Real-world treatment outcomes of patients with penile cancer in the Kyushu-Okinawa area of Japan in the pre-guideline era.

OBJECTIVES: To understand the real-world outcomes for patients with penile cancer in the Kyushu-Okinawa area before the introduction of practice guidelines in Japan. METHODS: We retrospectively collected medical information on patients with penile squamous cell carcinoma and penile intraepithelial neoplasia at 12 university hospitals and their affiliated hospitals in the Kyushu-Okinawa area from January 2009 to December 2020. Patients with unknown clinical stage were excluded. Patient background characteristics and survival, as well as pretreatment factors involved in survival, were investigated. RESULTS: A total of 196 patients were included. Patients with clinical stage 0, I, IIA, IIB, IIIA, IIIB and IV comprised 9.7, 26.0, 22.4, 2.6, 10.7, 14.3 and 14.3%, respectively. The median follow-up was 26 months, and the mean 5-year overall survival and cancer-specific survival rates were 74.3 and 79.8%, respectively. On univariate analysis, tumor diameter ≥ 30 mm, penile shaft tumor, Eastern Cooperative Oncology Group performance status ≥ 1, cT ≥ 3, cN ≥ 2 and cM1 were associated with significantly poorer cancer-specific survival. On multivariate analysis, pretreatment factors of cN ≥ 2 (hazard ratio, 32.5; 95% confidence interval, 5.08-208; P = 0.0002), Eastern Cooperative Oncology Group performance status ≥ 1 (4.42; 1.79-10.9; P = 0.0012) and cT ≥ 3 (3.34; 1.11-10.1; P = 0.0319) were identified as independent prognostic factors. CONCLUSIONS: The study revealed basic data for future penile cancer treatment and research, including survival rates according to clinical stages, and identified cN ≥ 2, Eastern Cooperative Oncology Group performance status ≥ 1 and cT ≥ 3 at initial diagnosis as independent prognostic factors. Evidence for penile cancer in Japan is particularly scarce, and future large-scale prospective studies are warranted.

Risk factors for rectal bleeding after volumetric-modulated arc radiotherapy of prostate cancer.

Background: It is crucially important to understand the risk factors for rectal bleeding after volumetric-modulated arc radiotherapy (VMAT) for prostate cancer to prevent subsequent rectal bleeding. We assayed clinical and dosimetric data to investigate the risk factors for rectal bleeding after VMAT of prostate cancer. Materials and methods: This study included 149 patients with prostate cancer who received VMAT from February, 2012 to June, 2020. Irradiated total doses were 78 Gy/39 fractions in 33 patients (22.1%), 76 Gy/38 fractions in 89 (59.7%), 74 Gy/37 fractions in 4 (2.7%), and 72 Gy/36 fractions in 23 (15.4%). We investigated multiple clinical and dosimetric factors with reference to rectal bleeding. Results: The median observation period was 38 months. Fourteen patients (9.4%) experienced rectal bleeding: five (3.4%) were classified as Grade 2, and nine (6.0%) as Grade 1. There were significant differences between Grade ≥ 1 and Grade 0 patients in the overlap region of the planning target volume (PTV) and the rectum, the rectal V30-75, and the mean rectal dose (p < 0.05). There were significant differences between Grade 2 and Grade 0-1 patients in rectal V30-65 and mean rectal dose (p < 0.05). Conclusions: Rectal bleeding occurred, but its grades and rate of occurrence were permissible. Higher rectal doses were shown to be related to rectal bleeding, and reduction of low/intermediate and mean rectal doses will be important for preventing rectal bleeding.

Evaluation of a newly proposed renal risk score for Japanese patients with ANCA-associated glomerulonephritis.

