Anti-CX3CL1 (fractalkine) monoclonal antibody attenuates lung and skin fibrosis in sclerodermatous graft-versus-host disease mouse model.

BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease characterized by vascular injury and inflammation, followed by excessive fibrosis of the skin and other internal organs, including the lungs. CX3CL1 (fractalkine), a chemokine expressed on endothelial cells, supports the migration of macrophages and T cells that express its specific receptor CX3CR1 into targeted tissues. We previously reported that anti-CX3CL1 monoclonal antibody (mAb) treatment significantly inhibited transforming growth factor (TGF)-ß1-induced expression of type I collagen and fibronectin 1 in human dermal fibroblasts. Additionally, anti-mouse CX3CL1 mAb efficiently suppressed skin inflammation and fibrosis in bleomycin- and growth factor-induced SSc mouse models. However, further studies using different mouse models of the complex immunopathology of SSc are required before the initiation of a clinical trial of CX3CL1 inhibitors for human SSc. METHODS: To assess the preclinical utility and functional mechanism of anti-CX3CL1 mAb therapy in skin and lung fibrosis, a sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) mouse model was analyzed with immunohistochemical staining for characteristic infiltrating cells and RNA sequencing assays. RESULTS: On day 42 after bone marrow transplantation, Scl-cGVHD mice showed increased serum CX3CL1 level. Intraperitoneal administration of anti-CX3CL1 mAb inhibited the development of fibrosis in the skin and lungs of Scl-cGVHD model, and did not result in any apparent adverse events. The therapeutic effects were correlated with the number of tissue-infiltrating inflammatory cells and α-smooth muscle actin (α-SMA)-positive myofibroblasts. RNA sequencing analysis of the fibrotic skin demonstrated that cGVHD-dependent induction of gene sets associated with macrophage-related inflammation and fibrosis was significantly downregulated by mAb treatment. In the process of fibrosis, mAb treatment reduced cGVHD-induced infiltration of macrophages and T cells in the skin and lungs, especially those expressing CX3CR1. CONCLUSIONS: Together with our previous findings in other SSc mouse models, the current results indicated that anti-CX3CL1 mAb therapy could be a rational therapeutic approach for fibrotic disorders, such as human SSc and Scl-cGVHD.

An Unusual Presentation of Chest Pain and Laryngeal Discomfort in a Pregnant Woman: A Case Report and Literature Review.

Intramural esophageal dissection (IED), characterized by bleeding into the submucosal space, leads to mucosal separation and dissection. The most prevalent symptoms are sudden chest or retrosternal pain, hematemesis, and dysphagia. Therefore, acute coronary syndrome and aortic dissection are among its most notable differential diagnoses. A 31-year-old pregnant woman presented with acute chest pain, laryngeal discomfort, and hematemesis. Emergency esophagogastroscopy revealed longitudinal mucosal dissection (upper esophagus to esophagogastric junction). The patient was successfully treated by avoiding the ingestion of solid foods. Clinicians should consider a diagnosis of IED for pregnant patients with acute chest pain, especially if hematemesis is present.

Serum APOA4 Pharmacodynamically Represents Administered Recombinant Human Hepatocyte Growth Factor (E3112).

BACKGROUND: Hepatocyte growth factor (HGF) is an endogenously induced bioactive molecule that has strong anti-apoptotic and tissue repair activities. In this research, we identified APOA4 as a novel pharmacodynamic (PD) marker of the recombinant human HGF (rh-HGF), E3112. METHODS: rh-HGF was administered to mice, and their livers were investigated for the PD marker. Candidates were identified from soluble proteins and validated by using human hepatocytes in vitro and an animal disease model in vivo, in which its c-Met dependency was also ensured. RESULTS: Among the genes induced or highly enhanced after rh-HGF exposure in vivo, a soluble apolipoprotein, Apoa4, was found to be induced by rh-HGF in the murine liver. By using primary cultured human hepatocytes, the significant induction of human APOA4 was observed at the mRNA and protein levels, and it was inhibited in the presence of a c-Met inhibitor. Although mice constitutively expressed Apoa4 mRNA in the small intestine and the liver, the liver was the primary organ affected by administered rh-HGF to strongly induce APOA4 in a dose- and c-Met-dependent manner. Serum APOA4 levels were increased after rh-HGF administration, not only in normal mice but also in anti-Fas-induced murine acute liver failure (ALF), which confirmed the pharmacodynamic nature of APOA4. CONCLUSIONS: APOA4 was identified as a soluble PD marker of rh-HGF with c-Met dependency. It should be worthwhile to clinically validate its utility through clinical trials with healthy subjects and ALF patients.

