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Background Multisite pain, including low-back and knee pain, is a major health issue that greatly decreases quality of life. Objectives This study analyzed the effects of l-serine, which provides necessary components for nerve function, and EPA, which exerts anti-inflammatory properties, on pain scores of adults with pain in at least the low back and knee for ≥3 mo. Methods This was a randomized, double-blind, placebo-controlled, parallel-group study. The Japan Low Back Pain Evaluation Questionnaire (JLEQ) and Japanese Knee Osteoarthritis Measure (JKOM) were applied as primary outcomes. The Brief Pain Inventory (BPI) and safety evaluation were secondary outcomes. We enrolled 120 participants aged ≥20 y (36 men and 84 women: mean ± SD age = 40.8 ± 10.9 y). The participants were randomly allocated to either the active group (daily ingestion of 594 mg l-serine and 149 mg EPA) or placebo group. The study period consisted of 8-wk dosing and 4-wk posttreatment observation. ANCOVA between groups for each time point was conducted using the baseline scores as covariates. Results The JLEQ scores (active compared with placebo: 14.2 ± 11.2 compared with 19.0 ± 10.2) at week 8 were lower in the active group (P

Purpose To report the 2-year outcomes of intravitreal aflibercept injections (IAIs) in Japanese patients with neovascular age-related macular degeneration (AMD) using a 1-month adjusted treat-and-extend (TAE) regimen. Design Multicenter, prospective, nonrandomized, interventional study. Participants Ninety-seven eyes of 97 patients with treatment-naive AMD were studied at 3 tertiary ophthalmological institutions. Methods The patients were treated with 3 consecutive monthly IAIs followed by the TAE regimen with a 1-month adjustment for a maximum of 3 months. Our TAE regimen allowed us to shorten and extend the treatment intervals even after a 3-month or 1-month treatment interval, or both, were reached. Best-corrected visual acuity (BCVA), central retinal thickness (CRT), and subfoveal choroidal thickness (SCT) were analyzed. Main Outcome Measures The mean changes in the BCVA, CRT, and SCT from the baseline to 2 years after initiating the treatment were determined. In addition, the number of injections also was determined. Results The mean BCVA significantly improved from 0.27 logarithm of the minimum angle of resolution (logMAR) units to 0.14 logMAR at 2 years (P Conclusions Intravitreal aflibercept injections with a 1-month adjusted TAE regimen significantly improved the BCVA and CRT with a reduced number of injections at 2 years. The treatment interval was adjusted to extend to 3 months in 60% and to shorten to 1 month in 20% of the eyes at 2 years.

To evaluate whether a computer-aided vessel-suppression system improves lung nodule detection in routine clinical settings. We used computer software that automatically suppresses pulmonary vessels on chest CT while preserving pulmonary nodules. Sixty-one chest CT images were included in our study. Three radiologists independently read either standard CT images alone or both computer-aided CT and standard CT images randomly to detect a pulmonary nodule ≥ 4 mm in diameter. After an interval of at least 15 days to avoid recall bias, the three radiologists interpreted the counterpart images of the same patients. The reference standard was decided by an expert panel. The primary endpoint was sensitivity. The secondary endpoint was interpretation time. The average sensitivity improved with computer-aided CT (72% for standard CT vs. 84% for computer-aided CT, p = 0.02). There was no difference in the false-positive rate (21% for both standard CT and computer-aided CT, p = 0.98). Although the average reading time was 9.5% longer for computer-aided plus standard CT compared with standard CT alone, the difference was not significant (p = 0.11). Vessel-suppressed CT images helped radiologists to improve the sensitivity of pulmonary nodule detection without compromising the false-positive rate.

In contrast to patients with viral hepatitis, patients with nonalcoholic fatty liver disease (NAFLD) can progress to hepatocellular carcinoma during the initial stages of liver fibrosis. Development and implementation of noninvasive methods for diagnosis and progression prediction are important for effective NAFLD surveillance. Mac-2 binding protein (Mac-2bp) is a useful nonalcoholic steatohepatitis (NASH) diagnosis biomarker and a powerful prediction biomarker for NAFLD fibrosis stage. Wisteria floribunda agglutinin (WFA)-positive Mac-2bp (WFA+-M2BP) is a novel serum fibrosis biomarker for chronic hepatitis C that has clinical validity. Mac-2bp and WFA+-M2BP are also clinical NAFLD biomarker candidates. We examined the efficacy of Mac-2bp and WFA+-M2BP for NAFLD assessment using patients with biopsy-proven NAFLD (n = 510; NAFLD cohort) and subjects who received a health check-up (n = 2,122; check-up cohort). In the NAFLD cohort, we set the fibrosis predicting cutoff values as 1.80 (F1), 2.21 (F2), and 2.24 μg/mL (F3). In the subjects with fatty liver from the check-up cohort (n = 1,291), the serum Mac-2bp levels were >1.80 μg/mL in 38.6% of the subjects (n = 498), and >2.24 μg/mL in 24.6% of the subjects (n = 318). The NAFLD cohort results indicated that Mac-2bp and WFA+-M2BP were equally useful for NASH diagnosis. During the early stages of fibrosis (F1, F2), the increase in Mac-2bp was statistically significant but WFA+-M2BP did not increase. Logistic regression analysis revealed that Mac-2bp was an independent determinant for the prediction of advanced fibrosis stage (≥F2), even when adjusted for WFA+-M2BP. Immunohistochemical staining of Mac-2bp revealed that hepatocytes strongly expressed Mac-2bp in patients with NAFLD. Conclusion: Our results indicated that hepatocyte-derived Mac-2bp would be a useful single biomarker for NASH diagnosis and fibrosis stage prediction in patients with NAFLD. (Hepatology Communications 2017;1:780-791).

