A phase I/II study of cancer peptide vaccine S-288310 in patients with advanced urothelial carcinoma of the bladder.

Background: S-288310, a cancer peptide vaccine composed of two HLA-A*24:02-restricted peptides derived from two oncoantigens, DEP domain-containing 1 (DEPDC1) and M-phase phosphoprotein 1 (MPHOSPH1), was investigated in urothelial carcinoma (UC) of the bladder. Patients and methods: Thirty eight HLA-A*24:02-positive patients with progressive UC were enrolled in this study. In the phase I part of the study, three patients each were treated with S-288310 at 1 mg or 2 mg/peptide subcutaneously once a week to evaluate safety and tolerability. In the phase II, 32 patients were randomized to receive either 1 mg or 2 mg to evaluate the difference in cytotoxic T lymphocytes (CTL) induction and safety. Results: S-288310 was safe and well tolerated in the phase I. Of 27 patients evaluable for immune responses in the phase II, there was no difference in CTL induction rate between the 1 mg (100%) and 2 mg (80.0%) groups. Of 32 patients receiving S-288310 in the phase II, the most frequent drug-related AE was the injection site reaction that was observed in 29 patients (90.6%), but none of the patients discontinued administration due to these reactions and no dose relationship in the frequency and severity was observed. The objective response rate of the 32 patients was 6.3% and the disease control rate was 56.3%. The median overall survival (OS) rates for patients vaccinated with S-288310 after one regimen of chemotherapy, 2 regimens, or 3 or more were 14.4, 9.1 and 3.7 months, respectively, and 32.2% of patients post first-line treatment were alive at 2 years. OS of patients who showed CTL induction to both peptides was longer than that of those with CTL induction to no or one peptide. Conclusion: S-288310 was well-tolerated and effectively induced peptide-specific CTLs, which were correlated with longer survival for patients with UC of the bladder. Trial registration ID: JapicCTI-090980.

Target structure induced suppression of the ionization cross section for very low energy antiproton-hydrogen collisions.

Low energy antiprotons have been used previously to give benchmark data for theories of atomic collisions. Here we present measurements of the cross section for single, nondissociative ionization of molecular hydrogen for impact of antiprotons with kinetic energies in the range 2-11 keV, i.e., in the velocity interval of 0.3-0.65 a.u. We find a cross section which is proportional to the projectile velocity, which is quite unlike the behavior of corresponding atomic cross sections, and which has never previously been observed experimentally.

Synthesis of cold antihydrogen in a cusp trap.

We report here the first successful synthesis of cold antihydrogen atoms employing a cusp trap, which consists of a superconducting anti-Helmholtz coil and a stack of multiple ring electrodes. This success opens a new path to make a stringent test of the CPT symmetry via high precision microwave spectroscopy of ground-state hyperfine transitions of antihydrogen atoms.

The use of recipient superficial femoral vein as a venous graft for portal vein reconstruction in right lobe living donor liver transplantation.

In living donor liver transplantation (LDLT), portal vein thrombosis (PVT) in the recipient is frequently regarded as a contraindication. To reconstruct the PV of a right-lobe liver graft (RLG) using an interposition or jump graft from the splenomesenteric junction, various vein grafts and technical modifications have been introduced. The internal jugular, external iliac, or great saphenous veins have been utilized in such reconstructive procedures. However, the superficial femoral vein (SFV) is preferable to the autologous vein grafts in terms of caliber, wall thickness, and length. We employed the recipient SFV to reconstruct PVT among 40 adult LDLT using RLG. Thirty-three were reconstructed by single end-to-end anastomosis with the right or left recipient PV. Three patients were transplanted with a RLG using 2 separated PVs reconstructed by double anastomoses with both the right and left PVs of the recipient. The remaining 4 patients required venous grafting for portal reconstruction. We used the recipient SFV as an interposition or jump graft from the splenomesenteric junction to the graft PV. There were 2 cases of anastomotic PV stenosis; 1 in portal reconstruction without a venous graft and the other with a SFV graft. Both were treated successfully by balloon angioplasty. The recipient SFV is an excellent size match for the PV reconstruction as a long interposition or jump conduit when the venous system from the deceased donor is not available. The indication for LDLT in patients with complete PVT should be carefully decided before transplantation in terms of portal reconstruction.

Drug-induced oral lichenoid reaction during nivolumab therapy.