Cavernous Branched Nerve Regeneration Using Non-Tubular Artificial Nerve Sheets Using Freeze-Dried Alginate Gel Combined With Polyglycolic Acid Mesh in a Rat Model.

INTRODUCTION: Neuroprotection and neuroregeneration of cavernous nerve plexus by biological/bioengineering solutions may have the potential to maintain erectile function. AIMS: We evaluated the efficacy of a newly developed artificial nerve sheet using freeze-dried alginate (ALG) with polyglycolic acid (PGA) mesh in a rat model. METHODS: Bilateral cavernous nerves of male rats were excised to make an approximately 2 mm gap. A piece of the sponge-like freeze-dried sheet created by covalent cross-linking of ALG gel combined with PGA mesh was placed over the gap to cover each stump without any neural anastomosis. We compared erectile functions in the ALG groups with those in the sham group and the bilateral nerve excision group (n = 12, each). MAIN OUTCOME MEASURES: Main outcome measure was a rat model with cavernous nerve excision. RESULTS: All rats in the sham group had erection at 63 or 64 days, and mating behavior was confirmed in 10 rats (83.3%) of the sham group at 56 to 62 days. No erection and mating behavior was observed in the excision group. Ten of the 12 (83.3%) rats in the ALG group had a mating behavior and an erection, and the rates of erection and mating behavior were significantly higher in the ALG group than those in the excision group (P < .01, P < .01, respectively). Using a retrograde FluoroGold, the rate of FluoroGold positive pelvic ganglia proximal to the gap at 61 or 62 days was significantly higher in the ALG group than that in the excision group (P = .014). CONCLUSION: The results of our animal study have demonstrated that simply filling the cavernous nerve gap using the non-tubular artificial nerve sheets made of ALG with PGA mesh restored erectile function after cavernous nerve excision. Narita S, Obara T, Ishikawa N, et al. Cavernous Branched Nerve Regeneration Using Non-Tubular Artificial Nerve Sheets Using Freeze-Dried Alginate Gel Combined With Polyglycolic Acid Mesh in a Rat Model. Sex Med 2021;9:100308.

Catalytic residues, substrate specificity, and role in carbon starvation of the 2-hydroxy FA dioxygenase Mpo1 in yeast.

The yeast protein Mpo1 belongs to a protein family that is widely conserved in bacteria, fungi, protozoa, and plants, and is the only protein of this family whose function has so far been elucidated. Mpo1 is an Fe2+-dependent dioxygenase that catalyzes the α-oxidation reaction of 2-hydroxy (2-OH) long-chain FAs (LCFAs) produced in the degradation pathway of the long-chain base phytosphingosine. However, several biochemical characteristics of Mpo1, such as its catalytic residues, membrane topology, and substrate specificity, remain unclear. Here, we report that yeast Mpo1 contains two transmembrane domains and that both its N- and C-terminal regions are exposed to the cytosol. Mutational analyses revealed that three histidine residues conserved in the Mpo1 family are especially important for Mpo1 activity, suggesting that they may be responsible for the formation of coordinate bonds with Fe2+ We found that, in addition to activity toward 2-OH LCFAs, Mpo1 also exhibits activity toward 2-OH very-long-chain FAs derived from the FA moiety of sphingolipids. These results indicate that Mpo1 is involved in the metabolism of long-chain to very-long-chain 2-OH FAs produced in different pathways. We noted that the growth of mpo1Δ cells is delayed upon carbon deprivation, suggesting that the Mpo1-mediated conversion of 2-OH FAs to nonhydroxy FAs is important for utilizing 2-OH FAs as a carbon source under carbon starvation. Our findings help to elucidate the as yet unknown functions and activities of other Mpo1 family members.

