En masse organoid phenotyping informs metabolic-associated genetic susceptibility to NASH.

Genotype-phenotype associations for common diseases are often compounded by pleiotropy and metabolic state. Here, we devised a pooled human organoid-panel of steatohepatitis to investigate the impact of metabolic status on genotype-phenotype association. En masse population-based phenotypic analysis under insulin insensitive conditions predicted key non-alcoholic steatohepatitis (NASH)-genetic factors including the glucokinase regulatory protein (GCKR)-rs1260326:C>T. Analysis of NASH clinical cohorts revealed that GCKR-rs1260326-T allele elevates disease severity only under diabetic state but protects from fibrosis under non-diabetic states. Transcriptomic, metabolomic, and pharmacological analyses indicate significant mitochondrial dysfunction incurred by GCKR-rs1260326, which was not reversed with metformin. Uncoupling oxidative mechanisms mitigated mitochondrial dysfunction and permitted adaptation to increased fatty acid supply while protecting against oxidant stress, forming a basis for future therapeutic approaches for diabetic NASH. Thus, "in-a-dish" genotype-phenotype association strategies disentangle the opposing roles of metabolic-associated gene variant functions and offer a rich mechanistic, diagnostic, and therapeutic inference toolbox toward precision hepatology. VIDEO ABSTRACT.

Modelling human hepato-biliary-pancreatic organogenesis from the foregut-midgut boundary.

Organogenesis is a complex and interconnected process that is orchestrated by multiple boundary tissue interactions1-7. However, it remains unclear how individual, neighbouring components coordinate to establish an integral multi-organ structure. Here we report the continuous patterning and dynamic morphogenesis of hepatic, biliary and pancreatic structures, invaginating from a three-dimensional culture of human pluripotent stem cells. The boundary interactions between anterior and posterior gut spheroids differentiated from human pluripotent stem cells enables retinoic acid-dependent emergence of hepato-biliary-pancreatic organ domains specified at the foregut-midgut boundary organoids in the absence of extrinsic factors. Whereas transplant-derived tissues are dominated by midgut derivatives, long-term-cultured microdissected hepato-biliary-pancreatic organoids develop into segregated multi-organ anlages, which then recapitulate early morphogenetic events including the invagination and branching of three different and interconnected organ structures, reminiscent of tissues derived from mouse explanted foregut-midgut culture. Mis-segregation of multi-organ domains caused by a genetic mutation in HES1 abolishes the biliary specification potential in culture, as seen in vivo8,9. In sum, we demonstrate that the experimental multi-organ integrated model can be established by the juxtapositioning of foregut and midgut tissues, and potentially serves as a tractable, manipulatable and easily accessible model for the study of complex human endoderm organogenesis.

Multilineage communication regulates human liver bud development from pluripotency.

Conventional two-dimensional differentiation from pluripotency fails to recapitulate cell interactions occurring during organogenesis. Three-dimensional organoids generate complex organ-like tissues; however, it is unclear how heterotypic interactions affect lineage identity. Here we use single-cell RNA sequencing to reconstruct hepatocyte-like lineage progression from pluripotency in two-dimensional culture. We then derive three-dimensional liver bud organoids by reconstituting hepatic, stromal, and endothelial interactions, and deconstruct heterogeneity during liver bud development. We find that liver bud hepatoblasts diverge from the two-dimensional lineage, and express epithelial migration signatures characteristic of organ budding. We benchmark three-dimensional liver buds against fetal and adult human liver single-cell RNA sequencing data, and find a striking correspondence between the three-dimensional liver bud and fetal liver cells. We use a receptor-ligand pairing analysis and a high-throughput inhibitor assay to interrogate signalling in liver buds, and show that vascular endothelial growth factor (VEGF) crosstalk potentiates endothelial network formation and hepatoblast differentiation. Our molecular dissection reveals interlineage communication regulating organoid development, and illuminates previously inaccessible aspects of human liver development.

High-Fidelity Drug-Induced Liver Injury Screen Using Human Pluripotent Stem Cell-Derived Organoids.

