profusion of rearranged genomes suggests that cells tolerate any dangers associated with extensive resection to inhibit mutagenic pathways such as break-distal recombination. The activation of break-distal recipient repeats and amplification of broken chromosomes when resection is limited raise the possibility that genome regions that are difficult to resect may be hotspots for rearrangements. These results may also explain why mutations in resection machinery are associated with cancer

Colonic epithelial ion transport is not affected in patients with diverticulosis

<p>Abstract</p> <p>Background</p> <p>Colonic diverticular disease is a bothersome condition with an unresolved pathogenesis. It is unknown whether a neuroepithelial dysfunction is present. The aim of the study was two-fold; (1) to investigate colonic epithelial ion transport in patients with diverticulosis and (2) to adapt a miniaturized Modified Ussing Air-Suction (MUAS) chamber for colonic endoscopic biopsies.</p> <p>Methods</p> <p>Biopsies were obtained from the sigmoid part of the colon. 86 patients were included. All patients were referred for colonoscopy on suspicion of neoplasia and they were without pathological findings at colonoscopy (controls) except for diverticulosis in 22 (D-patients). Biopsies were mounted in MUAS chambers with an exposed area of 5 mm². Electrical responses to various stimulators and inhibitors of ion transport were investigated together with histological examination. The MUAS chamber was easy to use and reproducible data were obtained.</p> <p>Results</p> <p>Median basal short circuit current (SCC) was 43.8 μA·cm^-2(0.8 – 199) for controls and 59.3 μA·cm^-2(3.0 – 177.2) for D-patients. Slope conductance was 77.0 mS·cm^-2(18.6 – 204.0) equal to 13 Ω·cm²for controls and 96.6 mS·cm^-2(8.4 – 191.4) equal to 10.3 Ω·cm²for D-patients. Stimulation with serotonin, theophylline, forskolin and carbachol induced increases in SCC in a range of 4.9 – 18.6 μA·cm^-2, while inhibition with indomethacin, bumetanide, ouabain and amiloride decreased SCC in a range of 6.5 – 27.4 μA·cm^-2, and all with no significant differences between controls and D-patients. Histological examinations showed intact epithelium and lamina propria before and after mounting for both types of patients.</p> <p>Conclusion</p> <p>We conclude that epithelial ion transport is not significantly altered in patients with diverticulosis and that the MUAS chamber can be adapted for studies of human colonic endoscopic biopsies.</p

Differences in cerebral response to esophageal acid stimuli and psychological anticipation in GERD subtypes - An fMRI study

<p>Abstract</p> <p>Background</p> <p>To evaluate whether there are differences in the cerebral response to intraesophageal acid and psychological anticipation stimuli among subtypes of gastroesophageal reflux disease (GERD).</p> <p>Methods</p> <p>Thirty nine patients with GERD and 11 healthy controls were enrolled in this study after gastroscopy and 24 hr pH monitoring. GERD subjects were divided into four subgroups: RE (reflux esophagitis), NERD+ (non-erosive reflux disease with excessive acid reflux), NERD-SI+ (normal acid exposure and positive symptom index) and NERD-SI+ (normal acid exposure and negative symptom index, but responded to proton pump inhibitor trial). Cerebral responses to intraesophageal acid and psychological anticipation were evaluated with fMRI.</p> <p>Results</p> <p>During intraesophageal acid stimulation, the prefrontal cortex (PFC) region was significantly activated in all subgroups of GERD; the insular cortex (IC) region was also activated in RE, NERD+ and NERD-SI- groups; the anterior cingulated cortex (ACC) region was activated only in RE and NERD-SI- groups. The RE subgroup had the shortest peak time in the PFC region after acid was infused, and presented the greatest change in fMRI signals in the PFC and ACC region (<it>P </it>= 0.008 and <it>P </it>= 0.001, respectively). During psychological anticipation, the PFC was significantly activated in both the control and GERD groups. Activation of the IC region was found in the RE, NERD-SI+ and NERD-SI- subgroups. The ACC was activated only in the NERD-SI+ and NERD-SI- subgroups. In the PFC region, the NERD-SI- subgroup had the shortest onset time (<it>P </it>= 0.008) and peak time (<it>P </it>< 0.001). Compared with actual acid infusion, ACC in RE and IC in NERD+ were deactivated while additional areas including the IC and ACC were activated in the NERD-SI+ group; and in NERD-SI- group, onset-time and peak time in the PFC and IC areas were obviously shorter in induced anticipation than in actual acid infusion.</p> <p>Conclusions</p> <p>The four subgroups of GERD patients and controls showed distinctly different activation patterns and we therefore conclude GERD patients have different patterns of visceral perception and psychological anticipation. Psychological factors play a more important role in NERD-SI+ and NERD-SI- groups than in RE and NERD+ groups.</p

Antitumor activity and mechanisms of action of total glycosides from aerial part of Cimicifuga dahurica targeted against hepatoma

<p>Abstract</p> <p>Background</p> <p>Medicinal plant is a main source of cancer drug development. Some of the cycloartane triterpenoids isolated from the aerial part of <it>Cimicifuga dahurica </it>showed cytotoxicity in several cancer cell lines. It is of great interest to examine the antiproliferative activity and mechanisms of total triterpenoid glycosides of <it>C. dahurica </it>and therefore might eventually be useful in the prevention or treatment of Hepatoma.</p> <p>Methods</p> <p>The total glycosides from the aerial part (TGA) was extracted and its cytotoxicity was evaluated in HepG2 cells and primary cultured normal mouse hepatocytes by an MTT assay. Morphology observation, Annexin V-FITC/PI staining, cell cycle analysis and western blot were used to further elucidate the cytotoxic mechanism of TGA. Implanted mouse H₂₂hepatoma model was used to demonstrate the tumor growth inhibitory activity of TGA <it>in vivo</it>.</p> <p>Results</p> <p>The IC₅₀values of TGA in HepG2 and primary cultured normal mouse hepatocytes were 21 and 105 μg/ml, respectively. TGA induced G₀/G₁cell cycle arrest at lower concentration (25 μg/ml), and triggered G₂/M arrest and apoptosis at higher concentrations (50 and 100 μg/ml respectively). An increase in the ratio of Bax/Bcl-2 was implicated in TGA-induced apoptosis. In addition, TGA inhibited the growth of the implanted mouse H₂₂tumor in a dose-dependent manner.</p> <p>Conclusion</p> <p>TGA may potentially find use as a new therapy for the treatment of hepatoma.</p