BACKGROUND: We determined the usefulness and prognostic ability of the renal risk score (RRS), proposed in Europe, for Japanese patients with antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (AAGN) and high myeloperoxidase (MPO)-ANCA positivity; these aspects remain to be verified. METHODS: This retrospective study was conducted on 86 Japanese patients with new, biopsy-confirmed AAGN. We calculated the RRS and analyzed the relationship between this classification, and clinicopathological features and prognosis. We also compared the predictive values between RRS for endpoints including renal death and conventional prognostic tools for patients with AAGN. RESULTS: There were 33, 37, and 16 patients in the low-, medium-, and high-risk groups, respectively. All patients were MPO-ANCA positive. The median follow-up period was 33 months; 16 (18.6%) patients progressed to end-stage renal disease (ESRD). In the high-risk group, 9/16 (56.3%) patients progressed to ESRD, and renal prognosis was significantly poorer than that in other groups (low-risk group, P < 0.001; medium-risk group, P = 0.004). In Cox multivariate regression analysis, RRS was an independent, poor renal prognostic factor (hazard ratio 5.22; 95% confidence interval 2.20-12.40; P < 0.001). The receiver-operating characteristic curves of the RRS for each endpoint were comparable with those of the 2010 histological classification and those of the severity classification of Japanese rapidly progressive glomerulonephritis. CONCLUSIONS: This is the first study to report the usefulness of the RRS for predicting renal outcomes among Japanese patients with AAGN. Our predictive value of the RRS was comparable with that of conventional prognostic tools.

Degarelix as a neoadjuvant hormonal therapy for acute urinary tract toxicity associated with external beam radiotherapy for intermediate- and high-risk prostate cancer: a propensity score matched analysis.

BACKGROUND: In prostate cancer treatment, lower urinary tract symptoms significantly improve with luteinizing hormone-releasing hormone antagonists use compared with agonists. However, it is unclear whether luteinizing hormone-releasing hormone antagonists can decrease acute urinary tract toxicity during external beam radiotherapy. This study aimed to assess whether luteinizing hormone-releasing hormone antagonists used as neoadjuvant therapy reduced acute urinary tract toxicity during external beam radiotherapy compared with luteinizing hormone-releasing hormone agonists. METHODS: The study included 78 patients who underwent intensity-modulated radiation therapy for intermediate- and high-risk prostate cancer between April 2013 and January 2020. Irradiation was initiated after 3-6 months of neoadjuvant therapy. Androgen deprivation therapy was given to the intermediate-risk group for 6 months and the high-risk group for 2-3 years. The European Organization for Research and Treatment of Cancer/Radiation Therapy Oncology Group toxicity grading scale was used to evaluate the urinary tract system toxicity. Relevant clinical factors were used in matching patients based on propensity scores to enable comparison between the groups. RESULTS: Each group had 27 matched patients. There was no reduction in urinary tract toxicity with the use of luteinizing hormone-releasing hormon antagonists (P = 0.624). For patients with an International Prostate Symptom Score of ≥11 at the start of treatment, 18 patients in each group were matched. Significantly lower scores were observed in the luteinizing hormone-releasing hormon antagonist group (P = 0.041). CONCLUSIONS: Luteinizing hormone-releasing hormon antagonists may reduce acute urinary tract toxicity during prostate cancer external beam radiotherapy compared with luteinizing hormone-releasing hormon agonists, in particular in patients with moderate to severe symptoms at the start of treatment.

Clinicopathological features and outcomes of diabetic kidney disease with extracapillary hypercellularity: a Japanese single-center experience.

BACKGROUND: The prognostic significance of glomerular extracapillary hypercellularity (EXHC) in diabetic kidney disease (DKD) is unclear. The aim of this study was to investigate the clinicopathological features and outcomes of DKD patients with EXHC. METHODS: We studied 70 cases of renal biopsy-confirmed type 2 DKD that were diagnosed between 2004 and 2014 and compared the clinicopathological features and outcomes of 22 patients with EXHC (EXHC group) with those of 48 patients without EXHC (control group). All of the patients were Japanese. We assessed the renal biopsy specimens based on the Renal Pathology Society classification system. Clinical and laboratory data were collected at the time of the renal biopsy, and renal outcomes were assessed based on progression to end-stage renal disease (ESRD) requiring renal replacement therapy. The median duration of the observation period was 3 years. RESULTS: In pathological features, nodular sclerosis (Kimmelstiel-Wilson lesions) was observed more frequently in the EXHC group than in the control group (63.6% vs. 35.4%, P = 0.027). There were no significant intergroup differences in clinical features or renal outcomes. Univariate and multivariate Cox regression analyses of all patients showed that a high level of proteinuria, a low initial eGFR, and severe interstitial inflammation were poor prognostic factors. CONCLUSIONS: EXHC is related to nodular sclerosis, which is a known risk factor for ESRD. Careful observation is needed during the follow-up of DKD patients with EXHC, although there were no significant differences in renal outcomes between the EXHC and control groups.

