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Introduction We performed autologous rectus abdominis fascia sling surgery using Advantage™ following an unsuccessful synthetic midurethral sling. Case presentation At the age of 76 years, the patient experienced stress urinary incontinence recurrence. A 1‐h pad test resulted in 259 g of leakage. A pressure flow study verified urine leakage while coughing and straining without detrusor overactivity. Abdominal leak point pressure was 10 cmH2O. Autologous rectus abdominis fascia sling surgery was performed using Advantage™. One month postoperatively, a 1‐h pad test resulted in 0 g of leakage. Conclusion We believe that this method will allow the fascia sling procedure to be performed reliably even if one is unfamiliar with conventional autologous rectus abdominis fascia sling surgery.

The vagus nerve belongs to the parasympathetic nervous system, which is involved in the regulation of organs throughout the body. Since the discovery of the non-neuronal cardiac cholinergic system (NNCCS), several studies have provided evidence for the positive role of acetylcholine (ACh) released from cardiomyocytes against cardiovascular diseases, such as sympathetic hyperreactivity-induced cardiac remodeling and dysfunction as well as myocardial infarction. Non-neuronal ACh released from cardiomyocytes is believed to regulate key physiological functions of the heart, such as attenuating heart rate, offsetting hypertrophic signals, maintaining action potential propagation, and modulating cardiac energy metabolism through the muscarinic ACh receptor in an auto/paracrine manner. Moreover, the NNCCS may also affect peripheral remote organs (e.g., liver) through the vagus nerve. Remote ischemic preconditioning (RIPC) and NNCCS activate the central nervous system and afferent vagus nerve. RIPC affects hepatic glucose and energy metabolism through the central nervous system and vagus nerve. In this review, we discuss the mechanisms and potential factors responsible for NNCCS in glucose and energy metabolism in the liver.

Abstract Objectives The objective of this work is to evaluate the additional oncological benefit of photodynamic diagnosis (PDD) using blue‐light cystoscopy in transurethral resection (TURBT) for primary non‐muscle‐invasive bladder cancer (NMIBC) based on the International Bladder Cancer Group (IBCG)‐defined progression and the subsequent pathological pathways. Patients and Methods We reviewed 1578 consecutive primary NMIBC patients undergoing white‐light TURBT (WL‐TURBT) or PDD‐TURBT during 2006–2020. One‐to‐one propensity score‐matching was performed using multivariable logistic regression to obtain balanced groups. IBCG‐defined progression of NMIBC included stage‐up and grade‐up as well as conventional definitions such as the development of muscle‐invasive BC or metastatic disease. Nine oncological endpoints were evaluated. Sankey diagrams were generated to visualize follow‐up pathological pathways after the initial TURBT. Results Comparison of event‐free survival between the matched groups revealed that PDD use decreased the bladder cancer recurrence risk and IBCG‐defined progression risk, whereas no significant difference was noted in conventionally defined progression. This was attributable to a reduced risk of stage‐up, from Ta to T1, and grade‐up. Sankey diagrams of the matched groups showed that patients with primary Ta low‐grade tumour and first‐recurrence Ta low‐grade tumour did not have bladder recurrence or progression, while some of those in the WL‐TURBT group developed recurrence after treatment. Conclusions The multiple survival analysis demonstrated that the risk of IBCG‐defined progression was significantly decreased by PDD use in NMIBC patients. Sankey diagrams revealed possible differences in pathological pathways after the initial TURBT between the two groups, demonstrating that repeated recurrence could be prevented by PDD use.

Abstract Background Ewing’s sarcoma is a malignant neoplasm that mainly occurs in skeletal tissue but can rarely arise in soft tissues. Recently, small round cell tumors (including Ewing’s sarcoma) caused by chromosomal translocations have been collectively termed Ewing’s sarcoma family of tumors. We report a rare case of primary adrenal Ewing’s sarcoma family of tumors with tumor thrombus. Case presentation A 22-year-old Asian woman was referred to our hospital with a left retroperitoneal tumor 19 cm in diameter. Tumor thrombus was identified from the left adrenal vein to the inferior vena cava, infiltrating the right atrium. Total tumor excision with left adrenalectomy, nephrectomy, and thrombectomy was performed under hypothermic circulatory arrest, followed by seven courses of adjuvant chemotherapy. The patient has shown no signs of recurrence as of 26 months postoperatively. Conclusion Radical surgery combined with systemic chemotherapy may contribute to good prognosis in patients with primary adrenal Ewing’s sarcoma family of tumors.

Introduction Immune checkpoint inhibitors such as programmed cell death/−ligand 1 inhibitor and cytotoxic T‐lymphocyte‐associated antigen‐4 inhibitors have been widely used for various advanced malignancies. The mechanism of action for these inhibitors is the improvement of antitumor immunity via T‐cell modulation. On the contrary, immune‐related adverse events such as autoimmune colitis might arise in association with T‐cell activation. Upper gastrointestinal adverse events related to pembrolizumab have rarely been reported. Case presentation A 72‐year‐old man underwent laparoscopic radical cystectomy for muscle‐invasive bladder cancer (pT2N0M0). Multiple lymph node metastases appeared in the paraaortic region. First‐line chemotherapy comprising gemcitabine and carboplatin failed to stop disease progression. After the administration of pembrolizumab as second‐line treatment, the patient showed symptomatic gastroesophageal reflux disease. Esophagogastroduodenoscopic biopsy of the gastric body showed severe lymphoplasmacytic and neutrophilic infiltration. Conclusion We present acute gastritis related to pembrolizumab. Early eradication therapy may be able to control immune checkpoint inhibitor‐related gastritis.

