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Patient profiles suitable for long-term lenvatinib treatment for unresectable hepatocellular carcinoma (uHCC) are yet to be fully understood. This post-hoc analysis aimed to identify such patient characteristics and explore the impact of treatment duration and relative dose intensity (RDI) on treatment outcomes. The data were obtained from 703 patients in a multicenter, prospective cohort study in Japan. Lenvatinib-naïve patients with uHCC were enrolled between July 2018 and January 2019 and were followed up for 12 months. Moreover, patients were dichotomized using the median treatment duration into the longer- (≥177 days; n = 352) or shorter-treatment (<177 days; n = 351) groups. The longer-treatment group often had better performance status, lower Child-Pugh score and better modified albumin-bilirubin grade than the shorter treatment group (p<0.05 for all). The objective response rate (47.6% vs. 28.2%; p<0.001) and disease control rate (92.4% vs. 60.2%; p<0.001) were both significantly higher in the longer-treatment groups than in the shorter-treatment groups. The proportion of patients with any adverse drug reactions was generally similar between the two treatment groups. Within the longer-treatment group, the disease control rate was high regardless of dose modification (i.e., RDI <100% vs. ≥100% during the initial 177 days) (91.2% vs. 98.0%). In conclusion, patients with longer treatment tended to have better overall conditions. Lenvatinib dose modifications at the physician's discretion, considering the balance between effectiveness and safety, may contribute to the long-term treatment., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Tatsuya Yamashita has received travel grants and honoraria for speaking or participation at meetings from Chugai Pharma, Eli Lilly Japan, and Eisai. Natsumi Suzuki, Katsuaki Motoyoshi, and Wanjun Zhu are employees of Eisai Co., Ltd. Junji Furuse received research grants from Astellas, Astra Zeneca, Incyte Biosciences Japan, Eisai, MSD, Ono Pharmaceutical, Sanofi, J-Pharma, Daiichi Sankyo, Sumitomo Dainippon, Taiho Pharmaceutical, Takeda, Delta-Fly-Pharma, Chugai Pharma. He has received travel grants and honoraria for speaking or participation at meetings from Ono Pharmaceutical, Chugai Pharma, Incyte Biosciences Japan, Eisai, Eli Lilly Japan, Astra Zeneca, Yakult Honsha, Servier Japan, MSD, Novartis Pharma, Takeda, Bayer, Taiho Pharmaceutical, EA Pharma, Teijin pharma, Daiichi Sankyo, Terumo, Fuji film, Astellas, Onco Therapy Science, Delta-Fly-Pharma, Merck Bio, Incyte Biosciences Japan, J-Pharma. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Yamashita et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Lenvatinib was approved for use in unresectable hepatocellular carcinoma (uHCC) in Japan in 2018. Patients with diverse clinical characteristics receive lenvatinib treatment in clinical practice. Thus, it is crucial to evaluate the safety and effectiveness of lenvatinib in real-world clinical settings., Objective: This study aimed to evaluate the real-world safety and effectiveness of lenvatinib for uHCC in clinical practice in Japan., Patients and Methods: Between July 2018 and January 2019, patients with uHCC who were administered lenvatinib for the first time were enrolled in this prospective, multicenter, observational post-marketing study (NCT03663114). Patients were orally administered lenvatinib and followed up for 12 months. For safety, adverse drug reactions (ADRs) were evaluated. For effectiveness, the objective response rate (ORR) was calculated to evaluate tumor response. Overall survival (OS) was estimated using the Kaplan-Meier method., Results: Data of 703 patients (median age, 73 years; 80.2% males) were analyzed. The median (range) treatment duration was 25.3 (0.3-68.9) weeks. The mean ± standard deviation initial dose was 7.37 ± 1.65 mg in patients with body weight < 60 kg and 10.43 ± 2.49 mg in those with body weight ≥ 60 kg. ADRs (any grade) were reported in 84.9% of the patients, with Grade ≥ 3 ADRs reported in 42.5% of the patients. The most common ADRs (> 10%) were decreased appetite, fatigue, hypertension, proteinuria, palmar-plantar erythrodysesthesia, hypothyroidism, and diarrhea. The median OS of the 703 patients was 498.0 days. In 494 patients assessed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST), the ORR was 39.5% (95% confidence interval: 35.1-43.9%). Patients with better liver or renal function at baseline achieved significantly higher ORR than those with worse liver or renal function., Conclusions: In patients with uHCC in real-world clinical practice in Japan, treatment with lenvatinib was generally well tolerated, and no new safety concerns were identified. The ORR and median OS were similar to or better than the results of the Japanese subset of the global Phase III REFLECT trial. Our results demonstrated that clinically meaningful treatment responses were achieved with lenvatinib in real-world clinical practice., (© 2023. The Author(s).)

