Nagoya City University Research Articles

Prognostic significance of hyponatremia induced by systemic chemotherapy in a hospital-based propensity score-matched analysis.

During chemotherapy, hyponatremia is one of the most frequently encountered adverse effects. This study aimed to investigate the prognostic impact of hyponatremia induced by systemic chemotherapy (HIC) using a propensity matching method in cumulative pooled data. Between January 2011 and July 2017, 2129 patients were administered systemic chemotherapy for malignancy in various organs at Nagoya City University Hospital. Patients were divided into two groups: a grade 0-1 group (control group) and a grade 3-4 group (severe group) according to the severity of HIC appearing within 30days after starting treatment. Kaplan-Meier curves were used for survival and recurrence analyses using a propensity case-matched analysis. The number of severe HIC patients was 93 (4.4%). In platinum-containing regimens, HIC appeared at higher frequencies. In the 21.2months median follow-up period, the median OS (mOS) in the severe group was 49.1months, which was significantly worse than the mOS in the control group; the OS in the control group did not reach the median. Univariate and multivariate analyses of associated factors in patients with grade 3-4 HIC revealed that renal dysfunction, cisplatin-containing regimen, and infusion of more than 5000mL fluid was associated with HIC. This study suggests that severe HIC in the first treatment cycle affects survival time. Chemotherapy patients receiving extensive hydration should be required to undergo frequent monitoring of serum sodium levels, especially patients receiving platinum-containing regimens.

513 Dynamic change of PD-L1 expression in cutaneous angiosarcoma

Cutaneous angiosaroma(CAS) is a rare type of soft tissue sarcoma (STS) from endothelial origin. The prognosis is poor and 5-year survival rate is around 20 to 35%. Recent years, immune checkpoints including programmed cell death ligand 1 (PD-L1) and its receptor programmed cell death (PD-1) blockade therapy for various cancers are showing successful results. PD-L1 is an immunoinhibitory molecule that suppresses the activation of T cells, leading to the cancer progression. Overexpression of PD-L1 in almost cancers such as malignant melanoma is associated with poor clinical prognosis. However, as regards CAS, little has been reported on the prognostic value of PD-L1 expression, and the results of obtained so far are controversial. To evaluate the prognostic value of PD-L1 in CAS, we are performing immunohistochemical analysis of immune response factors including PD-L1, PD-1 and CD8. using formalin-fixed paraffin-embedded (FFPE) samples obtained from CAS patients treated and followed in Nagoya City University Hospital. 27 cases (male/female: 19/8, median age: 75.3 years old) were analyzed. Average tumor size was 70.5 cm2 and median survival was 211 weeks. Surgical treatment is performed in 8 cases (30%) and radiation therapy (RT) is performed in 22 cases (81%). For chemotherapy, taxanes were used in 22 cases (81%) and eribulin is used in 5 cases (16%). In immunohistochemistry, PD-L1 expressions showed various strength and some cases showed dynamic changes during follow up even in the same case. Four cases showed recurrence after treatment. PD-L1 expression of these four recurrent cases decreased dramatically (in average, 73.35 to 46.83 pixel value). Five cases had surgical resection after biopsy of same lesion within a few weeks. These cases showed also heterogeneity of PD-L1 expression even in same lesion without therapeutic modification. Dynamic change of PD-L1 expression seems to reflect the immune sensitivity of CAS. These results make us expect potential of immune therapy for CAS.

Suicide, other externally caused injuries and cardiovascular death following a cancer diagnosis: study protocol for a nationwide population-based study in Japan (J-SUPPORT 1902)

IntroductionA growing body of literature has demonstrated that cancer patients have a higher risk of suicide and cardiovascular mortality compared with the general population, especially immediately after a cancer diagnosis....

Normalization of breathing with adenotonsillectomy in Japanese pediatric OSA

ObjectiveSince reports on surgical results for pediatric obstructive sleep apnea (OSA) in Japan are insufficient for debate, this study aimed to evaluate the feature of Japanese OSA children and surgical result and document whether is obesity and affecting factor similar to non-Asian countries. MethodsThis is a retrospective study. A total of 242 children with OSA at the Department of Otolaryngology and the Good Sleep Center, Nagoya City University Hospital and the Toyohashi Mates Sleep Disorders Center were included in the study. All children underwent pre- and postsurgical polysomnography. OSA was defined as an apnea hypopnea index (AHI) 5 or greater. Pre- and postsurgical respiratory parameters were compared using paired T test. ResultsNormalization of breathing after surgery for OSA children was 40% with AHI < 2 and 85% with AHI < 5. Japanese OSA children are not as obese as OSA children in many non-Asian countries. However, the normalization of breathing as a result of surgery in Japanese OSA children does not differ much from non-Asian countries. ConclusionJapanese pediatric OSA that is not normalized by surgery may be affected by factors other than obesity.

