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Background Rearranged during transfection (RET) rearrangements occur in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib administered at doses of 300 mg and 600 mg twice daily (BID) is approved for. Alk rearranged NSCLC in Japan and other countries, respectively. Since alectinib has activity against RET, we conducted a phase (P) 1/2 study of alectinib to determine its activity in Japanese patients with. Ret rearranged NSCLC. Methods This study was a single-arm, open-label, multi-institutional P1/2 trial. Previously treated patients with RET-rearranged NSCLC, screened by nation-wide network (LC-SCRUM-Japan), were recruited. In P1, alectinib (600 or 450 mg BID) was administered following a 3+3 design and its safety was assessed. During P2, alectinib was administered at the recommended dose (RD) determined in P1. The primary endpoint was the objective response rate (ORR) in RET inhibitor-naive patients treated with the RD of alectinib. Results Thirty-four patients were administered alectinib. In cohort 1 (600 mg BID) of P1, we observed 5 dose-limiting toxicities (DLTs), including grade 3 rash and thromboembolic event, in 3 of 6 patients. In cohort 2 (450 mg BID), we observed no DLTs in 3 patients. Pharmacokinetic analysis revealed that AUC0-10 to 600 mg BID was higher than that previously reported in global trials. We determined 450 mg BID as the RD for P2. In 25 RET inhibitor-naive patients, one achieved an objective response (4%) and 13 achieved disease control at 8 weeks (52%). The median progression-free survival (PFS) was 3.4 months (95% CI, 2.0-5.4), while the median overall survival was 19.0 months (5.4-NE). We observed grade 3 adverse events (AEs) (4%) including pneumonitis in P2. Conclusions Alectinib exerts limited activity against RET-rearranged NSCLC. Further investigation to elucidate the mechanisms underlying sensitivity and resistance of RET inhibitors is required to improve outcomes for these patients.

Background This study aimed to investigate the contribution of a proliferation-inducing ligand (APRIL), a member of the tumor necrosis factor (TNF) superfamily implicated in plasma cell survival, to the development of plasma cell–rich lesions in immunoglobulin G4–related disease (IgG4-RD). Methods We performed immunohistochemical staining for APRIL with Stalk-1 and Aprily-8 antibodies specifically recognizing APRIL-producing cells and secreted APRIL, respectively, in renal and submandibular lesions of IgG4-RD in comparison with those of Sjögren’s syndrome and sialolithiasis. Results Numerous Stalk-1-positive APRIL-producing cells were detectable in lesions of IgG4-RD. These cells, identified as CD163-positive M2 macrophages, secreted APRIL that distributed close to and even on infiltrating plasma cells. In contrast, APRIL-producing cells and the secreted form of APRIL were rarely detectable in lesions of Sjögren’s syndrome or sialolithiasis. Notably, APRIL expression decreased concomitantly with the level of plasma cell infiltration after successful glucocorticoid treatment. Conclusions Abundant infiltration into tissue lesions of APRIL-producing M2 macrophages and retention of secreted APRIL in plasma–cell–rich areas support a role for APRIL in the pathogenesis of plasma cell–rich lesions in IgG4-RD.

Background The rearranged during transfection (RET) fusion gene was discovered as a driver oncogene in 1-2% of non-small cell lung cancers (NSCLCs). Alectinib is an approved anaplastic lymphoma kinase (ALK) inhibitor that may also be effective for RET fusion-positive NSCLC. Methods/design RET fusion-positive NSCLC patients treated with at least one regimen of chemotherapy are being recruited. In step 1, alectinib (600 or 450 mg, twice daily) will be administered following a 3+3 design. The primary endpoint is safety. In step 2, alectinib will be administered at the recommended dose (RD) defined by step 1. The primary endpoint is the response rate of RET inhibitor treatment-naive patients. Conclusion This is the first study to investigate the safety and preliminary efficacy of alectinib in RET fusion-positive NSCLC patients. If successful, alectinib treatment may lead to substantial and important changes in the management of NSCLC with RET fusion genes. J. Med. Invest. 64: 317-320, August, 2017.