To evaluate the development and rate of growth in macular atrophy after intravitreal injections of aflibercept (IVAs) for neovascular age-related macular degeneration (AMD) over a 2-year period. Retrospective, interventional, consecutive case series. This study included 94 eyes of 92 patients with treatment-naive AMD involving the foveal center treated with IVAs at 3 university hospitals in Japan. The patients underwent IVAs bimonthly after 3 initial monthly doses in the first year. The protocol was converted to a treat-and-extend regimen in the second year. The incidence and growth rate of macular atrophy were quantified based on hypoautofluorescence detected by fundus autofluorescence images. Additionally, possible background factors related to the development and rate of growth of macular atrophy were investigated. Of 94 eyes, 39 (41.5%) had typical AMD and 55 (58.5%) had polypoidal choroidal vasculopathy. Ten eyes (10.6%) had macular atrophy at the baseline. Of the remaining 84 eyes, 14 (16.7%) had developed new macular atrophy at 2 years, the square root of the growth rate of atrophy was 0.52 mm/year. In multivariate analyses, a poorer best-corrected visual acuity (P = 0.01) and the presence of intraretinal fluid (P = 0.04) at baseline were found to be the independent predictors for the development of macular atrophy. No factors were found that were significantly related to the growth rate of the macular atrophy. Our study determined the incidence and rate of growth of macular atrophy after IVAs for neovascular AMD in clinical settings. Eyes with vision reduction and intraretinal fluid at the baseline develop macular atrophy more frequently after IVAs for neovascular AMD.

Purpose To investigate changes in subfoveal choroidal thickness after intravitreal aflibercept injections (IAIs) for neovascular age-related macular degeneration (AMD) at 12 months. Design Retrospective, consecutive, interventional case series. Participants One hundred forty-four patients with treatment-naive neovascular AMD examined at 3 university hospitals. Methods After a loading phase of 3 monthly 2.0-mg IAIs, the patients were injected bimonthly with additional rescue injections performed for worsening. Subfoveal choroidal thickness in IAI-treated eyes was evaluated using enhanced depth imaging optical coherence tomography (OCT) or swept-source OCT. Main Outcome Measures Changes in subfoveal choroidal thickness over a 12-month period. Results Of the 144 treated eyes, 58 (40.3%) had typical neovascular AMD and 86 (59.7%) had polypoidal choroidal vasculopathy (PCV). The mean subfoveal choroidal thickness of treated eyes decreased from 268.1±101.3 μm at baseline to 233.0±99.7 μm at 3 months and remained unchanged at 232.4±99.6 μm at 12 months (percentage decrease, 13.3% at 12 months compared with baseline; P P = 0.0087; R = 0.28), but not for eyes with typical neovascular AMD ( P = 0.17; R = 0.18). Eyes without persistent or recurrent retinal fluid after the loading phase showed greater decrease in subfoveal choroidal thickness compared with those with persistent or recurrent retinal fluid, in both typical neovascular AMD ( P = 0.042) and PCV ( P = 0.038) eyes. Conclusions Subfoveal choroidal thickness decreased over 12 months with IAI therapy in eyes with neovascular AMD. Changes in subfoveal choroidal thickness after IAIs seem to be related to visual and anatomic outcomes.

Capsinoids are some of the most promising ingredients to increase energy expenditure (EE) due to brown adipose tissue (BAT) activation. However, there is limited information regarding the effect of prolonged capsinoid ingestion (CI) on BAT activity and resting EE (REE) in healthy, middle-aged, normal to overweight subjects (Subhealthy) with distinct BAT characteristics. We examined the changes in BAT density (BAT-d), using near-infrared time-resolved spectroscopy, and REE/kg induced by daily CI. Forty Subhealthy [age, 43.8 (mean) years, BMI, 25.4 kg/m2] received either capsinoid (9 mg/day) or a placebo daily for 6 weeks in a double-blind design. Total hemoglobin concentration in the supraclavicular region ([total-Hb]sup), an indicator of BAT-d, and REE/kg were measured. The changes in post-intervention [total-Hb]sup were greater in the capsinoid group (CA-G) than in the placebo group (PL-G) [5.8 &micro, M (+12.4%) versus 1.0 &micro, M (+2.1%), p = 0.017]. There was a significant relationship between BAT-d and REE/kg, however, post-supplementation REE/kg was not significantly different between the two groups (p = 0.228). In the overweight subgroup, changes in REE/kg were greater in the CA-G than in the PL-G [0.6 cal/kg/min (+4.3%) versus &minus, 0.3 cal/kg/min (&minus, 2.1%), p = 0.021]. CI enhanced [total-Hb]sup, a reflection of BAT-d, showing a good correlation with REE in Subhealthy.