Inhibition of the Progression of Skin Inflammation, Fibrosis, and Vascular Injury by Blockade of the CX3 CL1/CX3 CR1 Pathway in Experimental Mouse Models of Systemic Sclerosis.

OBJECTIVE: To assess the preclinical efficacy and mechanism of action of an anti-CX3 CL1 monoclonal antibody (mAb) in systemic sclerosis (SSc). METHODS: Cultured human dermal fibroblasts were used to evaluate the direct effect of anti-CX3 CL1 mAb on fibroblasts. In addition, bleomycin-induced and growth factor-induced models of SSc were used to investigate the effect of anti-CX3 CL1 mAb on leukocyte infiltration, collagen deposition, and vascular damage in the skin. RESULTS: Anti-CX3 CL1 mAb treatment significantly inhibited Smad3 phosphorylation (P < 0.05) and expression of type I collagen and fibronectin 1 (P < 0.01) in dermal fibroblasts stimulated with transforming growth factor ß1 (TGFß1). In the bleomycin model, daily subcutaneous bleomycin injection increased serum CX3 CL1 levels (P < 0.05) and augmented lesional CX3 CL1 expression. Simultaneous administration of anti-CX3 CL1 mAb or CX3 CR1 deficiency significantly suppressed the dermal thickness, collagen content, and capillary loss caused by bleomycin (P < 0.05). Injection of bleomycin induced expression of pSmad3 and TGFß1 in the skin, which was inhibited by anti-CX3 CL1 mAb. Further, the dermal infiltration of CX3 CR1+ cells, macrophages (inflammatory and alternatively activated [M2-like] subsets), and CD3+ cells significantly decreased following anti-CX3 CL1 mAb therapy (P < 0.05), as did the enhanced skin expression of fibrogenic molecules, such as thymic stromal lymphopoietin and secreted phosphoprotein 1 (P < 0.05). However, the treatment did not significantly reduce established skin fibrosis. In the second model, simultaneous anti-mCX3 CL1 mAb therapy significantly diminished the skin fibrosis induced by serial subcutaneous injection of TGFß and connective tissue growth factor (P < 0.01). CONCLUSION: Anti-CX3 CL1 mAb therapy may be a novel approach for treating early skin fibrosis in inflammation-driven fibrotic skin disorders such as SSc.

Anti-Apoptotic Effects of Recombinant Human Hepatocyte Growth Factor on Hepatocytes Were Associated with Intrahepatic Hemorrhage Suppression Indicated by the Preservation of Prothrombin Time.

Hepatocyte growth factor (HGF) is an endogenously expressed bioactive substance that has a strong anti-apoptotic effect. In this study, we biochemically and histologically characterized the effects of rh-HGF on in vitro human hepatocyte injury and mouse acute liver failure (ALF) models, both of which were induced by antibody-mediated Fas signaling. rh-HGF inhibited intracellular caspase-3/7 activation and cytokeratin 18 (CK-18) fragment release in both models. Histologically, rh-HGF dramatically suppressed parenchymal damage and intrahepatic hemorrhage. Among the laboratory parameters, prothrombin time (PT) was strongly preserved by rh-HGF, and PT was well correlated with the degree of intrahepatic hemorrhage. These results showed that the anti-apoptotic effect of rh-HGF on hepatocytes coincided strikingly with the suppression of intrahepatic hemorrhage. PT was considered to be the best parameter that correlated with the intrahepatic hemorrhages associated with hepatocellular damage. The action of rh-HGF might derive not only from its anti-apoptosis effects on liver parenchymal cells but also from its stabilization of structural and vasculature integrity.

