Anti-PD-1 antibody monotherapy versus anti-PD-1 plus anti-CTLA-4 combination therapy as first-line immunotherapy in unresectable or metastatic mucosal melanoma: a retrospective, multicenter study of 329 Japanese cases (JMAC study).

BACKGROUND: Anti-programmed cell death protein 1 (PD-1) antibody monotherapy (PD1) has led to favorable responses in advanced non-acral cutaneous melanoma among Caucasian populations; however, recent studies suggest that this therapy has limited efficacy in mucosal melanoma (MCM). Thus, advanced MCM patients are candidates for PD1 plus anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) combination therapy (PD1 + CTLA4). Data on the efficacy of immunotherapy in MCM, however, are limited. We aimed to compare the efficacies of PD1 and PD1 + CTLA4 in Japanese advanced MCM patients. PATIENTS AND METHODS: We retrospectively assessed advanced MCM patients treated with PD1 or PD1 + CTLA4 at 24 Japanese institutions. Patient baseline characteristics, clinical responses (RECIST), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis, and toxicity was assessed to estimate the efficacy and safety of PD1 and PD1 + CTLA4. RESULTS: Altogether, 329 patients with advanced MCM were included in this study. PD1 and PD1 + CTLA4 were used in 263 and 66 patients, respectively. Baseline characteristics were similar between both treatment groups, except for age (median age 71 versus 65 years; P < 0.001). No significant differences were observed between the PD1 and PD1 + CTLA4 groups with respect to objective response rate (26% versus 29%; P = 0.26) or PFS and OS (median PFS 5.9 months versus 6.8 months; P = 0.55, median OS 20.4 months versus 20.1 months; P = 0.55). Cox multivariate survival analysis revealed that PD1 + CTLA4 did not prolong PFS and OS (PFS: hazard ratio 0.83, 95% confidence interval 0.58-1.19, P = 0.30; OS: HR 0.89, 95% confidence interval 0.57-1.38, P = 0.59). The rate of ≥grade 3 immune-related adverse events was higher in the PD1 + CTLA4 group than in the PD1 group (53% versus 17%; P < 0.001). CONCLUSIONS: First-line PD1 + CTLA4 demonstrated comparable clinical efficacy to PD1 in Japanese MCM patients, but with a higher rate of immune-related adverse events.

Micron-scale phenomena observed in a turbulent laser-produced plasma.

Turbulence is ubiquitous in the universe and in fluid dynamics. It influences a wide range of high energy density systems, from inertial confinement fusion to astrophysical-object evolution. Understanding this phenomenon is crucial, however, due to limitations in experimental and numerical methods in plasma systems, a complete description of the turbulent spectrum is still lacking. Here, we present the measurement of a turbulent spectrum down to micron scale in a laser-plasma experiment. We use an experimental platform, which couples a high power optical laser, an x-ray free-electron laser and a lithium fluoride crystal, to study the dynamics of a plasma flow with micrometric resolution (~1µm) over a large field of view (>1 mm2). After the evolution of a Rayleigh-Taylor unstable system, we obtain spectra, which are overall consistent with existing turbulent theory, but present unexpected features. This work paves the way towards a better understanding of numerous systems, as it allows the direct comparison of experimental results, theory and numerical simulations.

Liquid Structure of Tantalum under Internal Negative Pressure.

In situ femtosecond x-ray diffraction measurements and ab initio molecular dynamics simulations were performed to study the liquid structure of tantalum shock released from several hundred gigapascals (GPa) on the nanosecond timescale. The results show that the internal negative pressure applied to the liquid tantalum reached -5.6 (0.8) GPa, suggesting the existence of a liquid-gas mixing state due to cavitation. This is the first direct evidence to prove the classical nucleation theory which predicts that liquids with high surface tension can support GPa regime tensile stress.

Laser-driven shock compression of "synthetic planetary mixtures" of water, ethanol, and ammonia.