Nuclear depletion of TAR DNA-binding protein 43 kDa (TDP-43), encoded by TARDBP, is the histopathological hallmark of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting motor neurons. Besides motor symptoms, ALS patients often develop non-neuronal signs including glucose intolerance, but the underlying pathomechanism is still controversial, i.e., impaired insulin and/or insulin resistance. Here, we show that ALS subjects have reduced early-phase insulin secretion and loss of TDP-43 in the nuclei of pancreatic islets. Loss of TDP-43 inhibited exocytosis by down-regulating Cav1.2 calcium channels, thereby reducing early-phase insulin secretion in a cultured β cell line (MIN6). Furthermore, β cell-specific TDP-43 knock-out induced glucose intolerance via suppression of early-phase insulin secretion in mice. These results suggest that TDP-43 regulates cellular exocytosis mediated by L-type voltage dependent calcium channels and thus plays an important role in the early-phase of insulin secretion by pancreatic islets. Funding: This work was supported by Grants-in-Aid (KAKENHI) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan: Nos. 16K09742, 16K15480, 17H04195, and 17K08547 (M.K.); and 16K09392 and 16K09393 (H.I.). This work was partly supported by grants from the Japan Agency of Medical Research and Development (AMED): JP17dm0107105h0002 and JP16kk0205009h0001 (M.Y.). This work was also supported by Grants-in-Aid from the Research Committee of CNS Degenerative Diseases, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labor and Welfare Sciences Research Grants, the Ministry of Health, Labor and Welfare, Japan (M.Y.), a grant from the Naito Foundation (M.K.), and a grant from Hori Sciences & Arts Foundation (M.K.). Declaration of Interest: S.M. owns equity in a gene therapy company (Gene Therapy Research Institution) that commercializes the use of AAV vectors for gene therapy applications. To the extent that the work in this manuscript increases the value of these commercial holdings, S.M. has a conflict of interest. Ethical Approval: This study adhered to the Ethics Guidelines for Human Genome/gene Analysis Research and those for Medical and Health Research Involving Human Subjects endorsed by the Japanese government, and approved by the Ethics Committees of Nagoya University Graduate School of Medicine. All participants provided their written informed consent. Experimental procedures involving human subjects were conducted in conformance with the principles expressed in the Declaration of Helsinki.

Although cystic fibrosis is rare in Japanese, measurement of sweat Cl−has suggested mild dysfunction of cystic fibrosis transmembrane conductance regulator (CFTR) in some patients with chronic pancreatitis. In the present study, we have investigated the association of CFTR variants and chronic pancreatitis in Japanese and the functional characteristics of a Japanese- and pancreatitis-specific CFTR variant, L1156F. Seventy patients with alcoholic chronic pancreatitis, 18 patients with idiopathic chronic pancreatitis, and 180 normal subjects participated. All exons and their boundaries and promoter region of the CFTR gene were sequenced. Human embryonic kidney-293 cells were transfected with three CFTR variants (M470V, L1156F, and M470V+L1156F), and the protein expression was examined. Xenopus laevis oocytes were injected with the CFTR variants, and bicarbonate (HCO3−) transport activity was examined. CFPAC-1 cells were transfected with the CFTR variants and Cl−/HCO3−exchange activity was examined. Six variants (E217G, I556V, M470V, L1156F, Q1352H, and R1453W) were identified in the coding region of the CFTR gene. Cystic fibrosis-causing mutations were not found. The allele frequencies of L1156F and Q1352H in alcoholic chronic pancreatitis (5.0 and 7.9%) were significantly ( P < 0.01) higher than those in normal subjects (0.6 and 1.9%). L1156F was linked with a worldwide CFTR variant, M470V. Combination of M470V and L1156F significantly reduced CFTR expression to ∼60%, impaired CFTR-mediated HCO3−/Cl−transport activity to 50–60%, and impaired CFTR-coupled Cl−/HCO3−exchange activity to 20–30%. The data suggest that the Japanese-specific CFTR variant L1156F causes mild dysfunction of CFTR and increases the risk of alcoholic chronic pancreatitis in Japanese.

'Polypoid endometriosis' is a rare variant of endometriosis. We describe a case of an extremely large polypoid endometriosis mimicking a malignant tumor. A 37-year-old nulliparous woman was referred due to the rapid growth of an endometriotic cyst of the ovary and a high serum CA125 level. MRI revealed solid components in the pelvic mass. These preoperative clinical data were compatible with an ovarian carcinoma. A frozen section of the tumor biopsy showed as if an adenosarcoma, but finally the diagnosis of polypoid endometriosis with decidual change was made on permanent section. Polypoid endometriosis is a part of the differential diagnosis for malignant tumors in women with endometriosis, and we should consider carefully decision making for treatment.

To investigate short-term outcomes of intravitreal aflibercept injections (IAIs) for polypoidal choroidal vasculopathy (PCV).91 eyes of 88 consecutive patients with treatment-naive PCV examined at three university hospitals received IAI monthly for 3 months. One month after the third IAI, changes in best-corrected visual acuity (BCVA) and macular morphology were retrospectively evaluated. Additionally, possible baseline characteristics predictive of persistent retinal fluid were analysed.The mean BCVA (logarithm of the minimum angle of resolution units) of the 91 eyes improved from 0.31 at baseline to 0.21 at 3 months (p0.0001). The mean central retinal thickness and mean subfoveal choroidal thickness decreased from 323 μm and 270 μm at baseline to 185 μm and 232 μm at 3 months, respectively (p0.0001 for both). Seventy-three eyes (80.2%) achieved a dry macula defined as absence of retinal fluid. Presence of the baseline characteristics of subretinal haemorrhage and greater size of the largest polyp were significantly associated with inability to achieve a dry macula (p=0.008 and 0.03, respectively). However, this association was not found on multivariate logistic regression. Of the 90 eyes that underwent indocyanine green angiography at 3 months, 43 eyes (47.8%) showed complete and 28 eyes (31.1%) showed partial resolution of polyps. Twenty-four eyes (24.4%) also showed partial regression of branching choroidal vascular networks.IAIs for the treatment of a large number of PCV eyes were found to improve both visual acuity and macular morphology over the short term.

