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To examine the safety and efficacy of microwave tissue coagulation (MTC) for prostate cancer and assess its use in lesion-targeted focal therapy in a non-clinical study and a clinical phase II trial.In the non-clinical study using MicrotazeThe region of coagulative necrosis was predictable by monitoring of ultrasonically visible vaporization; thus, by placing the MTC needle at a certain distance, we were able to perform a safe procedure without adverse events affecting the surrounding organs. Based on the non-clinical study, which used various combinations of output and irradiation time, MTC with 30-W output for 60-s irradiation was selected for the prostate. Based on the predictable necrosis, the therapeutic plan (where to place the MTC needle to achieve complete ablation of the target and how many sessions) was strictly determined per patient. There were no serious adverse events in any patient and only temporary urinary symptoms related to MTC therapy were observed. Furthermore, post-treatment satisfaction was very high. All preoperative MRI-visible lesions disappeared, and PSA decreased by 55% 6 months after surgery.Microwave tissue coagulation may be an option for lesion-targeted focal therapy for prostate cancer.

Objectives To investigate the association between decreased serum IgG levels caused by remission-induction immunosuppressive therapy of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and the development of severe infections. Methods We conducted a retrospective cohort study of patients with new-onset or severe relapsing AAV enrolled in the J-CANVAS registry, which was established at 24 referral sites in Japan. The minimum serum IgG levels up to 24 weeks and the incidence of severe infection up to 48 weeks after treatment initiation were evaluated. After multiple imputations for all explanatory variables, we performed the multivariate analysis using a Fine–Gray model to assess the association between low IgG (the minimum IgG levels Results Of 657 included patients (microscopic polyangiitis, 392; granulomatosis with polyangiitis, 139; eosinophilic granulomatosis with polyangiitis, 126), 111 (16.9%) developed severe infections. The minimum serum IgG levels were measured in 510 patients, of whom 77 (15.1%) had low IgG. After multiple imputations, the confounder-adjusted hazard ratio of low IgG for the incidence of severe infections was 1.75 (95% confidence interval: 1.03–3.00). The RCS revealed a U-shaped association between serum IgG levels and the incidence of severe infection with serum IgG 946 mg/dl as the lowest point. Subgroup analysis showed no obvious heterogeneity between treatment regimens. Conclusion Regardless of treatment regimens, low IgG after remission-induction treatment was associated with the development of severe infections up to 48 weeks after treatment initiation.

Introduction: We have developed a fiducial imaging-guidance marker for prostate with less imaging-artifacts than the currently commercially available markers. The aim of this study was to evaluate the imaging-artifact and potential usefulness and safety of the novel fiducial imaging-marker under the preclinical experiments. Materials and Methods: We selected the specific metal materials and shape that can minimize artifacts, under having obtained a license for a metal with a gold-platinum (Au-Pt) alloy composition that maximized artifact-free MRI images. The both phantom test and dog-prostate test were conducted in order to evaluate the imaging-artifacts for three imaging modalities of MRI, CT, and ultrasound, and also the risk of migration of the markers from inserted site to other as well as their crushing. Results: Newly developed Au-Pt material is less imaging-artifact for all of MRI, CT, and ultrasound imaging modalities in comparison to currently commercially available fiducial markers made by gold material only, and the Au-Pt markers had sufficient strength and durability, and is considered as potential clinically useful and safe marker. Conclusion: The developed Au-Pt marker can be an indispensable device for accurate lesion-targeted organ-preserving therapy such as lesion-targeted focal therapy and active surveillance, than the conventional whole-gland surgical or radiation therapy.

Aim: This study aimed to evaluate the 2-year outcomes from a clinical trial of recombinant human FGF-2 (rhFGF-2) for osteonecrosis of the femoral head (ONFH). Patients & methods: Sixty-four patients with nontraumatic, precollapse and large ONFHs were percutaneously administered with 800 μg rhFGF-2 contained in gelatin hydrogel. Setting the end point of radiological collapse, we analyzed the joint preservation period of the historical control. Changes in two validated clinical scores, bone regeneration and safety were evaluated. Results: Radiological joint preservation time was significantly higher in the rhFGF-2 group than in the control group. The ONFHs tended to improve to smaller ONFHs. The postoperative clinical scores significantly improved. Thirteen serious adverse events showed recovery. Conclusion: rhFGF-2 treatment increases joint preservation time with clinical efficacy, radiological bone regeneration and safety.