Water, methane, and ammonia are commonly considered to be the key components of the interiors of Uranus and Neptune. Modelling the planets' internal structure, evolution, and dynamo heavily relies on the properties of the complex mixtures with uncertain exact composition in their deep interiors. Therefore, characterising icy mixtures with varying composition at planetary conditions of several hundred gigapascal and a few thousand Kelvin is crucial to improve our understanding of the ice giants. In this work, pure water, a water-ethanol mixture, and a water-ethanol-ammonia "synthetic planetary mixture" (SPM) have been compressed through laser-driven decaying shocks along their principal Hugoniot curves up to 270, 280, and 260 GPa, respectively. Measured temperatures spanned from 4000 to 25000 K, just above the coldest predicted adiabatic Uranus and Neptune profiles (3000-4000 K) but more similar to those predicted by more recent models including a thermal boundary layer (7000-14000 K). The experiments were performed at the GEKKO XII and LULI2000 laser facilities using standard optical diagnostics (Doppler velocimetry and optical pyrometry) to measure the thermodynamic state and the shock-front reflectivity at two different wavelengths. The results show that water and the mixtures undergo a similar compression path under single shock loading in agreement with Density Functional Theory Molecular Dynamics (DFT-MD) calculations using the Linear Mixing Approximation (LMA). On the contrary, their shock-front reflectivities behave differently by what concerns both the onset pressures and the saturation values, with possible impact on planetary dynamos.

Arterial Complication After Simultaneous Pancreas-Kidney Transplantation From an Abdominal Aortic Aneurysm Donor: A Case Report.

BACKGROUND: With the current disparity between the donor organ availability and recipient needs, various marginal organs with anatomical variations or concomitant diseases have begun to be used. We present a case of simultaneous pancreas-kidney transplantation (SPKTx) from a marginal donor with a giant abdominal aortic aneurysm who was incidentally found to be an organ donor after brain death. CASE PRESENTATION: The donor was a 66-year-old man who died of brain hemorrhage. We performed cannulation of the aorta from the distal part of left common iliac artery because the aneurysm extended from pararenal aorta to the bilateral common iliac artery. Furthermore, we prepared the left common carotid artery as the backup root of cannulation. Fortunately, we could perfuse the organs from the left common iliac artery. Subsequently, we retrieved the heart, liver, pancreas, and kidney grafts and performed SPKTx. The recipient received anatomically and functionally normal organs. At 19 days after transplantation, a rupture of the renal artery occurred on the graft side. We detected the bleeding point and it was managed quickly. CONCLUSIONS: We safely retrieved the organs from a marginal donor and performed the cooperative donation using a creative approach. We dealt with the complications through cautious postoperative management.

New Left Lobe Transplantation Procedure with Caval Reconstruction Using an Inverted Composite Graft for Chronic Budd-Chiari Syndrome in Living-Donor Liver Transplantation-A Case Report.

When the Budd-Chiari syndrome (BCS) lesion extends to the inferior vena cava (IVC) or the orifices of the hepatic vein, the thickened IVC and/or hepatic vein wall must be removed and IVC reconstruction is required in living-donor liver transplantation (LDLT). In various reports about IVC resection in LDLT for BCS, there are none about left lobe liver transplantation with reconstruction of the retrohepatic IVC (rhIVC). To overcome removal and reconstruction of the rhIVC in LDLT for BCS, we introduced a composite IVC graft that is applicable to both right and left lobe partial liver grafts for LDLT for BCS. Pathogenic IVC was removed together with the native liver between the lower edge of the right atrium and 5 cm above the renal vein junction with the use of venovenous bypass. The e-polytetrafluoroethylene graft was anastomosed to the suprarenal intact IVC. Then the native part was detached at the level of just above the renal junction. The composite graft was inverted and a half rim of the native part of the graft was anastomosed to the posterior wall of the right atrium. Next, the common venous orifice of the left lobe graft was anastomosed to the wall defect which was composed of the anterior wall of the right atrium and the distal end of the native part of the composite graft. In conclusion, our inverted composite graft technique will overcome the weak points of LDLT for BCS, such as incomplete removal of the pathogenic caval wall and reconstruction of the rhIVC.