Facial distribution of squamous cell carcinoma in Japanese.

Squamous cell carcinoma (SCC) is a malignant tumor of the skin. SCC is frequently distributed on highly exposed areas such as the face and dorsal surface of the hands because it is closely related to ultraviolet damage. We retrospectively analyzed 106 cases of SCC treated at Nagoya City University Hospital from April 2004 to October 2015 and examined regional features based on modified facial aesthetic units. SCC occurred more frequently on the cheek and forehead on the right side. The site of the tumor (nose and eyelid) was the only factor affecting tumor diameter.

Facial site distribution of basal cell carcinoma in Japanese.

Basal cell carcinoma (BCC) occurs preferentially on the face. We retrospectively analyzed 200 cases of BCC treated at Nagoya City University Hospital from April 2004 to October 2015 and examined regional features based on modified facial aesthetic units. BCC occurred more frequently on the cheek, nasal and orbital areas. There was no significant difference between sides, and age was the only factor affecting tumor size.

Identification of new urinary risk markers for urinary stones using a logistic model and multinomial logit model.

Risk assessment for urinary stones has been mainly based on urinary biochemistry. We attempted to identify the risk factors for urinary stones by statistically analyzing urinary biochemical and inflammation-related factors. Male participants (age, 20-79years) who visited Nagoya City University Hospital were divided into three groups: a control group (n = 48) with no history of stones and two stone groups with calcium oxalate stone experience (first-time group, n = 22; recurring group, n = 40). Using 25-µL spot urine samples, we determined the concentrations of 18 candidate urinary proteins, using multiplex analysis on a MagPix® system. In univariate logistic regression models classifying the control and first-time groups, interleukin (IL)-1a and IL-4 were independent factors, with significantly high areas under the receiver operating characteristic curve (1.00 and 0.87, respectively, P < 0.01 for both). The multivariate models with IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF) showed higher areas under the receiver operating characteristic curve (0.93) compared to that for the univariate model with IL-4. In the classification of control, first-time, and recurrence groups, accuracy was the highest for the multinomial logit model with IL-4, GM-CSF, IL-1b, IL-10, and urinary magnesium (concordance rate 82.6%). IL-4, IL-1a, GM-CSF, IL-1b, and IL-10 were identified as urinary inflammation-related factors that could accurately distinguish control individuals from patients with urinary stones. Thus, the combined analysis of urinary biochemical data could provide an index that more clearly evaluates the risk of urinary stone formation.

Anatomical Links between White Matter Hyperintensity and Medial Temporal Atrophy Reveal Impairment of Executive Functions.

Although several studies have demonstrated correlation between white matter hyperintensities (WMH) and impairment of executive functions, the underlying anatomical-functional relationships are not fully understood. The present study sought to investigate the correlations between the volume of WMH and medial temporal lobe atrophy (MTA) using quantitative magnetic resonance image (MRI) and a variety of executive function assessments. A total of 91 patients ranging in age from 58 to 90 years with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) or early phase AD were recruited from the outpatient clinic at the Department of Neurology of Nagoya City University Hospital. We administered neuropsychological batteries evaluating verbal memory, orientation, spatial ability, sustained attention, and a variety of executive functions, including verbal fluency, flexibility, inhibition, and working memory. Quantitative MRI analyses were performed using Dr. View/Linux software and a voxel-based specific regional analysis system. Significant correlations were observed between WMH, as well as MTA, and some executive function scores. Regression analysis revealed that MTA was the strongest predictor of flexibility and verbal fluency. These findings provide new insight into the relationship between quantitative MRI analyses and various types of executive dysfunction in elderly people with MCI due to AD and/or early phase AD. When cognitive function is examined in elderly patients with MCI due to AD or early phase AD, it is important to consider the involvement of WMH and MTA, which is indicative of AD pathology in cognitive dysfunction, particularly executive function.