Oral lichenoid reaction, an immune-related adverse event of immunotherapy, has been reported in very few patients receiving anti-programmed cell death receptor-1 (anti-PD-1) therapy. Here, we describe a case of severe stomatitis (grade ≥3 by the Common Terminology Criteria for Adverse Events, version 4.0) accompanied by pharyngolaryngitis that was observed in a patient receiving nivolumab therapy. The stomatitis was diagnosed as drug-induced lichenoid reaction. Nivolumab therapy was discontinued, and the patient was administered systemic prednisolone (1mg/kg). Most of the patient's mucosal changes in the oral cavity and pharyngolarynx resolved within approximately 3 weeks after starting the prednisolone. Clinicians should be aware that severe oral lichenoid reactions can occur in patients receiving anti-PD-1 therapy.

Pentax-AWS, a new videolaryngoscope, is more effective than the Macintosh laryngoscope for tracheal intubation in patients with restricted neck movements: a randomized comparative study.

BACKGROUND: We studied whether laryngoscopy and tracheal intubation were easier when using the Pentax-AWS (Tokyo, Japan), a new videolaryngoscope, than when applying the Macintosh laryngoscope, during manual in-line neck stabilization. METHODS: In 203 anaesthetized patients with manual in-line neck stabilization, we inserted the Pentax-AWS and a Macintosh laryngoscope, in turn, and recorded the view of the glottis and time taken to laryngoscopy. The success rate of tracheal intubation (within 120 s) and time to intubation were also recorded. RESULTS: The view of the glottis was significantly better with the Pentax-AWS than with the Macintosh laryngoscope (P<0.001). For the Macintosh laryngoscope, the view was obscured in 22 of 203 patients (11%) (Grade 3 in 21 patients and Grade 4 in one patient), whereas for the Pentax-AWS, the glottis was always clearly seen (Grade 1). Time taken to see the glottis with the Pentax-AWS [mean (sd): 6.0 (3.1) s] was significantly shorter than with the Macintosh laryngoscope [11.0 (5.0) s] (95% CI for difference: 4-6 s). The success rate of tracheal intubation with the Pentax-AWS (all of 99 patients) was significantly higher than with the Macintosh laryngoscope (93 of 104 patients) (P=0.001). Time taken for intubation was similar between the Macintosh laryngoscope [51 (27) s] and the Pentax-AWS [54 (14) s] (95% CI for difference: -9 to 3 s). CONCLUSIONS: In patients with stabilized neck, the Pentax-AWS provided a better view of the glottis and a higher success rate of tracheal intubation, compared with the conventional Macintosh laryngoscope.

Microsurgical back wall support suture technique with double needle sutures on hepatic artery reconstruction in living donor liver transplantation.

OBJECTIVES: In living-donor-liver transplantation (LDLT), microsurgical reconstruction of the hepatic artery is an essential but challenging issue. Especially using a living donor graft, the hepatic artery is short, the intimal damage may be severe, and the usable vessel grafts are limited compared with cadaveric donors. Thus, sometimes it is difficult to use a conventional twist reconstruction technique in which one needs to turn over the hepatic artery. METHODS: To overcome these difficulties, we began to use a back wall support suture technique. From July 1991 to June 2007, we performed 110 LDLTs. In 87 cases, we used the conventional twist technique. In the most recent 23 cases, we used a back wall support suture technique. To put it briefly, we placed 2 sutures at the deepest, most difficult points in the artery for backside support. Each stitch was placed from the inner side of the arterial wall to the outer side with double needle sutures. The subsequent sutures were placed forward on either side adjacent to the previous suture. RESULTS: The total ratio of hepatic artery thrombosis (HAT) was 8.2% (9/110). In the conventional twist technique group, HAT occurred in 8 cases (9.2%). In the new technique group, it occurred in only 1 case that had an intimal dissection in the recipient artery (4.3%). Thus there was no HAT associated with the arterial anastomosis in the new technique group. CONCLUSION: Our technique allows for safe intimal adaptation without turning over the artery. In conclusion, this back wall support suture technique may contribute to more satisfactory results.

Compact cryogenic system with mechanical cryocoolers for antihydrogen synthesis.

We have developed a compact cryogenic system which cools a vacuum chamber housing multi-ring trap electrodes (MRTs) of an antihydrogen synthesis trap using mechanical cryocoolers to achieve background pressure less than 10(-12) Torr. The vacuum chamber and the cryocoolers are thermally connected by copper strips of 99.9999% in purity. All components are installed within a diametric gap between the MRT of phi108 mm and a magnet bore of phi160 mm. An adjusting mechanism is prepared to align the MRT axis to the magnet axis. The vacuum chamber was successfully cooled down to 4.0 K after 14 h of cooling with heat load of 0.8 W.

