[Strangulation of the Penis by Four Metallic Washers].

We report here a case of strangulation of the penis. A 69-year-old male visited our hospital suffering from a swollen penis and dysuria after installation of four metallic washers to the penis. He had mischievously put them on his penis four days before and subsequently was unable to remove them. We found erosion on the surface of the penis, reduction in blood flow by ultrasonography, and high C-reactive protein levels. Because we could not remove washers by blood removal from glans penis or ring cutter, we performed percutaneous cystostomy and then cut the washers with an electric grinder under general anesthesia. The operation took 2 hours and 25 minutes. The postoperative course was uneventful. Neither disturbance of blood flow nor urethral stricture was found. He completely recovered without erectile dysfunction or difficult urination 7 months after the operation. Management of this rare condition is discussed.

Effects of insulin degludec and insulin glargine on day-to-day fasting plasma glucose variability in individuals with type 1 diabetes: a multicentre, randomised, crossover study.

AIMS/HYPOTHESIS: We compared the effects of insulin degludec (IDeg; Des(B30)LysB29(γ-Glu Nε-hexadecandioyl) human insulin) and insulin glargine (IGlar; A21Gly,B31Arg,B32Arg human insulin) on the day-to-day variability of fasting plasma glucose (FPG) levels in individuals with type 1 diabetes treated with basal-bolus insulin injections. METHODS: The effects of basal-bolus insulin therapy for 4 weeks with either IDeg or IGlar as the basal insulin in adult C-peptide-negative outpatients with type 1 diabetes were investigated in an open-label, multicentre, randomised, crossover trial. Randomisation was conducted using a centralised allocation process. The primary endpoints were the SD and CV of FPG during the final week of each treatment period. Secondary endpoints included serum glycoalbumin level, daily dose of insulin, intraday glycaemic variability and frequency of severe hypoglycaemia. RESULTS: Thirty-six randomised participants (17 in the IDeg/IGlar and 19 in the IGlar/IDeg groups) were recruited, and data for 32 participants who completed the trial were analysed. The mean (7.74 ± 1.76 vs 8.56 ± 2.06 mmol/l; p = 0.04) and SD (2.60 ± 0.97 vs 3.19 ± 1.36 mmol/l; p = 0.03) of FPG were lower during IDeg treatment than during IGlar treatment, whereas the CV did not differ between the two treatments. The dose of IDeg was smaller than that of IGlar (11.0 ± 5.2 vs 11.8 ± 5.6 U/day; p < 0.01), but other secondary endpoints did not differ between the treatments. CONCLUSIONS/INTERPRETATION: IDeg yielded a lower FPG level and smaller day-to-day variability of FPG at a lower daily dose compared with IGlar in participants with type 1 diabetes. IDeg serves as a good option for basal insulin in the treatment of type 1 diabetes. TRIAL REGISTRATION: University Hospital Medical Information Network 000009965. FUNDING: This research recieved no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Primary hyperoxaluria complicated with liver cirrhosis: A case report.

Primary hyperoxaluria (PH) is a rare, autosomal recessive disorder characterized by overproduction of oxalate caused by a deficiency in a hepatic enzyme. The excess oxalate combines with calcium in the kidneys to form deposits of calcium oxalate, which can lead to nephrocalcinosis and renal failure. PH type 1 (PH1), the most common form of this disease, is caused by a deficiency of the liver-specific enzyme alanine/glyoxylate aminotransferase (AGT). Liver transplantation is performed as a definitive therapy for PH to correct the enzyme defect. Usually, liver depositions are limited and liver function is normal without fibrosis. Here, we report an adult case of liver cirrhosis caused by PH1. A 28-year-old woman was admitted to our hospital under suspicion of PH1 and the presence of nephrocalcinosis. The patient had suffered from kidney stone recurrences from 17 years of age, and was initiated on hemodialysis due to renal failure at the age of 27 years. The serum level of oxalic acid was high, whereas the AGT level in the liver tissue was decreased. Thus, the patient was definitively diagnosed with PH1. Although she had normal liver function, surface nodularity and splenomegaly were detected by computed tomography, suggesting liver cirrhosis. The native liver showed micronodular cirrhosis and portal fibrosis. Several arterioles were filled with rhomboid and polyhedral refractile oxalate crystals and various portal tracts showed these crystals. Our case suggests that long-term oxalosis can lead to liver cirrhosis; thus, PH should be considered one of the causes of liver cirrhosis.