ObjectiveFollowing induction of remission with rituximab in anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) relapse rates are high, especially in patients with history of relapse. Relapses are associated with increased exposure to immunosuppressive medications, the accrual of damage and increased morbidity and mortality. The RITAZAREM trial compared the efficacy of repeat-dose rituximab to daily oral azathioprine for prevention of relapse in patients with relapsing AAV in whom remission was reinduced with rituximab.MethodsRITAZAREM was an international randomised controlled, open-label, superiority trial that recruited 188 patients at the time of an AAV relapse from 29 centres in seven countries between April 2013 and November 2016. All patients received rituximab and glucocorticoids to reinduce remission. Patients achieving remission by 4 months were randomised to receive rituximab intravenously (1000 mg every 4 months, through month 20) (85 patients) or azathioprine (2 mg/kg/day, tapered after month 24) (85 patients) and followed for a minimum of 36 months. The primary outcome was time to disease relapse (either major or minor relapse).ResultsRituximab was superior to azathioprine in preventing relapse: HR 0.41; 95% CI 0.27 to 0.61, pConclusionsFollowing induction of remission with rituximab, fixed-interval, repeat-dose rituximab was superior to azathioprine for preventing disease relapse in patients with AAV with a prior history of relapse.Trial registration numberNCT01697267; ClinicalTrials.gov identifier

We developed a questionnaire to examine the findings of cutaneous arteritis among dermatological specialists experienced in vasculitis as certified by the Committee for guidelines for the management of vasculitis and vascular disorders of the Japanese Dermatological Association. We sent a questionnaire to 12 dermatological facilities identified through the revised Committee for guidelines for the management of vasculitis and vascular disorders of the Japanese Dermatological Association. Retrospective data obtained from 84 patients at the 12 dermatological facilities between 2012 January 2016 December were evaluated. The 84 patients were categorized into two groups, a systemic steroid treatment group (group 1, n = 52) and a no systemic steroid treatment group (group 2, n = 32). C-reactive protein in group 1 patients was significantly higher than that in group 2 patients. Frequency of fever, arthritis, myalgia- and peripheral neuropathy in group 1 was significantly higher than that in group 2. We propose that these symptoms could serve as early markers for the transfer from cutaneous arteritis to systemic polyarteritis nodosa. We further suggest that patients who are subsequently associated with cerebral hemorrhage and infarction, who are originally diagnosed as having cutaneous arteritis, could progress to systemic polyarteritis nodosa. The study demonstrated that it is important for dermatologists to detect these findings early in order to establish an accurate diagnosis and a timely treatment.

BACKGROUND More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis. METHODS We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of

Background:. Although traditional wound dressings such as collagen scaffolds promote granulation tissue formation, the efficacy of these dressings in chronic wounds is limited because of high susceptibility to bacterial growth. Biomaterials that can be applied to chronic wounds should have an anti-bacterial function. We previously reported that administering a silk-elastin solution that forms moisturizing hydrogels to wound surfaces of diabetic mice reduced bacterial growth and promoted granulation tissue formation compared with control or carboxymethyl cellulose hydrogels. We hypothesized that silk-elastin promotes wound healing in human chronic wounds by suppressing bacterial growth. Methods:. An open-label, clinical case series was conducted with a prospective, single-arm design at Kyoto University Hospital in Kyoto, Japan. In this study, 6 patients with chronic skin ulcers of any origin (2 < ulcer area (cm2) < 25) on their lower extremities were included; patients with critical ischemia were excluded. Silk-elastin sponges were applied and covered with a polyurethane film without changing the dressing for 14 days. Inflammation triggered treatment discontinuation due to fear of infection. The primary study endpoint was adverse events, including inflammation and infection. Results:. Poor hydrogel formation, possibly due to continuous exudation, was observed. No serious adverse events were noted. Two patients discontinued treatment on day 6 and day 7, respectively, due to inflammation, but they were not infected. The other 4 patients completed the 14-day silk-elastin sponge treatment without infection. Conclusion:. Silk-elastin sponge is safe for chronic skin ulcers, and its ability to promote wound healing should be determined by confirmatory clinical trials.

