Pathological analysis of spermatic dysfunction following testicular ischemia-reperfusion injury\n

　Introduction & Objectives: Torsion, which may result in testicular ischemia, requires emergency surgery to restore testicular blood flow. However, the risk of spermatic dysfunction remains even if surgery is performed. The pathology of spermatic dysfunction in testicular ischemia-reperfusion injury (TIRI) remains unclear. A previous study showed the relevance of inflammation and oxidative stress in the other organs of ischemia-reperfusion injury. We hypothesized that inflammation and oxidative stress play key roles in causing spermatic dysfunction following TIRI. We investigated the pathophysiology of spermatic dysfunction in TIRI focusing on inflammatory changes using TIRI model mice.　Materials and Methods: The study used C57BL/6J male mice aged 10 to 15 weeks. To create TIRI model mice, the unilateral (left side) testicular vessels were clamped using Dieffenbach clamps (Bulldog clamps) for 1 hour and de-clamped. The bilateral testes were removed at 0 (ischemic state), 1, 3, and 5 weeks after creating the TIRI model mice. Spermatic changes following TIRI were investigated by analyzing the histology of the testes and semen and assessing levels of inflammation and oxidative stress. Semen was collected from the bilateral cauda epididymites and investigated using the sperm motility analysis system (SMAS).　Results: Histological analysis after hematoxylin-eosin staining showed tissue thickening in interstitial tissues at week 1 and 3 on the left (affected) testis, and week 1, 3 and 5 on the right (unaffected) testis. The infiltration of lymphocytes-predominant inflammatory cells were observed at week 1 and week 3 on the left (affected) testis. The destruction of ductal structures and giant cells were observed at weeks 3 and 5 on the left (affected) testis and week 5 on the right (unaffected) testis. SMAS showed significantly decreased spermatic concentration and motility in both testes of TIRI model mice compared with those of sham-operated mice at weeks 1, 3 and 5. Inflammation analysis using an inflammation-related proteome assay showed significantly increased levels of cytokines (IL-2, IL-3, IL-17A, and IL-23) and chemokines (CCL2, CCL5, CXCL1, and CX3CL1) at weeks 1, 3, and 5 in both testes of TIRI model mice. For the assessment of oxidative stress, enzyme-linked immuno-sorbent assay (ELISA) for 8-hydroxy-2’-deoxyguanosine (8-OHdG) was performed, which showed that levels of 8-OHdG were significantly increased in the left (affected) testis of TIRI model mice compared with that of sham-operated mice at all observation periods. Meanwhile, ELISA showed that levels of 8-OHdG in the right (unaffected) testis were significantly increased in TIRI model mice at weeks 3 and 5 compared with that of sham-operated mice.　Conclusions: Spermatic dysfunction following TIRI is induced by inflammation and oxidative stress. Inflammation and oxidative stress may be novel regulatory factors to prevent spermatic dysfunction following TIRI

Pathophysiological analysis of detrusor overactivity following partial bladder outlet obstruction

　Introduction: Detrusor overactivity (DO) following partial bladder outlet obstruction (PBOO) is a common urological condition in humans, with 50-70% patients with PBOO complicated with DO. The pathological mechanisms of DO following PBOO are largely unknown, but inflammatory changes may play a key role. We hypothesized that inflammation is important in the earlier pathophysiological phase before overproduction of oxidative stress in DO following PBOO. Therefore, we investigated the relationships among bladder function, ischemia, oxidative stress and inflammation in DO following PBOO in PBOO model mice.　Materials and Methods: C57BL/6J male mice aged 10 to 15 weeks were used in the study. PBOO model mice were created surgically by ligation of the proximal urethra with 5-0 nylon suture under inhalation anesthesia. Sham-operated mice were used as controls. Pathophysiological changes in the bladder at 1, 3 and 5 weeks after creation of the PBOO model mice were compared with those in sham-operated mice using functional, histological, biochemical and immunohistochemical analyses.　Results: Functional analysis using a pressure flow study showed increased maximum detrusor pressure at 1 week and DO from 3 to 5 weeks after creation of the PBOO model. Histological analysis using hematoxylin-eosin and Masson-Trichrome staining showed greater invasion of inflammatory cells and fibrosis in PBOO model mice compared with sham-operated mice at 3 and 5 weeks. Inflammatory cells were mainly present in interstitial tissue, and fibrosis gradually infiltrated from interstitial tissue to the muscular layer. Ischemia analysis showed significantlyincreased HIF-1α in PBOO model mice at all time points. Oxidative stress analysis indicated significantly increased levels of ROS from 1 week and 8-OHdG from 3weeks in PBOO model mice. An inflammation-related proteome assay showed high levels of colony stimulating factor (CSF) family proteins at 1 week and IL-2, IL-3, IL-17A, IL-23, MMP-3, MMP-9 and periostin from 3 to 5 weeks in PBOO model mice.　Conclusions: Oxidative stress and inflammatory changes showed contemporaneous increase in pathophysiology of detrusor overactivity following partial bladder outlet obstruction. Especially, CSF family and ROS changes are showed in the early stage, and might be a predict marker in the pathophysiology of DO following PBOO at the early stage