BACKGROUND & AIMS: Preclinical identification of compounds at risk of causing drug induced liver injury (DILI) remains a significant challenge in drug development, highlighting a need for a predictive human system to study complicated DILI mechanism and susceptibility to individual drug. Here, we established a human liver organoid (HLO)-based screening model for analyzing DILI pathology at organoid resolution. METHODS: We first developed a reproducible method to generate HLO from storable foregut progenitors from pluripotent stem cell (PSC) lines with reproducible bile transport function. The qRT-PCR and single cell RNA-seq determined hepatocyte transcriptomic state in cells of HLO relative to primary hepatocytes. Histological and ultrastructural analyses were performed to evaluate micro-anatomical architecture. HLO based drug-induced liver injury assays were transformed into a 384 well based high-speed live imaging platform. RESULTS: HLO, generated from 10 different pluripotent stem cell lines, contain polarized immature hepatocytes with bile canaliculi-like architecture, establishing the unidirectional bile acid transport pathway. Single cell RNA-seq profiling identified diverse and zonal hepatocytic populations that in part emulate primary adult hepatocytes. The accumulation of fluorescent bile acid into organoid was impaired by CRISPR-Cas9-based gene editing and transporter inhibitor treatment with BSEP. Furthermore, we successfully developed an organoid based assay with multiplexed readouts measuring viability, cholestatic and/or mitochondrial toxicity with high predictive values for 238 marketed drugs at 4 different concentrations (Sensitivity: 88.7%, Specificity: 88.9%). LoT positively predicts genomic predisposition (CYP2C9∗2) for Bosentan-induced cholestasis. CONCLUSIONS: Liver organoid-based Toxicity screen (LoT) is a potential assay system for liver toxicology studies, facilitating compound optimization, mechanistic study, and precision medicine as well as drug screening applications.

Four- and two-armed hetero porphyrin dimers: their specific recognition and self-sorting behaviours.

In this study we self-assembled the four-armed porphyrin hetero dimer capsule Cap4, stabilized through amidinium-carboxylate salt bridges, in CH2Cl2 and CHCl3. The dimer capsule Cap4 was kinetically and thermodynamically more stable than the corresponding two-armed dimer Cap2. The number of arms strongly influenced their recognition behaviour; guests possessing small aromatic faces (e.g., 1,3,5-trinitrobenzene) preferred residing in the cavity of the two-armed capsule Cap2, rather than in Cap4, both thermodynamically and kinetically; in contrast, large aromatic guests (e.g., 9,10-dibromoanthracene) were encapsulated predominantly by Cap4 because of favourable entropic effects. The number of arms enabled self-sorting behaviour of the dimer formation; complexation studies using an equimolar mixture of the four porphyrin constituents of the two capsules revealed the quantitative formation of the corresponding dimers Cap2 and Cap4. Furthermore, we examined the specific molecular recognition of Cap2 and Cap4; NMR experiments of mixtures of Cap2 and Cap4 in the presence of favourable guests for Cap2 and Cap4 revealed that these guest molecules were encapsulated selectively by their preferred hosts.

Incidence of genitourinary injuries in pelvic fractures: A 12-year single-center retrospective study.

OBJECTIVE: This study aimed to determine the epidemiology of genitourinary injuries in pelvic fractures and elucidate the clinical outcomes of patients with pelvic fractures with and without genitourinary injuries at a tertiary trauma center in Japan. METHODS: Patients with pelvic fractures in our tertiary trauma center between May 2009 and April 2021 were retrospectively assessed. The patients' demographics, mechanism of injury, and hospital course details were collected. The outcomes of patients with pelvic fractures with and without genitourinary injuries were compared. RESULTS: Of 402 patients with pelvic fractures, 18 (4.5%) had genitourinary injuries. Falls were the most common mechanisms of injury for all pelvic fractures The incidence of bladder, kidney, urethral, and testis injuries were 2.0%, 1.2%, 1.2%, and 0.5%, respectively. Patients with genitourinary injuries were significantly younger (median age, 26 vs. 51 years; p < 0.001), had a higher rate of intensive care unit admission (94% vs. 58%; p = 0.002), remained hospitalized longer (median duration, 82 vs. 45 days; p < 0.001), and had a longer intensive care unit stay (median duration, 6 vs. 2 days; p < 0.001) when compared to patients without genitourinary injuries. Genitourinary injuries were not associated with in-hospital mortality. CONCLUSIONS: The incidence of genitourinary injuries with pelvic fractures was 4.5%. The presence of genitourinary injuries was associated with a higher rate of intensive care unit admission, longer hospital stay, and longer intensive care unit stay, but it was not associated with in-hospital mortality.