To determine factors predictive of visual outcomes in eyes treated with intravitreal aflibercept injections (IAIs) for typical neovascular age-related macular degeneration (AMD) or polypoidal choroidal vasculopathy (PCV). Retrospective, multicenter, institutional, consecutive, interventional case series. One hundred nine eyes (107 patients) with treatment-naive neovascular AMD at 3 university hospitals were studied. After a loading phase of 3 monthly 2.0-mg IAIs, injections were administered every 2 months. The baseline clinical characteristics were investigated in relation to the 12-month visual outcomes. Changes in the mean best-corrected visual acuity (BCVA) were measured at 12 months after initiation of aflibercept therapy. Forty-five eyes (41.3%) had typical neovascular AMD, and 64 eyes (58.7%) had PCV. The changes in the mean BCVA at 12 months compared with baseline did not differ significantly (P = .737) between the 2 groups. Stepwise analysis showed that larger gains in the BCVA at 12 months were associated with poor BCVA (P < .001), no pigment epithelial detachment (P = .004), and subretinal fluid (P = .039) at baseline in eyes with typical neovascular AMD; larger gains in the BCVA were associated with poorer BCVA (P < .001), presence of choroidal vascular hyperpermeability (CVH) (P = .013), and subretinal fluid (P = .044) at baseline in eyes with PCV. Although poorer BCVA and the presence of subretinal fluid predicted larger gains in BCVA in both subtypes treated with aflibercept, eyes with typical neovascular AMD had greater improvement if no pigment epithelial detachment was present, while eyes with PCV had greater improvement if CVH was present.

To construct a diagnostic model for differentiating carcinosarcoma from carcinoma of the uterus. Twenty-six patients with carcinosarcomas and 26 with uterine corpus carcinomas constituted a derivation cohort. The following nine MRI features of the tumors were evaluated: inhomogeneity, predominant signal intensity, presence of hyper- and hypointense areas, conspicuity of tumor margin, cervical canal extension on T2WI, presence of hyperintense areas on T1WI, contrast defect area volume percentage, and degree of enhancement. Two predictive models—with and without contrast—were constructed using multivariate logistic regression analysis. Fifteen other patients with carcinosarcomas and 30 patients with carcinomas constituted a validation cohort. The sensitivity and specificity of each model for the validation cohort were calculated. Inhomogeneity, predominant signal intensity on T2WI, and presence of hyperintense areas on T1WI were significant predictors in the unenhanced-MRI-based model. Presence of hyperintensity on T1WI, contrast defect area volume percentage, and degree of enhancement were significant predictors in the enhanced-MRI-based model. The sensitivity/specificity of unenhanced MRI were 87/73 and 87/70% according to reviewer 1 and 2, respectively. The sensitivity/specificity of the enhanced-MRI-based model were 87/70% according to both reviewers. Our diagnostic models can differentiate carcinosarcoma from carcinoma of the uterus with high sensitivity and moderate specificity.

ObjectivesSimilar to primary debulking surgery, complete resection of all macroscopic diseases during interval debulking surgery (IDS) is the primary objective while using neoadjuvant chemotherapy followed by IDS for advanced ovarian, fallopian tube, and peritoneal cancers. However, most patients develop recurrent disease even after complete cytoreduction during IDS. This study aims to identify recurrence patterns of the ovarian, fallopian tube, and peritoneal cancers in patients who underwent complete cytoreduction during IDS.MethodsWe retrospectively reviewed data of patients with stage III or IV ovarian, fallopian tube, and peritoneal cancers who were treated at our hospital from January 1, 2005, to December 31, 2011.ResultsIn this study, 105 patients underwent neoadjuvant chemotherapy followed by IDS and achieved complete cytoreduction. The median follow-up period was 42.1 months. Recurrence was documented in 70 patients (66.7%), and 35 (33.3%) showed no evidence of disease. Peritoneal dissemination was the most common recurrence (60.0%) observed. In multivariate analysis, positive peritoneal cytology (P = 0.0003) and elevated pre-IDS serum CA125 levels (P = 0.046) were independent risk factors for recurrence.ConclusionsAfter complete cytoreduction during IDS in patients with stage III or IV ovarian, fallopian tube, and peritoneal cancers, positive peritoneal cytology at IDS and elevated pre-IDS CA125 levels are associated with an increased risk of cancer recurrence. Positive peritoneal cytology during IDS is a particularly strong predictive factor for poor outcomes in these patients.

Women with the BRCA1/2 mutations, which cause hereditary breast and ovarian cancer (HBOC), are 35–40 times more likely to develop ovarian cancer compared with the general population. We treated a patient in whom ovarian carcinosarcoma was identified during surveillance for HBOC. She had suffered from breast cancer at ages 45 and 50. At the age of 54 years, she was diagnosed as carrying an “uncertain significant” BRCA1 variant using a genetic mutation analysis. She was referred to our department, and surveillance was performed every 3–6 months for BRCA1 pathogenic mutation carriers due to her family history. At the age of 62 years, cervical and endometrial cytology suggested a diagnosis of adenocarcinoma. At this point, the CA125 level was 19.7 and positron emission tomography/computed tomography (PET/CT) images revealed a right ovarian tumor (SUVmax, 7.41). Surgery was performed, and ovarian carcinosarcoma (pT3cN0M0) was diagnosed. Adjuvant chemotherapy consisting of paclitaxel and carboplatin was initiated. In the month during which the cancer was identified, BRCA1 variant mutation was re-designated as “suspected deleterious,” and 8 years after the initial genetic diagnosis, the causative mutation was identified. The patient has been disease-free for 4 years since surgery. This case demonstrates both the importance and difficulty of surveillance.