Surfactant protein D inhibits activation of non-small cell lung cancer-associated mutant EGFR and affects clinical outcomes of patients.

Tyrosine kinase inhibitor (TKI)-sensitive and TKI-resistant mutations of epidermal growth factor receptor (EGFR) are associated with lung adenocarcinoma. EGFR mutants were previously shown to exhibit ligand-independent activation. We have previously demonstrated that pulmonary surfactant protein D (SP-D, SFTPD) suppressed wild-type EGFR signaling by blocking ligand binding to EGFR. We herein demonstrate that SFTPD downregulates ligand-independent signaling in cells harboring EGFR mutations such as TKI-sensitive exon 19 deletion (Ex19del) and L858R mutation as well as TKI-resistant T790M mutation, subsequently suppressing cellular growth and motility. Lectin blotting and ligand blotting in lung cancer cell lines suggested that EGFR mutants express oligomannose-type N-glycans and interact with SFTPD directly. Cross-linking assay indicated that SFTPD inhibits ligand-independent dimerization of EGFR mutants. We also demonstrated that SFTPD reduced dimerization-independent phosphorylation of Ex19del and T790M EGFR mutants using point mutations that disrupted the asymmetric dimer interface. It was confirmed that SFTPD augmented the viability-suppressing effects of EGFR-TKIs. Furthermore, retrospective analysis of 121 patients with lung adenocarcinoma to examine associations between serum SFTPD levels and clinical outcome indicated that in TKI-treated patients with lung cancer harboring EGFR mutations, including Ex19del or L858R, high serum SFTPD levels correlated with a lower number of distant metastases and prolonged overall survival and progression-free survival. These findings suggest that SFTPD downregulates both TKI-sensitive and -resistant EGFR mutant signaling, and SFTPD level is correlated with clinical outcome. These findings illustrate the use of serum SFTPD level as a potential marker to estimate the efficacy of EGFR-TKIs.

Suspected Metallic Embolism following Endovascular Treatment of Intracranial Aneurysms.

We describe a case series of suspected metallic embolism after coil embolization for intracranial aneurysms. Between January 2012 and December 2014, 110 intracranial aneurysms had been treated by coil embolization in our institution. In 6 cases, the postprocedural MR imaging revealed abnormal spotty lesions not detected on the preprocedural MR imaging. The lesions were also undetectable on the postprocedural CT scan. They were demonstrated as low-intensity spots on T1WI, T2WI, DWI, and T2*-weighted imaging. On DWI, they were accompanied by bright "halo," and on T2*-weighted imaging, they showed a "blooming" effect. In 3 of the 6 cases, follow-up MR imaging was available and all the lesions remained and demonstrated no signal changes. Although histologic examination had not been performed, these neuroradiologic findings strongly supported the lesions being from metallic fragments. No specific responsible device was detected after reviewing all the devices used for the neuroendovascular treatment in the 6 cases.

Intraoperative Oxygen Consumption During Liver Transplantation.