Clinicopathological and long-term prognostic features of membranous nephropathy with crescents: a Japanese single-center experience.

BACKGROUND: Three recent studies from the United States and China reported the clinicopathological features and short-term prognosis in patients with membranous nephropathy (MN) and crescents in the absence of secondary MN, anti-glomerular basement membrane (GBM) antibodies, and anti-neutrophil cytoplasmic antibodies (ANCA). METHODS: We compared clinicopathological and prognostic features in 16 MN patients with crescents (crescent group) and 38 MN patients without crescents (control group), in the absence of secondary MN, anti-GBM antibodies, and ANCA. Median follow-up periods in the crescent and control groups were 79 and 50 months, respectively. RESULTS: Decreased estimated glomerular filtration rates (<50 mL/min/1.73 m2), glomerulosclerosis, and moderate-to-severe interstitial fibrosis were more frequently observed in the crescent group than in the control group (P = 0.043, P = 0.004, and P = 0.035, respectively). Positive staining rates for glomerular IgG2 and IgG4 were significantly different between the 2 groups (P = 0.032, P = 0.006, respectively). Doubling of serum creatinine during follow-up was more frequently observed in the crescent group than in the control group (P = 0.002), although approximately two-thirds of patients in the crescent group were treated with immunosuppressive therapy. Crescent formation and interstitial fibrosis were risks for doubling of serum creatinine [hazard ratio (HR) = 10.506, P = 0.012; HR = 1.140, P = 0.009, respectively]. CONCLUSIONS: This is the first Japanese study demonstrating significant differences in clinicopathological and prognostic features between the 2 groups. Most patients in the crescent group may develop a long-term decline in renal function despite immunosuppressive therapy.

Biosynthesis of anthraquinone derivatives in a Sesamum indicum hairy root culture.

In order to investigate the intermediacy of 2-(4-methylpent-3-en-1-yl)anthraquinone (MPAQ), a possible intermediate for the biosynthesis of anthraquinone derivatives in sesame (Sesamum indicum), 2H-labeled MPAQ was administered to a hairy root culture of S. indicum. Efficient conversion of fed MPAQ to 2-[(Z)-4-methylpenta-1,3-dien-1-yl]anthraquinone ((Z)-MPDEAQ) was observed. Furthermore, administration experiment with 2H-labeled 2-geranyl-1,4-naphthohydroquinone, another possible intermediate, showed that it was converted to MPAQ and (Z)-MPDEAQ. The results clearly demonstrated that these substrates are the actual precursors for the production of (Z)-MPDEAQ. In contrast, neither MPAQ nor 2-geranyl-1,4-naphthohydroquinone was converted to anthrasesamone B and 2,3-epoxyanthrasesamone B, other anthraquinone derivatives in the hairy roots, suggesting that these substrates may not be the common precursors in the biosynthesis of anthraquinone derivatives.

Long-term prognosis of AL and AA renal amyloidosis: a Japanese single-center experience.

BACKGROUND: Few studies have been conducted on the long-term prognosis of patients with amyloid light chain (AL) and amyloid A (AA) renal amyloidosis in the same cohort. METHODS: We retrospectively examined 68 patients with biopsy-proven renal amyloidosis (38 AL and 30 AA). Clinicopathological findings at the diagnosis and follow-up data were evaluated in each patient. We analyzed the relationship between clinicopathological parameters and survival data. RESULTS: Significant differences were observed in several clinicopathological features, such as proteinuria levels, between the AL and AA groups. Among all patients, 84.2 % of the AL group and 93.3 % of the AA group received treatments for the underlying diseases of amyloidosis. During the follow-up period (median 18 months in AL and 61 months in AA), 36.8 % of the AL group and 36.7 % of the AA group developed end-stage renal failure requiring dialysis, while 71.1 % of the AL group and 56.7 % of the AA group died. Patient and renal survivals were significantly longer in the AA group than in the AL group. eGFR of >60 mL/min/1.73 m2 at biopsy and an early histological stage of glomerular amyloid deposition were identified as low-risk factors. A multivariate analysis showed that cardiac amyloidosis and steroid therapy significantly influenced patient and renal survivals. CONCLUSIONS: Our results showed that heart involvement was the major predictor of poor outcomes in renal amyloidosis, and that the prognosis of AA renal amyloidosis was markedly better than that in previously reported cohorts. Therapeutic advances in inflammatory diseases are expected to improve the prognosis of AA amyloidosis.