Low-temperature atmospheric-pressure plasma jets are generally considered a safe medical technology with no significant long-term side effects in clinical studies reported to date. However, there are studies emerging that show plasma jets can cause significant side effects in the form of skin burns under certain conditions. Therefore, with a view of developing safer plasma treatment approaches, in this study we have set out to provide new insights into the cause of these skin burns and how to tailor plasma treatments to mitigate these effects. We discovered that joule heating by the plasma bullet currents is responsible for creating skin burns during helium plasma jet treatment of live mice. These burns can be mitigated by treating the mice at a further distance so that the visible plasma plume does not contact the skin. Under these treatment conditions we also show that the plasma jet treatment still retains its medically beneficial property of producing reactive oxygen species in vivo. Therefore, treatment distance is an important parameter for consideration when assessing the safety of medical plasma treatments.

Abstract Background To evaluate whether urine laminin‐γ2 monomer (Ln‐γ2m) offers a useful biomarker for patients with non‐muscle‐invasive bladder cancer (NMIBC). Methods Participants comprised 297 patients, including 111 patients with NMIBC, 136 patients with benign genitourinary disease (BD) and 50 healthy donors (HD). Urine Ln‐γ2m was prospectively measured and accuracy was analyzed. Receiver operating characteristic (ROC) curves were determined and area under the ROC curve (AUC) was calculated for urine Ln‐γ2m, and compared to those of traditional urine tumor markers such as nuclear matrix protein 22 (NMP22), bladder tumor antigen (BTA) and cytology. The net benefits of combining urine markers were analyzed by decision curve analysis. Results Mean urine Ln‐γ2m was significantly higher in NMIBC than in BD or HD. The AUC for urine Ln‐γ2m was significantly higher than those for urine NMP22, BTA or cytology when comparing NMIBC with HD. In patients with low‐grade NMIBC, the AUC for urine Ln‐γ2m was higher than the AUCs for NMP22, BTA or cytology. A net benefit of combined examination using urine Ln‐γ2m/uCRN with NMP22 was demonstrated. Conclusion These results suggest urine Ln‐γ2m as a potentially useful biomarker for NMIBC, particularly in cases of low‐grade cancer.

Abstract Apathy is frequently observed in idiopathic normal pressure hydrocephalus (iNPH) and worsens cognitive impairment and gait disturbance. In this study, we evaluated the regions associated with apathy in iNPH using statistical imaging analysis on the whole brain, both in terms of cerebral blood flow and gray matter volume. Twenty-seven patients with iNPH were assigned to two groups based on their scores on the neuropsychiatric inventory items related to apathy; 18 patients were assigned to the group with apathy (iNPH + APA) and 9 to the group without apathy (iNPH − APA). The magnetic resonance images and cerebral blood flow single-photon emission computed tomography data of the two groups were compared using statistical parametric mapping 12. The regional gray matter volume of the right precuneus was significantly larger in the iNPH + APA group than in the iNPH − APA group, but the regional cerebral blood flow in any region of the brain was not significantly different between the two groups. These results suggested that the larger gray matter volume, which is thought to reflect gray matter compression, in the precuneus might be involved in apathy in iNPH.

Background: Site-specific postoperative risk models for localized upper tract urothelial carcinoma (UTUC) are unavailable. Objective: To create specific risk models for renal pelvic urothelial carcinoma (RPUC) and ureteral urothelial carcinoma (UUC), and to compare the predictive accuracy with the overall UTUC risk model. Design, setting, and participants: A multi-institutional database retrospective study of 1917 UTUC patients who underwent radical nephroureterectomy (RNU) between 2000 and 2018 was conducted. Outcome measurements and statistical analysis: A multivariate hazard model was used to identify the prognostic factors for extraurinary tract recurrence (EUTR), cancer-specific death (CSD), and intravesical recurrence (IVR) after RNU. Patients were stratified into low-, intermediate-, high-, and highest-risk groups. External validation was performed to estimate a concordance index of the created risk models. We investigated whether our risk models could aid decision-making regarding adjuvant chemotherapy (AC) after RNU. Results and limitations: The UTUC risk models could stratify the risk of cumulative incidence of three endpoints. The RPUC- and UUC-specific risk models showed better stratification than the overall UTUC risk model for all the three endpoints, EUTR, CSD, and IVR (RPUC: concordance index, 0.719 vs 0.770, 0.714 vs 0.794, and 0.538 vs 0.569, respectively; UUC: 0.716 vs 0.767, 0.766 vs 0.809, and 0.553 vs 0.594, respectively). The UUC-specific risk model can identify the high- and highest-risk patients likely to benefit from AC after RNU. A major limitation was the potential selection bias owing to the retrospective nature of this study. Conclusions: We recommend using site-specific risk models instead of the overall UTUC risk model for better risk stratification and decision-making for AC after RNU. Patient summary: Upper tract urothelial carcinoma comprises renal pelvic and ureteral carcinomas. We recommend using site-specific risk models instead of the overall upper tract urothelial carcinoma risk model in risk prediction and decision-making for adjuvant therapy after radical surgery.