Smartphone problem-solving and behavioural activation therapy to reduce fear of recurrence among patients with breast cancer (SMartphone Intervention to LEssen fear of cancer recurrence: SMILE project): protocol for a randomised controlled trial

IntroductionOne of the most common distressing conditions experienced by breast cancer survivors is fear of cancer recurrence (FCR). There is, however, no standard intervention for ameliorating FCR. Our clinical experience...

Endoscopic submucosal resection with an endoscopic variceal ligation device for the treatment of rectal neuroendocrine tumors.

Endoscopic resection is recommended for rectal neuroendocrine tumors < 1cm in diameter; the three techniques (mucosal resection, submucosal dissection, and mucosal resection with variceal ligation device) of endoscopic resection of neuroendocrine tumor were reported; however, the optimal endoscopic technique remains unclear. We compared the efficacy and safety of three endoscopic rectal neuroendocrine tumor resection methods. We retrospectively enrolled 52 patients with rectal neuroendocrine tumors treated by endoscopy at Aichi Medical University Hospital and Nagoya City University Hospital between May 2003 and June 2017. We compared clinical outcomes in three groups based on the endoscopic treatment method. Fifty-two patients underwent endoscopic rectal neuroendocrine tumor treatment (mucosal resection, 14; submucosal dissection, 19; mucosal resection with an endoscopic variceal ligation device, 19). In the endoscopic mucosal resection, submucosal dissection, and mucosal resection with variceal ligation device groups, R0 resection occurred in 50.0, 94.7, and 89.5%, respectively (mucosal resection vs. mucosal resection with variceal ligation device, p< 0.05; mucosal resection vs. submucosal dissection, p< 0.01), while the median procedure times were 6.5, 43, and 6.0min, respectively (submucosal dissection vs. mucosal resection with variceal ligation device procedure times, p < 0.01; mucosal resection vs. submucosal resection procedure times, p< 0.01). Postoperative bleeding occurred after endoscopic mucosal resection (1/14) and endoscopic submucosal dissection (4/19), but not after endoscopic mucosal resection with a ligation device. Endoscopic mucosal resection with an endoscopic variceal ligation device was a safe, effective treatment for rectal neuroendocrine tumors.

Six-month results of intravitreal ranibizumab for macular edema after branch retinal vein occlusion in a single-center prospective study: visual outcomes and microaneurysm formation.

PurposeThe aim of this study is to report the 6-month results after one intravitreal ranibizumab (IVR) injection followed by pro re nata dosing for macular edema (ME) after branch retinal vein occlusion.Patients and methodsThe inclusion criteria included a minimal patient age of 18 years, 20 letters or more best-corrected visual acuity (BCVA) (Early Treatment Diabetic Retinopathy Study [ETDRS] score, 77 letters or less), and central retinal thickness (CRT) of 250 microns or more. The primary outcome measure was the mean BCVA change from baseline at month 6; the secondary outcomes were mean changes in CRT, residual ME, and microaneurysm formation.ResultsTwenty patients were enrolled from March 2014 through October 2016 at Nagoya City University Hospital. The baseline mean ETDRS letters and CRT were 63.1 and 500 microns, respectively; mean time from symptom onset to initial therapy was 1.80 months; and mean ETDRS gain and CRT reduction were 15.2 letters and 230 microns, respectively. The percentages of patients with Snellen equivalent BCVAs of 20/40 (70 ETDRS letters) or better and 20/20 (85 ETDRS letters) were 90% and 15%, respectively. Residual ME and microaneurysms were observed in 85% and 35% of patients. Microaneurysm formation was associated with delayed initial therapy.ConclusionPrompt initiation of IVR injection provided a better visual prognosis at month 6 and suppressed the microaneurysm formation.

Performance and outcomes of noninvasive prenatal testing for twin pregnancies in Japan.

The purpose of this study was to describe the characteristics of women with twin pregnancies who undergo noninvasive prenatal testing (NIPT) as well as the post-partum and neonatal outcomes of such cases in Japan. The study population consisted of women who were pregnant with twins and who underwent NIPT using massively parallel sequencing (MPS) at Nagoya City University Hospital between April 2013 and June 2016. Questionnaires were completed pre-NIPT and post-partum. Among 4009 women who underwent NIPT during the study period, 75 women (1.9%) were pregnant with twins. Fifteen women (20%) experienced vanishing twin/intrauterine fetal deaths at <22 weeks, and 60 women (80%) had normal twin pregnancies at the time of genetic counseling for NIPT. The use of NIPT was correlated with increased proportions of women using assisted reproductive technology (ART). The test had a high performance, with a false-positive rate of 1.7% and no false negatives. In this study, NIPT had a high performance, with a false positive rate of 1.7% and no false negatives. When treating women with twin pregnancies, the efficacy of NIPT should be explained during genetic counseling. Further larger studies are required to assess the reliability and validity of NIPT in twin pregnancies.