VLCAD deficiency is an autosomal recessive disorder caused by a defect of fatty acid oxidation. The phenotype is classified into three clinical forms on the basis of the onset of symptoms: a severe form with neonatal onset; a milder form with childhood onset; and a late-onset form. The neonatal form is the most common, and has a higher mortality rate than the others. We report the case of a newborn infant with VLCAD deficiency who developed ventricular fibrillation, which was successfully treated by intensive care, but who suddenly died after a respiratory syncytial virus infection. Early institution of i.v. glucose treatment and active immunization with vaccine, such as palivizumab (anti-RSV mAb), may be important to reduce the frequency and severity of life-threatening episodes.

We report a case of a 19-year-old woman with multicystic peritoneal mesothelioma (MCPM) who had previously undergone left adnexectomy due to an ovarian tumor of borderline malignancy at the age of 17 years. Follow-up imaging studies after adnexectomy revealed multiple cystic lesions of increasing size and number, suggesting recurrence of the tumor. Diagnostic laparoscopic surgery was performed, and the cystic lesion was pathologically determined to be MCPM. To our knowledge, this is the first report of MCPM diagnosed and successfully treated by laparoscopic surgery during the course of follow-up for an ovarian tumor. It is important to recognize that MCPM can occur in patients who have previously undergone abdominal surgery, and laparoscopic surgery is recommended for patients of reproductive age, because of the potential risk of infertility associated with extensive pelvic surgery.

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly in most developed countries and is the fourth common cause of legal blindness for all ages in Japan.1 Ranibizumab, the recombinant, humanized antibody fragment against vascular endothelial growth factor (VEGF)-A was shown to improve mean visual acuity in eyes with exudative AMD in the MARINA and ANCHOR Phase III clinical trials, which used scheduled monthly doses.2,3 However, due to the high burden associated with monthly intravitreal injections, several regimens involving less frequent dosing have been investigated, including injections every 3 months (the PIER study),4 dosing as needed or pro re nata (PRN) (the PrONTO and SUSTAIN studies),5–7 and “treat and extend” dosing.8,9 These studies were all conducted in the United States or Europe, and therefore, it is unclear whether their treatment outcomes apply to Japanese and other Asian patients with exudative AMD. It has been reported that 23%–55% of exudative AMD in Japan is due to polypoidal choroidal vasculopathy (PCV),10–13 greatly exceeding those rates reported for patients in the United States.14 Preliminary studies using anti-VEGF agents in Japanese patients have shown mixed results. One study of 47 eyes described a good response to intravitreous bevacizumab in eyes with classic choroidal neovascularization (CNV) but only limited efficacy in eyes with occult CNV.15 Other studies using bevacizumab have suggested that anti-VEGF therapy was not very effective for PCV in Japanese eyes.13,16 A Phase I–II clinical trial comparing two doses of monthly administrations of ranibizumab for exudative AMD in Japan showed good clinical efficacy of both doses over 1 year.17 However, a subsequent study found that the response to ranibizumab therapy over the first 3 months was shown to be better in PCV eyes than in non-PCV eyes.18 In the current retrospective study, we describe 2-year outcomes of intravitreal ranibizumab for treatment-naive exudative AMD in Japanese patients who received three monthly injections (induction) followed by injections based on a PRN scheme.

We encountered a case of recurrent fallopian tube carcinoma in situ with para-aortic lymph node metastasis 9 months after the first surgery. The patient presented with genital bleeding, and endometrial cytology revealed extrauterine malignant cells. However, endometrial biopsy and imaging modalities could not detect any abnormalities. We performed a total abdominal hysterectomy and bilateral salpingo-oophorectomy after obtaining the patient’s consent. Histopathological examination revealed atypical cells in the fimbrial portion of the fallopian tube. A diagnosis of fallopian tube carcinoma in situ was made. No further adjuvant treatment was administered. Nine months later, fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography revealed pathologic activity in the para-aortic lymph node and CA125 elevation. A diagnosis of metastatic adenocarcinoma was established on the basis of histological examination of a frozen section. The patient underwent para-aortic and pelvic lymph node dissection and omentectomy. The pathology report revealed metastasis to 3 of 69 lymph nodes; however, peritoneal cytology was negative for cancer. To the best of our knowledge, this is the first reported case of recurrent fallopian tube carcinoma in situ.

Purpose: The aim of this study was to investigate the 1-year outcomes of treat-and-extend aflibercept for exudative age-related macular degeneration (AMD) in Japan. Procedures: Clinical records of 67 patients (67 eyes) were reviewed. Monthly aflibercept was administered until resolution of exudation and maximal reduction of pigment epithelial detachment. Injection intervals were extended by 2-week units up to 12 weeks if no exudation was observed and shortened for recurrence. Results: Mean best-corrected visual acuity (logarithm of the minimum angle of resolution) improved from 0.29 to 0.14 at 12 months (p < 0.0001). Mean central retinal thickness decreased from 430 μm to 236 μm at 12 months (p < 0.0001). Fifty-nine eyes (88.0%) achieved a dry macula with a mean of 8.3 injections by study end. The injection interval was extended to 10 weeks in 44.8% and to 12 weeks in 17.9% of eyes. Conclusions: At 1 year, good outcomes were obtained using treat-and-extend aflibercept for exudative AMD in Japan.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with pleiotropic functions. We report here that PACAP-deficient (PACAP-/-) mice showed increased immobility in a forced swimming test, which was reduced by the antidepressant desipramine, to a similar extent as in wild-type mice. The atypical antipsychotic risperidone and the selective serotonin (5-HT)(2) antagonist ritanserin normalized the depression-like behavior in PACAP-/- mice. The 5-HT(2) agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine-induced 5-HT syndrome was exaggerated in PACAP-/- mice, which suggests a 5-HT(2)-receptor-dependent mechanism in the depression-like behavior. The circadian rhythm of plasma corticosterone and body core temperature was significantly flattened in the mutants. mRNA expression of glucocorticoid receptor was reduced in the mutant hippocampus. The present results suggest that alterations in PACAP signaling might contribute to the pathogenesis of certain depressive conditions amenable to atypical antipsychotic drugs.