Introduction: Dehydrated hereditary stomatocytosis (DHSt) or hereditary xerocytosis (HX) is a form of congenital hemolytic anemia characterized by red blood cell (RBC) dehydration. Heterozygous mutations in PIEZO1, a mechanically-activated ion channel, cause DHSt. Recently, KCNN4, which encodes the Gardos channel, has been found to be the second pathogenic gene for DHSt. DHSt is characterized by an alteration in the RBC morphology in target cells, stomatocytes, and/or echinocytes, and RBC deformability assessments by ektacytometry as well as RBC ion flux measurements are currently the standard laboratory tests for DHSt, but their use in laboratories is limited. The flow cytometric osmotic fragility (FCM-OF) test is a useful diagnostic test for hereditary spherocytosis (HS) and also for hereditary elliptocytosis (HE). In this study, we showed that the FCM-OF test could also successfully diagnose DHSt. Subjects: A total of 46 cases of RBC membrane disorders were examined, and tentative diagnoses were made based on the RBC morphology, acid glycerol lysis time, and eosin 5'-maleimide binding tests, resulting in HS (n=31), HE (n=6), and DHSt (n=9). Methods: The number of RBCs in isotonic and hypotonic buffers were measured by flow cytometry. The degree of osmotic fragility was expressed as the "percentage residual RBCs (%RRC)". We confirmed the DHSt diagnosis by the massively paralleled sequencing using our custom panels targeting 68 hemolytic anemia-related genes with the next-generation sequencer. Results: Both HS and HE patients showed a decrease in %RRC; HS (18.0±8.9%, p Discussion: We examined 77 patients with congenital hemolytic anemia recently, and 59 cases were confirmed by diagnostic tests (76.6%). The results were as follows: 48 cases of RBC membrane abnormality (62.3%), 6 cases of RBC enzymopathy (7.8%), and 5 cases of hemoglobinopathy (6.5%). Of the cases of RBC membrane disorders, 31 cases of HS, 9 cases of DHSt, and 8 cases of HE were identified. These observations suggest that DHSt is the second-most common RBC membranopathy in Japan, and that the FCM-OF test and targeted sequencing efficiently discriminate DHSt from other RBC membrane disorders. Disclosures No relevant conflicts of interest to declare.

Photoluminescence and surface plasmon emission light have been investigated in the attenuated total reflection (ATR) Kretschmann configuration. Surface plasmons (SPs), two-dimensional optical waves, were excited when rhodamine-B (RB) dye Langmuir-Blodgett (LB) films on metal thin film were directly irradiated by laser beams in the Kretschmann configuration. Emission light, that is, three-dimensional optical waves through the prism were observed corresponding to the resonant conditions of SP excitations in the configuration. The intensity of the SP emission light was small for the RB LB film with 4 layers, but the intensities increased in proportion to the thickness for the LB films having above 8 layers. Photoluminescence intensities also strongly depended upon the nanostructured separation between the RB LB films and metal thin films. It is thought that the phenomena are very useful for applications utilizing dye molecules on metal and conversion between three- and two-dimensional optical waves.

Polystyrene submicron and micron sphere films were fabricated and the optical properties were investigated using surface plasmon spectroscopy (SPS) and reverse irradiation utilizing the SPS Kretschmann configuration. The diameters of the spheres were 0.1 and 1.0 µm. For the 0.1-µm-sphere films, the dip angles of the SPS curves shifted to higher angles with the amount of spheres in the films. However, for the 1.0-µm-sphere films, the SPS curves did not shift with the amount of spheres which is considered to be due to the change of the effective dielectric constant in the decay length of the evanescent field intensity of surface plasmon. Furthermore, emitted light due to reverse irradiation was also observed as a function of the emitted angle in the Kretschmann configuration. The peak angles of the emitted light almost corresponded to the dip angles of the SPS curves and the emitted light was considered to be due to surface plasmon excitation.