Preventive effect of indoleamine 2,3-dioxygenase 1 inhibition on lipopolysaccharide-induced prostatitis

　Introduction and Objectives: Bacterial infections are the main cause of acute prostatitis and are treated with appropriate antimicrobial therapy. However, approximately 5% of patients continue to have inflammatory symptoms even after receiving antibacterial therapy, leading to refractory conditions. Bacterial prostatitis requires additional therapy, focusing on inflammatory changes. Indoleamine 2,3-dioxygenase 1 (IDO1) catalysis is the first rate-limiting step of tryptophan metabolism. IDO1 is expressed in the prostate and plays a key role in the immune response. As the first step in investigating the relationship between acute prostatitis and IDO1, we investigated the preventive effect of IDO1 inhibition on lipopolysaccharide (LPS)- induced prostatitis using IDO knockout (Ido1 −/−) mice in this study.　Materials and Methods: The study used Ido1 −/− and wild-type (Ido1 +/+) C57BL/6J malemice aged 10–15 weeks. LPS Escherichia coli O26 (100μg/PBS, 100μL) was administered transurethrally into the lower urinary tract to create a mouse model of LPS-induced prostatitis. The prostates were removed 1, 3, 5, and 7 days after creating the model mice. Histological, immunohistochemical, and biochemical analyses were used to compare the preventive effect in Ido1 −/− mice compared with that in Ido1+/+ mice.　Results: HE staining showed suppression of ductal destruction following infiltration of inflammatory cells in Ido1 −/− mice compared with Ido1 +/+ mice. The enzyme-linked immunosorbent assay (ELISA) method was used for kynurenine pathway analysis, which showed significantly maintained tryptophan levels and decreased L-kynurenine levels in Ido1 −/− mice compared to Ido1 +/+ mice. The IDO1 assay in Ido1 +/+ mice showed significantly increased levels during all observation periods after creating the model compared with that under normal conditions. Immunofluorescent staining using five types of cytokines and chemokines (IL-2, IL-4, IL-17, CCL2, and CCL3) related to the pathophysiology of acute prostatitis showed decreased expression of these cytokines and chemokines in Ido1 -/- mice compared with Ido1 +/+ mice. Inflammation-related proteome assays showed decreased levels of IL-1β, IL-4, IL-5, IL-6, IL-17, CCL2, CCL3, CXCL1, CXCL11, and tissue inhibitor of matrix metalloproteinases (TIMP)-1 in Ido1 −/− mice compared with Ido1 −/− mice during all observation periods after model creation.　Conclusions: IDO1 is involved in LPS-induced prostatitis through cytokines and chemokines. IDO1 inhibition contributes to the prevention of LPS-induced prostatitis. IDO1 inhibition has the potential to serve as an additional therapy for acute prostatitis

Treatment outcomes of laparoscopic radical prostatectomy at Kawasaki Medical School Hospital