Efficacy of tapentadol for first-line opioid-resistant neuropathic pain in Japan

Cancer-related neuropathic pain is sometimes unresponsive to multidrug treatment. Novel drugs are required to treat such severe pain without necessitating the use of adjuvant analgesics. Tapentadol is a new drug that has a dual mechanism as both an opioid agonist and noradrenalin reuptake inhibitor. The study objective was to investigate the effectiveness of oral tapentadol for relieving cancer-related neuropathic pain. A retrospective, single-center, open, non-randomized study was conducted at the Nagoya City University Hospital. The study included 38 Japanese patients with advanced cancer who received opioids, such as tramadol, oral oxycodone and transdermal fentanyl, with or without adjuvant analgesics. Eastern Cooperative Oncology Group performance status, Numerical Rating Scale, primary tumor type, primary opioid and tapentadol doses, adjuvant analgesic prescriptions, outcomes and adverse events of opioid switching were assessed for 7 days. Eighteen (47.3%) out of 38 patients were enrolled in this study. The average performance status was 2.13 ± 0.94 (mean ± standard deviation). After switching to oral tapentadol, the pain score decreased from 3.78 to 2.78. The patients who had clinically improved effective pain scores had a higher percentage of prior opioid use for more than 2 months. After switching to tapentadol, adverse events were usually mild, with a grade of 1-2 by the Common Terminology Criteria for Adverse Events v4.03. Tapentadol appears to have an acceptable safety margin and promising efficacy to relieve cancer-related neuropathic pain that is refractory to first-line opioid treatment.

Refractory gastric antral ulcers without Helicobacter pylori infection and non-steroidal anti-inflammatory drugs

Herein, we describe a rare case of refractory gastric antral ulcers. A woman in her 50s was admitted to Nagoya City University Hospital with epigastric pain after being diagnosed with gastric antral submucosal tumor at another hospital. Findings from esophagogastroduodenoscopy and endoscopic ultrasound examination revealed that the lesion was a gastric ulcer. The patient had no Helicobacter pylori infection and no recent history of using non-steroidal anti-inflammatory drugs. On the basis of these findings, we diagnosed this as a case of refractory gastric antral ulcer (RGAU). RGAU is considered a new disease concept and detailed analyses are expected in the future.

Stiripentol for the treatment of super-refractory status epilepticus with cross-sensitivity.

Cross-sensitivity of rash has been reported between various antiepileptic drugs (AEDs). However, few studies have determined the frequency and management of cross-sensitivity in patients with super-refractory status epilepticus (SRSE). To examine the optimal AED for treating SRSE with cross-sensitivity. We performed a retrospective review of adult patients with SRSE treated at Nagoya City University Hospital, in which we investigated the frequency of cross-sensitivity among patients with SRSE and their clinical and medical profiles. We identified 10 adult patients with SRSE, 5 of whom had cross-sensitivity. Stiripentol (STP) was administered when previously used AEDs had demonstrated cross-sensitivity and failed to control seizures. After initiation of STP, the dose of general anaesthetics was reduced, and status epilepticus (SE) eventually ceased with co-administered AEDs without additional adverse effects. The mean time to SE cessation after initiation of STP was 30.8days (range, 18-46days), mean duration of general anaesthesia was 101.2days (range, 74-128days), and mean number of AEDs was 9.0 (range, 6-11). This study suggests that cross-sensitivity between AEDs is common in adults with SRSE and that STP may be useful for treating SRSE with cross-sensitivity.

Early abiraterone acetate treatment is beneficial in Japanese castration-resistant prostate cancer after failure of primary combined androgen blockade.