Current methods used to treat non-muscle invasive bladder cancer are inadequate due to a high recurrence rate after surgery and the occurrence of adverse events such as interstitial pneumonia following intravesical instillation therapy. Low-temperature plasma is a new form of physical therapy that provides a rich source of reactive oxygen species (ROS). Oxidative solutions, created by pre-treatment of aqueous media with plasma before application to target cells, lead to the destruction of cancer cells through oxidative stress pathways. This study focuses on the effects of plasma-activated media (PAM) in bladder cancer cells. PAM treatment increases oxidative stress that leads to cell cycle arrest and concomitantly depolarises the mitochondrial membrane leading to increased mitochondrial ROS production. Cell cycle arrest and increased mitochondrial ROS production led to an increase in caspase 3/cytochrome c activity, which might explain the induction of apoptosis in bladder cancer cells in vitro and in a bladder cancer tumour in vivo. These observations highlight the potential of plasma activated solutions as a new adjuvant therapy in the clinical treatment of bladder cancer.

Background: This multicenter prospective observational study examined the impact of additionally using a home electrocardiograph (ECG) to detect atrial fibrillation (AF) recurrence after ablation. Methods: Between May 2019 and December 2020, 128 patients undergoing ablation were enrolled in the study. After performing ablation, they were instructed to measure their ECGs at home using Complete (ECG paired with a blood pressure monitor; Omron Healthcare, Japan) every day and to visit the hospital every 3 months until after 12 months for 24-hour Holter ECG and 12-lead ECG as usual care (UC). Results: After ablation, 94 patients were followed up, and AF recurrence at 12 months was detected more commonly in adjudicators-interpreted Complete (31 [33 %]) than in UC (18 [9 %]) (hazard ratio 1.95, 95 % confidence interval [95 %CI] 1.35–2.81, P

Abstract Background To investigate risk factors for orally administered 5-aminolevulinic acid (ALA)-induced hypotension for bladder cancer patients receiving photodynamic diagnosis (PDD)-assisted transurethral resection of bladder tumor (TURBT). Methods Patients were categorized into two groups intraoperatively: a hypotensive group (minimum systolic blood pressure (SBP) ≤80 mmHg) and a non-hypotensive group (minimum SBP > 80 mmHg). We examined differences between the hypotensive group and non-hypotensive groups to identify clinical risk of ALA-induced hypotension using multivariate logistic regression analysis and decision tree analysis. Results Among 282 cases with ALA-PDD-assisted TURBT from three institutions who were screened, 245 patients were included in the final analysis. In total, 156 patients (63.7%) showed any grade of hypotension during ALA-PDD-assisted TURBT. General anesthesia and spinal anesthesia were induced intraoperatively in 113 patients (46.1%) and 132 patients (53.9%), respectively. Median SBP at baseline (before taking ALA) and at the beginning of anesthesia was 127 mmHg (range, 69–186 mmHg) and 124 mmHg (range, 69–186 mmHg), respectively. Median minimum SBP during ALA-PDD-assisted TURBT was 75 mmHg (range, 43–140 mmHg). Multivariate logistic regression analysis revealed that history of hypertension (odds ratio (OR) 7.568, p

Introduction Mixed tumor in the same lymph nodes is extremely rare and no previous reports have described mixed tumor comprising urothelial carcinoma and malignant lymphoma. Case presentation A 71‐year‐old woman visited a local clinic with a main complaint of hematuria. Imaging revealed right hydronephrosis and a mid‐ureter tumor shadow. Positron emission tomography–computed tomography showed high uptake of fluorodeoxyglucose in para‐aortic lymph nodes. Abdominal para‐aortic lymph node biopsy was performed. Pathology showed urothelial carcinoma and malignant lymphoma in the same lymph nodes, where a mixed tumor was diagnosed. Conclusion We encountered a case of mixed tumor of urothelial carcinoma and Hodgkin lymphoma, which metastasized to the same tissues.

Abstract Background To enhance the convenience and reduce the cost of prostate cancer (PC) screening, a one-step prostate-specific antigen (PSA) test was evaluated in a large population. The PSA SPOT test kit enables rapid detection of human PSA in serum or plasma at or above a cutoff level of 4 ng/mL to aid in the diagnosis of PC. Methods PC screening using the PSA SPOT test was offered to male participants in educational public lectures that we conducted in various cities. Test results were reported to participants at the end of the lectures. Blood samples from 1429 men were evaluated. Two independent observers interpreted the tests at 15 and 30 min. The remaining serum samples were subsequently tested using a conventional quantitative assay. Results The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the test were 79.9, 93.0, 65.4, 96.6, and 91.2%, respectively. The sensitivity and specificity of the test changed with variations in the reading time. Quantitative assessment of the intensity of the band was correlated with the PSA value. Conclusions PSA testing using this kit can be easily performed. The low cost and speed of the test make it a useful and convenient tool for primary PC screening.