Objective The aim of this study was to identify the risks and benefits of the stepladder V-Y advancement medial thigh flap for vulvovaginal reconstruction in comparison to direct skin closure. Methods Fifty-four patients with vulvar cancer treated in our hospital between 1992 and 2013 were enrolled in this study. The cohort group (group A) consisted of 25 patients who underwent surgery from August 2006 until April 2013. During this period, we changed our surgical paradigm to incorporate reconstructive plastic surgery immediately following surgery for vulvar cancer performed by gynecologic oncologists. The control group (group B) consisted of 29 patients treated between 1992 and August 2006. During this period, our surgical approach was limited to direct skin closure with no reconstructive plastic surgery. Perioperative findings and clinical outcomes were compared retrospectively. Results Patient characteristics and surgical procedures, other than the reconstructive surgery, were the same for the 2 groups. The mean blood loss and operative times were similar, and there were no major complications in either group; however, the average length of hospital stay was significantly shorter in group A (P = 0.04). Conclusions Stepladder V-Y advancement medial thigh flap lowers posttreatment morbidity and improves quality of life for patients with vulvar cancer. Rapid recovery from surgery is reflected in the short hospital stay, and it enables immediate induction of adjuvant therapy. It may possibly contribute to improved treatment outcome.

Nonalcoholic fatty liver disease (NAFLD) is a growing medical problem; thus, discriminating nonalcoholic steatohepatitis (NASH) from NAFLD is of great clinical significance. For the diagnosis of NASH, liver biopsy-proven histological examination is the current gold standard, and noninvasive and reliable biomarkers are greatly needed. Recently, we found that two glycobiomarkers, fucosylated haptoglobin (Fuc-Hpt) and Mac-2 binding protein (Mac2bp), are useful independently for NASH diagnosis. In this study, we confirmed that serum Fuc-Hpt is suitable for the prediction of ballooning hepatocytes and that serum Mac2bp is suitable for the prediction of liver fibrosis severity in 124 biopsy-proven NAFLD patients (training cohort). In addition, we found that the combination of serum Fuc-Hpt and Mac2bp levels was an excellent tool for NASH diagnosis. Using receiver operating characteristic analyses, the area under the receiver operating characteristic curve, sensitivity, and specificity of the combination of these two glycobiomarkers were 0.854, 81.1%, and 79.3%, respectively. We established a prediction model for NASH diagnosis using logistic regression analysis: logit (p) = −2.700 + 0.00242 × Fuc-Hpt + 1.225 × Mac2bp. To validate the prediction model, another 382 biopsy-proven NAFLD patients were enrolled (validation cohort). In the validation cohort, the area under the receiver operating characteristic curve of this model for NASH diagnosis was 0.844, with 71.4% and 82.3% sensitivity and specificity, respectively. In addition, we investigated the significance of our developed NASH diagnosis model in ultrasound-diagnosed NAFLD subjects who received medical health checkups (n = 803). Our model also could predict NAFLD disease severity in this larger population. Conclusion: The combination of serum Fuc-Hpt and Mac2bp can distinguish NASH from NAFLD patients. Our noninvasive model using two serum glycobiomarkers contributes to a novel NASH diagnostic methodology that could replace liver biopsy. (Hepatology 2015;62:1433–1443)

膵液中のHCO3－と水は，膵管の上皮細胞（導管細胞）から分泌される．HCO3－の輸送機構は，管腔内の陰イオン組成と導管系の部位により異なるが，cystic fibrosis transmembrane conductance regulator（CFTR）Cl－ channelに依存する．膵嚢胞線維症（CF）と一部の慢性膵炎では，CFTRの機能低下によりHCO3－と水の分泌が不足し，腺房細胞から分泌される消化酵素液を希釈/アルカリ化することができないため，膵液が粘稠になりタンパク栓が形成されやすくなる．特発性慢性膵炎（ICP）は，CFTR機能が5～50％残存するCFTR変異のcompound heterozygoteに発症しやすい．最近，Caucasianではmildな変異を有するCF carrier，日本人では多型の組み合わせによるCFTR機能低下がICPのriskになることがわかった．

BACKGROUND: Uncontrolled phagocytosis of normal hemopoietic cells by activated histiocytes in bone marrow is collectively referred to as hemophagocytic lymphohistiocytosis. CASE: We present a case of hemophagocytic lymphohistiocytosis associated with herpes simplex virus-2 infection in the second trimester. Cytopenia, elevated C-reactive protein, ferritin, soluble interleukin-2 receptor, and interleukin-6 with high-grade fever were observed following genital herpes infection, and the existence of hemophagocytes in bone marrow confirmed the diagnosis of hemophagocytic lymphohistiocytosis. Corticosteroid therapy failed to arrest the hemophagocytic process, whereas cyclosporin A was effective. The patient delivered a healthy infant after remission and has not experienced exacerbation. CONCLUSION: It is often important to take into consideration hemophagocytic lymphohistiocytosis when encountering cytopenia with high-grade fever. Cyclosporin A was a safe and available strategy for this corticosteroid-resistant case.