Chaga mushroom-induced oxalate nephropathy.

Chaga mushrooms have been used in folk and botanical medicine as a remedy for cancer, gastritis, ulcers, and tuberculosis of the bones. A 72-year-old Japanese female had been diagnosed with liver cancer 1 year prior to presenting at our department. She underwent hepatectomy of the left lobe 3 months later. Chaga mushroom powder (4 - 5 teaspoons per day) had been ingested for the past 6 months for liver cancer. Renal function decreased and hemodialysis was initiated. Renal biopsy specimens showed diffuse tubular atrophy and interstitial fibrosis. Oxalate crystals were detected in the tubular lumina and urinary sediment and oxalate nephropathy was diagnosed. Chaga mushrooms contain extremely high oxalate concentrations. This is the first report of a case of oxalate nephropathy associated with ingestion of Chaga mushrooms.

Relationship Between Adverse Events and Progression-free Survival in Patients Receiving Cabozantinib for Previously Treated Metastatic Renal Cell Carcinoma.

BACKGROUND/AIM: Although the adverse events (AEs) of drugs, such as sunitinib and axitinib, have been shown to predict treatment responses, evidence to support cabozantinib-induced AEs as predictors of responses to treatment for metastatic renal cell carcinoma (mRCC) is limited. Therefore, we herein investigated the relationship between AE profiles and progression-free survival (PFS) in patients receiving cabozantinib for previously treated mRCC. PATIENTS AND METHODS: The present study retrospectively analyzed 40 patients receiving cabozantinib for previously treated mRCC between July 2020 and August 2022. PFS was estimated using the Kaplan-Meier method and the impact of several parameters, including cabozantinib-induced AEs, on PFS was investigated by a Cox proportional regression analysis. RESULTS: The median observation period was 15 (2-29) months, during which time 31 patients (77.5%) progressed, with median PFS of 11 months. Thirty-nine patients (97.5%) developed at least one AE. Liver toxicity occurred in 16 patients (40.0%) and hand-foot syndrome, hypertension, and diarrhea in 14 each (17.5%). Only hypertension correlated with longer PFS. A multivariate analysis identified hypertension as an independent prognostic factor for PFS (p=0.049). CONCLUSION: These results suggest the potential of treatment-induced hypertension as a significant predictor of prolonged PFS in patients receiving cabozantinib for mRCC.

Axitinib controlled metastatic renal cell carcinoma for 5 years.

We present two patients with a long-term response to axitinib for cytokine-refractory metastatic renal cell carcinoma. One patient has had a continuing partial response for 58 months with cytokine-intolerant metastatic renal cell carcinoma and the other patient has had continuing stable disease accompanied by a mixed response for 57 months with cytokine-refractory and intolerant metastatic renal cell carcinoma. The condition of hypertension as an adverse event markedly depended on whether or not axitinib was administered. The patients responded to axitinib with an elevation of diastolic blood pressure to 90 mmHg or higher until 2 weeks after starting axitinib. To get a long-term response to axitinib, it may be important to control well the balance between treatment effect and adverse events while using drug withdrawal.

Silkworm plasmatocytes are more resistant than other hemocyte morphotypes to Bombyx mori nucleopolyhedrovirus infection.

Differences in the viral susceptibility of multiple insect hemocyte morphotypes have not been investigated to date. In this study, a Bombyx mori nucleopolyhedrovirus (BmNPV) derivative possessing a Drosophila hsp70 promoter-driven green fluorescent protein (GFP) gene was used to observe NPV tropism of B. mori larval hemocytes. The experiments clearly revealed that there were fewer GFP-positive plasmatocytes than those observed in other types of hemocytes, such as granulocytes, oenocytoids, and spherulocytes, when infected via the intrahemocoelic or oral route. Our results indicate that silkworm plasmatocytes are more resistant than other hemocyte morphotypes to BmNPV infection.

