Combination gemcitabine plus S-1 versus gemcitabine plus cisplatin for advanced/recurrent biliary tract cancer: the FUGA-BT (JCOG1113) randomized phase III clinical trial.

BACKGROUND: Gemcitabine plus cisplatin (GC) is the standard treatment of advanced biliary tract cancer (BTC); however, it causes nausea, vomiting, and anorexia, and requires hydration. Gemcitabine plus S-1 (GS) reportedly has equal to, or better, efficacy and an acceptable toxicity profile. We aimed to confirm the non-inferiority of GS to GC for patients with advanced/recurrent BTC in terms of overall survival (OS). PATIENTS AND METHODS: We undertook a phase III randomized trial in 33 institutions in Japan. Eligibility criteria included chemotherapy-naïve patients with recurrent or unresectable BTC, an Eastern Cooperative Oncology Group Performance Status of 0 - 1, and adequate organ function. The calculated sample size was 350 with a one-sided α of 5%, a power of 80%, and non-inferiority margin hazard ratio (HR) of 1.155. The primary end point was OS, while the secondary end points included progression-free survival (PFS), response rate (RR), adverse events (AEs), and clinically significant AEs defined as grade ≥2 fatigue, anorexia, nausea, vomiting, oral mucositis, or diarrhea. RESULTS: Between May 2013 and March 2016, 354 patients were enrolled. GS was found to be non-inferior to GC [median OS: 13.4 months with GC and 15.1 months with GS, HR, 0.945; 90% confidence interval (CI), 0.78-1.15; P = 0.046 for non-inferiority]. The median PFS was 5.8 months with GC and 6.8 months with GS (HR 0.86; 95% CI 0.70-1.07). The RR was 32.4% with GC and 29.8% with GS. Both treatments were generally well-tolerated. Clinically significant AEs were observed in 35.1% of patients in the GC arm and 29.9% in the GS arm. CONCLUSIONS: GS, which does not require hydration, should be considered a new, convenient standard of care option for patients with advanced/recurrent BTC. CLINICAL TRIAL NUMBER: This trial has been registered with the UMIN Clinical Trials Registry (http://www.umin.ac.jp/ctr/index.htm), number UMIN000010667.

Investigation of piezoelectric anisotropy of bovine cortical bone at an ultrasound frequency by coupling an experiment and a simulation.

An investigation of the piezoelectric anisotropy of bovine cortical bone at 1 MHz was attempted by coupling data obtained from an experiment and a simulation. In the experiment, a piezoelectric cell (PE-cell) was used as an ultrasound receiver. In the PE-cell, the cortical bone disk, which was cut in the direction perpendicular to the bone axis, was electrically shielded. The directivity of the PE-cell was measured at 0°-22.5° and was compared to four simulated results using the piezoelectric finite-difference time-domain method. It was shown that the piezoelectric signal in the bone could be generated by a transverse ultrasound wave.

Experimental observation of piezoelectric effect in cancellous bone generated by ultrasound irradiation.

In this study, piezoelectric cells (PE-cells) of cancellous bone were experimentally produced to receive an ultrasound wave. In the PE-cell, a bovine cancellous bone specimen, in which the pore spaces were saturated with air, was electrically shielded to prevent electromagnetic noise. As a result, the piezoelectric signal generated in the cancellous bone specimen by irradiating an ultrasound burst wave at 1.0 MHz could be clearly observed in water. The experimental results showed that the ultrasound sensitivity per unit area of cancellous bone was estimated to be below 1/100 and 1/100 000 of cortical bone and poly(vinylidene fluoride), respectively.

Randomized phase III study of bevacizumab plus FOLFIRI and bevacizumab plus mFOLFOX6 as first-line treatment for patients with metastatic colorectal cancer (WJOG4407G).