Pharmacokinetics, Pharmacodynamics, and Safety of E6011, a Novel Humanized Antifractalkine (CX3CL1) Monoclonal Antibody: A Randomized, Double-Blind, Placebo-Controlled Single-Ascending-Dose Study.

E6011 is a novel humanized antifractalkine (FKN) monoclonal antibody being developed as a therapeutic target for Crohn's disease, rheumatoid arthritis, and primary biliary cholangitis. This study was a randomized, double-blind, placebo-controlled single-ascending-dose study of intravenous administration of E6011 (0.0006-10 mg/kg) in healthy Japanese adult men (n = 64). The starting dose was the minimum anticipated biological effect level (MABEL). MABEL was estimated by extrapolating results of a pharmacokinetic/pharmacodynamic (PK/PD) model relating E6011 exposure and suppression of free soluble FKN using data obtained from cynomolgus monkeys. Safety assessments consisted of monitoring and recording adverse events, laboratory tests, vital signs, intensive electrocardiograms, and chest x-rays. Blood samples to determine PK, PD (serum total FKN concentration), and serum anti-E6011 antibody were collected. Noncompartmental analysis was used to derive PK parameters. Single intravenous infusions of E6011 were safe and well tolerated in healthy subjects. Serum E6011 concentrations showed triphasic elimination. An increase in serum total FKN concentration was observed, confirming target engagement. The dose strategy for patient studies is to select regimens that will attain a minimum serum E6011 exposure of 10 µg/mL, identified as the minimum concentration needed to saturate the target-mediated elimination pathway. Model-based drug development from preclinical stage was successful in identifying dose regimens for clinical testing.

Cystometric evaluation of recovery in hypocompliant defunctionalized bladder as a result of long-term dialysis after kidney transplantation.

OBJECTIVES: To evaluate the functional recovery of a pretransplant hypocompliant bladder in patients without neurological disorders, and to determine its relationship with ureteral complications, including vesicoureteral reflux. METHODS: A total of 61 patients without neurogenic disorders, who underwent video water cystometry pre- and 1 year post-transplantation, were enrolled. Cystometric bladder capacity and maximum intravesical pressure were measured, and compliance was calculated by the elevation in intravesical pressure as a result of an increase in volume. The frequencies of urinary complications, including urinary leakage, pyelonephritis and vesicoureteral reflux, were also evaluated. RESULTS: Pretransplant dialysis duration correlated with pretransplant bladder capacity and compliance (R(2) = 0.421, P < 0.001 and R(2) = 0.418, P < 0.001, respectively). A total of 16 (26.2%) patients had hypocompliant bladders <10 mL/cmH2 O, whereas 10 of the 12 patients (83.3%) with pretransplant dialysis duration of more than 5 years had a pretransplant hypocompliant bladder. Bladder compliance significantly recovered to >20 mL/cmH2 O (21.1-286.0) at 1 year post-transplantation in all 16 patients with a pretransplant hypocompliant bladder. No significant differences were observed for urinary leakage, pyelonephritis or vesicoureteral reflux between patients with and without a pretransplant hypocompliant bladder. CONCLUSIONS: Bladder compliance decreases logarithmically pretransplantation according to dialysis duration. Although the ability of the patients to recover varies, dysfunctions associated with a pretransplant hypocompliant bladder recover to normal ranges after renal transplantation. A pretransplant hypocompliant bladder seems not to be associated with the post-transplant prevalence of urinary complications or vesicoureteral reflux.

COMPARISON BETWEEN EXTRACORPOREAL SHOCK WAVE LITHOTRIPSY AT 120 AND 60 SHOCKWAVES PER MINUTE FOR TREATMENT OF URINARY STONES.