[Bilateral adrenal hemorrhage due to adrenal metastasis of lung cancer].

A 58-year-old man presented with nausea and left flank pain. The patient was referred to our hospital based on clear detection of anemia and computed tomography findings of bilateral adrenal tumors with hemorrhage and a mass in the apex of the left lung. Right adrenal artery embolization had no effect on enlargement of the right adrenal hematoma or advanced anemia. Right adrenalectomy was then performed in an attempt to control hemorrhaging and make a definitive diagnosis, and the patient's anemia improved following the operation. Histopathological diagnosis suggested adrenal metastasis of lung adenocarcinoma, which was subsequently diagnosed given similarities in transbronchial biopsy findings to those in the right adrenal gland. Adrenal hemorrhage due to metastasis of lung cancer is an extremely rare condition; indeed, to our knowledge, the present case is only the 26th reported worldwide. However, prognosis for this mortal condition may be improved should patients receive adrenalectomy followed by an appropriate treatment regimen.

[Salvage therapy for castration-refractory prostate cancer resistant to docetaxel].

OBJECTIVES: To evaluate the treatment for castration-refractory prostate cancer (CRPC) resistant to docetaxel MATERIALS AND METHODS: Among 45 patients with CRPC treated with docetaxel (70-75 mg/m2) every 3 to 4 weeks at Hamamatsu University Hospital from January 2004 to July 2012, 19 patients underwent salvage treatments. We retrospectively analyzed the medical records of 14 patients except for 5 patients who were enrolled in clinical trials. RESULTS: The median age and serum prostate-specific antigen (PSA) level at starting salvage treatments was 71 years (range 45 to 79) and 241.1 ng/mL (range 3.06 to 1,643.0), respectively. All patients maintained castration status. Salvage treatments include DTX (30 mg/m2) + cisplatin (CDDP) (70 mg/m2)/carboplatin (Area under the curve = 4), etoposide + CDDP, paclitaxel + CDDP, cyclophosphamide, S-l, tegaful-uracil. The reasons why 14 patients moved to salvage treatments after DTX were progressive disease in 12 patients and adverse events in 2. Eight patients had a PSA response, 3 patients>50% and 5 patients<50%. Six patients had a PSA progression. The median overall survival was 10.4 months (range 4.1 to 27.3). All patients died of cancer, 13 patients with prostate cancer and one patient with lung adenocarcinoma. Most adverse events were mild. Transitory grade 3 leukopenia was observed in 2 patients, and grade 3 anemia in 2. No grade 4 toxicities were noted. CONCLUSIONS: All salvage treatments without grade 4 toxicities described in this study may be acceptable in the patients with CRPC progressing after docetaxel although the effect would be limited.

[A clinical study of laparoscopic adrenalectomy for pheochromocytoma--analysis of clinical parameters influencing operative time and intraoperative systolic blood pressure].

PURPOSE: We retrospectively analyzed the preoperative clinical parameters which influence operative time and intraoperative maximum systolic blood pressure in patients undergoing laparoscopic adrenalectomy for pheochromocytoma. MATERIALS AND METHODS: Between January 1992 and September 2010, we performed 28 laparoscopic adrenalectomies for pheochromocytoma at Hamamatsu University School of Medicine. These 28 cases were characterized based on the following parameters: body mass index (BMI), tumor size, history of hypertension, preoperative blood pressure, serum concentration of catecholamine, and 24-h urinary excretion of catecholamine metabolite. We retrospectively analyzed whether or not these parameters influenced operative time or intraoperative maximum systolic blood pressure. RESULTS: All 28 cases of laparoscopic adrenalectomy were performed safely and without intraoperative complications and needed neither blood transfusion nor conversion to laparotomy. The median operative time was 203 minutes, and intraoperative hypertension (systolic blood pressure > 200 mmHg) occurred in 46% (13/28) of cases. Median day of discharge in all patients was post-operative day 5. Significant positive correlation was shown between tumor size and operative time and between intraoperative maximum systolic blood pressure and serum concentration of catecholamine or 24-h urinary excretion of catecholamine metabolite (p < 0.05). CONCLUSION: The lengthened operative time for large tumors and elevated intraoperative blood pressure for tumors with high preoperative catecholamine activity necessitate careful perioperative management in patients receiving laparoscopic adrenalectomy for pheochromocytoma.

