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Both natural viral infections and therapeutic interventions using viral vectors pose significant risks of malignant transformation. Monitoring for clonal expansion of infected cells is important for detecting cancer. Here we developed a novel method of tracking clonality via the detection of transgene integration sites. RAISING (Rapid Amplification of Integration Sites without Interference by Genomic DNA contamination) is a sensitive, inexpensive alternative to established methods. Its compatibility with Sanger sequencing combined with our CLOVA (Clonality Value) software is critical for those without access to expensive high throughput sequencing. We analyzed samples from 688 individuals infected with the retrovirus HTLV-1, which causes adult T-cell leukemia/lymphoma (ATL) to model our method. We defined a clonality value identifying ATL patients with 100% sensitivity and 94.8% specificity, and our longitudinal analysis also demonstrates the usefulness of ATL risk assessment. Future studies will confirm the broad applicability of our technology, especially in the emerging gene therapy sector., (© 2022. The Author(s).)

Objective Graft failure (GF) is a life-threatening complication of hematopoietic stem cell transplantation (HSCT). A standardized conditioning regimen and an appropriate graft source of salvage HSCT for GF have not yet been established. Some case series have shown good hematopoietic recoveries after salvage HSCT using a short-term reduced-intensity preparative regimen consisting of fludarabine (30-90 mg/m 2 ), cyclophosphamide (2 g/m 2 ), and total-body irradiation (2 Gy). However, the dose of fludarabine has varied in these reports based on the clinical condition of the patients, resulting in very limited experiences with each dose of fludarabine. Methods We retrospectively analyzed 10 patients who developed GF after allogeneic HSCT and underwent salvage cord blood transplantation (CBT) using the above-mentioned conditioning regimen with a fixed dose (90 mg/m 2 ) of fludarabine. Results Eight patients (80.0%) achieved neutrophil engraftment within 30 days from salvage HSCT with a median of 21 (range, 17-23) days. The 1-year overall survival (OS) rate after the salvage HSCT was 50.0%, and the median OS was 281 (range, 23-1,638) days. Cumulative incidences of non-relapse mortality and relapse at 1 year were 50.0% and 10.0%, respectively. Conclusion CBT using this short-term reduced-intensity conditioning regimen may be a promising salvage therapy for GF.

Background: Predictive factors for intrahepatic cholangiocarcinoma in long-term follow-up of hepatolithiasis are unknown. We thus conducted a cohort study to investigate the predictive factors for developing intrahepatic cholangiocarcinoma in hepatolithiasis., Methods: This cohort is comprised of 401 patients registered in a nationwide survey of hepatolithiasis for 18 years of follow-up. Cox regression analysis was used to elucidate predictive factors for developing intrahepatic cholangiocarcinoma., Results: The median follow-up period of patients was 134 months. Twenty-two patients developed intrahepatic cholangiocarcinoma and all died. Identified independent significant factors were as follows: age 63 years or older (hazard ratio [HR] 3.344), residual stones at the end of treatment (HR 2.445), and biliary stricture during follow-up (HR 4.350). The incidence of intrahepatic cholangiocarcinoma in patients with three factors was significantly higher than that in patients with one or two factors. The incidence in the groups with one or two predictive factors was not different. In 88.9% of patients with both biliary stricture and intrahepatic cholangiocarcinoma, the duration between the diagnoses of biliary stricture and intrahepatic cholangiocarcinoma was ≥ 5 years. However, once intrahepatic cholangiocarcinoma developed, 77.8% of patients died within 1 year. Of 24 patients with no symptoms, no previous choledocoenterostomy, no signs of malignancy, no biliary stricture, and no treatment for hepatolithiasis during follow-up, only one developed intrahepatic cholangiocarcinoma., Conclusions: Regarding carcinogenesis, complete stone clearance and releasing biliary stricture can prevent the development of intrahepatic cholangiocarcinoma and improve the prognosis of hepatolithiasis., (© 2022. Japanese Society of Gastroenterology.)

We report a cases report of colorectal cancer who underwent repeated resection for peritoneal recurrences by laparoscopic surgery. In 2013, a 70-year-old woman diagnosed with an ascending colon cancer underwent laparoscopic right hemicolectomy. The pathological diagnosis was tub2, pT4aN1M0, Stage Ⅲb. Postoperative adjuvant chemotherapy(uracil and tegafur/Leucovorin)was administered. PET-CT performed at 25 months after the surgery because of CEA elevation. It revealed a peritoneal recurrence in the pouch of Douglas. The following peritoneal recurrences were removed by laparoscopic Hartmann's procedure. Chemotherapy(5-fluorouracil/levofolinate/oxaliplatin/bevacizumab)was administered 11 courses and after that chemotherapy(5-fluorouracil/levofolinate/bevacizumab)was administered 6 courses. PET-CT performed 37 months after the second surgery revealed a peritoneal recurrence near the right ovary in the pouch of Douglas. The following peritoneal recurrences was removed. Chemotherapy(tegafur/gimeracil/oteracil/bevacizumab)was administered 11 courses. The long-term survival has been continued for 7 years and 7 months after first operation. It was considered that laparoscopic surgery for peritoneal recurrence in colorectal cancer is contributed to one of the surgical procedures in selected patients.

Aim: A reliable kit with high sensitivity and specificity is indispensable for diagnosing hepatitis C virus (HCV) infection. Detection kits for anti-HCV antibodies (anti-HCV) are used for screening, and quantification kits for HCV RNA and HCV antigen (Ag) are used for the definite diagnosis of HCV infection or the evaluation of the pathological condition of and therapeutic effects in patients with chronic hepatitis C. Several kits are currently available for these purposes and are provided for clinical use in Japan. In this study, we aimed to evaluate the performance of these kits., Methods: We used International Standards for HCV RNA and HCV Ag and a regional reference panel to evaluate the performance of thirteen anti-HCV, five HCV RNA, and two HCV Ag kits., Results: All specimens in the regional reference panel were diagnosed correctly by all anti-HCV kits, although the distributions of the quantified values varied, and the ratios of titer classification were not identical across kits. All HCV RNA kits quantified the International Standard with minimum deviation and diagnosed the specimens of the reference panel correctly. The quantified values of the International Standard by two HCV Ag kits were inconsistent. HCV Ag titers of some specimens were underestimated owing to the amino acid polymorphisms in comparison with HCV RNA titers., Conclusions: The evaluation with International Standards and the regional reference panel was useful for assessing the quality of screening and diagnostic kits for HCV infection, and such quality control is essential for the clinical usage of these kits., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Murayama, Momose, Yamada, Matsubayashi, Muramatsu, Hamaguchi and Kato.)