(Purpose) It has recently been suggested that a slow delivery rate of shockwaves by extracorporeal shock wave lithotripsy (SWL) improved treatment outcomes for urinary stones. We retrospectively analyzed the treatment outcomes of different shockwave delivery rates at 120 and 60 shockwaves per minute. (Patients and method) A total of 88 patients were treated at a fast delivery rate of 120 shockwaves per minute between July 2010 and April 2012, and 139 patients were treated at a slow delivery rate of 60 shockwaves per minute between May 2012 and May 2014 (n=227) using a Sonolith® Praktis lithotripter. The treatment outcome of stone-free rate (SFR) after one SWL session was assessed at four weeks. (Result) SWL at 60 shockwaves per minute resulted in a significantly higher SFR compared with SWL at 120 shockwaves per minute (39.8% and 59.0%, respectively, p=0.0047), particularly for upper ureter (U1) stones (53.1% and 72.0%, respectively, p=0.028). Multivariate analysis showed that younger age, stone sizes of 10 mm or less, U1 stones, and slow delivery rate were significant predictors of a stone-free outcome. There were fewer adverse events after the delivery rate of 60 shockwaves per minute (p=0.058). (Conclusion) Our study suggests that SWL at 60 shockwaves per minute should be recommended to successfully treat urinary stones using the Sonolith® Praktis lithotripter.

Identification of the phytosphingosine metabolic pathway leading to odd-numbered fatty acids.

The long-chain base phytosphingosine is a component of sphingolipids and exists in yeast, plants and some mammalian tissues. Phytosphingosine is unique in that it possesses an additional hydroxyl group compared with other long-chain bases. However, its metabolism is unknown. Here we show that phytosphingosine is metabolized to odd-numbered fatty acids and is incorporated into glycerophospholipids both in yeast and mammalian cells. Disruption of the yeast gene encoding long-chain base 1-phosphate lyase, which catalyzes the committed step in the metabolism of phytosphingosine to glycerophospholipids, causes an ~40% reduction in the level of phosphatidylcholines that contain a C15 fatty acid. We also find that 2-hydroxypalmitic acid is an intermediate of the phytosphingosine metabolic pathway. Furthermore, we show that the yeast MPO1 gene, whose product belongs to a large, conserved protein family of unknown function, is involved in phytosphingosine metabolism. Our findings provide insights into fatty acid diversity and identify a pathway by which hydroxyl group-containing lipids are metabolized.

Laparoendoscopic single-site plus one trocar donor nephrectomy using the GelPort: initial clinical experience.

OBJECTIVE: To achieve better cosmesis, less invasiveness, and less morbidity in donor nephrectomy without using specialized instruments, which is usually required in the laparoendoscopic single-site (LESS) procedure, we performed laparoendoscopic plus one trocar donor nephrectomy (LEPODN). METHODS: From October 2010 to December 2011, 20 living renal transplantation donors underwent the LEPODN procedure. Their mean age, body mass index (BMI), and preoperative creatinine clearance were 55.7 years, 23.2, and 118.4 mg/min, respectively. The GelPort laparoscopic system was inserted through a 5-6 cm pararectal incision at the umbilicus level. A subcostal 5-mm right-hand working trocar was placed under the left costal arch. The graft kidney was extracted using a retrieval bag. A 5-mm diameter drain was placed via a right-hand working trocar. Operative data of LEPODN were retrospectively compared to those of standard laparoscopic donor nephrectomy (standard-LDN, n = 27) previously performed at our hospital. RESULTS: The procedure was technically successful in all 20 patients. The mean operative time in the LEPODN group was significantly shorter than that in the standard-LDN group (229.1 vs 249.8 minutes, P = .033). Mean blood loss and warm ischemic time in the LEPODN group were 39.4 mL and 272.4 seconds, respectively. The mean serum creatinine concentrations of the recipients 7 and 30 days after operation were 1.57 and 1.13 mg/dL, respectively. These results were not significantly different from those in the standard-LDN group. CONCLUSION: The LEPODN procedure was feasible and performed without specialized instruments by surgeons experienced in only standard laparoscopic nephrectomy.