Aim: We evaluated the usefulness of Doppler ultrasonography (DUS) for the analysis of tumor hemodynamics in small hepatocellular carcinoma (HCC). Methods: We compared Doppler ultrasound (DUS) findings with angiography-assisted computed tomography (Angio-CT) such as CT during arterial portography and during hepatic arteriography in the evaluation of the intratumoral hemodynamics, and with pathologic findings in 45 small HCC nodules (≤3.0 cm in diameter) of 43 patients. DUS flow pattern of each nodule was categorized into three types: afferent continuous flow (Type 1), afferent pulsatile flow with afferent continuous flow (Type 2), and afferent pulsatile flow without afferent continuous flow (Type 3). Intratumoral blood supply was determined by Angio-CT, and pathologic findings were evaluated on resected or biopsied specimen. Results: Based on Angio-CT findings, Type 1 nodules showed decreased arterial blood supply (ABS) without decreased portal blood supply (PBS). Type 2 nodules showed unchanged ABS but decreased PBS. Type 3 nodules showed both increased ABS and decreased PBS. DUS findings well represented blood supply of HCC evaluated by Angio-CT. In addition, all Type 1 and 2 nodules were well-differentiated HCC, and all Type 3 nodules were moderately or poorly differentiated HCC; DUS findings well reflected differentiation of HCC. Conclusions: DUS is a non-invasive imaging method and can be used for the evaluation of the stage of malignancy of small HCC.

71歳, 男性。四肢に浸潤を触れる丘疹状の紫斑が出現。少し遅れて下腿浮腫, 蛋白尿も出現した。病理組織像では真皮上層を中心に壊死性血管炎の所見がみられ, 一部では真皮下層にまで同じような血管病変がみられた。また真皮下層の一部の血管病変でIgAの沈着が認められた。一方, 本例はネフローゼ症候群を合併したため, 内臓悪性腫瘍の有無について全身検索を行ったところ, 腎細胞癌が発見された。高齢者のアナフィラクトイド紫斑が内臓悪性腫瘍のデルマドロームであることを示唆する症例と思われた。

Our aim was to evaluate the efficacy and safety of S-1 in heavily pre-treated patients with advanced (FIGO stage IVB) or recurrent cervical cancer. The Institutional Review Board of our hospital approved the protocol for this retrospective phase II study. Patients with measurable disease received two oral doses of S-1 (35 mg/m2) daily for 4 weeks of a 6-week cycle or 2 weeks of a 3-week cycle. The antitumor effect, time to progression, overall survival, and adverse events were investigated. We retrospectively analyzed relevant data of 28 patients with advanced or recurrent cervical cancer. Twenty-two patients had prior chemotherapy (not including chemoradiotherapy) and 27 had prior radiotherapy. The median number of prior chemotherapy regimens and cycles was 2 (range 0–4) and 7 (range 0–35), respectively. Two patients (7.1 %) had partial response, and 10 patients (35.7 %) had stable disease. Ten patients (35.7 %) discontinued the therapy because of progressive disease. The response in 5 patients could not be evaluated because of termination of treatment in the middle of the first cycle. The disease control rate was 42.8 %. After a median follow-up duration of 7.5 months, the median time to progression was 4.2 months (95 % CI 2.7–5.4) and the median overall survival was 9.92 months (95 % CI 9.20–NA). The two patients with partial response had received less prior chemotherapy. Oral S-1 in palliative chemotherapy is a useful and well-tolerated treatment in heavily pre-treated patients with advanced or recurrent uterine cervical cancer.

Objective. The resection of bulky lymph nodes is occasionally required to achieve a complete cytoreductive surgery for ovarian cancer. The most common area in which bulky nodes are encountered is at the level of the renal veins [1]. The authors present a cytoreduction technique for bulkypara-aortic lymph nodes locatedbehindthe inferior vena cava (IVC) and the right renal vessels that involves the mobilization of the right kidney. Methods. A 68-year-old woman underwent a laparotomy for FIGO stage IIIC (pT2c N1 M0) fallopian tube cancer with up-front cytoreductive surgery. Para-aortic adenopathy behind the right renal vessels and right pelvic adenopathy was preoperatively demonstrated on an enhanced computed tomography examination. After performing a total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and pelvic lymphadenectomy, cytoreduction of the para-aortic lymph nodes behind the inferior vena cava and the right renal vessels was performed as follows: first, an incision was made along the peritoneal reflection in the right lumbar gutter. The right

Menstrual cycle has an influence on mind and body of any woman. A collection of symptoms that emerges one or two weeks before menstruation begins is called premenstrual syndrome (PMS), and that involves variety of complex emotional and physical changes. However, aggravation of epileptic attacks during premenstrual period alone has been focused in women with severe motor and intellectual disabilities (SMID). Exacerbation of various symptoms, other than epilepsy, was recognized as PMS in five cases, and these include muscular hypertonia, fever, tachycardia, flushing on face, nausea and vomiting. In these cases, the PMS symptoms were successfully managed with the low-dose oral contraceptive preparations. PMS among patients with SMID are often found to be difficult to diagnose. The use of the low-dose oral contraceptive was effective in women with SMID and improve the quality of their lives (QOL).

A 61-year-old female, with a history of uterine and cervical cancer treated with radical hysterectomy and 2 years of postoperative chemotherapy, presented to the emergency department with dyspnea on exertion. Computed tomography of the chest revealed a large pericardial effusion and a sacciform aneurysm of the ascending aorta. The patient subsequently underwent emergency pericardiocentesis with drainage of approximately 330 ml of a bloody and turbid effusion. Cultures from the effusion yielded group B streptococcus. Multiple organ failure and disseminated intravascular coagulation syndrome occurred in the acute phase, but gradually improved with continuous antibiotic therapy. On the 194th hospital day, in situ reconstruction of the ascending aorta was successfully performed using a synthetic graft. Although rarely reported, both purulent bacterial pericarditis and mycotic aneurysm can be life-threatening.