Background: Osteonecrosis of the femoral head (ONFH) is a rare disease requiring joint replacement even in young patients due to progressive femoral head collapse. Regenerative medicine is considered the next treatment of interest to prevent collapse. Methods: We percutaneously administered gelatin hydrogel containing 800-µg recombinant human fibroblast growth factor-2 (rhFGF-2) [TRION] to 64 patients with nontraumatic, precollapse, and large ONFHs. Using the endpoint of radiological collapse, we analyzed the joint-preservation period of the historical control comprising patients with nonsurgically treated ONFH. The primary outcome was an expected collapse rate

Aim: To evaluate the 5-year outcomes from the prospective study of recombinant human FGF-2 (rhFGF-2) for osteonecrosis of the femoral head (ONFH). Methods: Ten patients (average age 39.8 years) with nontraumatic, precollapse ONFH were percutaneously administered with 800 μg rhFGF-2 contained in gelatin hydrogel. Radiological changes and the prevalidated Harris hip score (HHS), visual analogue scale for pain and University of California, Los Angeles activity-rating scale scoring systems were evaluated. Results: The 5-year comparison in type C2 showed higher joint preservation in the rhFGF-2 group (71.4%) than in the natural course group (15.4%). Two of three clinical scores (Harris hip score and visual analogue scale for pain) improved significantly. Postoperative MRI demonstrated significant reduction in ONFH size. There were no adverse events. Conclusion: rhFGF-2 treatment for ONFH appears to be safe and effective and may have the potential to prevent disease progression.

ANCA-associated RPGN leads to renal failure through systemic vasculitis and diffuse crescentic glomerulonephritis. MPO-ANCA-RPGN patients are highly susceptible to infections. Our aim in this study was to uncover reasons why these patients were susceptible to infections. We analyzed various aspects of type I interferon system including HVJ-stimulated IFN-α producing capacity and plasmacytoid dendritic cell (pDC) number in whole blood in MPO-ANCA-RPGN patients. Compared with healthy subjects, MPO-ANCA-RPGN patients showed impaired HVJ-stimulated IFN-α producing capacity and lower pDC number with or without glucocorticoid treatment. Immuno-histological staining of MPO-ANCA-RPGN kidney samples revealed a few but apparent pDC in T cell infiltrating regions even in patients with low pDC number in their peripheral blood. Patients' low HVJ-stimulated IFN-α producing capacity and pDC numbers persisted even after patients underwent several years of treatment. Former infection was determined using patients' serum BPI, Lamp-2 and Calprotectin, since they are reflective of a history of infection. These markers were higher in MPO-ANCA-RPGN patients than in healthy subjects. These results indicate that impaired HVJ-stimulated IFN-α production as well as dysfunction of the IFN system might have resulted from a previous bout of infection and can be partially implicated in patients' long-term susceptibility and vulnerability to infection.

ObjectivesEvaluation of rituximab and glucocorticoids as therapy to induce remission after relapse in ANCA-associated vasculitis (AAV) in a prospective observational cohort of patients enrolled into the induction phase of the RITAZAREM trial.MethodsPatients relapsing with granulomatosis with polyangiitis or microscopic polyangiitis were prospectively enrolled and received remission-induction therapy with rituximab (4×375 mg/m2) and a higher or lower dose glucocorticoid regimen, depending on physician choice: reducing from either 1 mg/kg/day or 0.5 mg/kg/day to 10 mg/day by 4 months. Patients in this cohort achieving remission were subsequently randomised to receive one of two regimens to prevent relapse.Results188 patients were studied: 95/188 (51%) men, median age 59 years (range 19–89), prior disease duration 5.0 years (range 0.4–34.5). 149/188 (79%) had previously received cyclophosphamide and 67/188 (36%) rituximab. 119/188 (63%) of relapses had at least one major disease activity item, and 54/188 (29%) received the higher dose glucocorticoid regimen. 171/188 (90%) patients achieved remission by 4 months. Only six patients (3.2% of the study population) did not achieve disease control at month 4. Four patients died in the induction phase due to pneumonia (2), cerebrovascular accident (1), and active vasculitis (1). 41 severe adverse events occurred in 27 patients, including 13 severe infections.ConclusionsThis large prospective cohort of patients with relapsing AAV treated with rituximab in conjunction with glucocorticoids demonstrated a high level of efficacy for the reinduction of remission in patients with AAV who have relapsed, with a similar safety profile to previous studies.

