Mitsuru Noguchi

Epithelial-to-mesenchymal transition and slit function of mesothelial cells are regulated by the cross talk between mesothelial cells and endothelial cells.

Peritoneal dysfunction is a major factor leading to treatment failure of peritoneal dialysis (PD). However, the precise mechanism of the peritoneal diffusion changes related to PD remains to be elucidated. To this end, we have established a novel peritoneal diffusion model in vitro, which consists of a three-dimensional culture system using a collagen vitrigel membrane chamber and a fluid-stream generation system. This artificial peritoneal model revealed that high-glucose culture medium and fluid flow stress promoted the epithelial-mesenchymal transition (EMT) process of mesothelial cells and that endothelial cells inhibited this mesothelial EMT process. Mesothelial cells in the EMT state showed high expression of connective tissue growth factor and low expression of bone morphogenic protein-7, while non-EMT mesothelial cells showed the opposite expression pattern of these two proteins. In addition, these protein expressions were dependent on the presence of endothelial cells in the model. Our model revealed that the endothelial slit function was predominantly dependent on the covering surface area, while the mesothelial layer possessed a specific barrier function for small solutes independently of the surface area. Notably, a synergic barrier effect of mesothelial cells and endothelial cells was present with low-glucose pretreatment, but high-glucose pretreatment abolished this synergic effect. These findings suggest that the mesothelial slit function is not only regulated by the high-glucose-induced EMT process but is also affected by an endothelial paracrine effect. This peritoneal diffusion model could be a promising tool for the development of PD.

Adipose tissue behavior is distinctly regulated by neighboring cells and fluid flow stress: a possible role of adipose tissue in peritoneal fibrosis

Adipose tissue, together with the mesothelial layer and microvessels, is a major component of the mesenteric peritoneum, and the mesenterium is a target site for peritoneal fibrosis. Adipose tissue has been speculated to play a role in peritoneal dialysis (PD)-related fibrosis, but the precise cellular kinetics of adipose tissue during this process remain to be determined. To clarify this critical issue, we analyzed the kinetics of adipose tissue using a novel peritoneal reconstruction model in which the effects of mesothelial cells or endothelial cells could be identified. Adipose tissue was co-cultured with mesothelial cells or endothelial cells in a combined organ culture and fluid flow stress culture system. Spindle mesenchymal cells and immature adipocytes derived from adipose tissue were characterized by immunohistochemistry. Adipose tissue fragments cultured in this system yielded many spindle mesenchymal cells in non-co-culture conditions. However, the number of spindle mesenchymal cells emerging from adipose tissue was reduced in co-culture conditions with a covering layer of mesothelial cells. Mesothelial cells co-cultured in the separated condition did not inhibit the emergence of spindle mesenchymal cells from adipose tissue. Interestingly, endothelial cells promoted the emergence of lipid-laden immature adipocytes from adipose tissue under fluid flow stress. We have demonstrated that adipose tissue behavior is not only regulated by mesothelial cells and endothelial cells under fluid flow stress, but is also involved in fibrosis and fat mass production in the peritoneum. Our findings suggest that adipose tissue is a potential source of cells for peritoneal fibrosis caused by PD therapy.

Risk factors of postoperative urinary retention after hip surgery for femoral neck fracture in elderly women.

The aim of the present study was to evaluate risk factors for postoperative urinary retention (POUR) in female patients with femoral neck fractures.

Prolonged effect of fluid flow stress on the proliferative activity of mesothelial cells after abrupt discontinuation of fluid streaming.

Encapsulating peritoneal sclerosis (EPS) often develops after transfer to hemodialysis and transplantation. Both termination of peritoneal dialysis (PD) and transplantation-related factors are risks implicated in post-PD development of EPS, but the precise mechanism of this late-onset peritoneal fibrosis remains to be elucidated. We previously demonstrated that fluid flow stress induced mesothelial proliferation and epithelial-mesenchymal transition via mitogen-activated protein kinase (MAPK) signaling. Therefore, we speculated that the prolonged bioactive effect of fluid flow stress may affect mesothelial cell kinetics after cessation of fluid streaming. To investigate how long mesothelial cells stay under the bioactive effect brought on by fluid flow stress after removal of the stress, we initially cultured mesothelial cells under fluid flow stress and then cultured the cells under static conditions. Mesothelial cells exposed to fluid flow stress for a certain time showed significantly high proliferative activity compared with static conditions after stoppage of fluid streaming. The expression levels of protein phosphatase 2A, which dephosphorylates MAPK, in mesothelial cells changed with time and showed a biphasic pattern that was dependent on the duration of exposure to fluid flow stress. There were no differences in the fluid flow stress-related bioactive effects on mesothelial cells once a certain time had passed. The present findings show that fluid flow stress exerts a prolonged bioactive effect on mesothelial cells after termination of fluid streaming. These findings support the hypothesis that a history of PD for a certain period could serve as a trigger of EPS after stoppage of PD.