Utility of epirubicin-incorporating micelles tagged with anti-tissue factor antibody clone with no anticoagulant effect.

Tissue factor (TF), an initiator of the extrinsic blood coagulation cascade, is overexpressed in different types of cancer. Tissue factor overexpression is also known as a poor prognostic factor in pancreatic cancer. We recently developed anti-TF antibody (clone1849)-conjugated epirubicin-incorporating micelles (NC-6300), and reported that this anti-TF1849-NC-6300 showed enhanced antitumor activity against TF-high expressed human pancreatic cancer cells, when compared with NC-6300 alone. However, clone 1849 antibody inhibited TF-associated blood coagulation activity. We studied another anti-TF antibody, clone 1859, which had no effect on blood coagulation and prepared anti-TF1859-NC-6300. In addition, to determine the optimum size of the antibody fragment to conjugate with NC-6300, three forms of the 1859 antibody (whole IgG, F[ab']2 , and Fab') were conjugated to NC-6300. The antitumor effect of each anti-TF1859-NC-6300 was studied in vitro and in vivo, using two human pancreatic cancer cell lines, BxPC3 with high-expressed TF, and SUIT2 with low levels of TF. In vitro, all forms of anti-TF1859-NC-6300 showed higher cytocidal effects than NC-6300 in BxPC3, whereas this enhanced effect was not observed in SUIT2. Likewise, all forms of anti-TF1859-NC-6300 significantly suppressed tumor growth when compared to NC-6300 in the BxPC3, but not in the SUIT2, xenograft model. Among the three forms of conjugates, anti-TF1859-IgG-NC-6300 had a higher antitumor tendency in TF-high expressed cells. Thus, we have confirmed an enhanced antitumor effect of anti-TF1859-NC-6300 in a TF-high expressing tumor; anti-TF1859-IgG-NC-6300 could be used to simplify the manufacturing process of the antibody-micelle conjugation for future clinical studies.

Different Expression Patterns of Toll-Like Receptor mRNAs in Blood Mononuclear Cells of IgA Nephropathy and IgA Vasculitis with Nephritis.

Mucosal immunity may play a key role in IgA nephropathy (IgAN) and IgA vasculitis with nephritis (IgAVN). IgAVN is characterized by the presence of non-thrombocytopenic palpable purpura, associated with glomerulonephritis with IgA-dominant immune deposits. Recent studies have shown the up-regulation of Toll-like receptors (TLRs) in patients with IgAN or IgAVN. Among TLRs that mediate innate immune reactions, TLR2, TLR4, and TRL5 recognize bacterial components, while TLR3, TLR7, and TLR9 recognize viral components. Here we compared the expression levels of TLR mRNAs in peripheral blood mononuclear cells (PBMCs) from 49 IgAN patients, 20 IgAVN patients, and 20 patients with thin basement membrane nephropathy (TBMN), unrelated to immune-mediated pathogenesis, as a control. The real-time RT-PCR analysis revealed the significantly higher expression levels of TLR2, TLR3, TLR5, TLR7, and TLR9 mRNAs in PBMCs of IgAN and IgAVN patients, compared to TBMN patients. Importantly, TLR4 mRNA levels were significantly higher in IgAN patients than in IgAVN patients, while its expression levels were comparable in IgAVN patients and TBMN patients. In contrast, TLR5 and TLR9 mRNA levels were significantly higher in IgAVN patients than in IgAN patients. In IgAN patients, expression levels of TLR2, TLR3, TLR5, or TLR9 mRNA were correlated with proteinuria levels, and TLR4 mRNA levels were correlated with serum IgA levels. In IgAVN patients, however, there was no such correlation. The up-regulated expression of TLR mRNAs in PBMCs may be related to the development of IgAN and IgAVN. The distinct expression patterns between these two diseases may reflect their different pathogenetic mechanisms.

