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Yoshiyuki Wada, Yuko Takami, Masaki Tateishi, Tomoki Ryu, Kazuhiro Mikagi, Hideki SaitsuDepartment of Hepato-Biliary-Pancreatic Surgery, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, JapanBackground: Five or more colorectal liver metastases (CRLM) are considered marginally resectable and cannot be treated solely by hepatic resection (Hr). This study investigated the long-term effectiveness of surgical treatment using microwave coagulo-necrotic therapy (MCN) and/or Hr for marginally resectable or unresectable multiple CRLM.Methods: This study retrospectively analyzed 82 consecutive CRLM patients with ≥5 CRLM who underwent MCN, Hr, or both, at our institution from 1994 to 2012. Presuming all CRLM were resected curatively, virtual remnant liver volume was calculated using preoperative computed tomography or magnetic resonance imaging. Virtual remnant liver volume

V-type proton (H+) ATPase (v-ATPase) is a multi-subunit proton pump that regulates pH homeostasis in all eukaryotic cells; in neurons, v-ATPase plays additional and unique roles in synapse function. Through whole exome sequencing, we identified de novo heterozygous mutations (p. Pro27Arg, p. Asp100Tyr, p. Asp349Asn, p. Asp371Gly) in ATP6V1A, encoding the A subunit of vATPase, in four patients with developmental encephalopathy with epilepsy. Early manifestations, observed in all patients, were developmental delay and febrile seizures, evolving to encephalopathy with profound delay, hypotonic/dyskinetic quadriparesis and intractable multiple seizure types in two patients (p. Pro27Arg, p. Asp100Tyr), and to moderate delay with milder epilepsy in the other two (p. Asp349Asn, p. Asp371Gly). Modelling performed on the available prokaryotic and eukaryotic structures of v-ATPase predicted p. Pro27Arg to perturb subunit interaction, p. Asp100Tyr to cause steric hindrance and destabilize protein folding, p. Asp349Asn to affect the catalytic function and p. Asp371Gly to impair the rotation process, necessary for proton transport. We addressed the impact of p. Asp349Asn and p. Asp100Tyr mutations on ATP6V1A expression and function by analysing ATP6V1A-overexpressing HEK293T cells and patients' lymphoblasts. The p. Asp100Tyr mutant was characterized by reduced expression due to increased degradation. Conversely, no decrease in expression and clearance was observed for p. Asp349Asn. In HEK293T cells overexpressing either pathogenic or control variants, p. Asp349Asn significantly increased LysoTracker (R) fluorescence with no effects on EEA1 and LAMP1 expression. Conversely, p. Asp100Tyr decreased both LysoTracker (R) fluorescence and LAMP1 levels, leaving EEA1 expression unaffected. Both mutations decreased v-ATPase recruitment to autophagosomes, with no major impact on autophagy. Experiments performed on patients' lymphoblasts using the LysoSensor (TM) probe revealed lower pH of endocytic organelles for p. Asp349Asn and a reduced expression of LAMP1 with no effect on the pH for p. Asp100Tyr. These data demonstrate gain of function for p. Asp349Asn characterized by an increased proton pumping in intracellular organelles, and loss of function for p. Asp100Tyr with decreased expression of ATP6V1A and reduced levels of lysosomal markers. We expressed p. Asp349Asn and p. Asp100Tyr in rat hippocampal neurons and confirmed significant and opposite effects in lysosomal labelling. However, both mutations caused a similar defect in neurite elongation accompanied by loss of excitatory inputs, revealing that altered lysosomal homeostasis markedly affects neurite development and synaptic connectivity. This study provides evidence that de novo heterozygous ATP6V1A mutations cause a developmental encephalopathy with a pathomechanism that involves perturbations of lysosomal homeostasis and neuronal connectivity, uncovering a novel role for v-ATPase in neuronal development.

Yoshiyuki Wada, Yuko Takami, Masaki Tateishi, Tomoki Ryu, Kazuhiro Mikagi, Hideki Saitsu Department of Hepato-Biliary-Pancreatic Surgery, Clinical Research Institute, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan Background: Sorafenib therapy improves survival in unresectable hepatocellular carcinoma (HCC) patients without an objective response. The present study investigated whether the initial imaging response might be a prognostic indicator after administration of sorafenib therapy in HCC patients.Patients and methods: This retrospective study reviewed unresectable HCC patients undergoing sorafenib therapy. Patients evaluated without complete response, partial response (PR), or progressive disease (PD) at the initial imaging response evaluation by modified Response Evaluation Criteria in Solid Tumors were divided into three groups according to more detailed categorization of the shrinkage/progression ratio in initial imaging response. A comparison of progression-free and overall survival among these groups was performed.Results: Of the 43 non-PR non-PD patients with target lesions, ten (23.3%) exhibited mild response (MR; -30% to -5%), 14 (32.6%) exhibited no change (NC; -5% to +5%), and 19 (44.2%) exhibited mild-PD (MPD; +5% to +20%). There was no statistical difference in progression-free or overall survival between MR and NC patients. The median progression-free survivals in NC+MR and mild-PD patients were 15.0 and 5.3 months, respectively (P

Purpose Congenital cataract is one of the most frequent causes of visual impairment and childhood blindness. Approximately one quarter to one third of congenital cataract cases may have a genetic cause. However, phenotypic variability and genetic heterogeneity hamper correct genetic diagnosis. In this study, we used whole-exome sequencing (WES) to identify pathogenic mutations in two Korean families with congenital cataract. Methods Two affected members from each family were pooled and processed for WES. The detected variants were confirmed with direct sequencing. Results WES readily identified a CRYAA mutation in family A and a CRYGC mutation in family B. The c.61C>T (p.R21W) mutation in CRYAA has been previously reported in a family with congenital cataract and microcornea. The novel mutation, c.124delT, in CRYGC may lead to a premature stop codon (p.C42Afs*60). Conclusions This study clearly shows the efficacy of WES for rapid genetic diagnosis of congenital cataract with an unknown cause. WES will be the first choice for clinical services in the near future, providing useful information for genetic counseling and family planning.