BACKGROUND: The aim of this study was to investigate the changes in oxygen consumption during liver transplantation and to examine the relationship between intraoperatively elevated systemic oxygen consumption and postoperative liver function. METHODS: This study was performed in 33 adult patients undergoing liver transplantation between September 2011 and March 2014. We measured intraoperative oxygen consumption through the use of indirect calorimetry, preoperative and intraoperative data, liver function tests, and postoperative complications and outcomes. RESULTS: The mean age of patients was 52 ± 9.7 years; 14 (42%) of them were women. Average Model for End-Stage Liver Disease scores were 20 ± 8.9. Oxygen consumption significantly increased after reperfusion from 172 ± 30 mL/min during the anhepatic phase to 209 ± 30 mL/min (P < .0001). We divided patients into 2 groups according to the increase in oxygen consumption after reperfusion (oxygen consumption after reperfusion minus anhepatic phase oxygen consumption: 40 mL/min increase as cutoff). The higher consumption group had a longer cold ischemia time and higher postoperative aspartate aminotransferase and alanine aminotransferase levels as compared with the lower oxygen consumption group. There were no statistically significant differences in major postoperative complications, but the higher oxygen consumption group tended to have shorter hospital stays than the lower consumption group (58 versus 95 days). CONCLUSIONS: We have demonstrated that oxygen consumption significantly increased after reperfusion. Furthermore, this increased oxygen consumption was associated with a longer cold ischemia time and shorter hospital stays.

Risk factors for major morbidity after liver resection for hepatocellular carcinoma.

BACKGROUND: Bile leakage, and organ and/or space surgical-site infection (SSI) are common causes of major morbidity after partial hepatectomy for hepatocellular carcinoma (HCC). The purpose of this study was to analyse risk factors for major morbidity and to explore strategies for its reduction after partial hepatectomy for HCC. METHODS: Risk factors for bile leakage and organ/space SSI were analysed in patients who underwent partial hepatectomy for HCC between 2001 and 2010. The causes, management and outcomes of intractable bile leakage requiring endoscopic therapy or percutaneous transhepatic biliary drainage were analysed. In addition, causative bacteria, outcomes and characteristics of organ/space SSI were investigated. Risk factors were identified using multivariable analysis. RESULTS: Some 359 patients were included in the analysis. The prevalence of bile leakage and organ/space SSI was 12·8 and 8·6 per cent respectively. Repeat hepatectomy and an operating time of at least 300 min were identified as independent risk factors for bile leakage. The main causes of intractable bile leakage were latent strictures of the biliary system caused by previous treatments for HCC and intraoperative injury of the hepatic duct during repeat hepatectomy. Independent risk factors for organ/space SSI were repeat hepatectomy and bile leakage. Methicillin-resistant Staphylococcus aureus was detected more frequently in organ/space SSI after repeat hepatectomy than after initial partial hepatectomy. CONCLUSION: Repeat hepatectomy and prolonged surgery were identified as risk factors for bile leakage after liver resection for HCC. Bile leakage and repeat hepatectomy increased the risk of organ/space SSI.

Selective blockade of apoptosis by in vivo electroporation-mediated gene transfer combined with portal infusion of plasmid DNA attenuates liver cirrhosis.

AIM: The purpose of the present study was to determine whether in vivo electroporation could achieve selective blockade of apoptosis in a rat liver cirrhosis model. METHODS: A dimethylnitrosamine (DMN)-induced rat liver cirrhosis model was used. In vivo electroporation was performed after portal vein infusion of plasmid DNA. pFas-Fc plasmid DNA was used to block the apoptotic pathway. pUC/HGF and pCAGGS/EGFP were used as positive and negative controls, respectively. Liver collagen content was evaluated by hydroxyproline assay two weeks after gene transfer. Terminal deoxynucleotidyltransferase dUTP nick end-labeling was simultaneously performed in the liver to evaluate suppression of apoptosis. Survival analysis was performed using 10 rats that received the sFas gene, 10 that received the HGF gene, and 13 that received the GFP gene. RESULTS: The apoptotic cell index in the DMN-injected liver was significantly lower in rats that received the sFas gene compared with the negative control. The collagen content of the DMN-injected liver was also lower in rats that received the sFas gene compared with the negative control. There was no significant difference in the apoptotic cell index and collagen content of rats that received the sFas and HGF genes. Ten weeks after the initiation of DMN treatment, the survival rates with the sFas, HGF, and GFP genes were 56%, 100%, and 0, respectively. CONCLUSION: Selective blockade of apoptosis by in vivo electroporation-mediated gene transfer improved the apoptotic cell index, hydroxyproline content, and survival rate. Soluble Fas gene therapy using in vivo electroporation can be a safe and efficient therapy for liver cirrhosis in rats.