Background/aim: We investigated whether promoter methylation of the checkpoint-with-forkhead-and-ring-finger-domains (CHFR) gene is a predictor of the efficacy of irinotecan-based systemic chemotherapy for advanced colorectal cancer (CRC) patients., Materials and Methods: CHFR-promoter methylation was measured by quantitative methylation-specific PCR (qMSP). The histoculture drug response assay (HDRA) was used in vitro to analyze the correlation between CHFR-promoter methylation and the efficacy of the irinotecan-active-metabolite SN38 in colorectal-cancer tissues from 44 CRC patients. CHFR promoter-methylation was also analyzed for its correlation with clinical response to irinotecan-based systemic chemotherapy of 49 CRC patients., Results: CHFR-promoter methylation significantly-positively correlated with inhibition of colon cancer by SN38 in the HDRA (p=0.002). CHFR-promoter methylation also significantly-positively correlated with clinical response to irinotecan-based systemic chemotherapy (p=0.04 for disease control). CHFR-promoter methylation also significantly-positively correlated (p=0.01) with increased progression-free survival for patients treated with irinotecan-containing FLOFIRI in combination with bevacizumab, the most-frequent regimen in the cohort., Conclusion: Sensitivity of advanced CRC patients to irinotecan-based systemic chemotherapy can be predicted by the extent of CHFR-promoter methylation., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

In order to treat the iatrogenic ureteral stricture of more than 8 cm length after transurethral ureterolithotripsy, we planned to perform ureterocystoneostomy with psoas hitch and Boari flap. Because of the longer defect of the affected ureter than presurgically expected and the rigid and thickened ureteral stump resulting from chronic inflammation, anti-reflux technique by forming submucosal tunnel could not be achieved as in the standard Boari flap and we reluctantly anastomosed the ureteral stump to the end of the tubularized bladder wall flap in end-to-end fashion. In order to secure the anti-reflux mechanism we created a submucosal tunnel in the posterior bladder wall according to the technique reported by Casale and Rink where it originally worked as anti-incontinence mechanism of catheterizable vesicostomy. The follow-up examinations showed no recurrence of ureteral stricture nor occurrence of vesicoureteral reflux.

Objectives: The bladder urothelium is not always impermeable. During sleep, the bladder might absorb urine in healthy individuals who sleep through the night. This study aimed to determine whether the bladder absorbs urine by using a method other than ultrasonic scanning and to simultaneously evaluate sleeping conditions., Methods: Eleven participants (five males, six females) aged 20 to 49 years without lower urinary tract symptoms or urination while sleeping were enrolled. Bladder volume was estimated by studying the relationship between dilution and absorbance of indigo carmine dissolved in urine. A 12F Foley catheter was inserted into the bladder before sleep. Urine samples (5 mL) were extracted at 2, 3, 4, 5, and 6 am sleep stages were monitored with a single-channel portable electroencephalograph device., Results: The estimated bladder volume at 6 am and voided volume immediately after rising were significantly correlated (Spearman's ρ = 0.62, P = .046). Eight participants (three males, five females) showed an absorption pattern of the estimated bladder volume change. In a male participant, the blue dye's strength gradually decreased until 4 am (estimated 859 mL) and increased from 5 am (estimated 455 mL). In another, the blue dye's strength increased at 4 am (estimated 449 mL) vs at 3 am (estimated 757 mL). In all participants, electroencephalograph data demonstrated that sleep was maintained despite having a full bladder., Conclusions: The bladder absorbs urine and maintains an approximate volume of functional bladder capacity during sleep to avoid incontinence and maintain sleep in adults due to an urge to void urine during the sleep cycle., (© 2021 John Wiley & Sons Australia, Ltd.)

Objectives: To evaluate the efficacy, safety and tolerability of vibegron for the treatment of antimuscarinic-resistant neurogenic bladder dysfunction in patients with spina bifida., Methods: In this retrospective study, 15 patients with antimuscarinic-resistant neurogenic bladder dysfunction due to spina bifida underwent a video-urodynamic study before and during the administration of vibegron 50 mg once daily instead of antimuscarinic agents from February 2019 through April 2021. The video-urodynamic study was carried out to evaluate bladder compliance, maximum cystometric bladder capacity, detrusor overactivity, detrusor leak point pressure and vesicoureteral reflux before and >3 months after the beginning of vibegron administration., Results: Treatment with vibegron significantly improved bladder compliance and maximum cystometric bladder capacity compared with antimuscarinic agents, respectively (7.4 ± 4.2 vs 30.4 ± 48.2 mL/cmH 2 O, P = 0.0001; 231.4 ± 81.2 vs 325.2 ± 106.5 mL, P = 0.0005). Detrusor overactivity did not change after the administration of vibegron. Bladder deformity, which was confirmed in 12 patients, improved in half of the patients after taking vibegron. Vesicoureteral reflux, which was confirmed in two patients, was extinguished after taking vibegron. Newly occurring adverse events were not observed, and all patients continued to take vibegron during the treatment period., Conclusions: Favorable efficacy of vibegron for antimuscarinic-resistant neurogenic bladder dysfunction due to spina bifida was shown video-urodynamically without apparent adverse events. Vibegron is a favorable option for the treatment of antimuscarinic-resistant neurogenic bladder dysfunction in patients with spina bifida., (© 2021 The Japanese Urological Association.)

The importance of alveolar macrophages has been reported in many toxicology/immunology studies. Alveolar macrophages release interleukin (IL)-1α as a damage-associated molecular pattern (DAMP) when stimulated by fine particles. However, it is unclear whether cell isolation procedures affect ex vivo particle-induced responses in primary mouse alveolar macrophages (mAM). In this study, effects of injection buffer volume used to perform bronchoalveolar lavage fluid (BALF) collection to isolate mAM for use in ex vivo particle-induced responses were assessed. Among the mAM obtained from BALF collected using a 0.55 or 0.75 ml, but not a 1.0 ml buffer injection volume, decreased cell viability and IL-1α release were observed when cells were stimulated ex vivo with silica crystal or aluminum salt. Injected buffer composition did not affect the IL-1α release. On the other hand, IL-6 secretion induced by lipopolysaccharide (LPS) did not differ among mAM obtained from BALF collected using the different volumes. Expression levels of cell surface markers like CD11c, SiglecF, and CD64 did not differ among mAM obtained from BALF collected using the different injection buffer volumes. IL-1α release (and also necroptosis) induced by ex vivo particle stimulation was suppressed by RIPK3 inhibitor or cytochalasin D co-treatment. Decreases in RIPK3 phosphorylation were noted in mAM obtained in BALF collected using the 1.0 ml injection volume compared with mAM obtained in BALF using 0.55 or 0.75 ml buffer. These observations illustrate that larger volumes of buffer used to collect BALF from mice can affect sensitivity of the isolated mAM to ex vivo particle-induced responses by inhibiting their functions.

Background: Primary hepatic neuroendocrine carcinomas (NECs) are extremely rare. The rate of recurrence after resection is extremely high, and the prognosis is poor. It is debatable whether chemotherapy or surgical resection is the optimal initial treatment for primary hepatic NECs. Therefore, selecting an appropriate therapeutic approach for patients with primary hepatic NECs remains clinically challenging. We present a case of primary hepatic NEC in a patient who developed recurrence after undergoing surgical resection., Case Presentation: A 78-year-old man with bone metastases of prostate cancer was referred to our department because of a solitary 66-mm tumor in the left lateral segment of the liver, which was detected on annual follow-up by computed tomography after prostate resection. A biopsy and preoperative diagnostic workup identified the lesion as a primary hepatic neuroendocrine carcinoma; therefore, left lateral segmentectomy was performed. Immunohistochemically, the tumor was positive for chromogranin A, synaptophysin, and CD 56, and the Ki-67 index was 40%. This neuroendocrine carcinoma was classified as a large cell type. Adjuvant chemotherapy with carboplatin + etoposide was initially administered a month after surgery. However, lymph node recurrence occurred 4 months after surgery, and the patient died of systemic metastases 15 months after surgical resection., Conclusions: Due to the lack of availability of abundant quantities of relevant, high-quality data, there is no standard therapy for primary hepatic NECs. Selecting the most appropriate treatment for patients depending on several factors, such as the stage and differentiation of a tumor and a patient's performance status and clinical course, is consequently preferred. More cases need to be studied to establish the best treatment strategy for primary hepatic NEC., (© 2021. The Author(s).)