BACKGROUND: FOLFIRI and FOLFOX have shown equivalent efficacy for metastatic colorectal cancer (mCRC), but their comparative effectiveness is unknown when combined with bevacizumab. PATIENTS AND METHODS: WJOG4407G was a randomized, open-label, phase III trial conducted in Japan. Patients with previously untreated mCRC were randomized 1:1 to receive either FOLFIRI plus bevacizumab (FOLFIRI + Bev) or mFOLFOX6 plus bevacizumab (mFOLFOX6 + Bev), stratified by institution, adjuvant chemotherapy, and liver-limited disease. The primary end point was non-inferiority of FOLFIRI + Bev to mFOLFOX6 + Bev in progression-free survival (PFS), with an expected hazard ratio (HR) of 0.9 and non-inferiority margin of 1.25 (power 0.85, one-sided α-error 0.025). The secondary end points were response rate (RR), overall survival (OS), safety, and quality of life (QoL) during 18 months. This trial is registered to the University Hospital Medical Information Network, number UMIN000001396. RESULTS: Among 402 patients enrolled from September 2008 to January 2012, 395 patients were eligible for efficacy analysis. The median PFS for FOLFIRI + Bev (n = 197) and mFOLFOX6 + Bev (n = 198) were 12.1 and 10.7 months, respectively [HR, 0.905; 95% confidence interval (CI) 0.723-1.133; P = 0.003 for non-inferiority]. The median OS for FOLFIRI + Bev and mFOLFOX6 + Bev were 31.4 and 30.1 months, respectively (HR, 0.990; 95% CI 0.785-1.249). The best overall RRs were 64% for FOLFIRI + Bev and 62% for mFOLFOX6 + Bev. The common grade 3 or higher adverse events were leukopenia (11% in FOLFIRI + Bev/5% in mFOLFOX6 + Bev), neutropenia (46%/35%), diarrhea (9%/5%), febrile neutropenia (5%/2%), peripheral neuropathy (0%/22%), and venous thromboembolism (6%/2%). The QoL assessed by FACT-C (TOI-PFC) and FACT/GOG-Ntx was favorable for FOLFIRI + Bev during 18 months. CONCLUSION: FOLFIRI plus bevacizumab was non-inferior for PFS, compared with mFOLFOX6 plus bevacizumab, as the first-line systemic treatment for mCRC. CLINICAL TRIALS NUMBER: UMIN000001396.

Proton pump inhibitor after endoscopic resection for esophageal squamous cell cancer: multicenter prospective randomized controlled trial.

BACKGROUND: Whether proton pump inhibitors (PPIs) relieve heartburn or precordial pain after endoscopic resection (ER) for esophageal squamous cell carcinoma (ESCC) remains unclear. The aim of this study was to investigate the efficacy of PPI therapy for these symptoms after ER for ESCC. METHODS: We conducted a multicenter prospective randomized controlled trial among 15 hospitals in Japan. In total, 229 patients with cT1a ESCC were randomly assigned to receive PPI therapy for 5 weeks after ER (the PPI group, n = 115) or follow-up without PPI therapy (the non-PPI group, n = 114). The primary end point was the incidence of gastroesophageal reflux disease (GERD)-like symptoms after ER from a self-reported questionnaire (Frequency Scale for Symptoms of GERD). Secondary end points were ulcer healing rate at 5 weeks, incidence of pain, improvement rate of symptoms in those who started PPI therapy because of GERD-like symptoms in the non-PPI group, and adverse events. RESULTS: No significant difference was observed in the incidence of GERD-like symptoms after ER between the non-PPI and PPI groups (30 % vs 34 %, respectively). No significant differences were observed in the ulcer healing rate at 5 weeks (84 % vs 85 %) and incidence of pain within 1 week (36 % vs 45 %). In nine of ten patients (90 %) who started PPI therapy because of GERD-like symptoms in the non-PPI group, PPI administration relieved GERD-like symptoms. No adverse events related to PPI administration were observed. CONCLUSION: PPI therapy is not efficacious in reducing symptoms and did not promote healing of ulcers in patients undergoing ER for ESCC.