A cryogenic linear ion trap beamline for providing keV ion bunches.

A new cryogenic linear ion trap beamline has been constructed and commissioned, which serves to inject cold molecular and cluster ions into the RIKEN cryogenic electrostatic ring (RICE). Ions are created with an electrospray ion source, and a quadrupole mass filter is used for mass-selection prior to trap injection. The radio frequency octupole ion trap can be continuously loaded with ions and features a fast ion extraction mode to create short ion bunches with tens of µs duration. We report here on the simulations and development of the ion trap beamline and validate performance with the moderately heavy molecular cation methylene blue. Characterization of the novel trap design with additional wedge-shaped electrodes was carried out, which includes the determination of the temporal and spatial shape of the ion bunch and the total number of ions after extraction. Finally, these ion bunches are synchronized with the switching of a pulsed high-voltage acceleration device downstream of the trap, where the ions obtain a kinetic energy of up to 20 keV. The preparation and control of the keV ion beam are demonstrated for the ion injection into RICE.

[Epicardial atrial pacing using an active fixation bipolar endocardial lead in children].

Good performance was observed over 10 years after implantation of bipolar epicardial atrial pacing using an active fixation bipolar endocardial lead in 3 pediatric patients with congenital heart block. The bipolar endocardial lead which was supposed to be fixed transvenously was implanted on the atrial surface by first screwing the lead's helix into the myocardium. The catheter was then laid down on the atrial surface, and both electrodes were wrapped by the atrial tissue. The good performance of this pacing lead seemed to depend on stable positioning of the electrode. This lead is superior to the commercially available, and steroid eluting epicardial bipolar pacing lead, on the point of its small size in head and body, and could be applied to dual chamber pacing in smaller children.

Design and commissioning of the RIKEN cryogenic electrostatic ring (RICE).

A new electrostatic ion storage ring, the RIKEN cryogenic electrostatic ring, has been commissioned with a 15-keV ion beam under cryogenic conditions. The ring was designed with a closed ion beam orbit of about 2.9 m, where the ion beam is guided entirely by electrostatic components. The vacuum chamber of the ring is cooled using a liquid-He-free cooling system to 4.2 K with a temperature difference of 0.4 K at most within all the positions measured by calibrated silicon diode sensors. The first cryogenic operation with a 15-keV Ne+ beam was successfully performed in August 2014. During the measurement, the Ne+ beam was stored under a ring temperature of 4.2 K with a residual-gas lifetime of more than 10 min. This permits an estimation of the residual gas density at a few 104 cm-3, which corresponds to a room-temperature-equivalent pressure of around 1×10-10 Pa. An effect of longitudinal pulse compression at the bunching cavity in the ring was clearly identified by monitoring the pick-up beam detector. The detailed design and mechanical structure of the storage ring, as well as the results from the commissioning run, are reported.

Carotid-compression technique for the insertion of guiding catheters.

Inserting a guiding catheter into a tortuous artery for neurointerventional procedures can be difficult. In our technique, the carotid artery is manually compressed to stabilize and/or straighten the inserted wire before advancing the guiding catheter. Although this technique is not risk-free and care must be taken to avoid vascular injury by excessive compression, it is useful for the insertion of a guiding catheter into the carotid artery.

Continuous low-dose human atrial natriuretic peptide promotes diuresis in oliguric patients after living donor liver transplantation.

Human atrial natriuretic peptide (ANP) is beneficial for the prophylaxis of acute renal failure (ARF) after liver transplantation (OLT). We evaluated renal function in OLT patients with or without ARF, describing cases unresponsive to loop diuretics successfully treated with continuous low-dose ANP infusion without hemodialysis. Twenty-seven consecutive adult-to-adult living donor liver transplantations (LDLTs) were performed in 26 patients. One case was excluded due to the need for continuous hemodialysis (HD) during the operation. Of the 26 cases, 6 (23%, group 2) developed ARF in the first 30 days after LDLT; the other 20 were ARF-free (group 1). The median follow-up was 24 months. No patient required either continuous or intermittent HD. Only one patient died due to multiple liver abscesses. Mean preoperative serum creatinine (sCr) value and intraoperative blood loss in group 2 were significantly higher than those in group 1. Three cases in group 2 failed to improve on high-dose loop diuretics with low-dose dopamine, exhibiting fluid overload. The remaining three cases in group 2 responded to conventional diuretic treatments. Continuous low-dose ANP was started 2, 4, or 5 days after LDLT, and urine output significantly increased after ANP administration. The serum creatinine values were 1.1, 1.2, and 1.1 at 1 month and 1.0, 0.9, and 0.6 mg/dL at 6 months after LDLT. Massive blood loss during the operation caused ARF, but did not affect renal function after LDLT. Continuous low-dose ANP improved renal function and diuresis for oliguric ARF patients, preventing the need for HD or continuous venovenous hemodialysis.