We demonstrated pulmonary arteriolar blood flow-mediated CO 2 gas excretion in rabbit lungs. The shear stress stimulation produced CO 2 gas in cultured human endothelial cells of pulmonary arterioles via the activation of F 1 /F o ATP synthase. To confirm the findings in human subjects undergoing the operation with heart-lung machines, we aimed to evaluate the effects of a stepwise switch, from a partial to a complete cardiopulmonary bypass, of the circulatory blood volume (BV, 100% = 2.4 × cardiac index), on the end-expiratory CO 2 pressure (PetCO 2 ), maximal flow velocity in the pulmonary artery (Max Vp), the inner diameter (ID) of pulmonary artery, pulmonary arterial CO 2 pressure (P mix v CO 2 ), pulmonary arterial O 2 pressure (P mix v O 2 ), hematocrit (Hct), pH, the concentration of HCO 3 - , and base excess (BE) in mixed venous blood in 9 patients with a mean age of 72.3 ± 3.4 years. In addition, the effects of the decrease in Hct infused with physiological saline solution (PSS) on PetCO 2 were investigated in the human subjects. An approximately linear relationship between the PetCO 2 and Max Vp was observed. The pumping out of 100% BV produced little or no change in the Hct, pH, P mix v CO 2 , and P mix v O 2 , respectively. The hemodilution produced by intravenous infusion of PSS caused a significant decrease in the Hct, but not in the PetCO 2 . In conclusion, another route of CO 2 gas excretion, independent of red blood cells, may be involved in human lungs., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Resection of liver cancer involving the paracaval portion (PC) of the caudate lobe is challenging because the PC is located deepest in the liver. This study aimed to elucidate the utility of two parenchymal-sparing approaches of limited resection and central hepatectomy for resecting tumors located in the PC., Methods: In 2018 and 2020, 12 out of 143 patients underwent hepatectomy for tumors located in the PC of the liver. In six patients, limited resection (LR) of the PC after full mobilization of the liver off the inferior vena cava (IVC) was performed for tumors excluding the hilar plate or large hepatic veins (large HVs), including major hepatic veins or thick short hepatic veins. In six patients, central hepatectomy (CH) using liver tunnel was performed for tumors involving or close to the hilar plate and/or large HVs., Results: During CH, the surgical view of the cranial side of the hilar plate was wide enough to perform combined resection of the large HVs in front of the IVC. Five of the six CHs were performed with resection of the LHVs. No LRs were accompanied with resection of the LHVs. The CH was associated with longer Pringle's time (76 min vs. 29.5 min, p = 0.015) and blood loss (1104 ml vs. 370 ml, p = 0.041). The preserved liver parenchyma volumes were 82% and 95% of the total liver volume after CH and LR, respectively., Conclusion: Our parenchymal-sparing approach for resection of liver cancer located in the PC is feasible for curative resection., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aluminum hydroxide salts (alum) have been added to inactivated vaccines as safe and effective adjuvants to increase the effectiveness of vaccination. However, the exact cell types and immunological factors that initiate mucosal immune responses to alum adjuvants are unclear. In this study, the mechanism of action of alum adjuvant in nasal vaccination was investigated. Alum has been shown to act as a powerful and unique adjuvant when added to a nasal influenza split vaccine in mice. Alum is cytotoxic in the alveoli and stimulates the release of damage-associated molecular patterns, such as dsDNA, interleukin (IL)-1α, and IL-33. We found that Ag-specific IgA antibody (Ab) production was markedly reduced in IL-33-deficient mice. However, no decrease was observed in Ag-specific IgA Ab production with DNase I treatment, and no decrease was observed in IL-1α/β or IL-6 production in IL-33-deficient mice. From the experimental results of primary cultured cells and immunofluorescence staining, although IL-1α was secreted by alveolar macrophage necroptosis, IL-33 release was observed in alveolar epithelial cell necroptosis but not in alveolar macrophages. Alum- or IL-33-dependent Ag uptake enhancement and elevation of OX40L expression were not observed. By stimulating the release of IL-33, alum induced Th2 immunity via IL-5 and IL-13 production in group 2 innate lymphoid cells (ILC2s) and increased MHC class II expression in antigen-presenting cells (APCs) in the lung. Our results suggest that IL-33 secretion by epithelial cell necroptosis initiates APC- and ILC2-mediated T cell activation, which is important for the enhancement of Ag-specific IgA Ab production by alum., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Splenic vein (SV) ligation combined with portal vein (PV)/superior mesenteric vein (SMV) confluence resection during pancreaticoduodenectomy (PD) is reported to cause left-side portal hypertension (LPH). The purpose of this study was to present our technique of the SV reconstruction and to evaluate the surgical outcomes with/without SV ligation during PD., Methods: Twenty-four patients undergoing PD with PV and/or SMV resection and being followed over 4 months after surgery between March 2013 and December 2019 in our hospital were evaluated. Resection of the PV/SMV confluence were performed in 14, and SV reconstruction was successfully performed in 3. Presence of LPH was assessed by examining changes in splenic volume, newly venous collateral formation, and platelet counts before and 4-8 months after PD. Surgical technique is the direct anastomosis between SV and PV., Results: Splenic volume ratio was significantly higher in the SV ligation group (n = 11) than in the SV preservation group (n = 13) (median (range) 1.11 (0.57-1.62) vs. 1.68 (1.05-2.22), p < 0.01), but no significant differences were found in the incidence of newly formed venous collaterals or platelet counts between groups., Conclusion: SV ligation may represent the cause of LPH after PD combined with resection of PV/SMV confluence. Our simple procedure may help decrease the incidence of LPH., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Background: To clarify whether double-volume peritoneal lavage can decrease the risk of clinically relevant postoperative pancreatic fistula after pancreaticoduodenectomy., Materials and Methods: Forty-nine patients who underwent pancreaticoduodenectomy and intraoperative peritoneal lavage using 6000 mL of saline before abdominal closure were studied retrospectively. Bacterial cultures of the lavage fluid were taken twice, after irrigation using 3000 mL of saline and then after an additional 3000 mL of saline. Bacterial culture of the drainage fluid was taken on day 1, and the relationship between the results of bacterial cultures and clinically relevant postoperative pancreatic fistula was examined., Results: Double amount of peritoneal lavage significantly decreased the incidence of positive bacterial cultures than single amount of peritoneal lavage (45% vs. 29%, P < .05). Multivariate analysis showed that positive bacterial culture of drainage fluid on day 1 and main pancreatic duct size (<3 mm) were independent risk factors for clinically relevant postoperative pancreatic fistula. A positive bacterial culture of the final lavage fluid and preoperative biliary drainage were independent factors related to a positive bacterial culture on day 1., Discussion: A positive bacterial culture on day 1 is an independent risk factor for clinically relevant postoperative pancreatic fistula during pancreaticoduodenectomy. Double-volume intraperitoneal lavage may be effective for reducing the incidence of clinically relevant postoperative pancreatic fistula.