Higher serum alkaline phosphatase value indicates the need for bone mineral density testing in non-metastatic prostate cancer patients undergoing androgen deprivation therapy.

PURPOSE: Osteoporosis is a well-known adverse effect of androgen deprivation therapy for prostate cancer. This study aimed to reveal the factors associated with the diagnosis of osteoporosis in prostate cancer patients undergoing androgen deprivation therapy. METHODS: This retrospective cross-sectional study included 106 prostate cancer patients treated with androgen deprivation therapy. Patients with bone metastasis at the initiation of androgen deprivation therapy and those with castration-resistant prostate cancer were excluded. Bone mineral density was measured at the lumbar spine and femoral neck using dual-energy X-ray absorptiometry. Osteoporosis was defined as bone mineral density equal to or below either -2.5 SD or 70% of the mean in young adults. The association between clinicopathological variables and bone mineral density or diagnosis of osteoporosis was investigated. RESULTS: Thirty-six (34%) patients were found to have osteoporosis. The incidence of osteoporosis increased in a stepwise manner depending on the duration of androgen deprivation therapy. Multivariate logistic regression analysis identified a longer duration of androgen deprivation therapy (months, odd's ratio = 1.017, P = 0.006), lower body mass index (kg/m2, odd's ratio = 0.801, P = 0.005) and higher serum alkaline phosphatase value (U/l, odd's ratio 1.007, P = 0.014) as the factors independently associated with the diagnosis of osteoporosis. Eleven out of 50 (22%), 14 out of 35 (40%) and 11 out of 20 patients (55%) were osteoporotic in the patients with serum alkaline phosphatase values <238 U/l, 238-322 U/l and >322 U/l, respectively (P = 0.022). CONCLUSIONS: Osteoporosis is common in prostate cancer patients undergoing androgen deprivation therapy; furthermore, its incidence increases depending on the duration of androgen deprivation therapy. Bone mineral density testing should be considered for all patients on androgen deprivation therapy, especially for those with a lower body mass index and higher serum alkaline phosphatase value.

Diphthamide modification of eEF2 is required for gut tumor-like hyperplasia induced by oncogenic Ras.

Eukaryotic elongation factor 2 (eEF2) undergoes a unique post-translational modification called diphthamidation. Although eEF2 diphthamidation is highly conserved, its pathophysiological function is still largely unknown. To elucidate the function of diphthamidation in tumor, we examined the involvement of diphthamidation pathway enzyme Dph5 in tumor progression in Drosophila adult gut. Expression of oncogenic RasV12 in gut intestinal stem cells (ISCs) and enteroblasts (EBs) causes hypertrophy and disruption of gut epithelia, and shortened life span. Knockdown of Dph5 ameliorated these pathogenic phenotypes. Dph5 is required for gross translation activation and high dMyc protein level in RasV12 tumor-like hyperplasia. Transcriptome analysis revealed that Dph5 is involved in the regulation of ribosome biogenesis genes. These results suggest that diphthamidation is required for translation activation partly through the regulation of ribosome biogenesis in Ras-induced tumor-like hyperplasia model in Drosophila gut.

Rapid Increase of Gastrointestinal P-Glycoprotein Functional Activity in Response to Etoposide Stimulation.