IL-10-conditioned dendritic cells prevent autoimmune diabetes in NOD and humanized HLA-DQ8/RIP-B7.1 mice.

This study was to determine whether BMDCs cultured in the presence of IL-10 (G/10-DCs) could promote T cell tolerance and prevent autoimmune diabetes in two different animal models of T1D. Our results showed that G/10-DCs suppressed both insulitis and spontaneous diabetes in NOD and HLA-DQ8/RIP-B7.1 mice. The suppression was likely to be mediated by T cells, as we found that regulatory CD4(+)CD25(+)Foxp3(+) cells were significantly increased in G/10-DC treated animals. In vivo, the G/10-DCs inhibited diabetogenic T cell proliferation; in vitro, they had reduced expression of costimulatory molecules and produced little IL-12/23 p40 or IL-6 but a large amount of IL-10 when compared with DCs matured in the presence of IL-4 (G/4-DC). We conclude that IL-10-treated DCs are tolerogenic and induce islet-directed immune tolerance, which was likely to be mediated by T regulatory cells. This non-antigen-specific DC-based approach offers potential for a new therapeutic intervention in T1D.

Acceleration of autoimmune diabetes in Rheb-congenic NOD mice with ß-cell-specific mTORC1 activation.

The protein Ras homolog enriched in brain (Rheb) is a Ras-like small GTPase that activates the mechanistic target of rapamycin complex 1 (mTORC1), which promotes cell growth. We previously generated transgenic C57BL/6 mice overexpressing Rheb in ß-cells (B6(Rheb)), which exhibited increased ß-cell size and improved glucose tolerance with higher insulin secretion than wild type C57BL/6 mice. The mice also showed resistance to obesity-induced hyperglycemia, a model of type 2 diabetes, and to multiple low-dose-streptozotocin (MLDS)-induced hyperglycemia, a model of type 1 diabetes (T1D). To investigate whether the effects of mTORC1 activation by Rheb in B6(Rheb) mice would also be evident in NOD mice, a spontaneous autoimmune T1D model, we created two NOD mouse lines overexpressing Rheb in their ß-cells (NOD(Rheb); R3 and R20). We verified Rheb overexpression in ß-cells, the relative activation of mTORC1 and ß-cell enlargement. By 35 weeks of age, diabetes incidence was significantly greater in the R3 line and tended to be greater in the R20 line than in NOD mice. Histological analysis demonstrated that insulitis was significantly accelerated in 12-week-old R3 NOD(Rheb) mice compared with NOD mice. Furthermore, serum insulin autoantibody (IAA) expression was significantly higher than that of NOD mice. We also examined whether complete Freund's adjuvant (CFA) treatment alone or with glucagon-like peptide-1 (GLP-1) analog would reverse the hyperglycemia of NOD(Rheb) mice; unexpectedly, almost none achieved normoglycemia. In summary, diabetes progression was significantly accelerated rather than prevented in NOD(Rheb) mice. Our results suggest that the ß-cell enlargement might merely enhance the autoimmunity of pathogenic T-cells against islets, leading to acceleration of autoimmune diabetes. We conclude that not only enlargement but also regeneration of ß-cells in addition to the prevention of ß-cell destruction will be required for the ideal therapy of autoimmune T1D.

[Future perspective in the treatment of urolithiasis based on oxalate metabolism].

Urinary excretion of oxalate is one of risk factors in urinary stone formation. Prevention of undesirable overflow into the production of oxalate definitely leads to a decrease of urolithiasis. The activity of serine : pyruvate/alanine : glyoxylate aminotransferase (SPT/AGT) or glyoxylate reductase/hydroxypyruvate reductase (GRHPR), the key enzyme of primary hyperoxlauria type 1 and 2, respectively, and their subcellular distribution highly affects the oxalate production. On the other hand, urolithiasis is tightly related to lifestyle disease, such as diabetes mellitus and insulin resistance. The hypothesis that insulin resistance induces mitochondria dysfunction, resulting in the decrease of mitochondria-related enzyme activity is a very attractive new treatment strategy of urolithiasis. Namely, the improvement of insulin resistance might prevent stone formation.