Background: We previously developed the Japanese version of The Quality of Life Assessment of Spina Bifida in Teenagers, a health-related quality-of-life instrument specific to children aged 13-17 years with spina bifida (SB). The Quality of Life Assessment of Spina Bifida in Children is a version of this questionnaire for children aged 8-12 years. The purpose of this study was to develop a Japanese version of the Quality of Life Assessment of Spina Bifida in Children (QUALAS-C-J) and verify its reliability and validity., Methods: Three urologists specializing in SB, 2 nurses, and 1 statistician developed the QUALAS-C-J and conducted a pilot and main survey. Participants included children with SB and non-disabled (ND) children. Participants completed the QUALAS-C-J and the Japanese version of KIDSCREEN-27 (J-KIDSCREEN) without parental help., Results: Five children with SB participated in the pilot study and provided face and content validity. Sixty-three children with SB and 40 age- and sex-matched ND children participated in the main survey. The intraclass correlation coefficient in the retest was 0.80, and Cronbach's alpha in each domain was 0.73. The validity was verified by factor analysis, convergent / divergent validity, and known-groups validity. Factor analysis converged to the same two-factor structure as the original version. The correlation between QUALAS-C-J and J-KIDSCREEN-27 was weak (r=-0.06-0.30). The scores of both groups for the two domains of the QUALAS-C-J were significantly lower in SB than ND children., Conclusions: QUALAS-C-J is easy to answer, suitable for Japanese children with SB, reliable, and valid. It can be a communication tool for children with SB, medical staff, families, communities, and school teachers., (© 2020 Japan Pediatric Society.)

A 38-year-old woman with neurogenic bladder caused by myelomeningocele,who had been on clean intermittent self-catheterization for years,complained of gross hematuria. Computerized tomography, urinary cytology and cystoscopy failed to reveal causative lesions and the hematuria ceased spontaneously. Because gross hematuria recurred 2 years later,we examined the patient again and detected calcification of the urinary bladder. Mucosal lesions suspicious of bladder tumor were detected during the transurethral surgery for the calcified lesion,and we promptly performed biopsy. As a result,she was diagnosed with invasive bladder squamous cell carcinoma. Radical cystectomy and urinary diversion were performed and the histopathological diagnosis was pT3aN0. Adjuvant therapies were not performed. No recurrence has been observed for 36 months after the surgery.

Background: A history of preoperative obstructive pyelonephritis has been reported as a risk factor for febrile urinary tract infection (fUTI) after ureteroscopic lithotripsy (URSL). But there is no clear evidence of risk factors for developing fUTI including the optimal timing of URSL after obstructive pyelonephritis treatment., Methods: Of the 1361 patients, who underwent URSL at our hospital from January 2011 to December 2017, 239 patients had a history of pre-URSL obstructive pyelonephritis. The risk factors were analyzed by comparing the patients' backgrounds with the presence or absence of fUTI after URSL. The factors examined were age, gender, body mass index, comorbidity, presence or absence of preoperative ureteral stent, stone position, stone laterality, stone size, Hounsfield unit (HU) value on computed tomography scan, history of sepsis during obstructive pyelonephritis, period from antipyresis to URSL, ureteral stenting period, operation time, and presence or absence of access sheath at URSL. In addition, the stone components and renal pelvic urinary culture bacterial species during pre-URSL pyelonephritis were also examined., Results: Post-URSL fUTI developed in 32 of 239 patients (13.4%), and 11 of these 32 cases led to sepsis (34.4%). Univariate analysis showed that stone position, stone maximum HU value, presence of sepsis during obstructive pyelonephritis, period from antipyresis to URSL, pre-URSL ureteral stent placement, operation time were risk factors of fUTI. Stone components and urinary cultures during pyelonephritis were not associated with risk of fUTI. Multivariate analysis showed that renal stone position, pre-URSL ureteral stent placement > 21 days, and operation time > 75 min were independent risk factors of fUTI following the URSL., Conclusions: F-UTI following the URSL could be avoided by ureteral stent placement period 21 days or less and operation time 75 min or less in patients with obstructive pyelonephritis.

Background/purpose: We invented a sensor sheet with multiple electromyogram electrodes, which can be easily attached to the front of the neck, to evaluate surface electromyograms (sEMG) during swallowing function. In this paper, we evaluated sEMG in healthy volunteers and dysphagia patients using the sensor sheet and discussed its potential to evaluate swallowing function., Materials and Methods: Ten healthy volunteers (age, 29.5 ± 3.9 years) and 18 clinically diagnosed dysphagia patients (age, 67.8 ± 12.1 years) were included. The sensor sheet had four pairs of electrodes, and sEMG at the suprahyoid muscles (positions A and B) and the infrahyoid muscles (positions C and D) were recorded while swallowing water, thickened water, yogurt, and jelly; sEMG findings were compared between these positions., Results: Significant differences in the duration of muscle activity was observed when swallowing yogurt at position D and when swallowing jelly, thickened water, and water at position B (Mann-Whitney U test, p < 0.05). In healthy volunteers, muscle activation typically began from positions A or B to position D, whereas in dysphagia patients, it sometimes began from position D., Conclusion: There were significant differences in duration and sequence patterns of four sEMG activities between healthy young volunteers and dysphagia patients in the assessment using the sensor sheet, although some technical and scientific problems remained unresolved. These results indicate that swallowing function could be evaluated using the sensor sheet., Competing Interests: The institution of the authors (Shinshu University, Nagano Prefecture, SKINOS) have issued a patent (Patent number 6073709) issued and have the following pending patents: Patent publication number JP 2016-154857, JP 2018-029634, and JP 2018-134125. Mr. Momose is chief executive officer of SKINOS. The authors declare no conflicts of interest other than above., (© 2020 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

Major hepatectomy in patients with insufficient future liver remnant (FLR) volume and impaired liver functional reserve has considerable risks for posthepatectomy liver failure (PHLF). The patient was a male in his 70s with an intrahepatic cholangiocarcinoma in left hemiliver, involving the middle hepatic vein (MHV). Although FLR volume after left hemihepatectomy was estimated to be 64.4% of the total liver volume, an indocyanine green retention rate at 15 min (ICG-R15) value was 24.2%, thus the patient underwent left portal vein embolization. The FLR volume increased to 71.3%; however, the noncongestive FLR volume was re-estimated as 45.8% after resection of the MHV, the ICG-R15 value was 29.0%, and ICG-Krem was calculated as 0.037. We performed partial rescue Associating Liver Partition and Portal vein occlusion for Staged hepatectomy (ALPPS) for left hemihepatectomy with the MHV reconstruction. On the first stage, partial liver partition was done along Rex-Cantlie's line, preserving the MHV and sacrificing the remaining branches to segment 8. The FLR volume increased to 77.4% on day 14. The ICG-R15 value was 29.6%, but ICG-Krem after MHV reconstruction was estimated to be 0.059. The second-stage operation on day 21 was left hemihepatectomy with the MHV reconstruction using the left superficial femoral vein graft. The usage of rescue partial ALPPS may contribute to preventing PHLF by introducing occlusion of the portal and/or venous branches in the left hemiliver before curative hepatectomy., (© 2021 S. Karger AG, Basel.)