[Outcome of treatment for chest trauma at a single institution].

Between March 2005 and September 2009, 41,827 patients visited our emergency outpatient clinic, and 50 patients (0.12%) were admitted to our institution for chest trauma. Seventy percent of the chest traumas were caused by traffic accidents. Eighty-five percent of the traffic accidents were associated with car driving or motorcycle driving. Rib fracture, pneumothorax, hemothorax, and lung injury were seen in 56%, 40%, 22%, and 28% of the patients, respectively. Chest tube drainage was performed in 36% of the patients. Sixty-two percent of the patients with chest trauma underwent conservative follow-up. Only 1 patient underwent the ligation of the intercostal artery. One patient with chest trauma and fracture of the cervical vertebra and the pelvis died, who was in the state of cardio-pulmonary arrest on arrival. Forty-nine patients were discharged in 15.2 +/- 17.0 days. Twenty-two percent of the patients were hospitalized only 1 night.

Population pharmacokinetic analysis of meropenem in Japanese adult patients.

WHAT IS KNOWN AND OBJECTIVE: Meropenem is frequently employed as an empirical treatment for serious infections, but there has been no report on its population pharmacokinetic parameters for Japanese patients. Our aim is to undertake a population pharmacokinetic analysis of meropenem using non-linear mixed effects model (NONMEM). METHODS: Data from 68 patients were analysed via NONMEM with the first-order method. The participants' covariates, including gender, age, actual body weight, serum creatinine, serum albumin, serum total protein and creatinine clearance, were analyzed by the forward inclusion and backward elimination method to identify their potential influence on meropenem pharmacokinetics. The adequacy of the constructed model was assessed by goodness-of-fit plots and the precision of the parameter estimated at each step of the model development. To assess the robustness of the estimated parameter, bootstrap analysis was performed. RESULTS AND DISCUSSION: The data were best described by a one-compartment model. The serum creatinine values modified by the below normal limit in our hospital (mSCR) were an influential covariate for clearance (CL): CL (L/h) = 11·1 × (mSCR/0·7)(-1). The volume of distribution was estimated as 33·6 L. The coefficient of variation of the inter-individual variability of CL and the residual variability were 52·1% and 0·827% µg/mL, respectively. A comparison of the population pharmacokinetic parameters of meropenem in the final model estimated in NONMEM with original data, and 1000 bootstrap samples shows that both sets of estimates were comparable, thereby indicating the robustness of the proposed model. WHAT IS NEW AND CONCLUSION: A population pharmacokinetic model that satisfactorily described the disposition and variability of meropenem in our Japanese population is described. NONMEM analysis showed that the clearance of meropenem depended on modified serum creatinine. The results of this study should help Japanese patients on meropenem by improving the prediction accuracy of dosing using the Bayesian method.

Two cases of variceal haemorrhage during living-donor liver transplantation.

Some patients with cirrhosis experience rupture of venous varices before operation, and liver transplantation is a therapy of last resort for these patients. However, we have experienced two cases of intraoperative rupture in whom no abnormalities of the venous varices were seen on endoscopy before operation. One patient with ruptured gastrointestinal varices was treated by direct surgical ligation and the other with ruptured oesophageal gastric varices, spontaneously recovered with a Sengstaken-Blakemore tube. These cases suggest that acute variceal haemorrhage should always be considered as a possibility during living-donor liver transplantation in patients with a history of upper gastrointestinal bleeding. Careful observation of the nasogastic tube is important during clamping of the hepatic portal vein.

[Reconstruction of the left common carotid artery for dissective occlusion detected by intra-operative ultrasonography].