　Laparoscopic radical prostatectomy (LRP) was carried out in 196 patients with prostate cancer between December 2009 and November 2017 at Kawasaki Medical School Hospital, and the therapeutic outcomes were assessed. An extraperitoneal approach was used in all cases except 1 and the median follow-up period was 55 months (range, 10-117 months). The median patient age was 69 years (range, 56-79 years), median body mass index was 23.3 kg/m2 (range, 15.2-33.2 kg/m2 ), and median prostate-specific antigen (PSA) level at diagnosis was 7.4 ng/mL (range, 2.2-42.0 ng/mL). Clinical stages of T1c, T2a, T2b, T2c, T3a, and T3b accounted for 63, 43, 31, 57, 1, and 1 case, respectively, while Gleason scores at biopsy of ≥ 6, 7, and ≥ 8 accounted for 26, 138, and 32 cases, respectively. The median prostate volume was 22.0 mL (range, 7.3-65.6 mL), median operating time was 266 minutes (range, 142-540 minutes), and median blood loss (including in urine) was 650 mL (range, 10-5,800 mL). During the initial induction period, 94 patients received autologous blood transfusion and 7 received allogeneic blood transfusion. Nerve-sparing prostatectomy was performed in 17 cases (bilateral in 3, unilateral in 14). Capsular invasion was observed in 57 cases (29.1%) and positive resection margins were observed in 51 cases (26.4%). The median indwelling catheter duration was 6 days (range, 4-26 days) and the median hospital stay after surgery was 11 days (range, 8-34 days). The main complications were intraoperative rectal injury in 7 cases (3.6%), postoperative inguinal hernia in 28 (14.3%), and urethral stenosis in 8 (4.1%). The rate of urinary incontinence at ≥ 1 year after surgery was 32.7% and the rate of PSA recurrence was 15.8%. The overall survival rate was 95.6% at 5 years and 94.7% at 10 years. In conclusion, the oncological outcomes were similar to that reported by previous reports, but postoperative stress urinary incontinence and complications were slightly worse. In the future, further improvement of the surgical technique was desired

Outcomes of robot-assisted partial nephrectomy in the treatment of renal cell carcinoma at Kawasaki Medical School Hospital

　Robot-assisted partial nephrectomy (RAPN) was introduced in our hospital for treating small renal cell carcinoma in May 2018; we examined treatment outcomes in 24 patients (25 kidneys) who had undergone this procedure till 2019. The median observation period was 11 months (range, 1-17 months). The patients’ age range was 43-77 years (median, 68 years). Fourteen men and 10 women underwent the procedure. Their BMI was 17.9-39.7 (median, 24.1) kg/m2 . In one patient, RAPN was performed twice at different times for treating bilateral renal cancer. The right kidney was affected in 12 cases and the left kidney in 13 cases. The clinical cancer stage was T1a in 20 cases and T1b in 5 cases. Tumor sizes were 0.9-6.2 cm (median, 2.5 cm), and RENAL nephrometry scores were 4-10 (median, 7). The transperitoneal approach was used in 22 cases, and the retroperitoneal approach in 3. The operating durations were 147-358 min (median, 225 min), console durations were 59-394 min (median, 152 min), and renal ischemia durations were 8-54 min (median, 21 min). Blood loss was 10-700 ml (median 10 ml), and none of the patients underwent blood transfusion. The histopathological analysis of the resected tumors revealed clear cell renal cell carcinoma in 20 cases, chromophobe renal cell carcinoma in 2 cases, and papillary renal cell carcinoma, angiomyolipoma, and leiomyoma in 1 case each. All margins were negative. The postoperative hospital stay lengths were 5-14 days (median, 9 days). The postoperative deterioration in renal function was mild, and there were no severe complications. In the early stages after its introduction, RAPN was safely performed and allowed for the preservation of renal function. We plan to continue studying more cases going forward