A 50-year-old man demonstrated markedly increased number of white blood cells, anemia, severe splenomegaly, and bleeding tendency. Bone marrow analysis revealed remarkable hypercellularity; dysplasia in multilineage cells, including megakaryocytes; and fibrosis. He was eventually diagnosed with triple-negative myelofibrosis. A massive hematoma developed at the bone marrow biopsy site. A similar episode recurred after the second bone marrow biopsy. The von Willebrand factor and other coagulation factor activities were within normal ranges. Platelet aggregation analyses demonstrated highly impaired aggregation induced by ADP, collagen, and epinephrine. Treatment with hydroxyurea and ruxolitinib, a JAK inhibitor, was ineffective, and he eventually died on day 144 after hospitalization. Acquired platelet dysfunction uncommonly occurs in patients with myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), without precise elucidation of the frequency and underlying mechanism. The onset of bleeding tendency in the current patient suggested that platelet dysfunction may be caused by somatic genetic events. Here, we discuss the mechanisms of acquired platelet dysfunction in MDS or MPN with a literature review.

Objective: We previously developed genitourinary (GU) cancer-specific scoring system for prediction of survival in patients with bone metastasis (the Bone-Fujimoto-Owari-Miyake [B-FOM] scoring model) based on five prognostic factors: the type of primary tumor (prostate cancer (PCa) vs renal cell carcinoma (RCC) and PCa vs urothelial carcinoma (UC)), poor performance status (PS), visceral metastasis, high Glasgow-prognostic score (GPS), elevated neutrophil-to-lymphocyte ratio (NLR). The aim of this study was to externally validate and further improve the performance of the B-FOM score., Methods: The external validation cohort comprised 309 patients with GU cancer with bone metastasis from multiple institutions. Clinical factors were analyzed using Kaplan-Meier method and COX regression hazard model. Performance of a modified B-FOM score was compared to that of other scoring models by the Kaplan-Meier method and the area under the curve (AUC) of receiver operating characteristic curves., Results: The median follow-up period of development and validation cohort were 25 and 17 months, respectively. Kaplan-Meier curve demonstrated that the type of primary tumor (RCC and UC vs PCa), poor PS, presence of visceral metastasis, high GPS, elevated NLR were significantly associated with shorter cancer-specific survival. Risk groups were successfully stratified by the modified B-FOM score classification. Moreover, the AUC of the modified B-FOM scoring model for predicting mortality at 6, 12, and 24 months were 0.895, 0.856, and 0.815, respectively, which were the highest among evaluated models., Conclusions: The B-FOM scoring model is a simple and accurate prediction tool. By using this scoring model at the time of the diagnosis of bone metastasis in patients with GU cancers, an individualized optimal treatment strategy can be selected., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Authors.)

We previously constructed a perspiration ratemeter for the measurement of palmar sweating in human subjects. Although galvanic skin response (GSR) has been used to evaluate emotional responses in human subjects, little is known about the relationships between the phasic and baseline components in GSR and active palmar sweating. From the aforementioned, we aimed to investigate the relationships in human subjects with handgrip exercise and eyes closing or opening. Fifteen healthy volunteers (mean age: 26.9 ± 8.7 years) participated in the present experiments. We investigated the effects of maximal handgrip exercise, eyes closing or opening, and self-awareness of drowsy on the GSR, active palmar sweating, R-R interval in electrocardiograph (ECG), and percentage of α wave in EEG. The faster phasic component in GSR completely agreed with the starting point of active palmar sweating. Handgrip exercise induced significantly faster spike in GSR, active palmar sweating, and decrease in R-R interval in ECG. Eyes closing produced significant decreases in baseline GSR and active palmar sweating in all human subjects. The percentage of α wave in electroencephalograph (EEG) also increased. In contrast, eyes opening increased significantly the baseline GSR and active palmar sweating. In the equivalent electrical model of human skin, the eyes closing-mediated time-dependent decrease in the baseline GSR completely agreed with the hypothesis that the palmar skin voltage only in the model decreased time dependently to 0.4 of the control during 6 min. The self-awareness of drowsy in mid-night working with computer produced similar decreases in baseline GSR and active palmar sweating to the responses with eyes closing in all human subjects. In conclusion, the faster spike in GSR completely agreed with the starting point of active palmar sweating. Eyes closing and opening or self-awareness of drowsy significantly produced changes in baseline GSR and active palmar sweating, which may become useful tools for evaluating clearness or drowsiness in human subjects., Competing Interests: HM was employed by company SKINOS Co., Ltd. NM and EI were employed by company Rubycon Co., Ltd. SK was employed by company NEC Solution Innovators Co., Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Momose, Morimitsu, Ikeda, Kanai, Sakaguchi and Ohhashi.)

DNA methylation is an important epigenetic change that is biologically meaningful and a frequent focus of cancer research. Genome-wide DNA methylation is a useful measure to provide an accurate analysis of the methylation status of gastrointestinal (GI) malignancies. Given the multiple potential translational uses of DNA methylation analysis, practicing clinicians and others new to DNA methylation studies need to be able to understand step by step how these genome-wide analyses are performed. The goal of this protocol is to provide a detailed description of how this method is used for the biomarker identification in GI malignancies. Importantly, we describe three critical steps that are needed to obtain accurate results during genome-wide analysis. Clearly and concisely written, these three methods are often lacking and not noticeable to those new to epigenetic studies. We used 48 samples of a GI malignancy (gastric cancer) to highlight practically how genome-wide DNA methylation analysis can be performed for GI malignancies.

The efficacy of vaccine adjuvants depends on their ability to appropriately enhance the immunogenicity of vaccine antigens, which is often insufficient in non-adjuvanted vaccines. Genomic analyses of immune responses elicited by vaccine adjuvants provide information that is critical for the rational design of adjuvant vaccination strategies. In this study, biomarker genes from the genomic analyses of lungs after priming were used to predict the efficacy and toxicity of vaccine adjuvants. Based on the results, it was verified whether the efficacy and toxicity of the tested adjuvants could be predicted based on the biomarker gene profiles after priming. Various commercially available adjuvants were assessed by combining them with the split influenza vaccine and were subsequently administered in mice through nasal inoculation. The expression levels of lung biomarker genes within 24 h after priming were analyzed. Furthermore, we analyzed the antibody titer, cytotoxic T lymphocyte (CTL) induction, IgG1/IgG2a ratio, leukopenic toxicity, and cytotoxicity in mice vaccinated at similar doses. The association between the phenotypes and the changes in the expression levels of biomarker genes were analyzed. The ability of the adjuvants to induce the production of antigen-specific IgA could be assessed based on the levels of Timp1 expression. Furthermore, the expression of this gene partially correlated with the levels of other damage-associated molecular patterns in bronchoalveolar lavage fluid. Additionally, the changes in the expression of proteasome- and transporter-related genes involved in major histocompatibility complex class 1 antigen presentation could be monitored to effectively assess the expansion of CTL by adjuvants. The monitoring of certain genes is necessary for the assessment of leukopenic toxicity and cytotoxicity of the tested adjuvant. These results indicate that the efficacy and toxicity of various adjuvants can be characterized by profiling lung biomarker genes after the first instance of immunization. This approach could make a significant contribution to the development of optimal selection and exploratory screening strategies for novel adjuvants., (Copyright © 2020 Sasaki, Asanuma, Momose, Furuhata, Mizukami and Hamaguchi.)