We describe a case of Stanford type A acute aortic dissection. Replacement of the ascending aorta and aortic arch was performed using an "arch 1st technique". Following the completion of replacement, hypotension of the left superficial temporal artery pressure was detected. Ultrasonography revealed dissection of the left common carotid artery (LCCA) and compressive occlusion of the true lumen. Reconstruction of the LCCA was performed in the neck. The patient did well after the operation without any neurological abnormalities.

Refractory response to growth factors impairs liver regeneration after hepatectomy in patients with viral hepatitis.

BACKGROUND/AIMS: Liver regeneration after surgical resection is important. The present study was designed to understand the effect of background liver damage on the rate of liver tissue regeneration after hepatectomy and the mechanism of any defective regeneration. METHODOLOGY: The subjects were 40 patients who underwent liver resection. They comprised 22 patients with chronic viral hepatitis-hepatocellular carcinoma (liver damage group) and 18 patients with hepatic metastases from colorectal cancer (normal liver group). Liver regeneration was evaluated by histopathological and immunohistochemical examination of the surgically resected tissue and by CT-scanning of the regenerated liver mass. The resected liver specimens were stained for c-met, gp-130 and nuclear factor-kappaB (NF-kappaB) proteins. RESULTS: Liver regeneration was significantly less in the liver-damage group than in the normal-liver group. Histopathological examination showed marked inflammatory cell infiltration in the liver-damage group. Expression of c-met, but not gp-130, was significantly higher on parenchymal cells of the liver-damage group than the normal-liver group. NF-kappaB expression in parenchymal liver cells was significantly higher than in non-parenchymal cells of the normal-liver group. In the liver-damage group, liver regeneration correlated negatively with the staining intensity of NF-kappaB protein in non-parenchymal cells. These findings suggest that non-parenchymal cells are constitutively activated in the damaged liver, probably explaining the refractoriness of hepatocytes to cytokine-induced proliferation after hepatectomy, in spite of increased receptor (c-met) expression. CONCLUSIONS: The refractory response of injured hepatocytes to cytokines may explain the impaired postoperative liver regeneration in patients with damaged liver.

Idiopathic nodular glomerulosclerosis: three Japanese cases and review of the literature.

Idiopathic nodular glomerulosclerosis (ING) is characterized as diffuse nodular glomerulosclerotic lesions, closely resembling Kimmelstiel-Wilson lesions without diabetic mellitus. We report here three Japanese cases of ING and discuss the previous reports. The patients were 75-, 48- and 84-year-old males with a history of long-term hypertension. Laboratory examination revealed moderate proteinuria and mild renal dysfunction. Diabetes mellitus was excluded by repeated clinical and laboratory investigations. Renal histology revealed nodular glomerulosclerosis, and both afferent and efferent arteriolosclerosis in all patients. In electron microscopy, the glomerular basement membrane was markedly thick in all patients. A low-protein diet and potent anti-hypertensive treatment using angiotensin-converting enzyme inhibitors were initiated in all patients and urinary protein excretion significantly reduced without the progression of renal dysfunction. We reviewed 42 previously reported cases and our three cases. The analysis revealed that common clinical features of ING are being male (82.2%) of relatively advanced age (mean age 61.3 years), with hypertension (82.2%), mild renal dysfunction (mean serum creatinine 2.9 mg/dl) and moderate urinary protein excretion (mean 4.05 g/day). Common histopathological findings of ING are nodular glomerulosclerosis (100%), arterio-arteriolosclerosis (91.2 and 89.7%) and glomerular basement membrane thickening (85.7%). In conclusion, ING is one of the phenotypes of arteriosclerotic renal disease without diabetes mellitus. Severe arterio-arteriolosclerosis may contribute to the progression to glomerular nodular formation in ING. The combination of renin-angiotensin system inhibition and a low protein diet can be beneficial for the reduction of urinary protein excretion.