Fluid dwell impact induces peritoneal fibrosis in the peritoneal cavity reconstructed in vitro

Peritoneal fluid dwell impacts the peritoneum by creating an abnormal physiological microenvironment. Little is known about the precise effects of fluid dwell on the peritoneum, and no adequate in vitro models to analyze the impact of fluid dwell have been established. In this study, we developed a peritoneal fluid dwell model combined with an artificial peritoneal cavity and fluid stirring generation system to clarify the effects of different dwelling solutions on the peritoneum over time. To replicate the peritoneal cavity, we devised a reconstructed peritoneal cavity utilizing a mesothelial layer, endothelial layer, and collagen membrane chamber. The reconstructed peritoneal cavity was infused with Dulbecco’s modified Eagle’s medium, saline, lactated Ringer’s solution or peritoneal dialysis solution with repeated 4-h dwells for 10 or 20 consecutive days. The above-described solutions induced epithelial–mesenchymal transition (EMT) and hyperplasia of mesothelial cells. All solution types modulated nitric oxide synthase activities in mesothelial and endothelial cells and nitric oxide concentrations in dwelling solutions. Inhibition of nitric oxide synthase activity acted synergistically on mesothelial EMT and hyperplasia. The present findings suggest that solutions infused into the peritoneal cavity are likely to affect nitric oxide production in the peritoneum and promote peritoneal fibrosis. Our newly devised peritoneal cavity model should be a promising tool for understanding peritoneal cellular kinetics and homeostasis.

Age-related changes in bladder function with altered angiotensin II receptor mechanisms in rats

To examine alterations in expression of angiotensin II type 1 receptors (AT1R) which induce organ tissue remodeling, angiotensin II type 2 receptors (AT2R) which protect against it, and related molecules in the bladder of matured rats with bladder dysfunction.

Differential effects of adipose tissue stromal cells on the apoptosis, growth and invasion of bladder urothelial carcinoma between the superficial and invasive types

To clarify the interaction between adipose tissue stromal cells and bladder cancer cells.

Is the eGFR formula adequate for evaluating renal function before chemotherapy in patients with urogenital cancer? A suggestion for clinical application of eGFR formula

BackgroundAccurate evaluation of renal function is required before cancer chemotherapy. Various kinds of formula have been developed for estimating creatinine clearance (Ccr) or glomerular filtration rate (GFR) conveniently. We retrospectively examined the reliability of the GFR estimating formula using the renal function data in cancer chemotherapy.MethodsClinical data of 12 patients with urogenital cancer from 1998 to 2013 in Saga University Hospital were reviewed. Patients were treated with 6–21 (median 10.5) courses of chemotherapy and those patients underwent 9–29 (median 14.5) times of 24hrCcr tests before and during chemotherapy. We compared estimated GFR (eGFR) with 24hrCcr. In addition, we developed a novel method to estimate the Ccr using the patient-inherent 24hrCcr/eGFR ratio, which is calculated from initial 3 or 4 determinations of 24hrCcr and the corresponding eGFR. Those estimated Ccrs were also compared with 24hrCcr.ResultsThe dissociation between 24hrCcr and eGFR was not constant, and a large dissociation was observed in some cases. The newly devised estimated Ccr demonstrated less dissociation from 24hrCcr compared with eGFR.ConclusionsThe eGFR formula is not adequate for the clinical use in cancer chemotherapy. The absolute value of eGFR is not reliable, but clinical use of eGFR as relative value seems to be acceptable. To avoid troublesome 24hrCcr measurement in long-term cancer chemotherapy, eGFR formula can be used for estimating Ccr in combination with the specific inherent 24hrCcr/eGFR ratio, which is obtained from 3 or 4 times of actual 24hrCcr measurements.

A dedifferentiated liposarcoma with inflammatory myofibroblastic tumor-like features