Approximately 10-20 million of Human T-cell leukemia virus type-1 (HTLV-1)-infected carriers have been previously reported, and approximately 5% of these carriers develop adult T-cell leukemia/lymphoma (ATL) with a characteristic poor prognosis. In Japan, Southern blotting has long been routinely performed for detection of clonally expanded ATL cells in vivo, and as a confirmatory diagnostic test for ATL. However, alternative methods to Southern blotting, such as sensitive, quantitative, and rapid analytical methods, are currently required in clinical practice. In this study, we developed a high-throughput method called rapid amplification of integration site (RAIS) that could amplify HTLV-1-integrated fragments within 4 h and detect the integration sites in > 0.16% of infected cells. Furthermore, we established a novel quantification method for HTLV-1 clonality using Sanger sequencing with RAIS products, and the validity of the quantification method was confirmed by comparing it with next-generation sequencing in terms of the clonality. Thus, we believe that RAIS has a high potential for use as an alternative routine molecular confirmatory test for the clonality analysis of HTLV-1-infected cells.

Repeat hepatectomy for recurrent colorectal liver metastases (CRLM) for the remnant hemiliver is sometimes challenging due to the insufficient future liver remnant (FLR) volume. We present an aggressive strategy for resection of the recurrent CRLM involving bisegmentectomy of the remnant right hemiliver with the aid of portal vein embolization (PVE) and venous reconstruction. The patient was a 50-year-old woman who had undergone left hemihepatectomy for a CRLM 10 months ago. Three metastatic tumors were found in the remnant segments 7 and 8 (S7&8) of the liver, and one of them involved the right hepatic vein (RHV). Conducting bisegmentectomy of S7&8 with resection of the RHV, the non-congestive FLR volume was calculated as 34.9% of the remnant total liver volume, which was deemed insufficient considering the mild liver damage after repeated chemotherapy. After trans-ileocecal PVE of the portal branches in S7&8 in a hybrid angio room, the non-congestive FLR volume increased to 42.3%, which could be further advanced to 58.0% if the RHV was reconstructed. Segmentectomies of S7&8 with resection and reconstruction of the RHV using the right superficial femoral vein graft was performed. The patient was discharged without any complications, and the postoperative computed tomography (CT) scan showed the good patency of the reconstructed venous graft. Aggressive segmentectomies and venous reconstruction of the remnant hemiliver after PVE might be a new strategy to overcome the insufficient FLR volume., Competing Interests: Funding: None. Conflict of Interest: The authors have no competing interests to declare. Author Contribution: Study conception and design: Yoshihiro Sakamoto; Acquisition of data: Ryota Matsuki, Yutaka Suzuki, Masaharu Kogure, Hirokazu Momose; Analysis and interpretation of data and Drafting of manuscript: Ryota Matsuki; Critical revision of manuscript: Yoshihiro Sakamoto., (© 2020 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterology.)

Recurrent hotspot (p.Gly17Val) mutations in RHOA encoding a small GTPase, together with loss-of-function mutations in TET2 encoding an epigenetic regulator, are genetic hallmarks of angioimmunoblastic T-cell lymphoma (AITL). Mice expressing the p.Gly17Val RHOA mutant on a Tet2 -null background succumbed to AITL-like T-cell lymphomas due to deregulated T-cell receptor (TCR) signaling. Using these mice to investigate therapeutics for AITL, we found that dasatinib, a multikinase inhibitor prolonged their survival through inhibition of hyperactivated TCR signaling. A phase I clinical trial study of dasatinib monotherapy in 5 patients with relapsed/refractory AITL was performed. Dasatinib was started at a dose of 100 mg/body once a day and continued until days 10-78 (median day 58). All the evaluable patients achieved partial responses. Our findings suggest that AITL is highly dependent on TCR signaling and that dasatinib could be a promising candidate drug for AITL treatment. SIGNIFICANCE: Deregulated T-cell receptor signaling is a critical molecular event in angioimmunoblastic T-cell lymphoma and can be targeted with dasatinib., (©2020 American Association for Cancer Research.)

Background: Spina bifida (SB) is the second-most common birth defect in Japan. In recent years, health-related quality of life measurements have been used to assess the psychosocial status of children with SB. The Quality of Life Assessment of Spina Bifida in Teenagers (QUALAS-T) is a self-reported questionnaire for subjects aged 13-17 years with SB. It focuses particularly on factors related to independence, bladder and bowel. The purpose of this study was to develop and validate a Japanese version of QUALAS-T (QUALAS-T-J)., Methods: Three urologists specialized in SB, two nurses, one statistician, and the author of the original version developed the QUALAS-T-J. Subjects with SB completed the QUALAS-T-J and the Japanese version of KIDSCREEN-27 (J-KIDSCREEN-27) independently from their parents., Results: A pilot study involving seven adolescents with SB and confirmed face and content validity. Sixty-nine adolescents with SB participated in the main survey. The intraclass correlation coefficient in the retest was 0.77, and Cronbach's alpha in each domain was 0.83 and 0.79. Validity was verified on factor analysis and convergent/divergent validity. Five items converged in the one domain, Bladder and Bowel. The remaining five items converged in the concept of Family and Independence. The correlation between each domain of the QUALAS-T-J and J-KIDSCREEN-27 was low-moderate., Conclusion: The reliability and validity of the QUALAS-T-J were verified in Japanese adolescents with SB. The QUALAS-T-J would be a useful tool for communication between adolescents with SB and medical staff., (© 2019 Japan Pediatric Society.)

A 40-year-old man complaining of voiding symptoms was referred to our hospital for further examinations and treatment of giant bladder diverticulum and possibly underlying neurogenic bladder dysfunction. Because computed tomography and magnetic resonance imaging revealed the presence of a tumorous lesion covering the bladder diverticulum, transurethral biopsy was performed to elucidate its pathological characteristics. Through the histopathological examination of the biopsy specimens the tumorous lesion was diagnosed as ganglioneuroma which was benign. The whole diverticulum with the concomitant tumor lesion was surgically excised. Full examination of the surgical specimen concluded the final histopathological diagnosis of the tumor to be plexiform neurofibroma. As multiple café-au-lait spots were found on the patient's skin, he was clinically diagnosed with neurofibromatosis type 1.

The safety evaluation of vaccines is critical to avoid the development of side effects in humans. To increase the sensitivity of detection for toxicity tests, it is important to capture not only pathological changes but also physiological changes. 1 H nuclear magnetic resonance (NMR) spectroscopy analysis of biofluids produces profiles that show characteristic responses to changes in physiological status. In this study, mouse urine metabolomics analysis with 1 H NMR was performed using different influenza vaccines of varying toxicity to assess the usefulness of 1 H NMR in evaluating vaccine toxicity. Two types of influenza vaccines were used as model vaccines: a toxicity reference vaccine (RE) and a hemagglutinin split vaccine. According to the blood biochemical analyses, the plasma alanine transaminase levels were increased in RE-treated mice. Changes in metabolite levels between mice administered different types of influenza vaccines were observed in the 1 H NMR spectra of urine, and a tendency toward dosage-dependent responses for some spectra was observed. Hierarchical clustering analyses and principal component analyses showed that the changes in various urine metabolite levels allowed for the classification of different types of vaccines. Among them, two liver-derived metabolites were shown to largely contribute to the formation of the cluster. These results demonstrate the possibility that urine metabolomics analysis could provide information about vaccine-induced toxicity and physiological changes.