Endoscopic submucosal dissection for superficial esophageal neoplasms using the stag beetle knife.

Endoscopic submucosal dissection (ESD) is an accepted standard treatment for early gastric cancer but is not widely used in the esophagus because of technical difficulties. To increase the safety of esophageal ESD, we used a scissors-type device called the stag beetle (SB) knife. The aim of this study was to determine the efficacy and safety of ESD using the SB knife. We performed a single-center retrospective, uncontrolled trial. A total of 38 lesions were excised by ESD from 35 consecutive patients who were retrospectively divided into the following two groups according to the type of knife used to perform ESD: the hook knife (hook group) was used in 20 patients (21 lesions), and the SB knife (SB group) was used in 15 patients (17 lesions). We evaluated and compared the operative time, lesion size, en bloc resection rate, pathological margins free rate, and complication rate in both groups. The operative time was shorter in the SB group (median 70.0 minutes [interquartile range, 47.5-87.0]) than in the hook group (92.0 minutes [interquartile range, 63.0-114.0]) (P = 0.019), and the rate of complications in the SB group was 0% compared with 45.0% in the hook group (P = 0.004). However, the lesion size, en bloc resection rate, and pathological margins free rate did not differ significantly between the two groups. In conclusion, ESD using the SB knife was safer than that using a conventional knife for superficial esophageal neoplasms.

Randomised phase II study comparing dose-escalated weekly paclitaxel vs standard-dose weekly paclitaxel for patients with previously treated advanced gastric cancer.

BACKGROUND: This randomised phase II trial compared dose-escalated weekly paclitaxel (wPTX) vs standard-dose wPTX for patients with previously treated advanced gastric cancer (AGC). METHODS: Ninety patients were randomised to a standard dose of wPTX (80 mg m(-2)) or an escalated dose of wPTX (80-120 mg m(-2)) to assess the superiority of overall survival (OS) with a one-sided alpha error of 0.3 and a power of 0.8. RESULTS: The median OS showed a trend towards longer survival in the dose-escalated arm (11.8 vs 9.6 months; hazard ratio (HR), 0.75; one-sided P=0.12), although it was statistically not significant. The median progression-free survival (PFS) was significantly longer in the dose-escalated arm (4.3 vs 2.5 months, HR, 0.55; P=0.017). Objective response rate was 30.3% with dose escalation and 17.1% with standard dose (P=0.2). The frequency of all grades of neutropenia was significantly higher with dose escalation (88.7% vs 60.0%, P=0.002); however, no significant difference was observed in the proportion of patients experiencing grade 3 or more (40.9% vs 31.1%, P=0.34). CONCLUSION: Dose-escalated wPTX in patients with pretreated AGC met our predefined threshold of primary end point, OS (P<0.3); however, it did not show a significantly longer OS. Progression-free survival was significantly better with dose escalation.

Molecular diagnosis of Myxobolus spirosulcatus associated with encephalomyelitis of cultured yellowtail, Seriola quinqueradiata Temminck & Schlegel.

Mass mortality of cultured yellowtail, Seriola quinqueradiata, has recently been reported from fish farms in western Japan. Previous studies revealed that diseased fish were characterized by encephalomyelitis and presporogonic stages of a myxosporean-like parasite in the spinal cord. However, the parasite has remained unidentified because of the lack of mature stages being present. Thus, in the present study, analysis of the small subunit ribosomal DNA (18S rDNA) of the parasite as well as in situ hybridization (ISH) studies using histological sections of the infected tissue was conducted. The 18S rDNA of the myxosporean had higher sequence similarities with those of bile-duct-infecting myxosporeans rather than those infecting nervous tissues and was identified as Myxobolus spirosulcatus. The ISH using specific probes demonstrated that the DNA amplified was derived from the multinuclear organisms found in histological sections. A highly sensitive and specific PCR-based assay for M. spirosulcatus was developed, which revealed a high prevalence of infection in cultured yellowtail that exhibited the clinical signs of encephalomyelitis.