Emission light through the prism in the Kretschmann configuration of prism/Ag thin film/rhodamine-B (RB) Langmuir–Blodgett (LB) film has been observed by means of direct irradiation of a laser beam from air to the RB LB film, that is, the reverse irradiation method against the conventional attenuated total reflection (ATR) method. The emission light intensities and the spectra strongly depended upon the emission angle at the prism. The relation between the peak wavelengths of the spectra and the emission angles corresponded to the dispersion property of the resonant excitations of surface plasmons (SPs) in the ATR configuration. It was concluded that the emission light was caused by multiple excitations of SPs in the ATR configuration. Emission light through the prism was also observed below the reflection angle of the resonant one when the SP was resonantly excited in the conventional ATR measurement. This emission light also showed the same property as the one in the reverse irradiation method. It is thought that the phenomenon will be used as a new sensing device.

Surface plasmons (SPs) were resonantly excited for aluminum (Al) thin films and arachidate acid (C20) LB ultrathin films on the substrates in a Kretschmann configuration of the attenuated total reflection (ATR) method. Evanescent fields generating on the Al thin films and the LB films due to excitations of the SPs were detected as luminescent light from a metallic needle probe covered with CdS in the localized evanescent fields. The luminescent light, that is, the evanescent fields were measured as a function of the incident angle of the laser beam exciting the SPs and as a function of the distance from the surface. The luminescent light intensity was biggest at a lower angle than the resonant angle. These properties were calculated and discussed. Evanescent fields were also measured for C20 LB films on Al thin films.

[Case report] A 65-year-old male war admitted to a local hospital because of fever. He was treated with piperacillin and clindamycin without noticeable effect. He began to complain of loss of vision on the third hospital day and culture of the blood specimen yielded Klebsiella pneumoniae. He was diagnosed as endophthalmitis and referred to our hospital for further examination. The hematological laboratory test showed leukocytosis (12,700/microliter) and increased CRP (20.4 mg/dl). A computed tomographic (CT) scan of the thorax revealed multiple lung abscesses. An abdominal ultrasonographic scan and a CT scan of the abdomen revealed multiple liver abscesses. We drained the abscess in the liver and Klebsiella pneumoniae was detected from the sample of aspirated fluid and his sputum. Meropenem was administered intravenously. Fever started to improve on the tenth hospital day and the size of both liver and lung abscesses were reduced. He has lost vision of his right eye. He was discharged after sixty days. He did not have any immunosuppressive underlying disease including HIV infection and diabetes mellitus which cause these lesions.

Renal hypothermia using ice slush for retroperitoneal laparoscopic partial nephrectomy was performed in 2 patients. A cylindrical device was secured in the enlarged port site. Through the device, ice slush was introduced and placed around the kidney. The nadir renal temperature under renal ischemia in the 2 patients was 18.4 degrees C and 25.8 degrees C.

Purpose: Some nonseminomatous germ cell tumors are resistant to any type of chemotherapy. Control of embryonal carcinoma cells is crucial to manage nonseminomatous germ cell tumors. We established SOX2 targeting therapy in an embryonal carcinoma model.Materials and Methods: SOX2 expression was evaluated in a series of testicular germ cell tumor tissue samples. The antitumor effect of SOX2 knockdown was analyzed in vitro and in vivo using an embryonal carcinoma model.Results: In testicular germ cell tumor tissue SOX2 was expressed in the foci of embryonal carcinoma but negative in seminoma and yolk sac tumors. In an embryonal carcinoma model SOX2-siRNA induced apoptotic cell death in vitro and significant growth suppression in vivo.Conclusions: This study shows the therapeutic potential of SOX2 silencing for embryonal carcinoma. However, further improvements are needed in SOX2-siRNA delivery to the tumor.

Background: A 14-year-old boy was admitted because of lumbago and high fever. Methods/Results: Computed tomography scans revealed psoas, piriformis and gluteal abscesses as well as right iliac vein thrombus. A right femoral venogram demonstrated compression from the psoas abscess and thrombosis of the common iliac vein. Appropriate surgical drainage, administration of antibiotics and anticoagulant therapy were effective in the present case. Conclusions: This is the first report of primary psoas abscess associated with vein thrombosis and is also unique in that abscesses were multiple without predisposing diseases or trauma.

In this long term follow-up report, we presented a case of fibrous dysplasia of the left maxillo-facial region in a 4 year-old girl. The operation was performed 4 times (1st-Jun, 20, 1978. 2nd-Aug, 5, 1981. 3 rd-Jul, 28, 1986. 4 th-Aug, 3, 1988.) within the observation of 11 years follow-up.In the peak of her school age growth, the elevation of serum alkaline phosphatase and remarkable transformation of maxillo-facial region were observed.1 year has passed since the 4 th operation and the prognosis is favorable without any relapse tendency. However, from the nature of this disease we don't judge this case cured, it needs observation until adulthood is attained.