Objective: Edoxaban is sometimes given at reduced doses when used concomitantly with physical prophylaxis to prevent symptomatic venous thromboembolism (VTE) after total hip arthroplasty (THA). This study aimed to evaluate the safety of reduced doses of edoxaban administered independent of the dose-reduction criteria and their effects on D-dimer levels after THA in Japanese patients., Materials and Methods: This study enrolled 22 patients who received edoxaban 30 mg/day and 45 patients who received edoxaban 15 mg/day with dose adjustment as a standard-dose group, and 110 patients who received edoxaban 15 mg/day without dose adjustment as a low-dose group. The incidence of bleeding events was then compared between groups with patients wearing elastic stockings. Multivariate regression analysis was also performed to examine the effect of edoxaban administration on D-dimer levels after THA., Results: The incidence of bleeding events after THA did not differ significantly between groups. In the multivariate model, dose reduction of edoxaban did not correlate with D-dimer levels on postoperative days 7 and 14, but higher D-dimer levels at postoperative days 7 and 14 correlated significantly with longer duration of surgery (odds ratio (OR) 1.66, 95% confidence interval (CI) 1.20 - 2.29, p = 0.002; OR 1.63, 95% CI 1.17 - 2.29, p = 0.004, respectively)., Conclusion: These results suggest that information on the duration of surgery may be useful in the pharmaceutical management in edoxaban drug prophylaxis combined with physical prophylaxis after THA in Japanese patients.

Sphingolipids (SLs), such as ceramide, glucosylceramide (GlcCer), and sphingomyelin, play important roles in the normal development/functions of the brain and peripheral tissues. Disruption of SL homeostasis in cells/organelles, specifically up-regulation of ceramide, is involved in multiple diseases including Alzheimer's disease (AD). One of the pathological features of AD is aggregates of amyloid beta (Aβ) peptides, and SLs regulate both the formation/aggregation of Aβ and Aβ-induced cellular responses. Up-regulation of ceramide levels via de novo and salvage synthesis pathways is reported in Aβ-treated cells and brains with AD; however, the effects of Aβ on ceramide decomposition pathways have not been elucidated. Thus, we investigated the effects of the 25-35-amino acid Aβ peptide (Aβ 25-35 ), the fundamental cytotoxic domain of Aβ, on SL metabolism in cells treated with the fluorescent nitrobenzo-2-oxa-1,3-diazole-labeled C6-ceramide (NBD-ceramide). Aβ 25-35 treatment reduced the formation of NBD-GlcCer mediated by GlcCer synthase (GCS) without affecting the formation of NBD-sphingomyelin or NBD-ceramide-1-phosphate, and reduced cell viability. Aβ 25-35 -induced responses decreased in cells treated with D609, a putative inhibitor of sphingomyelin synthases. Aβ 25-35 -induced cytotoxicity significantly increased in GCS-knockout cells and pharmacological inhibition of GCS alone demonstrated cytotoxicity. Our study revealed that Aβ 25-35 -induced cytotoxicity is at least partially mediated by the inhibition of GCS activity.

Sphingolipids represent a family of cellular lipid-molecules that regulate physiological and pathophysiological processes. Glucosylceramide (GlcCer), the simplest glycosphingolipid (GSL), is synthesized from ceramide and UDP-glucose by GlcCer synthase (GCS). Both GlcCer (and resulting GSLs) and ceramide regulate various cellular functions including cell death and multiple drug resistance. Src family tyrosine kinases are up-regulated in various human cancer cells. We examined the effect of v-Src expression on GCS activity, the formation of 4-nitrobenzo-2-oxa-1,3-diazole (NBD)-labeled GlcCer from NBD-ceramide, and the effect of tyrosine 132 mutation in GCS on ceramide-induced cytotoxicity in HeLa cells. Expression of v-Src increased the formation of NBD-GlcCer in both intact cells without marked changes in other sphingolipid metabolites and cell homogenates without changing affinities of NBD-ceramide and UDP-glucose. Expression of v-Src also increased tyrosine-phosphorylated levels in GCS proteins in HeLa and HEK293T cells. In HEK293T cells transiently expressing the GCS mutant, GCS-Y132F-HA, showing replacement of the tyrosine 132 residue with phenylalanine, tyrosine-phosphorylated levels in GCS proteins were significantly lower than those in control cells expressing the GCS-wild-type-HA. The formation of NBD-GlcCer in HeLa cells stably expressing GCS-Y132F-HA was significantly lower than that in the control. Ceramide-induced cytotoxicity in HeLa-GCS-Y132F-HA cells was significantly greater than in the control. In this study, we showed for the first time that expression of v-Src up-regulated GCS activity via tyrosine phosphorylation of the enzyme in a post-translational manner. Mechanisms of Src-induced resistance to ceramide-induced cytotoxicity are discussed in relation to the Src-induced up-regulation of GCS activity., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Invariant natural killer T (iNKT) cells are innate-like CD1d-restricted T cells that express the invariant T cell receptor (TCR) composed of Vα24 and Vβ11 in humans. iNKT cells specifically recognize glycolipid antigens such as α-galactosylceramide (αGalCer) presented by CD1d. iNKT cells show direct cytotoxicity toward CD1d-positive tumor cells, especially when CD1d presents glycolipid antigens. However, iNKT cell recognition of CD1d-negative tumor cells is unknown, and direct cytotoxicity of iNKT cells toward CD1d-negative tumor cells remains controversial. Here, we demonstrate that activated iNKT cells recognize leukemia cells in a CD1d-independent manner, however still in a TCR-mediated way. iNKT cells degranulated and released Th1 cytokines toward CD1d-negative leukemia cells (K562, HL-60, REH) as well as αGalCer-loaded CD1d-positive Jurkat cells. The CD1d-independent cytotoxicity was enhanced by natural killer cell-activating receptors such as NKG2D, 2B4, DNAM-1, LFA-1 and CD2, but iNKT cells did not depend on these receptors for the recognition of CD1d-negative leukemia cells. In contrast, TCR was essential for CD1d-independent recognition and cytotoxicity. iNKT cells degranulated toward patient-derived leukemia cells independently of CD1d expression. iNKT cells targeted myeloid malignancies more than acute lymphoblastic leukemia. These findings reveal a novel anti-tumor mechanism of iNKT cells in targeting CD1d-negative tumor cells and indicate the potential of iNKT cells for clinical application to treat leukemia independently of CD1d., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Magnetic resonance imaging (MRI) enables the evaluation of organ structure and function. Oxygen-enhanced MRI (O2-enhanced MRI) is a method for evaluating the pulmonary ventilation function using oxygen as a contrast agent. We created the Cine View of Relative Enhancement Ratio Map (Cine RER map) in O2-enhanced MRI to easily observe the contrast effect for clinical use. Relative enhancement ratio (RER) was determined as the pixel values of the Cine RER map. Moreover, six healthy volunteers underwent O2-enhanced MRI to determine the appropriate scale width of the Cine RER map. We calculated each RER and set 0 to 1.27 as the scale width of the Cine RER map based on the results. The Cine RER map made it possible to observe the contrast effect over time and thus is a convenient tool for evaluating the pulmonary ventilation function in O2-enhanced MRI.