To the Editor: Although various degrees of inflammatory cell infiltration and fibrosis are commonly observed in liposarcoma, well-differentiated liposarcomas (atypical lipomatous tumors)—which show extensive inflammatory cell infiltration—have been classified as an inflammatory variant of well-differentiated liposarcoma. In 2010, Lucas et al. were the first to report cases of dedifferentiated liposarcoma (n1⁄4 6) with extensive lymphoplasmacytic infiltration and histology resembling that of inflammatory myofibroblastic tumor (IMT). They called these cases ‘dedifferentiated liposarcoma with IMT-like features’ and noted the risk of misdiagnosis as IMT, which is a much less aggressive neoplasm than dedifferentiated liposarcoma. Since then, no case of dedifferentiated liposarcoma with IMT-like features had been reported, but we recently encountered a case of dedifferentiated liposarcoma of the retroperitoneum which required a differential diagnosis from IMT, IgG4-related disease, and Castlemans disease. We eventually diagnosed the case as dedifferentiated liposarcoma with IMT-like features, and we report the case as follows. A 65-year-old Japanese man visited a nearby hospital for the examination of an abdominal mass lesion that had been revealed by an abdominal echo examination as part of his medical checkup. As a retroperitoneal tumor was confirmed, he was referred to our hospital for further examination and treatment. He had no remarkable medical history and no remarkable family history other than an appendectomy for acute appendicitis. Laboratory tests on admission showed no abnormality. Post-contrast abdominal CT demonstrated a well-circumscribed mass lesion measuring 11 8 cm in diameter at the retroperitoneum; the mass lesion was slightly enhanced in the delayed contrast phase (Fig. S1a). No fat component was found in the mass lesion by in-phase and opposed-phase MRI (Fig. S1b,c). Under the clinical diagnosis of retroperitoneal tumor without invasion of surrounding organs, we performed a laparoscopic resection of the retroperitoneal tumor. The postoperative course was uneventful, and no recurrence was found as of the time of this writing (2 years after surgery). The resected specimen showed an elastic, hard, welldefined and yellowish-white-colored tumor measuring 12.5 9.8 7.3 cm (Fig. S2). Histologically, the margin of the tumor was bordered by lymphoid tissues that partially formed lymphoid follicles (Fig. 1a). No atypia was observed at adipocytes surrounding the tumor (Fig. S3a). In the tumor, a significant deposition of collagen fibers with focal hyalinization and infiltration and aggregations of lymphocytes and plasma cells were extensively observed (Fig. 1b). Spindle-shaped cells with mild nuclear atypia were found between the collagenous fibers (Fig. 1c). No necrotic lesion was found in the tumor, and mitotic figures were not apparent. Small vessels with hyalinization which suggest the hyaline vascular type of Castlemans disease were also observed. No lipogenic lesion was found in the tumor by the pathological examination. As a differential diagnosis based on hematoxylin-eosin (HE) staining results, we considered IMT, the hyaline vascular type of Castlemans disease, IgG4-related diseases, and liposarcoma. In an immunohistochemical analysis, IgG4-positive plasma cells were scarcely found in the specimen; IgG4related disease was therefore ruled out. Although many aSMA-positive spindle-shaped cells were observed, we considered these cells reactive myofibroblasts because the spindle-shaped cells with nuclear atypia were negative for a-SMA and no anaplastic lymphoma kinase (ALK)-positive cells or pan-Trk positive cells were recognized. Therefore, the differential diagnosis of IMT was denied. Spindle-shaped cells with mild nuclear atypia diffusely expressed CDK4 (Fig. 1d), p16 (Fig. S3b), and MDM2 (Fig. S3c, performed at Kyushu University). Expressions of CDK4, p16, and MDM2 were not observed at the surrounding adipose tissue (Fig. S3d). The Ki-67 labeling index of the atypical cells was 14.8%. These immunohistochemical findings indicated the diagnosis of liposarcoma. The primary antibodies used are summarized in Table S1. Based on these HE and histochemical findings, we made the final diagnosis of dedifferentiated liposarcoma with IMT-like features. Typically, a dedifferentiated liposarcoma consists of a component of well-differentiated liposarcoma adjacent to a non-lipogenic sarcoma of dedifferentiated component. Usually, the dedifferentiated component shows high-grade morphology resembling undifferentiated pleomorphic sarcoma (which is a synonym for malignant fibrous histiocytoma: MFH). However, low-grade dedifferentiation characterized by the presence of fibroblastic spindle cells with mild nuclear atypia has been recognized. If the present case had contained high-grade morphology resembling an MFH, the diagnosis of dedifferentiated liposarcoma with an inflammatory MFH-like component would be considered.

Iliac Artery-Uretero-Colonic Fistula Presenting as Gastrointestinal Hemorrhage and Hematuria: A Case Report

Abstract Background: The experience with uretero-arterial fistulas has been limited. However, the aggressive treatment of pelvic tumors with surgical resection and radiotherapy, along with liberal use of ureteral catheters, has been attributed to an increase in their incidence. Unless they are promptly diagnosed and treated, uretero-arterial fistulas are associated with considerably high rates of morbidity and mortality. Urologists need maintain a high degree of suspicion for uretero-arterial fistula in high-risk patients. We herein present the clinical course of an iliac artery-uretero-colonic fistula. Case Presentation: A 67-year-old woman with a history of colon cancer who underwent laparoscopic high anterior resection in July 2010. A ureteral stent inserted to right ureteral stricture, which developed as a result of local recurrence of the tumor in September 2010. She had undergone chemoradiotherapy, but the lesion had slowly increased in size. During the replacement of the ureteral stent in April 2016, she immediately experienced bladder tamponade, bloody bowel discharge, and hypotension. Contrast CT revealed a complex fistula between the right distal ureter and the right internal iliac artery. Furthermore, contrast medium flowed into the intestinal tract through the tumor. The patient was therefore diagnosed with internal iliac artery-uretero-colonic fistula. Arteriography revealed a right uretero-internal iliac artery fistula, and the embolization of the right internal iliac artery was performed. The right ureteral stent was removed. Her hematuria and bloody bowel discharge disappeared, but right nephrostomy was performed because she presented with acute pyelonephritis to ureteral obstruction. Conclusion: In the present case, the uretero-arterial fistula was caused by the long use of an indwelling stent, chemoradiotherapy, infection, and an increase in the size of the lesion. When a suspected uretero-arterial fistula is accompanied by bloody bowel discharge, we should consider the possibility of traffic to the intestinal tract.