Abstract Cancer can develop into a recurrent metastatic disease with latency periods of years to decades. Dormant cancer cells, which represent a major cause of recurrent cancer, are relatively insensitive to most chemotherapeutic drugs and radiation. We previously demonstrated that cancer cells exhibited dormancy in a cell density-dependent manner. Dormant cancer cells exhibited increased porphyrin metabolism and sensitivity to 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT). However, the metabolic changes in dormant cancer cells or the factors that enhance porphyrin metabolism have not been fully clarified. In this study, we revealed that lipid metabolism was increased in dormant cancer cells, leading to ALA-PDT sensitivity. We performed microarray analysis in non-dormant and dormant cancer cells and revealed that lipid metabolism was remarkably enhanced in dormant cancer cells. In addition, triacsin C, a potent inhibitor of acyl-CoA synthetases (ACSs), reduced protoporphyrin IX (PpIX) accumulation and decreased ALA-PDT sensitivity. We demonstrated that lipid metabolism including ACS expression was positively associated with PpIX accumulation. This research suggested that the enhancement of lipid metabolism in cancer cells induces PpIX accumulation and ALA-PDT sensitivity.

Abstract Background and Aim Disorders in bone metabolism have long been recognized as typical sequelae of gastrectomy; however, the pathogenesis has not been fully elucidated, resulting in a variation of reported incidence. This study aimed to evaluate current bone health by measuring bone mineral density (BMD) in patients treated by gastrectomy for gastric cancer, with a focus on incidence and risk factors of osteoporosis. Methods The study enrolled 81 patients who underwent gastrectomy for gastric cancer at Kochi Medical School. BMD of the lumbar spine was measured by dual‐energy X‐ray mineral absorptiometry, with the results expressed as a percentage of the young adult mean (YAM). Clinical data were also obtained to investigate associations with BMD. Results Of the 81 study patients, 12 (14.8%) were deemed to have osteoporosis, defined by a percentage of YAM

Introduction Bilateral renal cell carcinomas with different histological types are rare. We report herein the first description of bilateral renal carcinomas with clear cell renal cell carcinoma and mucinous tubular and spindle cell carcinoma occurring synchronously. Case presentation A 62‐year‐old man was referred to our hospital with bilateral renal tumors. The tumors on each side showed different findings from both contrast‐enhanced computed tomography and magnetic resonance imaging. The tumors were partially resected. Histopathological and immunohistochemical examination of the left renal tumor diagnosed clear cell renal carcinoma. Histopathological and immunohistochemical examination of the right renal tumor diagnosed mucinous tubular and spindle cell carcinoma. Conclusion We encountered a case with clear cell renal cell carcinoma and mucinous tubular and spindle cell carcinoma occurring simultaneously in bilateral kidneys.

Abstract Background 5-Aminolevulinic acid (5-ALA) is useful as a photodynamic agent, but its use commonly leads to hypotension. Although avoiding a mean arterial pressure (MAP) < 60 mmHg is important, the incidence of MAP < 60 mmHg when using 5-ALA is unclear. Therefore, we conducted a retrospective study to assess the incidence of post-induction hypotension and identified risk factors of this phenomenon. Methods One-hundred and seventy-two consecutive patients who underwent transurethral resection of the bladder tumor or craniotomy with the use of 5-ALA were enrolled. The primary outcome was the incidence of post-induction hypotension, defined as MAP < 60 mmHg during the first 1 h after anesthesia induction. We divided participants into the normal blood pressure group (group N) and the hypotension group (group L). Results The incidence of post-induction hypotension was 70% (group L = 121, group N = 51). Multivariate analysis revealed that female sex was an independent factor of post-induction hypotension (odds ratio [OR] 3.95; 95% confidence interval [CI] 1.21–12.97; p = 0.02). Systolic blood pressure < 100 mmHg before anesthesia induction and general anesthesia were also identified as significant independent factors (OR 13.30; 95% CI 1.17–151.0; p = 0.04 and OR 25.84; 95% CI 9.80–68.49; p < 0.001, respectively). Conclusions The incidence of post-induction hypotension was 70% in patients using 5-ALA. Female sex, systolic blood pressure < 100 mmHg before anesthesia induction, and general anesthesia might be independent factors of post-induction hypotension when using 5-ALA.

Abstract Background Schistosomiasis is prevalent in tropical and subtropical areas and rarely reported in developed countries. Schistosomiasis often occurs as a chronic illness, which can cause liver and intestinal damage. Appendicitis is an unusual complication of schistosomiasis. We herein present a case of acute appendicitis associated with the presence of schistosome eggs in a sailor from the Philippines. Case presentation A 34-year-old Filipino man who worked as a sailor presented to our hospital with a 2-day history of acute right lower quadrant abdominal pain and fever. A physical examination revealed right lower quadrant abdominal pain with signs of peritoneal irritation, including rebound tenderness. Computed tomography revealed thickening of the appendix associated with mural calcification and fluid collection around the cecum. Based on these findings, the preoperative diagnosis was acute appendicitis. Laparoscopic appendectomy was performed. Swelling of the appendix and contaminated ascites were observed intraoperatively, but there was no evidence of appendiceal perforation. A histopathological examination showed inflammation of the appendix wall and numerous ovoid bodies present within the submucosa, many of which were calcified. Severe infiltration of lymphocytes and fibrosis were recognized around the oval bodies. The numerous oval bodies were morphologically consistent with schistosomiasis. The final diagnosis was acute phlegmonous appendicitis associated with the presence of schistosome eggs. We examined the patient for signs of adult worm activity, but the results of stool ova and parasite examinations performed twice were negative. He was discharged and returned to his country on postoperative day 9. Conclusions The incidence of schistosomal appendicitis, which is seldom reported in developed countries, is expected to increase in Japan in the near future. Clinicians should suspect schistosome eggs as a cause of acute appendicitis in patients who have emigrated from or are traveling from endemic areas, and when mural calcification of the appendix is observed on imaging.