We intend to develop earphone-type wearable devices to measure occlusal force by measuring ear canal movement using an ear sensor that we developed. The proposed device can measure occlusal force during eating. In this work, we simultaneously measured the ear canal movement (ear sensor value), the surface electromyography (EMG) of the masseter muscle and the occlusal force six times from five subjects as a basic study toward occlusal force meter development. Using the results, we investigated the correlation coefficient between the ear sensor value and the occlusal force, and the partial correlation coefficient between ear sensor values. Additionally, we investigated the average of the partial correlation coefficient and the absolute value of the average for each subject. The absolute value results indicated strong correlation, with correlation coefficients exceeding 0.9514 for all subjects. The subjects showed a lowest partial correlation coefficient of 0.6161 and a highest value of 0.8286. This was also indicative of correlation. We then estimated the occlusal force via a single regression analysis for each subject. Evaluation of the proposed method via the cross-validation method indicated that the root-mean-square error when comparing actual values with estimates for the five subjects ranged from 0.0338 to 0.0969., Competing Interests: The authors declare no conflict of interest.

Background: For the diagnosis of hepatitis B virus (HBV) infection, the detection and quantification of hepatitis B surface antigen (HBsAg) and HBV DNA are used. Several kits are available for this purpose, and there is a growing need for the evaluation of these kits because their performance may be affected by HBV genotype- or strain-specific polymorphisms., Objectives and Study Design: In this study, we used International Standards and the established regional reference panel to evaluate the performance of two HBV DNA quantitative kits, five HBsAg qualitative kits, seven HBsAg quantitative kits and three rapid immune-chromatographic tests for HBsAg., Results: The quantification values of two HBV DNA quantitative kits exhibited excellent correlation. In the evaluation of HBsAg qualitative and quantitative kits, the titers of several specimens in the HBV-positive panel were below the detection limits of a few kits, and the specimens were determined as HBV-negative. Notably, the quantitative kit results exhibited low correlation values. However, when these data were analyzed for each genotype, the correlations improved. These results suggest that the HBsAg quantification data are influenced by HBV genotypes. The novel rapid immune-chromatographic test exhibited the comparable level of sensitivity to the HBsAg quantitative kits., Conclusions: We evaluated the performance of kits for the detection of HBV infection. The HBV DNA quantification data correlated with an excellent agreement, whereas the HBsAg quantification data were affected by HBV genotype. Such evaluations will be useful for estimating the quality of currently available and new HBV assay kits, and for the quality control of these kits., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: To evaluate the clinical benefit of bone-modifying agents and identify the risk factors of skeletal-related events in patients with genitourinary cancer with newly diagnosed bone metastasis., Methods: This was a multicenter retrospective study including a total of 650 patients with bone metastasis of the following cancer types: hormone-sensitive prostate cancer (n = 443), castration-resistant prostate cancer (n = 50), renal cell carcinoma (n = 80) and urothelial carcinoma (n = 77). Clinical factors at the time of diagnosis of bone metastasis were analyzed. Early treatment with bone-modifying agents was defined as follows: administration of bone-modifying agents before the development of skeletal-related events and within 6 months from the diagnosis of bone metastasis., Results: During the follow-up period (median 19.0 months, interquartile range 6.0-43.8 months), skeletal-related events were reported in 88 (20%) patients with hormone-sensitive prostate cancer, 17 (34%) patients with castration-resistant prostate cancer, 58 (73%) patients with renal cell carcinoma and 34 (44%) patients with urothelial carcinoma. Early treatment with bone-modifying agents significantly prolonged the time to the first skeletal-related event in castration-resistant prostate cancer, renal cell carcinoma and urothelial carcinoma, but not in hormone-sensitive prostate cancer. Bone pain and elevated alkaline phosphatase levels were independent predictive risk factors of the first skeletal-related event. The subgroup analysis showed that early treatment with bone-modifying agents was associated with prolonged time to the first skeletal-related events in patients with bone pain or elevated alkaline phosphatase levels., Conclusions: Early treatment with bone-modifying agents should be considered, especially for patients with bone pain and elevated alkaline phosphatase levels, to prevent skeletal-related events in patients with genitourinary cancer with bone metastasis., (© 2019 The Japanese Urological Association.)

We report a case of systemic chemotherapy after biliary stent placement for obstructive jaundice due to hepatic portal lymph node metastasis after colorectal cancer surgery. The patient was a 40s woman. Laparoscopic anterior resection for rectosigmoidRS cancer was performed. The pathological diagnosis was T3N0M0PUL0R0, pStage Ⅱ according to the 8th edition of colorectal cancer handling regulations. Because multiple liver metastases were observed 8 months after the surgery, partial resection of the posterior region of the liver was performed. Multiple lung metastases were observed 1 year after hepatectomy, but she wantedto undergo follow-up observation. Jaundice was observed 1 year after the diagnosis of lung metastasis, and obstructive jaundice due to hepatic portal lymph node metastasis was diagnosed. Endoscopic retrograde biliary drainage(ERBD)was performed, and a bile duct stent was placed. After improving jaundice, 12 courses of mFOLFOX6 plus cetuximab therapy were performed. Currently, because of the exacerbation of lung metastasis, FOLFIRI plus bevacizumab therapy is being administered. Systemic chemotherapy containing a molecular-targeted drug is being administered in our case, but complications relatedto the biliary stent have not been observed. There are few reports on similar cases, andfollow - up observation with careful attention to long-term safety is necessary.

We report a case of misdirection of a catheter for clean intermittent catheterization (CIC) into the ureter. A four-year-old girl with neurogenic bladder due to myelomeningocele had been managed with CIC by her parents for several years. From about a month before her visit, macroscopic hematuria appeared intermittently followed by abdominal pain and fever-up for a short time which ceased spontaneously. As cystography demonstrated bilateral vesicoureteral reflux, we performed endoscopic intraureteral injection of Deflux[TM] and during the operation we confirmed influx of bloody urine from the right ureteral orifice but not from the left one. As computed tomography revealed a tubular foreign body located in the upper portion of the right ureter, another endoscopic operation was performed and it was removed successfully. The removed foreign body was identified as a disposable catheter that was used for CIC.

Background: Retroperitoneal tumors are an uncommon disease known to consist of a diverse group of benign and malignant neoplasms. Treatment of unresectable retroperitoneal lesions requires pathological diagnosis. Here, we report the utility and safety of retroperitoneoscopic biopsy for unresectable retroperitoneal lesions excluding urogenital cancers., Methods: We analyzed 47 patients consisting of 23 (49%) and 24 (51%) cases that underwent retroperitoneoscopic tissue biopsy and open biopsy, respectively. The clinicopathological features, including postoperative complications, were compared between the two groups., Results: Tumor pathology was diagnosed successfully with a single operation in all patients. Malignant pathology (68%) was more common than benign pathology (32%). The most common pathology was malignant lymphoma, which accounted for about 50% of all cases. There was no significant difference with respect to the age, sex, tumor size, presence of tumor-related symptom, histopathology, operative time, and complications. Three (13%) of 23 patients in the retroperitoneoscopic biopsy group received percutaneous needle biopsy before laparoscopic excisional biopsy because the evaluation of needle cores failed to confirm subclasses of diagnosed pathologies. One patient was converted to open surgery just after the initiation of operation due to severe adhesion of adjacent structures. We had two cases with iatrogenic urinoma due to ureteral injury after retroperitoneoscopic biopsy., Conclusions: We conclude that retroperitoneoscopic biopsy is a safe and useful tool for benign and malignant retroperitoneal lesions, in comparison to open biopsy. It is critical to carefully examine the preoperative imaging for the location of tumors, especially those close to the renal pelvis and ureter.