A frequency-resolved optical gating (FROG) technique that combines autocorrelation (second-harmonic-generation FROG, SHG-FROG) and cross correlation FROG (XFROG) is reported for simultaneous characterization of two unknown optical pulses. Two SHG-FROG signals and a XFROG signal are acquired in a single measurement using a single diagnostic system. Unlike the conventional combination of SHG-FROG for reference-pulse characterization and XFROG for test-pulse characterization, the ambiguity in the direction of time in SHG-FROG is removed during phase retrieval by simultaneously analyzing the three FROG signals. Furthermore, overall characterization is faster, more robust, and highly convergent than the conventional combination of SHG-FROG and XFROG techniques.

We compared age-related changes in the intrinsic laryngeal muscles of aged and young adult rats by determining the number and diameter of muscle fibers, contractile muscle protein (myosin heavy chain isoforms, MHC) composition, and the morphology of the subneural apparatuses. In aged rats, both the numbers and the diameters of muscle fibers decreased in the cricothyroid (CT) muscle. The number of fibers, but not diameter, decreased in the thyroarytenoid (TA) muscle. In the posterior cricoarytenoid (PCA) muscle, neither the number nor the diameter of fibers changed significantly. Aging was associated with a decrease in type IIB and an increase in type IIA MHC isoform levels in CT muscle, but no such changes were observed in the TA or PCA muscles. Morphological examination of primary synaptic clefts of the subneural apparatus revealed that aging resulted in decreased labyrinthine and increased depression types in only the CT muscle. In the aged group, morphologically immature subneural apparatuses were found infrequently in the CT muscle, indicating continued tissue remodeling. We suggest, therefore, that age-related changes in the intrinsic laryngeal muscles primarily involve the CT muscle, whereas the structures of the TA and PCA muscles may better resist aging processes and therefore are less vulnerable to functional impairment. This may reflect differences in their roles; the CT muscle controls the tone of the vocal folds, while the TA and PCA muscles play an essential role in vital activities such as respiration and swallowing.

To study the effects of M-CSF administration on long-term outcomes of unrelated BMT, we retrospectively analyzed data from patients transplanted through the Japan Marrow Donor Program. We obtained data from 54 patients who received M-CSF just after BMT and 500 patients who did not receive M-CSF or G-CSF acted as controls. There were no significant differences between the two cohorts with respect to OS, acute GVHD or relapse. Although the incidence of chronic GVHD was comparable between the two groups, extensive chronic GVHD was observed significantly less often in the M-CSF cohort than in the control group. Multivariate analysis identified M-CSF as a significant factor for attenuating extensive chronic GVHD (relative risk: 0.73; 95% confidence interval: 0.55-0.94; P=0.012). We also found the same results in matched-pair analysis. Our observation suggests the potential for clinical use of M-CSF to dampen severe chronic GVHD.

Purpose: We assessed the wait time of non-contrast renal artery magnetic resonance (MR) angiography with a single breath hold using inflow inversion recovery-fan shaped inward outward view ordering technique in normal volunteers., Methods: The wait time (WT)-the duration between the data acquisition and the following inversion recovery pulse-was varied from 10 ms to 2000 ms, and the contrast ratio between the renal artery and the background structures for each WT was assessed quantitatively. A simulation was also performed., Results: The contrast ratio between the renal artery and each background structure with 2000 ms of WT was higher than that with 10 ms of WT. The contrast ratio between the renal artery and renal cortex with 1500 ms of WT was also higher than that with 10 ms of WT. In the simulation, when WT lengthened, the residual longitudinal magnetization of each background structure lowered., Conclusion: The WT affects contrast; adjustment of WT should be added to the assessment of the imaging parameter.