We previously reported that exposure of human colon adenocarcinoma (Caco-2) cells to the bitter substance phenylthiocarbamide (PTC) rapidly enhanced the transport function of P-glycoprotein (P-gp). In this study, we investigated the short-term effect of etoposide, another bitter-tasting P-gp substrate, on P-gp transport function in the same cell line. We found that etoposide exposure significantly increased both the P-gp protein level in the plasma membrane fraction and the efflux rate of rhodamine123 (Rho123) in Caco-2 cells within 10 min. The efflux ratio (ratio of the apparent permeability coefficient in the basal-to-apical direction to that in the apical-to-basal direction) of Rho123 in etoposide-treated cells was also significantly increased compared with the control. These results indicated that etoposide rapidly enhances P-gp function in Caco-2 cells. In contrast, P-gp expression in whole cells at both the mRNA and protein level was unchanged by etoposide exposure, compared with the levels in non-treated cells. Furthermore, etoposide increased the level of phosphorylated ezrin, radixin and moesin (P-ERM) proteins in the plasma membrane fraction of Caco-2 cells within 10 min. P-gp functional changes were blocked by YM022, an inhibitor of cholecystokinin (CCK) receptor. These results suggest that etoposide induces release of CCK, causing activation of the CCK receptor followed by phosphorylation of ERM proteins, which recruit intracellular P-gp for trafficking to the gastrointestinal membrane, thereby increasing the functional activity of P-gp.

Measurement algorithm for real front and back curved surfaces of contact lenses.

The optical measurement algorithm for the real front and back surfaces of contact lenses from their center to periphery accurately and simultaneously is proposed. It is an algorithm that makes light incident vertically along the curved surfaces of contact lenses under the condition that the difference of curvature radii between the front and back surfaces is small enough within the NA of the optical probe. For this purpose, we adopted time-domain optical coherence tomography (OCT) with translation and rotation mechanisms. The shape, thickness distribution, and curvature radii of both surfaces were estimated with OCT signal analysis and circular approximation. The measured results were compared with the designed values and the measured data from a conventional shape measurement device. The curved shape of both surfaces and thickness were well matched with the designed values from lens center to periphery. In a curvature radius of the front surface, there was a proportional bias with a limit of agreement of -0.77% to -2.09%, and the correlation coefficient was 0.57. On the back surface, there was no systematic bias, and minimal detectable change was 0.178 mm, in a range of 95% confidential interval. The proposed algorithm well visualized the real shape and optical characteristics of the contact lens with enough accuracy to the design.

The Effects of Continuous and Withdrawal Voluntary Wheel Running Exercise on the Expression of Senescence-Related Genes in the Visceral Adipose Tissue of Young Mice.

Obesity has become a global medical problem. The upregulation of senescence-related markers in adipose tissue may cause impairment of adipose tissue and disorders of systemic metabolism. Weight control through diet has been found to ameliorate senescence in the adipose tissue. Exercise is also important in maintaining a healthy lifestyle, however, very few researchers have examined the relationship between senescence-related markers in adipose tissue. Dietary restriction is also reported to have a legacy effect, wherein the effects are maintained for some periods after the termination of the intervention. However, very few researchers have examined the relationship between exercise and senescence-related markers in adipose tissue. Besides, there is no study on the long-term effects of exercise. Hence, we investigated whether the exercise could change the expression of senescence-related genes in the visceral adipose tissue of young mice and whether there was a legacy effect of exercise for 10 weeks after the termination of exercise. Four-week-old male ICR mice were assigned to one of the three groups: 20 weeks of sedentary condition, 20 weeks of voluntary wheel running exercise, or 10 weeks of exercise followed by 10 weeks of sedentary condition. The mice showed decreased expression in genes related to senescence and senescence-associated secretory phenotype, such as p53, p16, and IL-6, in the visceral adipose tissue in response to exercise. These effects were maintained for 10 weeks after the mice stopped exercising. Our study is the first report that exercise reduces the expression of senescence-related genes in the visceral adipose tissue of young mice, and that exercise causes the legacy effect.

[Effective S-1 plus Oxaliplatin(SOX)Therapy in Two Cases of Advanced Gastric Cancer That Was Difficult to Resect and R0 Surgery Could Be Performed].