[Repeated Rupture of Bilateral Internal Carotid Artery Aneurysms in a Short Period in Association with Polyarteritis Nodosa:A Case Report].

Cerebral involvement is rare in polyarteritis nodosa(PAN);furthermore, secondary intracranial hemorrhage due to cerebral aneurysm is extremely rare. We describe an unusual case of repeated subarachnoid hemorrhage(SAH)in a 64-year-old woman with a history of PAN. Initially, she developed severe headache(probable first SAH, day 0), and presented at our hospital with second severe headache with disturbed consciousness on day 6. Computed tomography(CT)revealed that SAH was mainly distributed in the right basal cistern and sylvian fissure(second SAH). Three aneurysms were detected using CT angiography on the bilateral internal carotid arteries. An intentionally delayed surgery was planned because of the high risk period of cerebral vasospasm and takotsubo cardiomyopathy. On day 15, she complained of headache and had a convulsion. CT revealed a third SAH in the left sylvian fissure;cerebral angiography revealed enlargement of the left internal carotid-posterior communicating artery(IC-PC)aneurysm. Coil embolization of the aneurysm was performed on day 16, and she was treated using prednisolone(20mg/day)for PAN. However, on day 20, the patient became comatose, and CT revealed a fourth SAH in the right sylvian fissure. Cerebral angiography revealed enlargement of the right IC-PC aneurysm. Clipping of the aneurysm was successfully performed in spite of ventricular dysfunction, and the dose of prednisolone was increased to 40mg/day. After treatment, the ventricular dysfunction gradually resolved. Cerebral aneurysms with PAN are candidates for intervention because of their strong tendency to rupture. In our case, takotsubo cardiomyopathy might have been associated with impairment of the coronary microcirculation due to PAN. We suggest that aggressive immunosuppressive treatment for PAN and curative treatments for cerebral aneurysms should be considered with careful radiological examination and follow-up monitoring.

Antitumor effect of antitissue factor antibody-MMAE conjugate in human pancreatic tumor xenografts.

Tissue factor (TF) triggers the extrinsic blood coagulation cascade and is highly expressed in various types of cancer. In this study, we investigated the antitumor effect of an antibody-drug conjugate (ADC) consisting of an anti-TF monoclonal antibody and monomethyl auristatin E (MMAE). MMAE was conjugated to an anti-human TF or anti-mouse TF antibody using a valine-citrulline linker that could be potentially hydrolyzed by cathepsin B in the acidic environment of the lysosome. The cytotoxic and antitumor effects of the ADCs against four pancreatic cancer cell lines were analyzed. Both the ADC with the anti-human TF antibody and that with the anti-mouse TF antibody were stable under physiological conditions. The anti-human ADC was internalized in TF-expressing human tumor cell lines, followed by effective MMAE release. The half maximal inhibitory concentration (IC50 ) of MMAE was approximately 1 nM for all of the cell lines used. Meanwhile, the IC50 of anti-human ADC was 1.15 nM in the cell lines showing high TF expression, while exceeding 100 nM in the cells showing low TF expression levels. Anti-human ADC with passive and active targeting ability exerted significant suppression of tumor growth as compared to that observed in the saline group (p < 0.01). Also significant tumor growth suppressions were seen at the anti-mouse ADC and control ADC groups compared to the saline group (p < 0.01) due to EPR effect. Because various clinical human cancers express highly amount of TF, this new anti-TF ADC may deserve a clinical evaluation.

Enhanced antitumor effect of anti-tissue factor antibody-conjugated epirubicin-incorporating micelles in xenograft models.