A 51-year-old man visited our hospital for voluntary cancer screening. Positron emission tomography and computed tomography (PET-CT) incidentally found a mass in the left scrotum. The patient was referred to our department. Magnetic resonance imaging suggested a diagnosis of a fat-containing tumor of the spermatic cord and excluded an inguinal hernia. High orchiectomy was performed due to a diagnosis of lipoma or liposarcoma. Histopathological diagnosis was well-differentiated liposarcoma. He has survived 28 months after surgery without recurrence. Spermatic cord tumors are difficult to diagnose with imaging, and attention must be paid to the possibility of malignant tumors.

Abstract Background Xp11.2 translocation renal cell carcinoma (RCC) is a rare variety of a kidney neoplasm. We report a case of bilateral Xp11.2 translocation RCC occurring metachronously and discuss this very rare entity with reference to the literature. Case presentation The patient was a 56-year-old woman who presented with a right renal tumor. The patient had undergone left radical nephrectomy 7 years previously, which resulted in a histopathological diagnosis of clear cell RCC. Open right partial nephrectomy was performed under the presumptive diagnosis of recurrence of clear cell RCC. The present right renal tumor was pathologically diagnosed Xp11.2 translocation RCC. More than 70% of the tumor cells in the present right tumor were strongly positive for transcription factor E3 (TFE3) expression by immunohistochemical analysis with an anti-TFE3 antibody. A break-apart of the TFE3 genes in the bilateral tumors was identified by fluorescence in situ hybridization analysis. Real time-polymerase chain reaction analysis for the alveolar soft part sarcoma locus-TFE3 fusion gene was performed, which gave a positive result in the bilateral tumors. Pathological comparison of each of the tumors might lead to a final diagnosis of Xp11.2 translocation RCC occurring metachronously. Conclusions We present the bilateral Xp11.2 translocation RCC. A combination of immunohistochemical, cytogenetic and molecular biological approaches allowed the final diagnosis of such a rare RCC.

Abstract Background Although 5-aminolevulinic acid (5-ALA) is used for the photodynamic diagnosis of bladder tumors, hypotension is the most commonly observed adverse effect. We present a case of 5-ALA-induced severe hypotension during transurethral resection of a bladder tumor. Case presentation A 68-year-old man underwent transurethral resection of a bladder tumor using 5-ALA under general anesthesia. Three hours before anesthesia induction, ALA 20 mg/kg was administered orally. After anesthesia induction, his blood pressure decreased to 47/32 mmHg. Although we used phenylephrine and ephedrine, hypotension persisted at 50/33 mmHg. Bolus administration of noradrenaline slightly increased his blood pressure to 65/39 mmHg. Following this, bolus administration of adrenaline elevated his blood pressure. We decided to perform surgery under continuous administration of adrenaline. Conclusions Our case report suggests that anesthesiologists should consider 5-ALA-induced hypotension as a differential diagnosis for hypotension occurring after anesthesia induction. Moreover, ephedrine and phenylephrine might be less effective in treating this condition.

Abstract Background Monomeric laminin-γ2 in urine is a potential biomarker for bladder cancer. However, the current detection system uses an antibody that cannot discriminate between monomeric laminin-γ2 and the heterotrimeric γ2 chain of laminin-332, which may cause false-positive reactions. The present study aimed to develop a fully automated chemiluminescence immunoassay system using a specific monoclonal antibody against monomeric laminin-γ2. Methods In total, 237 urine specimens (84 from patients with bladder cancer, 48 from patients with benign urological disease, and 105 from healthy donors) were collected, and monomeric laminin-γ2 values in the urine were measured using a fully automated chemiluminescence immunoassay. Results The results revealed that laminin-γ2 values in patients with benign urological disease were comparable to those of healthy donors and that the chemiluminescence immunoassay’s lower limit of detection was 10 pg/mL (approximately 20-fold better than the sandwich enzyme-linked immunosorbent assay’s limit of 200 pg/mL). Moreover, the chemiluminescence immunoassay demonstrated that patients with bladder cancer, including non-muscle invasive bladder cancer (≤pT1), had higher laminin-γ2 values than patients with benign urological disease or healthy donors. Conclusions These results suggest that urine monomeric laminin-γ2 may be a promising biomarker to diagnose cases of non-muscle invasive bladder cancer using a fully automated chemiluminescence immunoassay system.