The present study investigated the serial changes in serum magnesium (Mg) and erythrocyte concentration of Mg in patients with acute myocardial infarction (AMI) and the relationship between these changes and left ventricular ejection fraction (LVEF) at 1 month after the onset of infarction. The study group comprised 26 patients with AMI (mean age, 57.9+/-8.9 years). Serum Mg and erythrocyte Mg were measured on hospital days 1, 2, 4, 7 and 21. The change in erythrocyte Mg during the acute phase was calculated as a ratio: [(erythrocyte Mg at day 2)-(erythrocyte Mg at day 1)]/(erythrocyte Mg at day 1). The change in serum Mg was calculated similarly. The following results were obtained. (1) Serum Mg tended to increase from the onset of myocardial infarction (day 1: 1.86+/-0.19, day 2: 1.93+/-0.22, day 4: 2.17+/-0.23; day 7: 2.25+/-0.20; day 21: 2.12+/-0.15 mg/dl). (2) Erythrocyte Mg on day 2 and day 4 showed a significant decrease compared with day 1 (day 1: 2.45+/-0.40, day 2: 2.09+/-0.41, day 4: 2.07+/-0.37, day 7: 2.22+/-0.33, day 7: 2.34+/-0.28 mg/dl per 400x10(4)/mm3 cells). (3) A significant positive correlation was observed between the change in serum Mg and LVEF (r=0.55, p

Recent observations have shown that plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) correlate with cardiac function or prognosis in heart failure patients. However, relatively little is known about changes in their plasma concentration during commonly occurring physiological states such as fatigue. Therefore, this study was designed to examine the physiological changes of plasma ANP and BNP concentrations using a chronic sleep-deprivation model. Bicycle ergometer cardiopulmonary exercise tests were performed in 10 healthy volunteers (mean age: 22.7 years). Blood samples for measuring ANP and BNP were drawn during the resting state and immediately after each exercise test. Cardiac output (CO) was measured during the exercise test by the impedance method. The study conditions were designed as follows: (A) a day following a period of normal sleep (control state) and (B) a day preceded by 1 month during which sleep lasted

Brain natriuretic peptide (BNP) secretion increases after myocardial infarction (MI); its plasma level may reflect the degree of left ventricular dysfunction. This study examines how aerobic exercise therapy for MI influences BNP secretion. Subjects included 70 patients (mean age, 62.0±11.3 years) who were divided into four groups: (1) 20 patients with an anterior MI and exercise training; (2) 20 patients with an anterior MI and no exercise training; (3) 15 patients with an inferior MI and exercise training; and (4) 15 patients with an inferior MI and no exercise training. The training groups performed aerobic exercise 3 times a week for 2 months. Exercise intensity was defined as a heart rate of anaerobic threshold (AT), derived from the treadmill cardiopulmonary exercise testing at 1 month after the onset of MI. The subjects underwent cardiopulmonary exercise testing again at 3 months after the onset of MI. To measure BNP, blood samples were obtained in the resting state and immediately after the peak exercise. AT and peak oxygen uptake increased in the training group with anterior MI and in both the training and nontraining groups with inferior MI. Significant serial change in plasma BNP level was not observed in the inferior MI groups. Plasma BNP level decreased longitudinally only in the nontraining anterior MI group. It was concluded that exercise training in patients with an anterior MI could delay the recovery of left ventricular function, but will increase exercise tolerance. (Jpn Circ J 1998; 62: 658 - 664)

We have previously reported that chronic sleep deprivation causes a deficiency of intracellular magnesium (Mg) and decreased exercise tolerance. The aim of this study was to clarify whether oral administration of Mg could be effective in restoring the exercise tolerance that is decreased by chronic sleep deprivation. A bicycle ergometer cardiopulmonary exercise test was performed by 16 healthy volunteers (mean age 21.9 years). They were divided into 2 groups: 8 received doses of 100 mg of Mg orally per day for 1 month (Mg group) and the remaining 8 received no Mg and served as the control group. The study conditions were designed as follows: (1) the usual state (good sleep); and (2) the sleep-deprived state (sleeping time up to 60% less than the usual state for 1 month). The ratio of intracellular Mg content of the sleep-deprived state to the usual sleep state was significantly higher in the Mg group (p

ObjectiveThe purpose of this study was to determine whether the platinum-free interval (PFI) was a predictive indicator in second-line treatment of cervical cancer in patients who had undergone prior platinum-based chemotherapy. The role of the PFI in selecting the second-line regimen in other gynecologic malignancies is also discussed.MethodsIn this retrospective study, we examined the clinical records of patients with recurrent or metastatic cervical cancer who had received platinum-containing combination regimens as second-line chemotherapy. All patients had received prior platinum-containing chemotherapy or concurrent chemoradiotherapy.ResultsThe overall response rate to second-line chemotherapy was 25.8%; 7 patients achieved a complete response and 17 a partial response. The median progression-free survival (PFS) was 5.1 months and median overall survival (OS) was 13.5 months. The response rate was 12.5%, 14.2%, 20.0%, 22.2%, and 55.0%; median PFS was 4.0, 5.1, 4.4, 5.8, and 7.4 months; and median OS was 10.2, 14.4, 11.9, 16.3, and 19.7 months when PFI was within 3, 3 to 5, 6 to 11, 12 to 23, and more than 24 months, respectively. Age (>50 years), size (>3 cm), prior radiotherapy, and PFI (>24 months) were identified as prognostic factors in the multivariate analysis for PFS and OS.ConclusionsThe results indicate that a PFI of more than 24 months is the discriminating point between platinum-sensitive and platinum-resistance cervical cancer. This indicates that PFI offers a useful tool in selecting agents for second-line chemotherapy in a wide range of gynecologic malignancies.