Comparison of surgical stress in patients undergoing open versus laparoscopic radical prostatectomy by measuring perioperative serum cytokine levels.

PURPOSE: We evaluated the perioperative serum levels of inflammatory cytokines in patients with prostate cancer (PCa) treated with open or laparoscopic radical prostatectomy (RP) and assessed the surgical stress based on the cytokine levels in addition to conventional clinical stress markers after surgery. PATIENTS AND METHODS: One hundred sixty-five patients who received RP for clinically localized PCa were enrolled. Serum levels of interleukin (IL)-10, IL-6, tumor necrosis factor-α, IL-1ß, IL-8, and IL-12p70 were quantitatively measured using a multiplex bead array at three time points (i.e., before the operation [pre-OP], immediately after the operation [post-OP], and on postoperative Day 1 [POD1]). The perioperative changes in serum stress markers, including cytokines, were compared between patients who underwent open and laparoscopic RP, and the predictors for high levels of postoperative cytokines were assessed. RESULTS: The median age and estimated blood loss were significantly lower in the laparoscopic RP group than in the open RP group (P=.003 and P<.01, respectively). In all patients, body temperature, white blood cell count, and serum IL-10 and IL-6 levels were significantly higher at post-OP and POD1 than at pre-OP. Patients who underwent laparoscopic RP had significantly lower levels of serum IL-10, IL-6, and IL-1ß at post-OP and POD1 than those who underwent open RP. Multivariate regression analyses showed that the surgical group (open versus laparoscopic) was an independent influencing factor on the levels of serum IL-6 and IL-10 at POD1 (P=.031 and P<.004, respectively) among various clinical perioperative parameters. CONCLUSIONS: Several inflammatory cytokines, particularly IL-6 and IL-10, are potential surgical stress markers in patients with PCa treated with RP. Based on cytokine production, our data support the view that laparoscopic RP is less invasive than open RP.

Association between various indices of obesity and intraoperative factors in laparoscopic donor nephrectomy.

PURPOSE: Obesity has been considered a potential risk factor for complications during laparoscopic surgery. The purpose of this study is to retrospectively investigate the association of various obesity indices and intraoperative factors in laparoscopic donor nephrectomy. PATIENTS AND METHODS: This study included 70 and 44 patients who underwent laparoscopic donor nephrectomy by a transperitoneal approach and retroperitoneal approach, respectively. We measured fat thickness and fat areas on preoperative computerized tomography (CT) images. The median value of fat thickness or of the subcutaneous fat area, visceral fat area, perirenal fat area, or total fat area among subjects was used as a cutoff to define fatty and non-fatty groups. The operative time and estimated blood loss were then compared between the two groups. RESULTS: In the transperitoneal approach group, there was no statistically significant difference in any of the indices or intraoperative factors between the fatty and non-fatty groups defined using any of the fat parameters. In the retroperitoneal approach group, patients in the fatty group categorized by perirenal fat thickness and visceral fat area had significantly greater estimated blood loss than those in the non-fatty group. Also, in the retroperitoneal approach group, patients in the fatty group categorized by perirenal fat area had significantly greater estimated blood loss and longer operating time than those in the non-fatty group (P=.02 and P=.014, respectively). CONCLUSIONS: The results indicate that the visceral fat, and in particular the perirenal fat area measured using CT scan imaging, influences operating time and estimated blood loss after retroperitoneal approach surgery but not in transperitoneal approach surgery. In donors with a high volume of perirenal fat, the transperitoneal approach may be recommended for laparoscopic nephrectomy.

Hyperuricemia at 1 year after renal transplantation, its prevalence, associated factors, and graft survival.