For the creation of a successful antibody-drug conjugate (ADC), both scientific and clinical evidence has indicated that highly toxic anticancer agents (ACA) should be conjugated to a monoclonal antibody (mAb) to administer a reasonable amount of ADC to patients without compromising the affinity of the mAb. For ordinary ACA, the conjugation of a mAb to ACA-loaded micellar nanoparticles is clinically applicable. Tissue factor (TF) is often overexpressed in various cancer cells and tumor vascular endothelium. Accordingly, anti-TF-NC-6300, consisting of epirubicin-incorporating micelles (NC-6300) conjugated with the F(ab')2 of anti-TF mAb was developed. The in vitro and in vivo efficacy and pharmacokinetics of anti-TF-NC-6300 were compared to NC-6300 using two human pancreatic cancer cell lines, BxPC3 (high TF expression) and SUIT2 (low TF expression), and a gastric cancer cell line, 44As3 (high TF expression). The intracellular uptake of epirubicin was faster and greater in BxPC3 cells treated with anti-TF-NC-6300, compared with NC-6300. Anti-TF-NC-6300 showed a superior antitumor activity in BxPC3 and 44As3 xenografts, compared with NC-6300, while the activities of both micelles were similar in the SUIT2 xenograft. A higher tumor accumulation of anti-TF-NC-6300 compared to NC-6300 was seen, regardless of the TF expression levels. However, anti-TF-NC-6300 appeared to be localized to the tumor cells with high TF expression. These results indicated that the enhanced antitumor effect of anti-TF-NC6300 may be independent of the tumor accumulation but may depend on the selective intratumor localization and the preferential internalization of anti-TF-NC-6300 into high TF tumor cells.

Validation of the Japanese histologic classification 2013 of immunoglobulin A nephropathy for prediction of long-term prognosis in a Japanese single-center cohort.

BACKGROUND: A new Japanese histologic classification (JHC) of immunoglobulin A nephropathy (IgAN) for prediction of long-term prognosis was proposed in 2013. The goal of this study was to validate the JHC system in a Japanese single-center cohort. METHODS: A retrospective study was conducted in 198 Japanese adult patients with IgAN. Clinical findings including blood pressure, urinary protein, estimated glomerular filtration rate (eGFR), and outcomes were evaluated in these patients. The glomerular lesion percentage score (GLPS) [number of glomeruli with cellular crescents, fibrocellular crescents, global sclerosis, segmental sclerosis, or fibrous crescents/number of total obtained glomeruli × 100 (%)] was assessed in each patient and categorized into histologic grades (HGs) of HG1 (<25 %), HG2 (25-49 %), and HG3/4 (≥50 %). Associations of GLPS (HG) with disease progression (50 % eGFR decline or end-stage renal disease requiring dialysis) within 10 years after biopsy and the rate of annual eGFR decline were examined. RESULTS: During a median follow-up period of 12.0 years after biopsy, disease progression occurred in 12.8 % (12/94) of HG1 patients, 32.3 % (21/65) of HG2 patients, and 46.2 % (18/39) of HG3/4 patients. The risk of disease progression was significantly higher in the HG2 and HG3/4 groups than in the HG1 group (odds ratios: 3.3 and 5.9 vs. 1). A higher GLPS was significantly associated with a higher risk of disease progression and a greater annual eGFR decline. CONCLUSION: The newly proposed JHC system 2013 based on GLPS (HG) was well correlated with long-term prognosis in our cohort of Japanese adult patients with IgAN.

Preparation and characterization of anti-tissue factor single-chain variable fragment antibody for cancer diagnosis.

Tissue factor (TF), which serves as the initiator of the extrinsic blood coagulation cascade, has been found to be overexpressed in various solid tumors, especially brain tumors, pancreatic cancer, and gastric cancer. Overexpression of TF is considered to contribute to the high incidence of thrombotic complications and poor prognosis in patients with such cancers. Therefore, detection or targeting of TF may be a promising approach for the diagnosis and treatment of solid tumors that are known to overexpress the protein. Here, we used the recombinant DNA technology to develop an anti-TF single-chain Fv (scFv) of small size and high affinity for its target. The biochemical characteristics of the anti-TF scFv were evaluated using surface plasmon resonance (SPR) sensing and flow cytometry. The data obtained showed that the affinity of the anti-TF scFv was 2.04 × 10(-8) (KD), and that the protein showed significant binding to the cancer cells. Then, Alexa 647-labeled anti-TF scFv and anti-TF IgG were administered to mice bearing chemically induced spontaneous tumors. The maximum tumor to background ratios of anti-TF scFv and anti-TF IgG were obtained 3 and 24 h after the injections, respectively. This study indicates anti-TF scFv may be suitable as an imaging probe for the diagnosis of solid tumors.