Objectives To analyze the methylation status and expression profiles of multiple tumor suppressor genes in renal cell carcinoma-derived cell lines. Aberrant promoter methylation is commonly found in human cancers. Nonetheless, it is challenging to demonstrate that methylation of a specific gene results in gene inactivation. Methods We simultaneously analyzed methylation and expression profiles of five putative tumor suppressor genes ( p15, p16, Rb, BRCA1, and E-cadherin ) in 14 different cell lines using bisulfite genomic sequencing and reverse transcriptase-polymerase chain reaction. We also used multiplex polymerase chain reaction to identify homozygous deletions at the p15 and p16 loci. Results Expression of p16, BRCA1, and E-cadherin was maintained in 4 (29%) of 14 cell lines, regardless of the presence of methylation. Aberrant methylation of p16 was observed in 2 (14%), of BRCA1 in 1 (7%), and of E-cadherin in 9 (64%) of 14 cell lines. Concurrent methylation was observed among p16 and BRCA1 (1 [7%] of 14 cell lines) and among p16 and E-cadherin (1 [7%] of 14 cell lines). We detected homozygous deletion of p16 and p15 in 11 (78%) and 6 (43%) cell lines, respectively. Conclusions The present data shows the presence of methylation does not always contribute to the loss of expression of tumor suppressor genes. Therefore, we must be cautious in interpreting the results of methylation assays—in particular, detection of methylation by nonquantitative methods. The data also demonstrated that multiple tumor suppressor genes are simultaneously inactivated in renal cell carcinoma-derived cell lines by distinctive mechanisms.

Aims: Glial cell-line derived neurotrophic factor (GDNF) and related factors neurturin (NRTN), artemin, and persephin are members of the GDNF family of neurotrophic factors. GDNF and NRTN bind to the tyrosine kinase receptor Ret and the receptors GFRα1 and GFRα2. The objective was to examine the developmental expression of GDNF, NRTN, and their receptors within the rat urinary bladder. Methods: Rat bladders dissected from embryonic day (E) 15, postnatal day (P) 0, P14, P28, and adult rats (P60) were investigated by semiquantitative reverse transcriptase polymerase chain reaction. Embryos (E15, E16, and E17) were immunohistochemically stained for neurofilament. Results: GDNF and Ret mRNA levels at E15 were the highest of all the stages we examined and then immediately decreased. In contrast, NRTN mRNA levels did not change between E15 and postnatal day 14; thereafter, they gradually but insignificantly increased. GFRα1 and GFRα2 mRNA levels were high at E15, after which their signal intensities decreased. In whole-mounted specimens, neurofilament-positive axons were first detected in the bladder at E16. Conclusions: Our results suggest that GDNF and NRTN may act as trophic factors for neural in-growth to the bladder and/or for the maintenance of mature neurons innervating the bladder. These factors might also be involved in bladder morphogenesis. Neurourol. Urodynam. 22:83–88, 2003. © 2003 Wiley-Liss, Inc.

Organic light emitting diodes (OLEDs) containing cathode buffer layers of nanometer thickness were fabricated and their electrical and emitting properties were investigated. The OLEDs have an indium tin oxide (ITO) anode/ copper phthalocyanine (CuPc) / N, N'-dephenyl-N,N'-bis(3-methylphenyl)-1,1'-diphenyl-4,4'-diamine (TPD) / 8- hydroxyquinoline aluminum (Alq3) / buffer layer / Al cathode structure with the buffer layers made from alternating thin films of Alq3 and Al with nanometer thickness. Improvement of driving voltage and the efficiency for the devices were observed by insertion of the buffer layer. It was estimated that some modulations of the Schottky barrier at the Alq3 and the Al cathode interface were induced due to the insertion of the buffer layer and it caused an enhancement of electron injection from the Al cathode. A model of the band structure at the buffer layer was proposed.