[A case of proliferative cystitis forming ureterovesical junction obstruction].

We report a case of proliferative cystitis forming ureterovesical junction obstruction. A 28-year-old man presented with a complaint of gross hematuria. Abdominal ultrasonography revealed left hydronephrosis and bladder tumor. Drip infusion pyelography (DIP) demonstrated left ureterovesical junction obstruction and cystoscopic findings appeared papillary sessile tumor around the bladder neck, trigone, and bilateral ureteral orifice. Transurethral resection of the bladder tumor (TURBT) was performed. The pathological diagnosis of the tumor was proliferative cystitis and confirmed that left ureterovesical junction obstruction was derived from proliferative cystitis. The tumor was not responsive to medical treatment. After the 4th TURBT, the tumor was completely resected, and left hydronephrosis and ureterovesical junction obstruction were improved. One year after the last operation, there is no evidence of recurrence of the tumor. Tumor formation arising from proliferative cystitis is relatively rare. Pathogenesis and management of this rare condition are discussed.

[Changes in serum prostate specific antigen and testosterone levels after chlormadinone acetate treatment in patients with benign prostatic hyperplasia : a prospective multicenter clinical study].

In this prospective multicenter study, we investigated the changes in serum prostate-specific antigen (PSA) and testosterone levels after treatment with antiandrogen chlormadinone acetate (CMA) in patients with benign prostatic hyperplasia (BPH). The inclusion criteria for the patients were as follows : PSA value of C10 ng/ml, maximum urine flow rate of ＜15 ml/s, estimated prostate volume of B20 ml, International Prostate System Score (IPSS) of B8, and IPSS-quality of life (QOL) index of B2. Of the 115 patients who registered, 114 qualified for this study. The patients were treated with CMA (50 mg/day) for 16 weeks ; this was followed by a no-CMA phase of 32 weeks. When compared with the baseline PSA level, the levels at 8 and 16 weeks of treatment had decreased by 56.4% (95% confidence interval [CI], 51.1-1.2) and 57.6% (95% CI, 52.3-62.4), respectively. Similarly, when compared with the baseline testosterone level, the levels at 8 and 16 weeks of treatment had decreased by 90.1% (95% CI, 87.8-91.9) and 84.4% (95% CI, 80.7-87.4), respectively. After treatment discontinuation, the PSA levels gradually increased and returned to baseline in 32 weeks. However, the testosterone levels returned to baseline in only 8 weeks. Although patients over 80 years of age showed a gradual decrease in these levels when compared with younger patients, the changes in the levels of PSA and testosterone were not affected by age. Thus, in order to use antiandrogen agents including CMA for treating BPH, we need to determine the PSA value that converted it into double.

[Pharmacotherapy for preventing calcium containing stone formation].

Many urinary tract stones consist of calcium, and has high relapse rate. Accordingly, it is very important to prevent calcium-containing stone formation. This paper describes about effects and mechanisms for Xanthine oxidase inhibitor, citrate formulation, magnesium formulation, thiazides, vitamin B(6), extract of Quercus salicina Blume and chorei-to (medical herb) . Recent new drugs and the elucidation of new metabolic pathways may lead to the development of prevention of urolithiasis.

Pembrolizumab Versus Combined Chemotherapy With Gemcitabine and Paclitaxel: A Comparative Assessment of Clinical Outcomes in Patients With Platinum-refractory Advanced Urothelial Cancer.