[New method for localization of the small ground-glass opacity lesion in resected lung].

A small lesion showing ground-glass opacity (GGO) by preoperative computed tomography (CT) is sometimes difficult to detect after lobectomy when it locates in the central part of the lobe. In order to facilitate to identify the lesion for marking pathological specimen, we developed a new method using CT. After surgery, the resected pulmonary lobe was expanded with airflow through the bronchial stump and the target lesion was examined with CT. The laser beam of the CT on the surface of the lung is used as a guiding line for cutting. Through the application of this method for 2 clinical cases, it was found to be possible to exactly identify the GGO lesion from the surface of the resected lung enabling to visualize a fresh surface of the lesion like a CT image with minimal destruction of the structure.

Alterations by saponins of passive Ca2+ permeability and Na+-Ca2+ exchange activity of canine cardiac sarcolemmal vesicles.

Saponins can both permeabilize cell plasma membranes and cause positive inotropic effects in isolated cardiac muscles. Different saponins vary in their relative abilities to cause each effect suggesting that different mechanisms of action may be involved. To investigate this possibility, we have compared the effects of seven different saponins on the passive Ca2+ permeability and Na+-Ca2+ exchange activity of isolated canine cardiac sarcolemmal membranes. Saponins having hemolytic activity reversibly increased the passive efflux of Ca2+ from sarcolemmal vesicles preloaded with 45Ca2+ with the following order of potency: echinoside-A greater than echinoside-B greater than holothurin-A greater than holothurin-B greater than sakuraso-saponin. Ginsenoside-Rd and desacyl-jego-saponin, which lack hemolytic activity, had no significant effect on this variable. The saponins also stimulated Na+-Ca2+ exchange activity measured as Na+-dependent Ca2+ uptake by sarcolemmal vesicles. Ginsenoside-Rd and desacyl-jego-seponin, which did not affect passive Ca2+ permeability, stimulated the uptake, while in contrast, echinoside-A and -B only slightly increased or decreased this latter variable. Thus, the abilities of these compounds to enhance Na+-Ca2+ exchange activity seem to be inversely related to their abilities to increase the Ca2+ permeability. Effects by the echinosides on Na+-Ca2+ exchange may be masked by the loss of Ca2+ from the vesicles due to the increased permeability. These results suggest that the saponins interact with membrane constituent(s) that can influence the passive Ca2+ permeability and the Na+-Ca2+ exchange activity of cardiac sarcolemmal membranes.

Molecular diversity of precursor B acute lymphoblastic leukemias identified by the immunoglobulin heavy chain gene organization.

Acute leukemias with morphological, cytochemical, and immunological characteristics correlating to precursor B lymphocyte and with germ line configuration of immunoglobulin heavy (IgH) chain loci were studied for the organization of antigen receptor genes including C mu, Ig light (IgL) chain, T cell receptor (TCR) beta and gamma. Three of the five lymphoblast samples retained the germ line configuration of both Ig JH and C mu region. The other two samples showed deletion of the entire JH region resulting in the rearrangement of the C mu region. None of these five cases had a Ig L chain gene rearrangement. The three cases with germ line IgJH and C mu loci were revealed to belong to stage I (HLA DR+), stage II (HLADR+, CD19+), and stage III (HLADR+, CD19+, CD10+) B precursor ALLs, respectively. The two cases with deletion of IgJH region also belonged to stage II and III B precursor ALL. Thus immunologically classified stage II and III B precursor ALLs include those with germ line IgH region, representing ALLs at a very early stage of B cell development. A subgroup of B precursor ALL with deleted IgJH region, which is abortive at the molecular genetic level, was also identified. Karyotype abnormalities involving chromosomal region 11q23 in the leukemias with germ line IgH region are also discussed.