Objective: To characterize the long-term adverse effects of radiotherapy on the ears in patients with nasopharyngeal carcinoma (NPC), we investigated ipsilateral and contralateral ototoxicities in the external, middle, and inner ear., Methods: The records of 48 ears in 24 radiotherapy-treated NPC patients were retrospectively analyzed. Radiotherapy doses varied between 60 and 70 Gy in 2-Gy fractions at 5 fractions/week. Ototoxicities were identified by otoscope and pure-tone audiograms conducted at 2-3 month intervals for ≥12 months. The relationship between radiation dosage and sensorineural threshold deterioration was statistically compared using the Mann-Whitney U-test., Results: Post-radiotherapy, 50% of all ears (3 of 6) that developed severe otitis externa were on the contralateral side. There was a post-radiotherapy increase in contralateral otitis media with effusion (OME) (1-7 ears), but a decrease in ipsilateral cases (16-12 ears), with 2 ears on either side subsequently developing chronic otitis media (COM). All ears that showed sensorineural hearing loss (SNHL) before radiotherapy exhibited a further threshold deterioration of more than 15 dB. No statistically significant difference (p=0.086) in average radiation dose was seen between ears with sensorineural threshold deterioration (50.0 Gy) and those without (48.2 Gy)., Conclusion: Long-term ototoxicity following radiotherapy for NPC can occur in either the ipsilateral or contralateral ears. Pathophysiology varies between and within each side. The post-therapy increase in OME on the contralateral side was thought to be due to radiotherapy-induced Eustachian tube damage, and the sensorineural threshold deterioration in at least 4 ears was thought to be due to chronic cochlea damage secondary to COM., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Macrophage colony-stimulating factor (M-CSF) regulates the production, survival and function of macrophages through Fms, the receptor tyrosine kinase. Recently, interleukin-34 (IL-34), which shares no sequence homology with M-CSF, was identified as an alternative Fms ligand. Here, we provide the first evidence that these ligands indeed resemble but are not necessarily identical in biological activity and signal activation. In culture systems tested, IL-34 and M-CSF showed an equivalent ability to support cell growth or survival. However, they were different in the ability to induce the production of chemokines such as MCP-1 and eotaxin-2 in primary macrophages, the morphological change in TF-1-fms cells and the migration of J774A.1 cells. Importantly, IL-34 induced a stronger but transient tyrosine phosphorylation of Fms and downstream molecules, and rapidly downregulated Fms. Even in the comparison of active domains, these ligands showed no sequence homology including the position of cysteines. Interestingly, an anti-Fms monoclonal antibody (Mab) blocked both IL-34-Fms and M-CSF-Fms binding, but another MAb blocked only M-CSF-Fms binding. These results suggested that IL-34 and M-CSF differed in their structure and Fms domains that they bound, which caused different bioactivities and signal activation kinetics/strength. Our findings indicate that macrophage phenotype and function are differentially regulated even at the level of the single receptor, Fms.

Block copolymer nanopaticles were prepared from the mixture solutions containing good/poor solvents by a simple evaporation process. The block copolymers formed disorder, unidirectionally stacked lamellar, and onion-like structures in nanoparticles depending on preparation temperatures. Thermal annealing induced the disorder-order phase transition and order-order phase transformation in the block copolymer nanoparticles, even though the annealing temperature is lower than the of one polymer segment. The unusual thermal behaviors suggest that the glass transition temperature of the block copolymer is decreased by the effect of nanoparticle, whose surface areas are larger than their volumes., (Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This paper describes the first preparation of diblock-copolymer blend particles with hierarchical inner structures. AB/AC type diblock-copolymer blend particles were successfully prepared by a simple solvent evaporation method. The inner phase separation structures can be controlled by changing the molecular weight combinations of common polymer segments. Furthermore, the one-to-one blend of two diblock-copolymers formed Janus particles with two different domains of microphase separation. Pd ions were successfully introduced into the particles with the onion-like structure. These organic-inorganic composite particles can be used as a novel class of nanomaterials applicable to photonics and electronics.