BackgroundDevelopment of novel agents targeting the androgen axis has led to improved overall survival in castration-resistant prostate cancer (CRPC). This study aimed to investigate the optimal timing of treatment with one such agent, abiraterone acetate (AA), in Japanese patients.Materials and methodsBetween July 2014 and February 2016, 106 CRPC patients were administered AA in Nagoya City University Hospital, Nagoya, Japan and in four affiliated hospitals following failure of primary combined androgen blockade (CAB). Of these, records of 69 patients treated before chemotherapy were retrospectively analyzed. Patients were divided into two AA treatment groups: (1) first- or second-line after diagnosis of CRPC, designated the Early Group, and (2) third-line onwards, designated the Deferred Group. Prostate-specific antigen (PSA) response rate, ≥ 50% PSA decline rate with treatment, progression-free survival (PFS), and overall survival (OS) were compared between the two groups. National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 was used to classify adverse events.ResultsIn 24 patients in the Early Group and 45 patients in the Deferred Group, no significant differences in baseline parameters were observed between groups. PSA response rate, ≥ 50% PSA decline rate and PFS (but not OS) were significantly better in the Early Group than in the Deferred Group. Serum aspartate aminotransferase/alanine aminotransferase elevations were the most common Grade 3 treatment-related toxicities, and were clinically manageable. In subgroup analyses of the Early Group, comparison of first-line AA with second-line AA after flutamide treatment showed no changes in PSA response rate, PFS, or OS.ConclusionThis study suggests improved favorable outcomes of first- or second-line AA treatment in Japanese chemotherapy-naïve CRPC patients after failed CAB; statistical confirmation of such improvement was evident for PFS, but not OS. In addition, early AA treatment exhibited an acceptable safety profile.

MP62-04 IDENTIFICATION OF THE RECOMMENDED TECHNIQUES, CASE SELECTION, AND INVENTION TO IMPROVE EXTRACORPOREAL SHOCK WAVE LITHOTRIPSY SUCCESS RATES

You have accessJournal of UrologyStone Disease: Shock Wave Lithotripsy1 Apr 2017MP62-04 IDENTIFICATION OF THE RECOMMENDED TECHNIQUES, CASE SELECTION, AND INVENTION TO IMPROVE EXTRACORPOREAL SHOCK WAVE LITHOTRIPSY SUCCESS RATES Atsushi Okada, Teruaki Sugino, Rei Unno, Kazumi Taguchi, Shuzo Hamamoto, Ryosuke Ando, Keiichi Tozawa, and Takahiro Yasui Atsushi OkadaAtsushi Okada More articles by this author , Teruaki SuginoTeruaki Sugino More articles by this author , Rei UnnoRei Unno More articles by this author , Kazumi TaguchiKazumi Taguchi More articles by this author , Shuzo HamamotoShuzo Hamamoto More articles by this author , Ryosuke AndoRyosuke Ando More articles by this author , Keiichi TozawaKeiichi Tozawa More articles by this author , and Takahiro YasuiTakahiro Yasui More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1935AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES We previously reported that the success rates of extracorporeal shock wave lithotripsy (ESWL) were increased from 66.3% to 87.2% by technical training (Okada et al. Urolithiasis 2013). In the present study, we analyzed how the technical skills acquired by this training directly affected subsequent ESWL results. METHODS Among 335 ESWL treatments performed at Nagoya City University Hospital from December 2011 to August 2016, we analyzed the 324 cases that could be evaluated by CT three months post-ESWL treatment. All 17 urologists in charge of treatment attended the technical training. We analyzed associations between success rate and the following parameters: patient factors (age and body mass index), kidney stone factors (size, CT value, constituents, intervening period and skin-to-stone distance), conformity to the recommended techniques from training, number of ESWL sessions, grade of hydronephrosis, indwelling of ureteral stents, therapeutic position, use of stretcher wedges, targeting methods, air removal between cushion and skin, type of ESWL apparatus (Gemini or Lithotripter S, Dornier MedTech, Japan), shock wave frequency, and period from apparatus adjustment (stone model tests). The techniques recommended in training were 1) combined use of fluoroscopy and ultrasonography for targeting renal and proximal ureter stones, 2) use of stretcher wedges for middle ureter stones, and 3) semi-supine position with stretcher wedges for distal ureter stones. RESULTS The average total success rate was 84.3% over the study period. Average conformity to the training techniques was 80.2%, and the average success rates of the conformity and nonconformity groups were 86.2% and 76.6%, respectively (p<0.0001). There was a significant difference in the success rates between the types of apparatuses used, where the Gemini group success rate was 90.1% and the Lithotripter S group success rate was 82.0% (p<0.0001). The number of the selected cases with conformity of the recommended techniques, air removal, low CT values (≤1000HU), appropriate stone size (≤10mm), and the first therapy were 90 and their success rate was 95.6%. CONCLUSIONS Conforming to recommended techniques, air removal, and appropriate case selection can all lead to higher success rates in ESWL. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e828-e829 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Atsushi Okada More articles by this author Teruaki Sugino More articles by this author Rei Unno More articles by this author Kazumi Taguchi More articles by this author Shuzo Hamamoto More articles by this author Ryosuke Ando More articles by this author Keiichi Tozawa More articles by this author Takahiro Yasui More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Relationship between dexmedetomidine dose and plasma dexmedetomidine concentration in critically ill infants: a prospective observational cohort study.