BACKGROUND/AIM: There are limited data on comprehensive assessments of several treatments as second-line therapy against advanced urothelial cancer (UC). The objective of this study was to compare clinical outcomes between advanced UC patients receiving either pembrolizumab (Pem) or combined chemotherapy with gemcitabine and paclitaxel (GP) as second-line therapy. PATIENTS AND METHODS: This study retrospectively analyzed the clinical outcomes of 89 patients with platinum-refractory advanced UC, consisting of 46 and 43 who received Pem and GP therapy, respectively, as second-line treatment. RESULTS: There were no significant differences in major clinicopathological parameters between Pem and GP groups. No significant difference in the objective response rate was noted between the two groups. Progression-free survival (PFS) in the Pem group was significantly longer than that in the GP group; however, there was no significant difference in overall survival (OS) between them. Multivariate analyses identified performance status ≤2 and liver metastasis as independent factors associated with poor outcomes in both PFS and OS. The incidence of adverse events in the GP group was significantly higher than that in the Pem group. CONCLUSION: Pem could be regarded as standard agent for platinum-refractory advanced UC patients.

Administration of a determinant of preproinsulin can induce regulatory T cells and suppress anti-islet autoimmunity in NOD mice.

Antigen-specific immunotherapy is expected to be an ideal strategy for treating type 1 diabetes (T1D). We investigated the therapeutic efficacy of a peptide in the leader sequence of preproinsulin, which was selected because of its binding affinity to the MHC I-A(g7) molecule. Preproinsulin-1 L7-24 peptide (L7-24) emulsified in Freund's incomplete adjuvant was administered subcutaneously to NOD mice. Administration of L7-24 increased the proportion of regulatory T cells in the spleen. Splenocytes of NOD mice immunized with this peptide secreted IL-4 and IL-10 in response to L7-24. This peptide also significantly prevented the development of diabetes and cured some newly diabetic NOD mice without recurrence. L7-24 peptide, which has a high affinity for pockets of I-A(g7), induced regulatory T cells and showed therapeutic effects. This peptide may provide a new approach for developing antigen-specific immunotherapy for autoimmune diabetes.

Regulatory CD8+ T cells induced by exposure to all-trans retinoic acid and TGF-beta suppress autoimmune diabetes.

Antigen-specific regulatory CD4(+) T cells have been described but there are few reports on regulatory CD8(+) T cells. We generated islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific regulatory CD8(+) T cells from 8.3-NOD transgenic mice. CD8(+) T cells from 8.3-NOD splenocytes were cultured with IGRP, splenic dendritic cells (SpDCs), TGF-beta, and all-trans retinoic acid (ATRA) for 5days. CD8(+) T cells cultured with either IGRP alone or IGRP and SpDCs in the absence of TGF-beta and ATRA had low Foxp3(+) expression (1.7+/-0.9% and 3.2+/-4.5%, respectively). In contrast, CD8(+) T cells induced by exposure to IGRP, SpDCs, TGF-beta, and ATRA showed the highest expression of Foxp3(+) in IGRP-reactive CD8(+) T cells (36.1+/-10.6%), which was approximately 40-fold increase compared with that before induction culture. CD25 expression on CD8(+) T cells cultured with IGRP, SpDCs, TGF-beta, and ATRA was only 7.42%, whereas CD103 expression was greater than 90%. These CD8(+) T cells suppressed the proliferation of diabetogenic CD8(+) T cells from 8.3-NOD splenocytes in vitro and completely prevented diabetes onset in NOD-scid mice in cotransfer experiments with diabetogenic splenocytes from NOD mice in vivo. Here we show that exposure to ATRA and TGF-beta induces CD8(+)Foxp3(+) T cells ex vivo, which suppress diabetogenic T cells in vitro and in vivo.

[Clinical course of patient with malignant pheochromocytoma who was treated with CVD chemotherapy and alpha-methyl-p-tyrosine].

A 31-years-old woman was diagnosed as pheocromocytoma by the various endocrine testings and 131I-MIBG scintigraphy. The CT scan and bone scintigraphy showed right adrenal tumor, along with liver metastasis, lymph nodes swelling around aorta and multiple bone metastases. She underwent chemotherapy consisting with Cyclophosphamide, Vincristine, Dacarbazine (CVD) and alpha-methyl-p-tyrosine (alphaMT), resulting in stable disease for 27 months. However, catecholamine levels increased gradually four weeks later. We would have planned 131I-MIBG therapy, but bone marrow suppression did not allow us to do it. She died of DIC.