The modified glucose clearance test: a novel non-invasive method for differentiating non-erosive reflux disease and erosive oesophagitis.

BACKGROUND: Impaired salivary secretion has been reported to cause abnormal acid clearance from the oesophagus in gastro-oesophageal reflux disease (GERD). However, few studies have explained the differences between non-erosive reflux disease (NERD) and erosive oesophagitis (EO) with respect to salivary secretion. Aim To elucidate these differences, we measured salivary secretion by using the modified glucose clearance test (mGCT). METHODS: All subjects completed endoscopic examinations, the frequency scale for the symptoms of GERD questionnaire and the mGCT comprising a resting GCT (measured as RGC time) and a chewing-stimulated GCT (SGC time). RESULTS: Resting glucose clearance time was 18.5 min in control group and significantly longer in NERD and EO groups (28.5 and 39.0 min respectively). SGC time was 6.1 min in control group and 7.2 min in NERD group and significantly longer in EO group (10.2 min) than in the control and NERD groups. CONCLUSIONS: In the EO group, both resting and stimulated salivary secretions were less than in control group. However, in the NERD group, resting salivary secretion was decreased, but stimulated salivary secretion was similar to that of the control group. Therefore, these results may help in explaining the differences in the pathogenesis of NERD and EO.

Indoxyl sulfate induces skeletal resistance to parathyroid hormone in cultured osteoblastic cells.

Skeletal resistance to parathyroid hormone (PTH) is well known to the phenomenon in chronic renal failure patient, but the detailed mechanism has not been elucidated. In the process of analyzing an animal model of renal failure with low bone turnover, we demonstrated decreased expression of PTH receptor (PTHR) accompanying renal dysfunction in this model. In the present study, we focused on the accumulation of uremic toxins (UTx) in blood, and examined whether indoxyl sulfate (IS), a UTx, is associated with PTH resistance. We established primary osteoblast cultures from mouse calvariae and cultured the cells in the presence of IS. The intracellular cyclic adenosine 3',5' monophosphate (cAMP) production, PTHR expression, and free radical production in the primary osteoblast culture were studied. We found that the addition of IS suppressed PTH-stimulated intracellular cAMP production and decreased PTHR expression in this culture system. Free radical production in osteoblasts increased depending on the concentration of IS added. Furthermore, expression of organic anion transporter-3 (OAT-3) that is known to mediate cellular uptake of IS was identified in the primary osteoblast culture. These results suggest that IS taken up by osteoblasts via OAT-3 present in these cells augments oxidative stress to impair osteoblast function and downregulate PTHR expression. These finding strongly suggest that IS accumulated in blood due to renal dysfunction is at least one of the factors that induce skeletal resistance to PTH.

Magnetic anisotropies of iron on the Pt(111) surface.

We have studied magnetic anisotropies of Fe atoms on the platinum (111) surface, employing a fully relativistic pseudopotential and plane wave method with the local spin density approximation. We investigated three surface structures with different Fe monolayer coverages: full coverage, half-coverage and quarter-coverage. The effect of surface relaxation has been included. It was found that the magnetic easy axis of the system is within the surface plane for all systems investigated. In the system of an Fe chain on Pt(111), having an anisotropic local structure, the magnetic anisotropy energy is much enhanced after surface relaxation. This absolute value is larger compared with the value for bulk alloy and the magnetic easy axis is directed parallel to the alignment of Fe atoms.

Insufficiency of PTH action on bone in uremia.