Au nanoparticles (NPs) and polymer composite particles with phase-separation structures were prepared based on phase separation structures. Au NPs were successfully synthesized in amphiphilic block-copolymer micelles, and then composite particles were formed by a simple solvent evaporation process from Au NPs and polymer solution. The phase separated structures (Janus and Core-shell) were controlled by changing the combination of polymers having differing hydrophobicity., (Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

HIV-1 Nef accelerates the progression to AIDS by binding with and activating a Src kinase Hck, but underlying molecular basis is not understood. We revealed that Nef disturbed N-glycosylation/trafficking of a cytokine receptor Fms in an Hck-dependent manner, a possible trigger to worsen uncontrolled immune system. Here, we provide direct evidence that dys-regulated activation of Hck pre-localized to the Golgi apparatus causes this Fms maturation arrest. A striking change in Hck induced by Nef other than activation was its skewed localization to the Golgi due to predominant Golgi-localization of Nef. Studies with different Nef alleles and their mutants showed a clear correlation among higher Nef-Hck affinity, stronger Hck activation, severe Golgi-localization of Hck and severe Fms maturation arrest. Studies with a newly discovered Nef-Hck binding blocker 2c more clearly showed that skewed Golgi-localization of active Hck was indeed the cause of Fms maturation arrest. 2c blocked Nef-induced skewed Golgi-localization of an active form of Hck (Hck-P2A) and Fms maturation arrest by Nef/Hck-P2A, but showed no inhibition on Hck-P2A kinase activity. Our finding establishes an intriguing link between the pathogenesis of Nef and a newly emerging concept that the Golgi-localized Src kinases regulate the Golgi function.

The mechanism that is responsible for mature neutrophil overproduction in the chronic phase (CP) of chronic myeloid leukemia (CML), a neoplastic disease of hematopoietic stem cells carrying a constitutively active tyrosine kinase BCR-ABL, remains obscure. In this study, microarray analysis revealed that c-Jun, a monopoiesis-promoting transcription factor, was downregulated in CML neutrophils. BCR-ABL directly inhibited c-Jun expression, as c-Jun downregulation in primary CML neutrophils and in the CML blast cell lines, KCL22 and K562, was reversed by the tyrosine kinase inhibitor imatinib. We established a myeloid differentiation model in KCL22 cells using zinc-inducible CCAAT/enhancer-binding protein (C/EBP)alpha (KCL22/alpha). Myeloid differentiation was observed in C/EBP-induced KCL22/alpha cells. Imatinib-induced c-Jun upregulation promoted the monocytic differentiation of KCL22/alpha cells. c-Jun knockdown in KCL22/alpha cells by a short interfering RNA redirected their differentiation from the monocytic to the neutrophilic lineage, even after imatinib treatment. A blockade of PI3K-Akt signaling with an Akt inhibitor upregulated c-Jun and induced the monocytic differentiation of KCL22, K562, and C/EBP-induced KCL22/alpha cells. Thus, BCR-ABL downregulates c-Jun expression by activating the PI3K-Akt pathway during CML-CP, thereby allowing C/EBPs to promote neutrophil differentiation.

Background: Endobronchial aspergillosis is still an insufficiently recognized concept., Patients and Methods: Ten patients who did not have obvious predisposing factors and parenchymal fungal infection were analyzed. They were confirmed to have endobronchial Aspergillus by histology and culture, and were classified according to the presence of bronchiectasis, allergic reaction, and asthmatic symptom., Results: Bronchiectasis was detected in all 10 patients, IgE elevation (>370 IU/ml) in 7, Aspergillus specific IgE-RAST in 8, eosinophilia in 7, and asthmatic symptom in 5. Cases were classified into allergic bronchopulmonary aspergillosis (ABPA) (5 cases), ABPA not fulfilling Rosenberg's criteria (2 cases), and endobronchial aspergilloma (3 cases)., Conclusion: We proposed classifying endobronchial aspergillosis without obvious systemic predisposing factors into "ABPA", "ABPA without asthma", "ABPA-S (seropositive)", and "Endobronchial aspergilloma". A fifth subtype of endobronchial aspergillosis containing "saprophyte" is warranted.

We report a tracheobronchial pulmonary manifestation caused by pyoderma gangrenosum, a neutrophilic dermatosis of unknown etiology. A 54-year-old man presented with pulmonary infiltrates followed by multiple painful cutaneous pustules on the scrotum. Skin biopsy showed pronounced neutrophilic infiltration without microorganism or granuloma, consistent with pyoderma gangrenosum. Bronchoscopy revealed multiple scattered polypoid nodules with a yellowish irregular surface from the trachea to bilateral bronchi; the appearance closely mimicked that of a skin lesion. Endobronchial biopsy demonstrated inflamed granulation and necrosis with infiltration by numerous neutrophils without vasculitis or granulomas, interpreted as pyoderma gangrenosum of the bronchi. Although the etiology of pyoderma gangrenosum is poorly understood, this case suggests that a common pathogenesis may account for the simultaneous cutaneous and airway inflammation.

Bronchoscopic lung-volume reduction for hyperinflated air-trapping disease is currently being investigated. A 41-year-old woman with pulmonary lymphangioleiomyomatosis presented with exertional dyspnea. A chest computed tomographic scan showed hyperinflation with diffuse cystic lesions throughout both lung fields. To reduce lung volume, transbronchial autologous blood was followed by thrombin solution, which was infused into cystic areas under fluoroscopic guidance. A post-treatment computed tomographic scan showed volume reduction corresponding to decreased total lung capacity by 240 mL on body plethysmography. Dyspnea was significantly improved. Bronchoscopic treatment by blood infusion is less invasive and appears clinically valuable, potentially providing therapeutic benefit in hyperinflated lung diseases such as lymphangioleiomyomatosis.