BACKGROUND: The present study investigated the prevalence and predictors for the development of hyperuricemia within 1 year after transplantation and their associations with genetic polymorphisms and graft outcome in patients taking tacrolimus and mycophenolate mofetil. METHODS: One hundred twenty-one renal allograft recipients transplanted between January 2001 and March 2009 were studied. Patients with serum uric acid concentrations above 7.0 mg/dL within 1 year after transplantation were defined as having hyperuricemia, and all were treated with allopurinol. Genetic polymorphisms of nitric oxide synthase, angiotensin-converting enzyme, methylenetetrahydrofolate reductase, and 3 uric acid transporters were examined. RESULTS: At 1 year after transplantation, 46 (38%) recipients developed hyperuricemia. Male gender, higher body mass index, long-term pretransplantation dialysis, and hypertension were associated with the development of hyperuricemia. The estimated glomerular filtration rate (eGFR) at 1 year after transplantation was lower in the patients with hyperuricemia than in those without. There were no differences in graft survival between the two groups. The pharmacokinetics of tacrolimus and mycophenolic acid and 6 polymorphisms were not associated with hyperuricemia. In the multivariate analysis, male gender, long-term pretransplantation dialysis (>36 months), and eGFR (<60 mL/min) were independently associated with the development of hyperuricemia. CONCLUSION: The incidence of hyperuricemia in our cohort was 38%. Male gender and long-term pretransplantation dialysis were predictors for the development of hyperuricemia. The eGFR was lower in patients with hyperuricemia, but graft survival did not differ between the patients with hyperuricemia treated with alloprinol and those without hyperuricemia. We could not define the significance of the pharmacokinetics of immunosuppressants and genetic risk factors for hyperuricemia.

Comparison of the clinical outcome and systemic inflammatory marker levels between retroperitoneal and transperitoneal laparoscopic donor nephrectomy.

BACKGROUND AND PURPOSE: Whether the retroperitoneal approach (RA) or the transperitoneal approach (TA) for performing laparoscopic donor nephrectomy (LDN) in kidney transplant donors is less invasive is unclear. In this study, we compared the clinical outcome and systemic inflammatory marker levels between RA and TA to assess surgical invasiveness. PATIENTS AND METHODS: We enrolled 105 donors (RA: 41, TA: 64) who underwent LDN in our hospital. Evaluation of both approaches included comparison of conventional clinical parameters and preoperative, immediate postoperative, and 1-day postoperative levels of the following circulating inflammatory cytokines: Tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, IL-8, IL-10, and IL-12p70. RESULTS: The frequency of right nephrectomy being performed was significantly lower in the TA than in the RA group (3/64 vs 12/41, P<0.001). Other clinical parameters in the TA group, including the frequency of surgical complications and incidence of delayed graft function, were comparable to those in the RA group. Immediate and 1-day postoperative mean serum IL-6 levels were significantly higher in the RA than in the TA group (P=0.023 and 0.044, respectively). The 1-day postoperative mean serum IL-10 level was also significantly higher in the RA than in the TA group (P=0.041). Meanwhile, the mean serum IL-6 and IL-10 levels were not associated with surgical duration or estimated intraoperative blood loss. CONCLUSIONS: Conventional clinical parameters related to surgical invasiveness were comparable in both approaches, thus indicating that both LDN approaches were similar and equally effective as minimally invasive procedures. The clinical significance of the higher postoperative mean serum IL-6 and IL-10 levels in the RA group remains to be clarified in a future study.

The complex of immunoglobulin A and uromodulin as a diagnostic marker for immunoglobulin A nephropathy.