Case 1: A 59-year-old man was diagnosed with type 3 gastric cancer cStage Ⅲ(MU, Gre, tub2>por, cT4aN2M0)induced by gastric perforation. The first surgery involving resection of the lesser curvature of stomach lymph node was judged to be difficult, and eventually exploratory laparotomy was performed. He received 3 courses of chemotherapy using S-1 plus oxaliplatin(SOX)(S-1 120mg/m2/day, day 1-14, oxaliplatin 100 mg/m2, day 1, followed by 7 days of rest). He subsequently underwent curative laparotomy gastrectomy plus D2(-No. 10)lymph node dissection, and Roux-en-Y reconstruction. Histological type was judged to be Grade 3. Case 2: A 69-year-old man was diagnosed with type 2 esophageal gastric junctional cancer,(GE, Less, tub2, cT4aN3M1[LYM])of cStage Ⅳ. He received 6 courses of chemotherapy using trastuzu- mab plus S-1 plus oxaliplatin(HER plus SOX)(trastuzumab 8mg/kg[2nd course 6mg/kg], day 1, S-1 120mg/m2/day, day 1-14, oxaliplatin 100mg/m2[5th course 80 mg/m2], on day 1, followed by 7 days of rest). He subsequently underwent laparotomy of the lower esophageal total gastrectomy plus D2(-No. 10, +No. 16, No. 110)lymph node dissection, and Roux-en-Y reconstruction as conversion surgery. Histological type was Grade 3. Both were impressive cases suggesting the usefulness of SOX therapy as a multidisciplinary treatment strategy for advanced gastric cancer.

Vascularized and functional human liver from an iPSC-derived organ bud transplant.

A critical shortage of donor organs for treating end-stage organ failure highlights the urgent need for generating organs from human induced pluripotent stem cells (iPSCs). Despite many reports describing functional cell differentiation, no studies have succeeded in generating a three-dimensional vascularized organ such as liver. Here we show the generation of vascularized and functional human liver from human iPSCs by transplantation of liver buds created in vitro (iPSC-LBs). Specified hepatic cells (immature endodermal cells destined to track the hepatic cell fate) self-organized into three-dimensional iPSC-LBs by recapitulating organogenetic interactions between endothelial and mesenchymal cells. Immunostaining and gene-expression analyses revealed a resemblance between in vitro grown iPSC-LBs and in vivo liver buds. Human vasculatures in iPSC-LB transplants became functional by connecting to the host vessels within 48 hours. The formation of functional vasculatures stimulated the maturation of iPSC-LBs into tissue resembling the adult liver. Highly metabolic iPSC-derived tissue performed liver-specific functions such as protein production and human-specific drug metabolism without recipient liver replacement. Furthermore, mesenteric transplantation of iPSC-LBs rescued the drug-induced lethal liver failure model. To our knowledge, this is the first report demonstrating the generation of a functional human organ from pluripotent stem cells. Although efforts must ensue to translate these techniques to treatments for patients, this proof-of-concept demonstration of organ-bud transplantation provides a promising new approach to study regenerative medicine.

Nrf2-mediated anti-oxidant effects contribute to suppression of non-alcoholic steatohepatitis-associated hepatocellular carcinoma in murine model.

The exact mechanisms of hepatocellular carcinoma development in non-alcoholic steatohepatitis remain unclear. In this study, we used a new class of high-fat diet, which could induce hepatocellular carcinoma development without the use of general chemical carcinogens or knockout mice. We investigated the correlation between hepatocellular carcinoma and oxidative stress/anti-oxidant effects after depletion of the gut microbiota by treatment with antibiotics. Mice fed with the steatohepatitis-inducing high-fat diet (STHD-01) for 41 weeks developed hepatocellular carcinoma. Antibiotic-treatment in mice fed with STHD-01 significantly depleted the gut microbiota and significantly ameliorated liver injury/histology. The tumor numbers of hepatocellular carcinoma were dramatically decreased by the antibiotics-treatment. We analyzed the factors involved in oxidative stress and anti-oxidant effects. Oxidative stress was elevated in mice fed with STHD-01, whereas some anti-oxidant factors were significantly elevated after antibiotics treatment. These results suggest that the gut microbiota is a key factor in improving oxidative stress induced by STHD-01 feeding.

Cluster microRNAs miR-194 and miR-215 suppress the tumorigenicity of intestinal tumor organoids.