Emission light from Ag/ Rhodamine-B (RB) Langmuir-Blodgett (LB) films due to surface plasmon (SP) excitations has been investigated using the Kretschmann configuration of the attenuated total reflection (ATR) method and the reverse irradiation of laser beam from air to the samples. The conventional photoluminescence (PL) of the RB LB films showed a broad spectrum and the peak wavelength was about 600 nm. In the reverse irradiation, emission light was observed through the prism, and the intensities and the spectra strongly depended upon the emission angle where the light was observed. The wavelengths of the emission light became shorter as the emission angles increased. The relation between the wavelength and the emission angle agreed with the resonant condition of excitations of SPs in the Kretschmann configuration of ATR method. It was concluded that the emission light was caused by excitations of multiple SPs at the Ag/RB LB films.

In this paper, we introduce a useful composite layer, comprising hole-transporting materials with molybdenum oxide. By using the composite as a buffer layer on an anode, an OLED with low drive voltage can be obtained, and pixel defect formation can be effectively suppressed.

Fabrication of surface relief gratings (SRGs) on azo dye thin films has been investigated utilizing an interference of evanescent waves. SRGs of approximately 210 nm were inscribed on the photoisomerized azo dye films, that were smaller than a half wavelength of an incidence laser of 488.0 nm. The films were set on a right-angled triangular prism surface and were in the interference of evanescent waves of totally reflected laser beams at the prism surface. The interference at the surface was performed using a laser beam through the one side of the isosceles and the returned beam at the other side of the isosceles where a mirror was set. The SRG patterns of azo dye films due to trans–cis transition of the dyes were observed in situ using an atomic force microscope above the prism surface.

Surface plasmon (SP) emission light has been investigated for rhodamine-B (RB) dye Langmuir-Blodgett (LB) films on silver (Ag) thin film in the attenuated total reflection (ATR) Kretschmann configuration by means of reverse irradiation of a laser beam. Emission light through the prism was clearly observed for the configuration of prism/Ag/LB films corresponding to the resonant excitation conditions for SPs using the reverse irradiation. The intensities of the SP emission light increased with the thickness of the RB LB films, but nonlinear reductions of the SP emission light and photoluminescence (PL) were observed due to nonradiative energy transfer at the very small separations between the RB and Ag films. It is thought that the SPs, that is, two-dimensional optical waves, are excited by PL of the RB dyes on the Ag film and that this phenomenon is very useful for applications utilizing dye molecules on metal thin films.

We examined a case of lateral cervical cyst in the right lateral cervical region of a 39-year-old male. The cyst was surgically removed under general anesthesia.According to Bailey's classification, this case was considered to be Type II Histopathologically, the inner wall of the cyst was covered by the squamous epithelium, and the lymphatic tissue was observed below the epithelium. Biochemically, the cyst content showed high activities of γ-GPT, GOT, LDH, and amylase. In this case it was considered that the cells from salivary glands were secreting high amylase in the cyst wall.

Recently, low power density lasers have been used in dental and oral surgical treatments. We had an experience of using low power density He-Ne laser (Soft laser 632 by Mainfar Co.) on stellate ganglion. We evaluated the clinical effect of the low power density He-Ne laser irradiation by thermograph “TVS-4300 ME”.It seemed that the effect of relieving pain was result of laser irradiation.

We reported a rare case of malignant fibrous histiocytoma (MFH) of the left maxilla in a 76-year-old woman. The tumor destroyed the alveolar bone of the left maxilla. Moreover, it not only filled the left maxillary sinus but also invaded its surrounding walls. The tumor was diagnosed histologically as MFH. After surgical removal of the tumor, it recurred in seven weeks. The patient died about a year after her first examination.

Emission light through the prism has been investigated from the Kretschmann configuration of the prism/ Ag thin film/ rhodamine-B (RB) LB film in the resonant excitation of the attenuated total reflection (ATR) measurement. The emission light and the spectra strongly depended upon the emission angles where the light was observed. The emission properties corresponded to the dispersion relation of the resonant excitations of surface plasmons (SPs) in the ATR configuration. It was concluded that the emission light was caused by multiple excitations of SPs in the ATR configuration. It is thought that the phenomenon will be used as a new sensing device.