Induced pluripotent stem cells (iPSCs) from type 1 long QT (LQT1) patients can differentiate into cardiomyocytes (CMs) including ventricular cells to recapitulate the disease phenotype. Although optical recordings using membrane potential dyes to monitor action potentials (APs) were reported, no study has investigated the disease phenotypes of cardiac channelopathy in association with the cardiac subtype at the single-cell level. We induced iPSC-CMs from three control and three LQT1 patients. Single-cell analysis using a fast-responding dye confirmed that ventricular cells were the dominant subtype (control-iPSC-CMs: 98%, 88%, 91%; LQT1-iPSC-CMs: 95%, 79%, 92%). In addition, LQT1-iPSC-ventricular cells displayed an increased frequency of early afterdepolarizations (pvalue=0.031). Cardiomyocyte monolayers constituted mostly of ventricular cells derived from LQT1-iPSCs showed prolonged AP duration (APD) (pvalue=0.000096). High-throughput assays using cardiomyocyte monolayers in 96-well plates demonstrated that IKr inhibitors prolonged APDs in both control- and LQT1-iPSC-CM monolayers. We confirmed that the optical recordings of APs in single cells and monolayers derived from control- and LQT1-iPSC-CMs can be used to assess arrhythmogenicity, supporting the feasibility of membrane potential dye-based high-throughput screening to study ventricular arrhythmias caused by genetic channelopathy or cardiotoxic drugs.

The involvement of cholesterol crystals (CCs) in plaque progression and destabilization of atherosclerotic plaques has been recently recognized. This study aimed to evaluate the association between the intraplaque localization of CCs and plaque vulnerability.We investigated 55 acute coronary syndrome (ACS) and 80 stable angina pectoris (stable AP) lesions using optical frequency domain imaging (OFDI) prior to percutaneous coronary intervention. The distance between CCs and the luminal surface of coronary plaques was defined as CC depth.Although the incidence of CCs had similar frequencies in the ACS and stable AP groups (95% vs. 89%, p = 0.25), CC depth was significantly less in patients with ACS than in those with stable AP (median [25th to 75th percentile]: 68 μm [58 to 92 μm] vs. 152 μm [115 to 218 μm]; p < 0.001). The incidences of plaque rupture, thrombus, lipid-rich plaques, and thin-cap fibroatheroma were significantly greater in patients with ACS than in those with stable AP (62% vs. 18%, p < 0.001; 67% vs. 16%, p < 0.001; 84% vs. 57%, p < 0.01; and 56% vs. 19%, p < 0.001, respectively).OFDI analysis revealed that CCs were found in the more superficial layers within the coronary atherosclerotic plaques in patients with ACS than in those with stable AP, suggesting that CC depth is associated with plaque vulnerability. CC depth, a novel OFDI-derived parameter, could be potentially used as an alternative means of evaluating plaque vulnerability in coronary arteries.

A 50-year-old male was examined at another hospital for fever, general fatigue and slight abdominal pain. He was treated with antibiotics and observed. However, his symptoms did not lessen, and laboratory tests revealed liver dysfunction, jaundice and an increased inflammatory response. He was then admitted to our hospital and underwent an abdominal computed tomography scan and magnetic resonance cholangiopancreatography (MRCP), which revealed common bile duct (CBD) stones. He was diagnosed with mild acute cholangitis. As the same time, he was admitted to our hospital and an emergency endoscopic retrograde cholangiopancreatography was performed. Vater papilla opening in the third portion of the duodenum and presence of a peripapillary duodenal diverticulum made it difficult to perform cannulation of the CBD. In addition, MRCP revealed that the CBD was extremely narrow (diameter 5 mm). We therefore performed laparoscopic cholecystectomy and endoscopic sphincterotomy using the rendezvous technique for choledocholithiasis simultaneously rather than laparoscopic CBD exploration. After the operation, the patient was discharged with no complications. Although the rendezvous technique has not been very commonly used because several experts in the technique and a large operating room are required, this technique is a very attractive and effective approach for treating choledocholithiasis, for which endoscopic treatment is difficult.

Photodynamic diagnosis (PDD) can improve diagnostic accuracy by using PDD agents such as 5-aminolevulinic acid (ALA). However, the weakness and photobleaching of fluorescence of PDD agents may lead to insufficient fluorescence visibility for the detection of cancer during resection operations. We focused on the “fluorescence enhancement effect” resulting from the addition of polyethylene glycol-modified titanium dioxide nanoparticles (TiO2-PEG NPs) to address these problems. The results showed that the combined administration of TiO2-PEG NPs and ALA could enhance and prolong fluorescence in bladder cancer cells, similar to in the mixture alone. It was suggested that the fluorescence enhancement was related to the accumulation of TiO2-PEG NPs in cells via endocytosis, causing the light scattering and enhancement of fluorescence. This fluorescence enhancement effect could be applicable for PDD.

A 44-year-old woman was referred to our hospital with pathological nipple discharge from her left breast. Ultrasonography revealed a solid tumor beneath her left areola that measured 17 mm in diameter with a dilated mammary duct. Contrast-enhanced magnetic resonance imaging showed an early-enhanced cystic tumor and a dilated mammary duct. We performed a duct-lobular segmentectomy using near-infrared indocyanine green (ICG)-fluorescence imaging. Under general anesthesia, a silicone tube was inserted into an orifice of a fluid-discharging mammary duct, and 1 mL dye-fluorescence liquid containing ICG and indigo carmine was injected into the mammary duct. A periareolar incision was made, and the fluorescence image of the demarcated mammary duct segment was obtained. The mammary duct segment was dissected, along with the demarcation line. The cystic lesion and dilated mammary duct were fully resected, and the pathological diagnosis was intraductal papilloma of the breast. We report that near-infrared ICG fluorescence could be applied for imaging of the mammary duct segment, and the fluorescence image allowed for easier duct-lobular segmentectomy for nipple discharge.