Imatinib mesylate is very effective in the treatment of chronic myelogenous leukemia (CML) and 400 mg/day imatinib is considered the standard treatment dose for chronic-phase (CP) patients. However, despite its relative tolerability, some patients require a lower dosage or temporary cessation of treatment because of severe adverse events. It remains unclear whether reduced-dose imatinib is as effective as the standard dose in achieving and maintaining a major molecular response (MMolR), an important goal of imatinib therapy. In this study, Japanese patients with CML-CP, as classified by their Sokal scores, were treated with imatinib. MMolR was observed in all patients with low Sokal scores who were treated with 300 or 400 mg/day imatinib, suggesting that low scores predict favorable response to treatment even at lower dosages, which is preferable since it is associated with fewer adverse events. Low-dose therapy also achieved MMolR in patients with intermediate or high scores. However, loss of complete cytogenetic response (CCgR) or an increase in BCR-ABL transcripts was noted shortly after these patients achieved CCgR, suggesting that a CCgR short of MMolR still indicated a risk of loss of response in these risk categories. MMolR was maintained in these patients by timely increases in dosage. Achieving CCgR within 12 months and maintaining it without an increase in BCR-ABL transcripts might indicate that low-dose imatinib therapy can produce acceptable outcomes without excess toxicity.

Objectives: Laterofixation of the vocal fold is a simple and reliable surgical intervention for laryngeal obstruction due to bilateral vocal fold fixation to obtain sufficient glottal space. Nevertheless, it has some technical disadvantages. This report summarizes the surgical outcomes in patients who underwent laterofixation of the vocal fold with or without the use of an endo-extralaryngeal needle carrier (EENC)., Methods: A prospective study of 11 consecutive patients with bilateral vocal fold paralysis. All of the patients underwent unilateral vocal fold laterofixation. Six patients were assigned to the non-EENC group and five to the EENC group. The surgical outcomes were evaluated, including the operating time and respiratory and phonatory functions., Results: The operating time was 44% shorter in the EENC group and less skin incisions were required. Postoperatively, the dyspnea was eliminated in all of the patients in both groups, and the six patients who required a tracheotomy were successfully decannulated. Spirometry confirmed the improvements in %FEV(1) and %PEF in the two groups. Postoperative voice function was socially acceptable in all patients, and it tended to be better in the non-EENC group. In the EENC group, one patient developed a minor submucosal hematoma and another patient had a recurrence of dyspnea 2 months postoperatively, probably due to thread disruption., Conclusion: The present study confirms that laterofixation of the vocal fold with or without EENC relieves laryngeal obstruction. Surgery with the EENC is simpler and quicker than the conventional procedure. However, the surgery with the EENC has some disadvantages, including likely problems with the thread and downward traction on the vocal fold. Surgeons should be aware of these possible shortcomings.

Divide and conquer: Polymer nanoparticles with phase-separation structures prepared with block copolymers and homopolymer blends were used to fabricate unique suprapolymer structures by cross-linking one polymer moiety and dissolving the other (see scheme; PI = polyisoprene, PSt = polystyrene).

A 65-year-old woman whose parents were from Okinawa Prefecture, had productive cough and bilateral diffuse nodular lesions on chest X-ray. She had been shown a human T-cell lymphotropic virus type-1 (HTLV-1) carrier. Video-assisted thoracoscopic lung biopsy showed marked peribronchiolar infiltration of lymphocytes and stenosis of bronchioles. HTLV-1 associated bronchiolo-alveolar disorder (HABA) was diagnosed. The symptoms, hypoxemia and chest X-ray findings improved with oral erythromycin. However, expiratory chest CT showing mosaic perfusion, pulmonary function test demonstrating increased thoracic gas volume, and ventilation scintigraphy resulting in decreased clearance during 8 years, all of those findings indicated progression of air trapping. Abnormalities on chest CT partially improved, but bronchiolar lesions have deteriorated. Expiratory chest CT, body phlethysmography and ventilation scintigraphy were recommended to clarify the course of HABA.

We report a case of bird-related chronic hypersensitivity pneuminitis exhibiting the fluctuation of serum markers for interstitial lung disease along with the changes in life environment. A 65-year-old man had had an abnormal chest radiograph for 2 years and had complained of a non-productive cough. He had had 30 parakeets 20 years previously and had used feather products for 15 years. In autumn and early winter wild birds had visited persimmons trees in the neighboring garden. Antibodies to bird-related antigens in the broncho-alveolar lavage fluids and sera were positive and the thoracoscopic lung biopsy specimens histologically revealed airway-centered fibrosis. We then determined he was having bird-related chronic hypersensitivity pneumonitis. After avoidance of feather products, all of serum SP-A, SP-D and KL-6 decreased. But three markers elevated and radiographic findings worsened accompanied with the increase of visiting wild birds in next autumn. After pruning persimmon trees and starting corticosteroid with cyclosporine, disease activity gradually improved.