BackgroundDexmedetomidine is a highly selective central α2-agonist used as a sedative in pediatric intensive care unit (PICU). However, little is known about the relationship between dexmedetomidine dose and its plasma concentration during long-term infusion. We have previously demonstrated that the sedative plasma dexmedetomidine concentration is moderately correlated with the administered dose in adults (r = 0.653, P = 0.001). We hypothesized that there would be a similar relationship between the sedative dexmedetomidine concentration and administered dose in infants.MethodsAll patients admitted to the PICU at Nagoya City University Hospital, Japan, between November 2012 and March 2013 were eligible for inclusion in the study. Plasma dexmedetomidine concentration was measured by ultra-performance liquid chromatography coupled with tandem mass spectrometry.ResultsWe measured the plasma dexmedetomidine concentration in 203 samples from 45 patients. Of these, 96 samples collected from 27 patients < 2 years old were included in this study. All patients received dexmedetomidine at 0.12–1.40 µg/kg/h. The median administration duration was 87.6 hours (range: 6–540 hours). Plasma dexmedetomidine concentration ranged from 0.07 to 3.17 ng/ml. Plasma dexmedetomidine concentration was not correlated with the administered dose (r = 0.273, P = 0.007). The approximate linear equation was y = 0.690x + 0.423.ConclusionsIn infants, plasma dexmedetomidine concentration did not exhibit any correlation with administered dose, which is not a reliable means of obtaining optimal plasma concentration.

Anti-Myeloma Activity of a Syringolin Analog: A Dual 20S Proteasome Inhibitor of Beta 2 and 5 Subunits