Abnormal bone turnover and mineral metabolism is observed in patients on dialysis. Secondary hyperparathyroidism (SHP) develops in response to mineral metabolism changes accompanying renal failure. As a factor of disease progression, the phenomenon of skeletal resistance to parathyroid hormone (PTH) is observed. With recent advances in the treatment of SHP, over-secretion of PTH can now be controlled. However, blood PTH levels 2 to 3 times higher than normal are considered necessary to maintain normal bone turnover in patients with renal failure. Various causes of skeletal resistance to PTH have been reported, including decrease in PTH receptor in osteoblasts, accumulation of 7-84 PTH fragment, and accumulation of osteoprotegerin. This skeletal resistance to PTH is not only a high-turnover bone accompanying SHP, but may also play a crucial role in the onset of low-turnover bone disease. We have produced a rat model of renal failure with normal level of PTH secretion and analyzed the bone of this model. Our results confirmed that bone turnover is lowered accompanying renal function impairment. We also found that this lowered bone turnover is improved by intermittent administration of PTH. In addition, PTH receptor gene expression is also decreased in low-turnover bone, as is observed in high-turnover bone disease. These findings confirm the presence of skeletal resistance to PTH in low-turnover bone accompanying renal failure. Control of calcium, phosphorus, and PTH levels with the target to maintain normal bone turnover is important in maintaining the quality of life of patients on dialysis.

Ultrasonic pulse waves in cancellous bone analyzed by finite-difference time-domain methods.

The trabecular frame of cancellous bone has a high degree of porosity, anisotropy and inhomogeneity. The propagation of ultrasonic waves in cancellous bone is significantly affected by the trabecular structure. In this paper, two two-dimensional finite-difference time-domain (FDTD) methods, which were the popular viscoelastic FDTD method for a viscoelastic medium and Biot's FDTD method for a fluid-saturated porous medium, have been applied to numerically analyze the ultrasonic pulse waves propagating through bovine cancellous bone in the directions parallel and perpendicular to the trabecular alignment. The Biot's fast and slow longitudinal waves, which were identified in previous experiments for the propagation parallel to the trabecular orientation, could be analyzed using Biot's FDTD method rather than the viscoelastic FDTD method. For the single wave propagation in the perpendicular direction, on the other hand, the viscoelastic FDTD result was found to be in more good agreement with the experimental result.

Simulation of ultrasound propagation through bovine cancellous bone using elastic and Biot's finite-difference time-domain methods.

The propagation of ultrasonic pulse waves in bovine cancellous bone has been numerically analyzed in two dimensions by using two finite-difference time-domain (FDTD) methods: the commonly used elastic FDTD method and an FDTD method extended with Biot's theory for a porous elastic solid saturated with viscous fluid. Both FDTD results were compared with the results of previous experiments by Hosokawa and Otani [J. Acoust. Soc. Am. 101, 558-562 (1997)], in which the Biot's fast and slow longitudinal waves were clearly identified. It was difficult to analyze both the fast and slow waves with the elastic FDTD method because of the inadequate 2D model of cancellous bone. On the other hand, in Biot's FDTD results that consider the pore fluid motion relative to the solid frame, both waves could be clearly observed. The experimental and simulated values of the speeds of these waves were in good agreement. Using the modified Biot's FDTD equations containing the possible attenuations for the fast wave other than the viscous loss due to the pore fluid motion, the amplitude ratio of the slow wave to the fast wave largely increased with the porosity, which also agrees with the experimental results.

Synthesis of optically active N-(2-pyridyloxiran-2-ylmethyl) benzenesulfonamide derivatives and their herbicidal activity.

Novel herbicidally active sulfonamide compounds having a 2-arylsubstituted oxiranylmethyl structure are racemates due to a chiral carbon in the oxirane moiety. To clarify the stereochemical structure-activity relationship, we synthesized each enantiomer of 4-chloro-N-[2-(6-chloropyridin-2-yl)-2-oxiran-2-ylmethyl]-3,N-dimethylbenzenesulfonamide and N-[2-(6-chloropyridin-2-yl)-2-oxiran-2-ylmethyl]-N-methyl-5,6,7,8-tetrahydronaphthalene-2-sulfonamide by chemical methods including Sharpless asymmetric chlorohydroxylation. The results of herbicidal tests indicated that the (S)-isomers were the active forms.

Analysis of the KAL1 gene in 19 Japanese patients with Kallmann syndrome.