Background: GM1 and GalNAc-GD1a are located on the axolemma of the motor nerves and are believed to be the antigens associated with pure motor Guillain-Barré syndrome (GBS). Furthermore, GM1 and GalNAc-GD1a may exist nearby and colocalize on the axolemma. Ganglioside complex (GSC) antigens associated with GM1 or GalNAc-GD1a can be target antigens in pure motor GBS. We investigated GBS sera for antibodies to a GSC consisting of GM1 and GalNAc-GD1a (GM1/GalNAc-GD1a) and analyzed the clinical and electrophysiologic findings of patients with antibodies to GM1/GalNAc-GD1a., Methods: Sera from 224 patients with GBS were surveyed for antibodies to GSCs consisting of two of nine gangliosides (GM1, GM2, GM3, GD1a, GD3, GT1a, GT1b, GQ1b, and GalNAc-GD1a). We analyzed the clinical and electrophysiologic features of patients with IgG antibodies to the GM1/GalNAc-GD1a complex., Results: Ten patients with GBS had IgG antibodies to the GM1/GalNAc-GD1a complex. The clinical findings of the 10 patients with GBS were characterized by preserved sensory system and infrequent cranial nerve deficits. According to the criteria established by Hadden et al., electrodiagnostic studies showed a demyelinating pattern in four patients and axonal neuropathy pattern in two. Early motor conduction block at intermediate nerve segments was found in five patients., Conclusions: GM1 and GalNAc-GD1a may form a complex in the axolemma at nodes of Ranvier or paranodes of the motor nerves, and may be a target antigen in pure motor Guillain-Barré syndrome, especially in the form of acute motor conduction block neuropathy.

Background: Although the AB0 blood group is one of two major antigen systems of relevance for transplantation in humans, there are still conflicting data concerning the influence of AB0 incompatibility on transplant outcome. This study investigated the effect of AB0 incompatibility in recipients of bone marrow transplants from unrelated donors., Design and Methods: We retrospectively analyzed data from 5,549 patients who underwent bone marrow transplantation from unrelated donors in the Japan Marrow Donor Program., Results: Overall survival rates in the group with major and minor mismatches were significantly lower than the rate in the AB0-identical group (AB0-identical 63.0%; major mismatch, 56.9%; minor mismatch, 57.1% at 1 year). Treatment-related mortality was higher in the major and minor mismatch groups, but there was no significant difference in the rate of relapse. Cox proportional hazards modeling showed that both major and minor AB0 incompatibility were significant risk factors for transplant-related mortality, independently of disease, patients' age, and HLA incompatibility. Delayed engraftment of neutrophils, platelets, and erythrocytes was observed in transplants with major incompatibility. There was a high incidence of grade 3 and 4 acute graft-versus-host disease in the groups with major and minor mismatches, which was caused by a high incidence of stage 2 to 4 liver graft-versus-host disease. Interestingly, the risk of grade 2 to 4 graft-versus-host disease in the major mismatch group was higher in patients with early engraftment of erythrocytes. Among the patients receiving reduced-intensity conditioning, the transplant-related mortality was also increased in AB0-incompatible transplants., Conclusions: Major and minor AB0 incompatibility have specific effects on transplant-related mortality and acute graft-versus-host disease in recipients of bone marrow transplants from unrelated donors.

Background: Serum antibodies to GQ1b are associated with Miller Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS) with ophthalmoplegia. Antibodies to ganglioside complexes (GSCs) have not yet been examined in a large population of patients with MFS or GBS. This study aimed to determine the clinical significance of antibodies to GSCs in MFS and GBS., Methods: The study investigated serum anti-GSC antibodies and the clinical features in 64 MFS patients, 53 GBS patients with ophthalmoplegia (GBS-OP(+)) and 53 GBS patients without ophthalmoplegia (GBS-OP(-))., Results: Thirty patients with MFS (47%), 25 with GBS-OP(+) (47%) and none with GBS-OP(-) had antibodies to GSCs containing GQ1b or GT1a. Patients with MFS and GBS-OP(+) were subdivided according to the antibody reactivities; patients with antibodies specific to GQ1b and/or GT1a (without anti-GSCs antibodies) were placed in Group 1, those with antibodies against GSCs with a total of two sialic acids in the terminal residues, such as GQ1b/GM1, were placed in Group 2, and those with antibodies against GSCs with a total of three sialic acids in the terminal residue, such as GQ1b/GD1a, were placed in Group 3. In MFS, sensory disturbances were infrequent in Group 2 compared with the other groups (p<0.0001). Antibodies specific to GQ1b were observed more often in MFS than in GBS-OP(+) (p = 0.0002)., Conclusions: IgG antibodies to GSCs containing GQ1b or GT1a were closely associated with the development of ophthalmoplegia in GBS, as well as MFS. Both GQ1b and clustered epitopes of GSCs containing GQ1b or GT1a may be prime target antigens for MFS and GBS-OP(+).