当院の女性過活動膀胱患者における抗コリン薬とβ3アドレナリン受容体作動薬の内服継続率に関する検討

　過活動膀胱（overactive bladder：以下OAB）は，尿意切迫感や頻尿などの下部尿路症状を有し，加齢とともに増加する傾向がある．OAB 患者の治療薬として，本邦では抗コリン薬とβ3アドレナリン受容体作動薬が推奨，使用されている．今回，女性OAB 患者に対する，抗コリン薬とβ3アドレナリン受容体作動薬の内服継続率，副作用，内服中止理由に関してretrospective に検討した．対象は，2013年１月から12月の１年間に当院泌尿器科を受診した初診の女性OAB 患者，87名とした．β3アドレナリン受容体作動薬投与群と抗コリン薬投与群の内服継続率は，β3アドレナリン受容体作動薬投与群は，12か月で38.8％，60か月で18.1％，抗コリン薬投与群は，12か月18.4%，60か月で7.9％であり，β3アドレナリン受容体作動薬投与群の方が若干継続率は良いものの，両群間に差は認めなかった．副作用に関しては，抗コリン薬投与群の方が多く，口喝が17例（44.7%），便秘が15例（39.5%）であった．薬剤中止の理由は両群とも自然寛解によるものが多かった．　Overactive bladder (OAB) involves lower urinary tract symptoms such as urinary urgency and polyuria, and tends to increase with age. In Japan, the drugs recommended and used for treatment of OAB patients are anticholinergic agents and β3 adrenalin receptor agonists. The present study was a retrospective investigation of the rates of long-term administration of anticholinergic agents and β3 adrenalin receptor agonists, adverse effects with these drugs, and reasons for discontinuation of administration, with female OAB patients. The subjects were 87 female patients who were examined at this hospital\u27s Urology Dept. over 1 year between January and December 2013, and diagnosed as having OAB for the first time. With respect to the rates of long-term administration, in the β3 adrenalin receptor agonist group the rates of administration for 12 and 60 months, respectively, were 38.8% and 18.1%, and these rates in the anticholinergic agent group were 18.4% and 7.9%, so the long-term administration rates were somewhat higher in the β3 adrenalin receptor agonist group, but no difference between the groups was found. Adverse effects were more frequent in the anticholinergic agent group, with 17 subjects in that group (44.7%) developing buccal dryness, and 15 (39.5%) developing constipation. In both groups, the most frequent reason for discontinuation of administration was spontaneous remission

ヒショウ サイボウ ハイガン ニ オケル MUC1 ハツゲン ノ シンキ ブンルイホウ ワ シュヨウ ブンカド オヨビ ジュツゴ セイメイ ヨゴ ニ カンヨスル

京都大学0048新制・課程博士博士(医学)甲第14129号医博第3279号新制||医||971(附属図書館)UT51-2008-N446京都大学大学院医学研究科外科系専攻(主査)教授 三嶋 理晃, 教授 武藤 誠, 教授 杉田 昌彦学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA

Successful resection of large mediastinal mature cystic teratoma immediately after evacuation of fluid content

Ryo Miyahara, Shinjiro Nagai, Toshihiko Sato, Chen Fengshi, Toru Bando, Kenichi Okubo, Hiroshi DateDepartment of Thoracic Surgery, Kyoto University, Kyoto, JapanAbstract: In this report, we presented a case of urgent resection of mature giant mediastinal teratoma. Its characteristic radiologic findings allowed us to plan evacuation of intratumoral fluid in order to make the surgical procedure safe and less invasive. In addition, a hybrid thoracoscopic-open approach also provided safety and allowed a somewhat less invasive tumor resection than otherwise would have been required. The patient recovered well without recurrence at nine months’ follow-up, with full expansion of the right middle and lower lobes. Here we discuss the diagnosis and surgical procedure with reference to the literature.Keywords: mediastinal mature teratoma, rupture, acute pleuriti

First Clinical Report of the Intraoperative Macro- and Micro-Photodiagnosis and Photodynamic Therapy Using Talaporfin Sodium for a Patient with Disseminated Lumbar Medulloblastoma

Photodiagnosis (PD) and photodynamic therapy (PDT) using the second-generation photosensitizer talaporfin sodium together with an exciting laser for primary intracranial malignant tumors is well recognized in Japan, and many medical institutions are introducing this new therapeutic option. In particular, intraoperative PDT using talaporfin sodium for infiltrating tumor cells in the cavity walls after the resection of malignant glioma is now covered by health insurance after receiving governmental approvement, and this method has been recommended in therapeutic guidelines for primary malignant brain tumors in Japan. On the other hand, experimental and clinical studies on the development of novel therapeutic strategies for malignant spinal cord tumors have not been reported to date, although their histological features are almost identical to those of intracranial malignant tumors. Therefore, the clinical outcomes of malignant spinal cord tumors have been less favorable than those of malignant brain tumors. In this report, we performed the PD and PDT using talaporfin sodium on a patient with a metastatic lumbar lesion that was detected on magnetic resonance image (MRI) 50 months after the resection of cerebellar medulloblastoma who presented with lumbago and sciatica. We were able to detect the target lesion in the conus medullaris using a surgical microscope, and detected the disseminated medulloblastoma cells floating in the cerebrospinal fluid using a compact fluorescence microscope. Furthermore, we performed PDT to the resected lumbar lesion with the adjuvant platinum-based chemotherapy, and the patient survived a meaningful life for more than 2 years after the lumbar surgery. This report describes the first case of a human patient in whom the efficacy of PD and PDT was demonstrated for a malignant spinal cord tumor