Kallmann syndrome is defined by the association of hypogonadotropic hypogonadism and anosmia. The KAL1 gene is responsible for the X-linked form of Kallmann syndrome. We analyzed the KAL1 gene in 19 Japanese patients with Kallmann syndrome, including 3 patients reported previously, using PCR-direct sequencing method. All of 19 patients were sporadic, except for 2 monozygotic twins. In this study, there were 3 kinds of mutations in the KAL1 gene. One of them was a novel mutation consisting of a G to A substitution in the acceptor site at the junction of intron 6/exon 7. None of the mutations have been reported in countries other than Japan. In male sporadic patients with Kallmann syndrome, the incidence of mutations in Japanese patients (14%: 2 of 14 cases) was slightly higher than that in patients in USA (8%). Also, we found 2 polymorphisms, which were always found together in 6 patients. The severity of hypogonadism was not related to the presence of mutations. Unilateral renal aplasia and mirror movement, which are frequently found in patients with the KAL1 gene mutation, were not related to the sites of mutations.

Pre-exposure with low-dose UVA suppresses lesion development and enhances Th1 response in BALB/c mice infected with Leishmania (Leishmania) amazonensis.

This study was conducted to determine whether exposing mice to ultraviolet (UV) radiation would alter the pathogenesis of infection with Leishmania (Leishmania) amazonensis (L. amazonensis) which causes progressive cutaneous disease in susceptible mouse strains. BALB/c mice were irradiated with 10 and 30 J/cm(2) UVA on shaved skin of the back from Dermaray (M-DMR-100) for 4 consecutive days before infection with Leishmania promastigotes. The course of disease was recorded by measuring the size of lesions at various times after infection. Mice groups irradiated with UVA 10 and 30 J/cm(2) showed significantly suppressed lesion development compared with the non-irradiated mice. Light and electron microscopy revealed a few parasites at the site of inoculation in UVA-irradiated subjects. Sandwich enzyme-linked-immunosorbent-assay (ELISA) examination of sera showed dose dependently upregulated interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-12, and downregulated interleukin (IL)-4 and interleukin (IL)-10 levels in UVA-irradiated as compared with the non-irradiated mice. Positive signals for IFN-gamma mRNA in irradiated mice were obtained by RT-PCR, while non-irradiated mice showed negative results. None of the examined samples showed signal for IL-4 mRNA. The present study disclosed that exposure of mice to different low-doses of UVA irradiation prior to infection may interfere with immunity to L. amazonensis in the murine model. This indicates that the cell-mediated response switch from Th2 to Th1 pattern suppressed the cutaneous lesions of L. amazonensis.

A novel mutation of the KAL1 gene in monozygotic twins with Kallmann syndrome.

OBJECTIVE: Kallmann syndrome is defined by the association of hypogonadotropic hypogonadism and anosmia. The KAL1 gene is responsible for the X-linked form of Kallmann syndrome. In this study we describe monozygotic twins with Kallmann syndrome due to the same mutation in the KAL1 gene. DESIGN: We studied male monozygotic twins with Kallmann syndrome. METHODS: We analyzed the KAL1 gene using the PCR-direct sequencing method. The twins' mother was examined for the identified mutation. RESULTS: We identified a 14 bp deletion from codon 419 in exon 9 (Pro419del14) in both KAL1 genes of the twins. This was a novel mutation in the KAL1 gene and was responsible for Kallmann syndrome. As Pro419del14 was not detected in the mother of the twins, Pro419del14 was a germline mutation originating from them. These monozygotic twins showed different LH and FSH responses to LH-RH stimulation and different phenotypes such as complications, physiques and psychiatric characters. CONCLUSIONS: We report an identical KAL1 gene mutation in the monozygotic twins with Kallmann syndrome. As these monozygotic twins showed different phenotypes in some respects, we suggest that factors other than mutations in the KAL1gene affect the symptomatic features of Kallmann syndrome.