Metastasis of testicular germ cell tumor should be included in the differential diagnosis when young male patient have multiple pulmonary metastases. However burned-out tumors cannot be easily detected on inspection and palpation of the testis. A 19 year-old man visited to our hospital complaining of anorexia, weight loss and dyspnea. Chest X-ray films showed multiple lung nodules. Physical examination revealed gynecomastia, and many cervical, axillary, and inguinal lymph nodes with a diameter of 1 cm were palpable. Physical examination of testis revealed no laterality. Multi-detector CT showed multiple lung nodules, a hepatic and a retroperitoneal large mass and a tiny calcification in the right testis. Histological findings of the lung obtained by percutaneous biopsy and the presence of a calcification in the testis led to a diagnosis of testicular choriocarcinoma showing burned-out tumor. However there was no previous report of burned-out tumor detected by CT, MD-CT including that of the testis was valuable at the first diagnostic stage when germ cell tumor was suspected.

A 29-year-old woman was admitted because of chest radiograph abnormality. She had no respiratory complaints. Chest CT demonstrated an ill-defined nodule of 20mm with the "sarcoid galaxy sign" in the right upper lobe. Transbronchial biopsy (TBB) specimens from right S2 revealed non-caseating epithelioid cell granuloma. Initial clinical findings suggested mycobacterial infection. However, while waiting for the results of mycobacterial cultures in bronchial washing fluid, the tuberculin skin reaction was found to be negative, and enlargement of nodule, mediastinal lymphadenopathy and elevated soluble IL-2R were observed. Cultures for mycobacterium were negative and repeat TBB specimens revealed granulomatous inflammation. We diagnosed with sarcoidosis based on these findings. Solitary nodular sarcoidosis is rare with only 17 cases having been reported. These cases were diagnosed with difficulty because of non-specific clinical findings and of the 17, 16 cases (94%) were diagnosed by surgical procedures. We observed the clinico-radiological course of solitary nodules and the change in tuberculin reaction. Although a negative tuberculin skin reaction was commonly recognized in sarcoidosis patients, we confirmed that initial positive tuberculin reaction changed to negative according to disease progress. To the best of our knowledge, this is the first case report in adults.

Influenza virus infection is an important cause of mortality after hematopoietic stem cell transplantation (HSCT). Although early diagnosis followed by standard therapy with oseltamivir is thought to prevent influenza complications in myeloablative bone marrow transplant recipients, the optimal duration of therapy in these patients has not yet been determined. We describe a case of influenza virus reactivation, after remission had been achieved with standard oseltamivir therapy, in a patient undergoing nonmyeloablative bone marrow transplantation (NMBMT). A rapid diagnostic test (RDT) for influenza virus detection was performed with the ESPLINE Influenza A&B-N kit, which is a rapid, readily available, and widely used approach enabling highly specific and sensitive detection, as well as monitoring, of influenza A and B viruses. However, our case shows that a very low viral load that is undetectable by this RDT can reactivate influenza during the early phase of NMBMT. Our case suggests that oseltamivir administration for influenza infection should be continued, at least until successful engraftment, to prevent virus reactivation. The patient must be frequently and carefully monitored even after the resolution of symptoms and the clearance of viruses from respiratory secretions. The decision to cease oseltamivir therapy safely can be assisted by negative results on reverse transcription polymerase chain reaction (RTPCR) analysis.

A 63-year-old woman complained of continuous dry cough and high fever for two months. Chest radiography showed no abnormality, but inspiratory fine crackles were audible. Interstitial lung disease was suspected and bronchoalveolar lavage was performed via a bronchoscope. Disseminated minute granular lesions with redness and hypervascularity from the upper trachea to bilateral lober bronchi were detected. Lesions were also present in the membranous portion of the left main bronchus. Histological results for bronchial biopsy and transbronchial lung biopsy showed non-caseous epithelioid cell granuloma. This, together with a high CD4/8 lymphocyte ratio (4.11) in bronchoalveolar lavage fluid and the gallium scintigraphic findings, confirmed the diagnosis of sarcoidosis. To the best of our knowledge there are no other reports of cases with a similar bronchoscopic appearance in which the chest roentgenologic classification was stage 0, despite severe respiratory symptoms. Nodular lesions are seen in some cases of endobronchial sarcoidosis, but in this case, these widespread granular lesions were a unique feature that prompted us to make this report.

Previous studies have shown the efficacy of betacellulin (BTC) to promote beta-cell regeneration. Because of its short half-life, however, the effect of BTC may have been underestimated. This study was conducted to assess the effect of continuous administration of BTC on beta-cell regeneration. Adenovirus vectors encoding proBTC (Ad-proBTC) and mature BTC (Ad-mBTC) were prepared, and the efficacy of secretion of BTC was compared in AML12 hepatocytes. When AML12 cells were infected with Ad-proBTC or Ad-mBTC, cells infected with Ad-mBTC secreted considerably larger amount of BTC. We then infused Ad-mBTC into the mouse tail vein. Expression of BTC was detected in the liver for at least 21 days, and serum BTC was maintained at approximately 1 ng/ml for 7 days. When Ad-mBTC was infused immediately after administration of STZ (170 mg/kg), elevation of the plasma glucose induced by STZ was markedly inhibited, and the plasma glucose concentration remained at less than 200 mg/dl for 21 days. The insulin content and the beta-cell mass were significantly increased in Ad-mBTC-infused mice. These results indicate that continuous administration of BTC is quite effective in promoting regeneration of beta-cells.