BACKGROUND: The only tool to diagnose immunoglobulinn A nephropathy (IgAN) is renal biopsy which requires hospitalization; moreover, renal biopsy has a risk of critical bleeding. Therefore, a non-invasive method for accurate diagnosis of IgAN is desirable and a must-to-have tool for the clinics. For this purpose, we evaluated the diagnostic value of the IgA-uromodulin complex in the urine of patients with IgAN for its feasibility and adequacy. METHOD: We determined the IgA-uromodulin complex as a candidate for a diagnostic marker of IgAN by immunoprecipitation, liquid chromatography-mass spectrometry (LC-MS) and Western blot analysis. The enzyme-linked immunosorbent assay (ELISA) for the IgA-uromodulin complex was developed and applied to urine samples obtained from various kidney disease patients. RESULT: One hundred and three of 126 urine samples (81.7%) from IgAN patients were positive for the IgA-uromodulin complex, while only 25 out of 94 urine samples (26.6%) in other kidney disease patients were positive. Sensitivity was 81.7%, specificity was 73.4%, and diagnosis efficiency was 78.2%. The complex was negative in eight urine samples obtained from patients with Alport syndrome which is almost impossible to discriminate from IgAN by routine urinalysis. CONCLUSION: Detection of the urinary IgA-uromodulin complex by ELISA is a useful non-invasive method to diagnose IgAN.

Short-term clinicopathological outcome of neoadjuvant chemohormonal therapy comprising complete androgen blockade, followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy in Japanese patients with high-risk localized prostate cancer.

BACKGROUND: To assess the outcome of neoadjuvant chemohormonal therapy comprising complete androgen blockade followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy in Japanese patients with a high risk of localized prostate cancer (PCa). METHODS: Complete androgen blockade followed by 6 cycles of docetaxel (30 mg/m2) with estramustine phosphate (560 mg) were given to 18 PCa patients before radical prostatectomy. Subsequently, the clinical and pathological outcomes were analyzed. RESULTS: No patients had severe adverse events during chemohormonal therapy, and hence they were treated with radical prostatectomy. Two patients (11.1%) achieved pathological complete response. Surgical margins were negative in all patients. At a median follow-up of 18 months, 14 patients (77.8%) were disease-free without PSA recurrence. All 4 patients with PSA recurrence had pathologic T3b or T4 disease and 3 of these 4 patients had pathologic N1 disease. CONCLUSION: We found that neoadjuvant chemohormonal therapy with complete androgen blockade followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy was safe, feasible, and associated with favorable pathological outcomes in patients with a high risk of localized PCa.

Outcome, clinical prognostic factors and genetic predictors of adverse reactions of intermittent combination chemotherapy with docetaxel, estramustine phosphate and carboplatin for castration-resistant prostate cancer.

OBJECTIVES: Docetaxel-based chemotherapy is effective in patients with castration-resistant prostate cancer (CRPC). This phase II study assessed the outcome and predictive factors for prognosis and toxicity following intermittent chemotherapy with docetaxel, estramustine phosphate, and carboplatin (DEC) in patients with CRPC. METHODS: Thirty-five patients were treated with a DEC regimen that consisted of a 28-day cycle of drugs as follows: docetaxel (60 mg/m(2) on day 1), carboplatin (AUC 5 on day 1) and estramustine phosphate (560 mg daily). Treatment was continued intermittently. The end point was to test the effect of DEC on the response rate and overall survival (OS). Statistical correlations between the outcomes and predictive factors, including clinical parameters and 8 single-nucleotide polymorphisms (SNPs) related to drug metabolism, were assessed. RESULTS: Prostate-specific antigen levels decreased by more than 30% in 65.7% of the patients. The median OS following DEC was 17.8 months, and the median total time of chemotherapy holiday was 7.7 months (range 1.7-35.8). On multivariate analysis, serum lactate dehydrogenase (LDH) was an independent prognostic factor for OS (p = 0.007). On SNP analysis, patients carrying the TT genotype of the ABCB1 C3435T polymorphism showed a significantly more severe leukocytopenia during the first cycle of DEC therapy compared to patients with the CC + CT genotype (p = 0.036). CONCLUSION: Combination chemotherapy with DEC has a potential effect on CRPC with acceptable toxicity. Serum LDH may be a promising predictor of prognosis, and the ABCB1 C3435T polymorphism may be a genetic predictor of the severity of leukocytopenia in patients with CRPC treated with DEC.