Background: Bortezomib (BTZ), a proteasome inhibitor (PI), mainly targets the beta 5 subunit of the 20S proteasome, and is widely used in the treatment of multiple myeloma (MM). However, inhibitory effects on other subunits of the proteasome are not well understood. Therefore, we examined the anti-MM activity of novel syringolin analogs that inhibit the activity of both beta 5 and 2 subunits. After examination, we investigated the activity of compound 19a, developed as a syrbactin-class PI to improve cytotoxic activity and membrane permeability (Chiba T et al. Angew Chem Int Ed. 2014).Materials and method: First, the cytotoxic and inhibitory effects of compound 19a on 20S proteasomes of MM cells, including BTZ-resistant MM cells and primary samples derived from MM patients, were examined. The primary MM specimens were collected after obtaining written informed consent at Nagoya City University Hospital, and the mechanism of antitumor activity of compound 19a on MM cells was evaluated by focusing on the unfolded protein response and endoplasmic reticulum (ER) stress. Finally, to evaluate the toxicity of compound 19a, BALB/c mice were intraperitoneally injected with either 19a or BTZ and body weight change was analyzed. These in vivo experiments were performed in accordance with the United Kingdom Coordinating Committee on Cancer Research Guidelines for the Welfare of Animals in Experimental Neoplasia, Second Edition, and were approved by the Ethics Committee of the Center for Experimental Animal Science, Nagoya City University Graduate School of Medical Sciences.Results: The cytotoxic activity of compound 19a, observed in various MM cell lines at nanomolar concentrations, was found to be similar to the activity observed when BTZ-resistant MM and T-cell lymphoma cell lines were tested. More precisely, the two BTZ-resistant cell lines KMS-11/BTZ and OPM-2/BTZ showed 44.4-fold and 52.1-fold higher resistance, respectively, to BTZ than that shown by their parental cell lines KMS-11 and OPM-2. However, the two BTZ-resistant cells showed only 3.2-fold (IC50: 18.0 nM) and 4.3-fold (IC50: 5.1 nM) higher resistance to compound 19a than that shown by their parental cell lines KMS-11 (IC50: 5.7 nM) and OPM-2 (IC50: 1.2 nM), suggesting that compound 19a exhibits less cross-resistance to BTZ. Evaluation of 20S proteasome activity showed time-dependent inhibition of both beta 5 and 2 subunits in MM cells on treatment with compound 19a. Treatment with 10 nM 19a induced remarkable apoptosis of the MM cells, accompanied by elevated CHOP and NOXA expression, indicating excessive ER stress. A similar activity was also observed in primary MM samples derived from the patients. Furthermore, to clarify the effect of beta 2 inhibition on anti-MM activity, two MM cell lines, U266 and AMO1, and one T-cell lymphoma cell line, Hut78, were transfected with either siRNA-targeting PSMB7 encoding beta 2 subunit or control siRNA and were subjected to the analysis of cell growth and viability. Specific knocking down of PSMB7 was observed, which resulted in the progression of apoptosis of the two MM cell lines and Hut78 when compared with the control. In addition, knocking down of both PSMB7 and PSMB5 encoding beta 5 subunits triggered more potent apoptosis of U266 and Hut78 cells when compared with the knocking down of either PSMB7 or PSMB5 alone. This result suggests that dual-inhibitory activities of beta 5 and 2 subunits have an additive or a synergistic effect on cytotoxicity when compared with single inhibitory activity. Finally, to examine the toxicity of compound 19a, BALB/c mice were administrated with it in a dose-escalation manner and subjected to the analysis of alteration of body weight. No significant difference in loss of body weight was observed between 19a-treated and BTZ-treated mice when administered with the same dose. Study of in vivo cytotoxic activity of 19a on xenografted MM cells is currently underway.Conclusion: We demonstrated the cytotoxic activity of a syringolin analog on various MM cells at nanomolar levels, which was attributed to the dual inhibition of beta 5 and 2 subunits of the 20S proteasome. Compound 19a, as a dual inhibitor of beta 2 and 5, was observed to be a more potent PI than BTZ, and could overcome the acquired BTZ resistance. The findings provide new insight into the treatment of relapse and/or refractory MM. [Display omitted] DisclosuresIshida:Celgene KK: Research Funding; Kyowa Hakko Kirin, Co., Ltd.: Honoraria, Research Funding; Bayer Pharma AG: Research Funding. Iida:Janssen Pharmaceuticals: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Effect of obesity on sperm retrieval outcome and reproductive hormone levels in Japanese azoospermic men with and without Klinefelter syndrome.

Obesity is reported to have adverse effects on semen quality and the endocrine system. In this study, we evaluated the effect of obesity on sperm retrieval outcome and reproductive hormone levels in Japanese men with non-obstructive azoospermia (NOA). This study is based on the clinical records of 217 men [172 with a 46,XY karyotype, 45 with Klinefelter syndrome (KS)] with NOA who underwent microdissection testicular sperm extraction at Nagoya City University Hospital between January 2004 and December 2014. Body mass index (BMI) and serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and total testosterone (TT) were measured in all patients. In a subset of patients, bioavailable testosterone (cBAT) also was calculated. Values were evaluated separately in patients with and without KS. Sperm retrieval rates (SRRs) in 46,XY men with a BMI <25kg/m2 and ≥25kg/m2 were 29.3% and 18.4%, respectively (p=0.142), while SRRs in KS men with a BMI <25kg/m2 and ≥25kg/m2 were 25.0% and 35.3%, respectively (p=0.460). TT level in men with a BMI ≥25kg/m2 was lower than that in men with a BMI <25kg/m2 , regardless of KS status. According to Pearson product-moment correlation coefficients, TT and cBAT levels tended to have negative correlations with BMI; however, statistical significance was observed only for TT level in 46,XY men (r=0.340, p<0.001). LH and FSH levels were negatively correlated with BMI in KS men (r=-0.466, p=0.001 and r=-0.647, p<0.001, respectively), but not in 46,XY men. These results suggest that obesity may be irrelevant to sperm retrieval outcome in patients with NOA. The negative correlations between gonadotropins and BMI in patients with KS suggest an underlying suppressive effect on gonadotropin excretion, which is distinctive in obese patients with KS.