Tumor stem cells with self-renewal and multipotent capacity play critical roles in the initiation and progression of cancer. Recently, a new 3-D culture system known as organoid culture has been developed, allowing Lgr5-positive stem cells to form organoids that resemble the properties of original tissues. Here we established organoids derived from intestinal tumors of Apcmin/+ mice and normal intestinal epithelia of C57BL/6J mice and investigated the roles of microRNA (miRNA) in intestinal tumor organoids. The results of microarray analyses revealed that expression of the cluster miRNAs, miR-194 and miR-215 was markedly suppressed in intestinal tumor organoids in comparison with organoids derived from normal intestinal epithelia. Enforced expression of miR-194 resulted in inhibition of E2f3, a positive regulator of the cell cycle and growth suppression of intestinal tumor organoids. In addition, enforced expression of miR-215 suppressed the cancer stem cell signature through downregulation of intestinal stem cell markers including Lgr5. These findings indicate that the miRNA cluster including miR-194 and miR-215 plays important roles in suppressing the growth and attenuating the stemness of intestinal tumor organoids.

Gut microbiota-mediated generation of saturated fatty acids elicits inflammation in the liver in murine high-fat diet-induced steatohepatitis.

BACKGROUND: The gut microbiota plays crucial roles in the development of non-alcoholic steatohepatitis (NASH). However, the precise mechanisms by which alterations of the gut microbiota and its metabolism contributing to the pathogenesis of NASH are not yet fully elucidated. METHODS: Mice were fed with a recently reported new class of high-fat diet (HFD), steatohepatitis-inducing HFD (STHD)-01 for 9 weeks. The composition of the gut microbiota was analyzed by T-RFLP. Luminal metabolome was analyzed using capillary electrophoresis and liquid chromatography time-of-flight mass spectrometry (CE- and LC-TOFMS). RESULTS: Mice fed the STHD-01 developed NASH-like pathology within a short period. Treatment with antibiotics prevented the development of NASH by STHD-01. The composition of the gut microbiota and its metabolic activities were markedly perturbed in the STHD-01-fed mice, and antibiotic administration normalized these changes. We identified that long-chain saturated fatty acid and n-6 fatty acid metabolic pathways were significantly altered by STHD-01. Of note, the changes in gut lipidome caused by STHD-01 were mediated by gut microbiota, as the depletion of the gut microbiota could reverse the perturbation of these metabolic pathways. A saturated long-chain fatty acid, palmitic acid, which accumulated in the STHD-01 group, activated liver macrophages and promoted TNF-α expression. CONCLUSIONS: Lipid metabolism by the gut microbiota, particularly the saturation of fatty acids, affects fat accumulation in the liver and subsequent liver inflammation in NASH.

microRNA-mediated resistance to hypoglycemia in the HepG2 human hepatoma cell line.

BACKGROUND: It is generally accepted that the energy resources of cancer cells rely on anaerobic metabolism or the glycolytic system, even if they have sufficient oxygen. This is known as the Warburg effect. The cells skillfully survive under hypoglycemic conditions when their circumstances change, which probably at least partly involves microRNA (miRNA)-mediated regulation. METHODS: To determine how cancer cells exploit miRNA-mediated epigenetic mechanisms to survive in hypoglycemic conditions, we used DNA microarray analysis to comprehensively and simultaneously compare the expression of miRNAs and mRNAs in the HepG2 human hepatoma cell line and in cultured normal human hepatocytes. RESULTS: The hypoglycemic condition decreased the expression of miRNA-17-5p and -20a-5p in hepatoma cells and consequently upregulated the expression of their target gene p21. These regulations were also confirmed by using antisense inhibitors of these miRNAs. In addition to this change, the hypoglycemic condition led to upregulated expression of heat shock proteins and increased resistance to caspase-3-induced apoptosis. However, we could not identify miRNA-mediated regulations, despite using comprehensive detection. Several interesting genes were also found to be upregulated in the hypoglycemic condition by the microarray analysis, probably because of responding to this cellular stress. CONCLUSION: These results suggest that cancer cells skillfully survive in hypoglycemic conditions, which frequently occur in malignancies, and that some of the gene regulation of this process is manipulated by miRNAs.

Impact of aging and comorbidity on the efficacy of low-intensity shock wave therapy for erectile dysfunction.