Hypercalcemic Crisis Due to Parathyroid Adenoma Improved by Continuous Hemodialysis with a Common Calcium Concentration Dialysate: Discussion of Therapeutic Management.

A hypercalcemic crisis due to primary hyperparathyroidism is a life-threatening condition. We herein report a 71-years-old man with hypercalcemic crisis due to primary hyperparathyroidism with parathyroid adenoma. Generally, hemodialysis or continuous hemodiafiltration using calcium-free or low-calcium dialysate is performed early for hypercalcemic crisis. In this case, continuous hemodialysis with a common calcium concentration dialysate improved the hypercalcemic crisis, and parathyroidectomy was performed. The patient recovered sufficiently. Prediction of hypercalcemia crisis, appropriate introduction and methods of blood purification therapy, and timing decisions for parathyroidectomy are required for therapeutic management of hypercalcemic crisis with parathyroid adenoma.

Effects of various prosthetic methods for patients with Kennedy Class I partial edentulism on oral hypofunction, subjective symptoms, and oral health-related quality of life.

PURPOSE: This propensity score matching, multicenter, cross-sectional study was performed to examine the effects of various prosthetic methods for dental clinic outpatients with Kennedy Class I partial edentulism (KCIPE) on oral hypofunction, subjective frailty symptoms, and oral health-related quality of life (QOL). METHODS: Patients (n = 348) were classified into the following three groups for analysis: NT, patients with natural dentition providing intermaxillary contact in four occlusal supporting zones; RPD, patients with KCIPE who received removable partial dentures; and ISFP, patients with KCIPE who received implant-supported fixed prostheses. Participants' basic characteristics were recorded, and oral function tests were conducted. Subjective symptoms of physical and oral frailty were investigated via questionnaire. Oral health-related QOL was assessed using the Japanese short version of the Oral Health Impact Profile (OHIP-JP16). Propensity score matching was performed to adjust for patient background factors that could influence oral hypofunction in each group. RESULTS: Compared with the ISFP group, the RPD group had significantly higher rates of poor oral hygiene, reduced occlusal force, decreased masticatory function, and declines in swallowing function and oral hypofunction; the odds ratio for oral hypofunction was 4.67. Compared with the ISFP group, the RPD group had significantly greater subjective symptoms of physical frailty and oral frailty, as well as higher OHIP scores. CONCLUSIONS: Prosthetic treatment of KCIPE affected oral hypofunction, subjective frailty symptoms, and oral health-related QOL in dental clinic outpatients.

Targeting the Vav3 oncogene enhances docetaxel-induced apoptosis through the inhibition of androgen receptor phosphorylation in LNCaP prostate cancer cells under chronic hypoxia.