An eighty-year-old female was transferred to the hospital after experiencing abdominal pain and nausea. She had had a history of total gastrectomy for gastric cancer 14 years previously. Abdominal X-ray revealed a localized expansion of the small bowel. Computed tomography revealed a mass with a lamellar structure in a concentric circle. With a tentative diagnosis of small bowel obstruction due to intussusception, she underwent emergency operation. Laparotomy revealed a retrograde jejuno-jejunal intussusception. Bowel resection was performed due to the severe ischemic damage. All reported intussusception cases after total gastrectomy displayed retrograde characteristics and could occur both during the early and late period after surgery. It is important to consider the possibility of intussusception for patients presenting with acute abdomen who have previously undergone gastric resection.

A decreased prostatic blood flow could be one of the risk factors for benign prostatic hyperplasia/benign prostatic enlargement. The spontaneously hypertensive rat (SHR) shows a chronic prostatic ischemia and hyperplastic morphological abnormalities in the ventral prostate. The effect of silodosin, a selective alpha1A-adrenoceptor antagonist, was investigated in the SHR prostate as a prostatic hyperplasia model focusing on prostatic blood flow.Twelve-week-old male SHRs were administered perorally with silodosin (100 μg/kg/day) or vehicle once daily for 6 weeks. Wistar Kyoto (WKY) rats were used as normotensive controls and were treated with the vehicle. The effect of silodosin on blood pressure and prostatic blood flow were estimated and then the prostates were removed and weighed. The tissue levels of malondialdehyde (MDA), interleukin-6 (IL-6), chemokine (C-X-C motif) ligand 1/cytokine-induced neutrophil chemoattractant 1 (CXCL1/CINC1), tumor necrosis factor-alpha (TNF-α), transforming growth factor beta 1 (TGF-β1), basic fibroblast growth factor (bFGF) and alpha-smooth muscle actin (α-SMA) were measured. The histological evaluation was also performed by hematoxylin and eosin staining.There was a significant increase in blood pressure, prostate weight, prostate body weight ratio (PBR), tissue levels of MDA, IL-6, CXCL1/CINC1, TNF-α, TGF-β1, bFGF and α-SMA in the SHR compared to the WKY rat. The ventral prostate in the SHR showed the morphological abnormalities compared to the WKY rat. Prostatic blood flow was decreased in the SHR. However, treatment with silodosin significantly restored the decreased prostatic blood flow in the SHR. Moreover, silodosin normalized tissue levels of MDA, IL-6, CXCL1/CINC1, TNF-α, TGF-β1, bFGF and α-SMA, and it ameliorated ventral prostatic hyperplasia in the SHR excluding blood pressure. Silodosin decreased PBR but not prostate weight in the SHR.Silodosin can inhibit the progression of prostatic hyperplasia through a recovery of prostatic blood flow.

Recently, photodynamic therapy using 5-aminolevulinic acid (ALA-PDT) has been widely used in cancer therapy. ALA administration results in tumor-selective accumulation of the photosensitizer protoporphyrin IX (PpIX) via the heme biosynthetic pathway. Although ALA-PDT has selectivity for tumor cells, PpIX is accumulated into cultured normal cells to a small extent, causing side effects. The mechanism of tumor-selective PpIX accumulation is not well understood. The purpose of the present study was to identify the mechanism of tumor-selective PpIX accumulation after ALA administration. We focused on mitochondrial labile iron ion, which is the substrate for metabolism of PpIX to heme. We investigated differences in iron metabolism between tumor cells and normal cells and found that the amount of mitochondrial labile iron ion in cancer was lower than that in normal cells. This finding could be because of the lower expression of mitoferrins, which are the mitochondrial iron transporters. Accordingly, we added sodium ferrous citrate (SFC) with ALA as a source of iron. As a result, we observed the accumulation of PpIX only in tumor cells, and only these cells showed sensitivity to ALA-PDT. Taken together, these results suggest that the uptake abilities of iron ion into mitochondria play a key role in tumor-selective PpIX accumulation. Using SFC as a source of iron might thus increase the specificity of ALA-PDT effects.

To evaluate the diagnostic value of a new photodynamic diagnosis (PDD) system using 5-aminolevulinic acid (ALA) for the diagnosis of bladder tumors. To validate whether false-positive findings caused by tangent effects in PDD can be resolved, we compared diagnostic accuracies between the new PDD system and a conventional PDD system.Among 30 transurethral bladder biopsies, 15 cases received ALA-PDD using rigid fluorescence cystoscopy (conventional PDD system), and flexible fluorescence cystoscopy with a twin mode monitor (new PDD system) was used in a separate set of 15 cases. To evaluated the usefulness of ALA-PDD, diagnostic accuracies were retrospectively compared between the conventional PDD system and the new PDD system.Of 207 specimens from 30 cases, we obtained 110 specimens using the conventional PDD system and 97 specimens using the new PDD system. Of these samples, we selected 30 distal bladder specimens each from both the conventional PDD system and the new PDD system. The overall sensitivity, specificity and false-positive rate for the new PDD system were 100%, 82.6%, and 17.4%, respectively. Those of the conventional PDD system were 83.3%, 66.2% and 33.8%, respectively. The overall false-positive rate of the new PDD system improved to 16.4% when compared with the conventional PDD system. Furthermore, the false-positive rate of the new PDD system in distal bladder samples improved to 11.8%. The overall AUC of the new PDD system was significantly greater compared with that of the conventional PDD system (P