OBJECTIVES: To evaluate the efficacy of low-intensity shock wave therapy and to identify the predictive factors of its efficacy in Japanese patients with erectile dysfunction. METHODS: The present study included 57 patients with erectile dysfunction who satisfied all the following conditions: more than 6-months history of erectile dysfunction, sexual health inventory for men score of ≤ 12 without phosphodiesterase type-5 inhibitor, erection hardness score grade 1 or 2, mean penile circumferential change by erectometer assessing sleep related erection of < 25 mm and non-neurological pathology. Patients were treated by a low-energy shock waves generator (ED1000; Medispec, Gaithersburg, MD, USA). A total of 12 shock wave treatments were applied. Sexual health inventory for men score, erection hardness score with or without phosphodiesterase type-5 inhibitor, and mean penile circumferential change were assessed at baseline, 1, 3 and 6 months after the termination of low-intensity shock wave therapy. RESULTS: Of 57 patients who were assigned for the low-intensity shock wave therapy trial, 56 patients were analyzed. Patients had a median age of 64 years. The sexual health inventory for men and erection hardness score (with and without phosphodiesterase type-5 inhibitor) were significantly increased (P < 0.001) at each time-point. The mean penile circumferential change was also increased from 13.1 to 20.2 mm after low-intensity shock wave therapy (P < 0.001). In the multivariate analysis, age and the number of concomitant comorbidities were statistically significant predictors for the efficacy. CONCLUSIONS: Low-intensity shock wave therapy seems to be an effective physical therapy for erectile dysfunction. Age and comorbidities are negative predictive factors of therapeutic response.

Opportunities for targeted focal treatment in Japan.

PURPOSE OF REVIEW: Widespread prostate-specific antigen screening has led to an increase in prostate cancer diagnoses in Asian populations, reflecting changes in socioeconomic status and epidemiological features in these countries. In this setting, the present review explores opportunities for target focal therapy in Japan. RECENT FINDINGS: Our review examines several topics relating to focal therapy in Asia, and discusses the current status of prostate cancer diagnosis and treatment in that region. First, we summarize the prevalence of prostate cancer in Asian populations. Second, we examine prostate cancer diagnosis and treatment options such as mapping biopsy and MRI fusion biopsy in Japan. Third, we review treatment strategies for localized prostate cancer, especially robotic-assisted surgery, active surveillance, and high-intensity focused ultrasound. Lastly, we discuss the potential for focal therapy in Japan. SUMMARY: The number of localized prostate cancer patients is expected to increase in Asia. Accordingly, the need for precise diagnosis in terms of localization of prostate cancer foci will also expand. MRI fusion target biopsies are being performed in Asia, particularly in some Japanese academic institutions, but as pilot studies. In recent years, an increase in robotic-assisted surgery in East Asia has yielded new options in prostate cancer treatment. Although active surveillance is a practical choice for low-risk prostate cancer in some Asian countries, focal therapy is expected to see increasing interest as another alternative in Japan.

Autoimmune hemolytic anemia associated with renal urothelial cancer: A case report and literature review.

BACKGROUND: Autoimmune hemolytic anemia (AIHA) is hemolytic anemia characterized by autoantibodies directed against red blood cells. AIHA can be induced by hematological neoplasms such as malignant lymphoma, but is rarely observed in the urological field. We report a case of renal urothelial cancer inducing Coombs-positive warm AIHA and severe thrombocytopenia that was responsive to nephroureterectomy. CASE PRESENTATION: A 52-year-old man presented with a 1-month history of general weakness and dizziness. Hemoglobin level was 4.2 g/dL, and direct and indirect Coombs tests both yielded positive results. Abdominal computed tomography revealed huge left hydronephrosis due to a renal pelvic tumor measuring 4.0 x 4.0 x 3.0 cm, and renal regional lymph-node involvement was also observed and suspected as metastasis. Corticosteroid therapy was administered, and nephroureterectomy was performed. After surgical resection, the hemoglobin level gradually normalized, and direct and indirect Coombs tests yielded negative results. We thus diagnosed warm AIHA associated with renal urothelial cancer. CONCLUSION: To the best of our knowledge, this represents the first report of AIHA associated with renal urothelial cancer and severe thrombocytopenia responsive to nephroureterectomy. Renal urothelial cancer needs to be included in the differential diagnoses for warm AIHA, and nephroureterectomy represents a treatment option for AIHA.