A 84-year-old female visited our hospital with the chief complaint of asymptomatic gross hematuria. The computed tomography and magnetic resonance imaging revealed a large invasive tumor in the right renal pelvis. Metastatic workup was negative. On imaging studies and voided urine cytology, diagnosis of right renal pelvic cancer (cT3N0M0) was made. Laparoscopic right nephroureterectomy was performed. Histopathological examinations revealed a small cell carcinoma of the renal pelvis. The patient declined adjuvant chemotherapy and died 5 months after surgery. Primary small cell carcinoma of the renal pelvis is a rare disease. To our knowledge, this is the 29th case of primary small cell carcinoma of the renal pelvis in the world literature.

A 75-year-old man, highly suspected as having malignant lymphoma originating from his left testis, underwent exploratory orchiectomy for a definitive diagnosis. Laboratory examinations before the surgery showed high lactate dehydrogenase (652 IU/l), elevated serum creatinine level (1.85 mg/dl) and sIL-2R level (8,930 U/ml). As the postoperative course passed uneventfully, the patient was discharged from the hospital on the eighth day after the surgery. Ten days after the surgery the patient was transferred to the emergency room of the hospital complaining of severe abdominal pain and malaise. Laboratory examinations revealed highly elevated lactate dehydrogenase (2,807 IL/l), uric acid (24.9 mg/dl) and serum creatinine (5.31 mg/dl). Computed tomography demonstrated rapid growth of the retroperitoneal mass and occurrence of bilateral hydronephroses. Under the diagnosis of spontaneous tumor lysis syndrome, the patient was urgently treated with hemodialysis, steroidal pulse and rituximab following percutaneous nephrostomy for the right kidney. After improvement of the laboratory data, the patient was transferred to another hospital for the treatment of malignant lymphoma.

Vaccines are inoculated in healthy individuals from children to the elderly, and thus high levels of safety and consistency of vaccine quality in each lot must meet the required specifications by using preclinical and lot release testing. Because vaccines are inoculated into humans, recapitulation of biological reactions in humans should be considered for test methods. We have developed a new method to evaluate the safety of influenza vaccines using biomarker gene expression in mouse and rat models. Some biomarker genes are already known to be expressed in human lymphocytes, macrophages and dendritic cells; therefore, we considered some of these genes might be common biomarkers for human and mice to evaluate influenza vaccine safety. In this study, we used human peripheral blood mononuclear cells (PBMC) as a primary assessment tool to confirm the usefulness of potential marker genes in humans. Analysis of marker gene expression in PBMC revealed biomarker gene expressions were dose-relatedly increased in toxic reference influenza vaccine (RE)-stimulated PBMC. Although some marker genes showed increased expression in hemagglutinin split vaccine-stimulated PBMC, their expression levels were lower than that of RE in PBMC from two different donors. Many marker gene expressions correlated with chemokine production. Marker genes such as IRF7 were associated with other Type 1 interferon (IFN)-associated signals and were highly expressed in the CD304 + plasmacytoid dendritic cell (pDC) population. These results suggest PBMC and their marker genes may be useful for vaccine safety evaluation in humans.

Vaccines effectively prevent infectious diseases. Many types of vaccines against various pathogens that threaten humans are currently in widespread use. Recently, adjuvant adaptation has been attempted to activate innate immunity to enhance the effectiveness of vaccines. The effectiveness of adjuvants for vaccinations has been demonstrated in many animal models and clinical trials. Although a highly potent adjuvant tends to have high effectiveness, it also has the potential to increase the risk of side effects such as pain, edema, and fever. Indeed, highly effective adjuvants, such as poly(I:C), have not been clinically applied due to their high risks of toxicity in humans. Therefore, the task in the field of adjuvant development is to clinically apply highly effective and non- or low-toxic adjuvant-containing vaccines. To resolve this issue, it is essential to ensure a low risk of side effects and the high efficacy of an adjuvant in the early developmental phases. This review summarizes the theory and history of the current safety assessment methods for adjuvants, using the inactivated influenza vaccine as a model. Our novel method was developed as a system to judge the safety of a candidate compound using biomarkers identified by genomic technology and statistical tools. A systematic safety assessment tool for adjuvants would be of great use for predicting toxicity during novel adjuvant development, screening, and quality control., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Influenza becomes epidemic worldwide every year, and many individuals receive vaccination annually. Quality control relating to safety and potency of influenza vaccines is important to maintain public confidence. The safety of influenza vaccines has been assessed by clinical trials, and animal safety tests are performed to monitor the consistent quality between vaccines used for clinical trials and marketing; the biological responses in vaccinated animals are evaluated, including changes in body weight and white blood cell count. Animal safety tests have been contributing to the quality relating to the safety of influenza vaccines for decades, but improvements are needed. Although precise mechanisms involving biological changes in animal safety tests have not been fully elucidated, the application of cDNA microarray technology make it possible to reliably identify genes related to biological responses in vaccinated animals. From analysis of the expression profile of >10,000 genes of lung in animals treated with an inactivated whole virion influenza vaccine, we identified 17 marker genes whose expression patterns correlated well to changes in body weight and leukocyte count in vaccinated animals. In influenza HA vaccine-treated animals exhibiting subtle changes in biological responses, a robust expression pattern of marker genes was found. Furthermore, these marker genes could also be used in the evaluation of adjuvanted influenza vaccines. The expression profile of marker genes is expected to be an alternative indicator for safety control of various influenza vaccines conferring high sensitivity and short turnaround time. Thus, gene expression profiling may be a powerful tool for safety control of vaccines in the future., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Recently, many vaccine adjuvants have been developed; however, most of the newly developed adjuvants have been dropped out of preclinical and clinical trials owing to their unexpected toxicity. Thus, the development of highly quantitative and comparable screening methods for evaluating adjuvant safety is needed. In a previous study, we identified specific biomarkers for evaluating the safety of an intranasal influenza vaccine with CpG K3 adjuvant by comparing biomarker expression. We hypothesized that these biomarkers might be useful for screening newly developed adjuvant safety. We compared the expression of biomarkers in mouse lungs by the intranasal administration of 4 types of adjuvants: Alum, Pam 3 CSK 4 , NanoSiO 2 , and DMXAA with subvirion influenza vaccine. The control adjuvant alum did not show any significant increase in biomarker expression or preclinical parameters; however, NanoSiO 2 and Pam 3 CSK 4 increased the expression of biomarkers, such as Timp1 and Csf1. DMXAA at 300 μg induced the expression of over 80% of biomarkers. Hierarchical clustering analysis showed that 300 μg DMXAA was classified in the toxicity reference whole-particle influenza vaccine cluster. FACS analysis to confirm specific phenotypes that the number of T cells decreased in DMXAA-treated mouse lungs. Thus, our biomarkers are useful for initial adjuvant safety and toxicity screening., (Copyright © 2018 International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.)