Our conditional VHL knockout (VHL-KO) mice, having VHL gene deletion induced by tamoxifen, developed severe hypoglycemia associated with disproportionately increased storage of PAS-positive substances in the liver and resulted in the death of these mice. This hypoglycemic state was neither due to impaired insulin secretion nor insulin receptor hypersensitivity. By focusing on insulin-like growth factor I (IGF-I), which has a similar effect on glucose metabolism as the insulin receptor, we demonstrated that IGF-I receptor (IGF-IR) protein expression in the liver was upregulated in VHL-KO mice compared to that in the mice without VHL deletion, as was the expression of glucose transporter (GLUT) 1. The interaction of the receptor for activated C kinase (RACK) 1, which predominantly binds to VHL, was enhanced in VHL-KO livers with IGF-IR, because VHL deletion increased free RACK1 and facilitated the IGF-IR-RACKI interaction. An IGF-IR antagonist retarded hypoglycemic progression and sustained an euglycemic state. These IGF-IR antagonist effects on restoring blood glucose levels also attenuated PAS-positive substance storage in the liver. Because the effect of IGF-I on HIF-1α protein synthesis is mediated by IGF-IR, our results indicated that VHL inactivation accelerated hepatic glucose storage through the upregulation of IGF-IR and GLUT1 and that IGF-IR was a key regulator in VHL-deficient hepatocytes.

Nephrotoxicity is a frequent and major limitation in cisplatin (CDDP)-based chemotherapy. 5-Aminolevulinic acid (ALA) is widely distributed in animal cells, and it is a precursor of tetrapyrole compounds such as heme that is fundamentally important in aerobic energy metabolism. The aim of this study is to evaluate the protective role of ALA in CDDP-induced acute kidney injury (AKI).We used CDDP-induced AKI rat model and cultured renal tubular cells (NRK-52E). We divided four groups of rats: control, CDDP only, CDDP + ALA(post);(ALA 10 mg/kg + Fe in drinking water) after CDDP, CDDP + ALA(pre & post).CDDP increased Cr up to 6.5 mg/dl, BUN up to 230 mg/dl, and ALA significantly reduced these changes. ALA ameliorates CDDP-induced morphological renal damages, and reduced tubular apoptosis evaluated by TUNEL staining and cleaved caspase 3. Protein and mRNA levels of ATP5α, complex(COX) IV, UCP2, PGC-1α in renal tissue were significantly decreased by CDDP, and ALA ameliorates reduction of these enzymes. In contrast, Heme Oxigenase (HO)-1 level is induced by CDDP treatment, and ALA treatment further up-regulates HO-1 levels. In NRK-52E cells, the CDDP-induced reduction of protein and mRNA levels of mitochondrial enzymes was significantly recovered by ALA + Fe. CDDP-induced apoptosis were ameliorated by ALA + Fe treatment. Furthermore, we evaluated the size of transplantated bladder carcinoma to the rat skin, and ALA did not change the anti cancer effects of CDDP.These data suggested that the protective role of ALA in cisplatin-induced AKI is via protection of mitochondrial viability and prevents tubular apoptosis. Also there are no significant effects of ALA on anticancer efficiency of CDDP in rats. Thus, ALA has the potential to prevent CDDP nephrotoxicity without compromising its anticancer efficacy.

Accumulation of protoporphyrin IX (PpIX) in malignant cells is the basis of 5-aminolevulinic acid (ALA)-mediated photodynamic therapy. We studied the expression of proteins that possibly affect ALA-mediated PpIX accumulation, namely oligopeptide transporter-1 and -2, ferrochelatase and ATP-binding cassette transporter G2 (ABCG2), in several tumor cell lines. Among these proteins, only ABCG2 correlated negatively with ALA-mediated PpIX accumulation. Both a subcellular fractionation study and confocal laser microscopic analysis revealed that ABCG2 was distributed not only in the plasma membrane but also intracellular organelles, including mitochondria. In addition, mitochondrial ABCG2 regulated the content of ALA-mediated PpIX in mitochondria, and Ko143, a specific inhibitor of ABCG2, enhanced mitochondrial PpIX accumulation. To clarify the possible roles of mitochondrial ABCG2, we characterized stably transfected-HEK (ST-HEK) cells overexpressing ABCG2. In these ST-HEK cells, functionally active ABCG2 was detected in mitochondria, and treatment with Ko143 increased ALA-mediated mitochondrial PpIX accumulation. Moreover, the mitochondria isolated from ST-HEK cells exported doxorubicin probably through ABCG2, because the export of doxorubicin was inhibited by Ko143. The susceptibility of ABCG2 distributed in mitochondria to proteinase K, endoglycosidase H and peptide-N-glycosidase F suggested that ABCG2 in mitochondrial fraction is modified by N-glycans and trafficked through the endoplasmic reticulum and Golgi apparatus and finally localizes within the mitochondria. Thus, it was found that ABCG2 distributed in mitochondria is a functional transporter and that the mitochondrial ABCG2 regulates ALA-mediated PpIX level through PpIX export from mitochondria to the cytosol.