BACKGROUND: The Vav family of Rho/Rac guanosine nucleotide exchange factors comprises three members in mammalian cells. Vav3 enhances androgen receptor (AR) activity during progression to androgen independence in prostate cancer. We examined Vav3 small interfering RNA (siRNA) effects on cell proliferation and apoptosis in docetaxel-treated LNCaP cells under chronic hypoxia (LNCaPH). METHODS: We examined individual and combined effects of Vav3 siRNA (si-Vav3) and docetaxel on cell growth and apoptosis under chronic hypoxia by cell proliferation, flow cytometric, DNA fragmentation, and immunoblot analyses. To clarify the molecular basis of si-Vav3- and docetaxel-induced apoptosis, we analyzed alterations in phosphatidylinositol 3-kinase (PI3K)/Akt, extracellular signal-regulate kinase (ERK), c-jun N-terminal kinase (JNK), and AR pathways using kinase inhibitors in LNCaPH cells. The effects of si-Vav3/atelocollagen complex alone or in combination with docetaxel were assessed on xenografts in nude mice by tumor growth delay. RESULTS: Vav3 overexpression was observed in LNCaPH compared with the expression under normoxia. Interrupting Vav3 signaling using siRNA enhanced docetaxel-induced cell growth suppression compared with that induced by docetaxel alone by inhibition of Akt and ERK phosphorylation, resulting in AR phosphorylation inhibition. In addition to increased B-cell lymphoma 2 (Bcl-2) phosphorylation through JNK signaling in response to docetaxel, si-Vav3 enhanced docetaxel-induced apoptosis, as characterized by the accumulation of sub-G1 phase cells and DNA fragmentation, through Bcl-xL/Bcl-2-associated death promoter (Bad) dephosphorylation, resulting in increased caspase-9, caspase-3, and cleaved poly(ADP-ribose) polymerase activation. Xenograft tumor growth was slightly inhibited by si-Vav3/atelocollagen complex injection and combined use of si-Vav3/atelocollagen complex and docetaxel produced a greater effect than docetaxel alone. CONCLUSIONS: Interrupting Vav3 signaling enhances docetaxel-induced apoptosis in LNCaP cells under chronic hypoxia by inhibiting the PI3K/Akt, ERK, and AR signaling pathways. Therapy targeting Vav3 in combination with docetaxel may have practical implications for managing castration-resistant prostate cancer.

Distribution of glomerular IgG subclass deposits in patients with membranous nephropathy and anti-U1 ribonucleoprotein antibody.

BACKGROUND: It is known that a predominant glomerular deposition of IgG4 is characteristic of idiopathic membranous nephropathy (MN) and that significant deposition of other IgG subclasses is also observed in lupus MN. However, there is no report focusing on the distribution of glomerular IgG subclass deposits in MN patients with anti-U1 ribonucleoprotein (RNP) antibody. METHODS: We evaluated clinicopathological features and the distribution patterns of glomerular IgG subclass deposits in seven MN patients with positive anti-RNP antibody and negative antibodies to double-stranded DNA (dsDNA) and Smith antigen (Sm) (RNP-MN group) and in seven age- and sex-matched lupus MN patients with positive anti-dsDNA antibody and negative antibodies to RNP and Sm (L-MN group). RESULTS: Mixed connective tissue disease was diagnosed in four patients in the RNP-MN group. Two patients in the RNP-MN group and three patients in the L-MN group developed nephrotic syndrome. Renal insufficiency was not present in all patients in both groups. Hypocomplementemia was found in two patients in the RNP-MN group and six patients in the L-MN group. In the RNP-MN group, positive stainings for glomerular IgG1, IgG2, IgG3 and IgG4 were observed in one, seven, zero and five patients, respectively. On the contrary, in the L-MN group, positive stainings for glomerular IgG1, IgG2, IgG3 and IgG4 were observed in seven, seven, seven, and six patients, respectively. CONCLUSIONS: This is the first study showing striking differences in the distribution of glomerular IgG subclass deposits between RNP-MN and L-MN groups. RNP-MN and L-MN may result from different immunological mechanisms.

Renal biopsy in patients aged 80 years and older: a single-center experience in Japan.

BACKGROUND: There is a paucity of data on renal biopsy in a large number of the very elderly (age ≥ 80 years) worldwide. METHODS: Clinicopathological features in 73 patients aged ≥ 80 years were evaluated and compared with control groups of 172 patients aged 60 - 61 years and 128 patients aged 70 - 71 years. RESULTS: The common indications for biopsy in the very elderly were nephrotic syndrome (NS), followed by proteinuria without NS and/or hematuria, and acute kidney injury (AKI). Histological diagnoses were considered to potentially modify treatment in 57 cases (78.1%): the most frequent diagnosis was membranous nephropathy, followed by minimal change disease, and various other diseases. There were no biopsy procedure-related serious complications. Clinical assessment of treatments was evaluated in 38 of 54 patients with AKI and/or NS. Improvement in renal dysfunction or NS was observed in 24 of 30 (80%) patients who received immunosuppressive therapy. There were statistically significant differences in the disease spectrum between the very elderly and control groups. CONCLUSIONS: This is the first report of renal biopsy findings in a relatively large number of Japanese very elderly patients. Histological observations are useful aids in estimating the prognosis and therapy selection for renal disorders, even in the very elderly.