Purpose The present study aimed to examine the differences between enrolled subject populations and use of combination therapies as defined by the pivotal clinical trial protocols and the approved indications of anticancer drugs as determined by 3 major regulatory agencies. Methods Thirty-eight approvals were collected that received market authorization from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), and the Pharmaceuticals and Medical Devices Agency (PMDA) between January 2010 and September 2018 for initial approval of an anticancer drug or for an expanded therapeutic indication for a previously approved anticancer drug, based on the same pivotal clinical trial(s). The subject eligibility criteria of the pivotal clinical trials and the approved indications as established by these agencies were compared, and the differences were categorized according to patient biomarkers status, prior treatment status, and the use of combination therapies. Findings In 20 (53%) approvals, there was a discrepancy between biomarker status of enrolled subjects in the pivotal trial and the therapeutic indication. In 7 of these cases, the biomarkers were used to diagnose the target cancer or to stratify the study subjects in the pivotal trial. In 9 cases, the biomarker discrepancies were related to minor histologic subtypes of the target cancer. Regarding prior treatment status, the FDA and the EMA generally approved indications for the same treatment line as the pivotal trials, whereas the PMDA did not restrict approval to untreated patients when the pivotal trial included only treatment-naive subjects. In 14 approvals, the FDA and the EMA designated the same co-administered drugs as part of the approved indications in line with the pivotal trials. However, the PMDA did not specify the co-administered drugs in 2 approvals and did not require combination therapy in 1 case. Implications In principle, the approved therapeutic indications should be determined by the characteristics of the pivotal trial subjects and combination therapies. The use of biomarkers can be essential for identifying those patients who are most likely to benefit from a drug. Unfortunately, biomarker-defined subgroups are often insufficient in size to allow meaningful interpretation of results. Consequently, regulatory agencies may deviate from one another and from the pivotal trial protocol when interpreting study results and attempting to define the optimal treatment population. The PMDA-approved indications deviated more liberally from the pivotal trial protocols regarding specification of prior treatment status and the use of co-administered drugs.

The epidemiology of renal vasculitis in different populations is poorly understood. A recent study from Japan suggests that whilst the overall incidence is similar to that reported from Europe, the clinical phenotype is different, with Wegener's granulomatosis being very much less common. The aim of this study was to compare the incidence of renal vasculitis in the UK with recent data from a Japanese population. Methods. Incident patients with renal vasculitis were identified prospectively between 2000 and 2004 from a well-defined UK population. The case notes were reviewed and clinical features extracted. Classification between Wegener's granulomatosis, microscopic polyangiitis and Churg Strauss syndrome was performed using a predetermined algorithm. Inclusion criteria were (i) new patients with vasculitis with or without histological confirmation, (ii) renal involvement and (iii) positive serology for anti-neutrophil cytoplasmic antibody (ANCA).We identified 27 cases of renal vasculitis (Wegener's granulomatosis 13, microscopic polyangiitis 11, Churg Strauss syndrome 3) fulfilling the case definition. The overall average age was 63.5 years which is less than those of the Japanese patients. The overall annual incidence of renal vasculitis was 12.2/million similar to Japan. The annual incidence of Wegener's granulomatosis was 5.8/million, microscopic polyangiitis 4.9/million and Churg Strauss syndrome 1.4/million. ENT and neurological involvement were much less common in Japan. No patients with cANCA/PR3 were seen in Japan. Wegener's granumolatosis seems to be much less common in Japan than the UK. Discussion. Whilst the overall occurrence of renal vasculitis is similar in Japan to the UK, the clinical phenotype is very different with microscopic polyangiitis predominating in Japan.

As a form of therapeutic angiogenesis, we sought to investigate the safety and efficacy of a sustained-release system of basic fibroblast growth factor (bFGF) using biodegradable gelatin hydrogel in patients with critical limb ischemia (CLI). We conducted a phase I–IIa study that analyzed 10 CLI patients following a 200-μg intramuscular injection of bFGF-incorporated gelatin hydrogel microspheres into the ischemic limb. Primary endpoints were safety and transcutaneous oxygen pressure (TcO2) at 4 and 24 weeks after treatment. During the follow-up, there was no death or serious procedure-related adverse event. After 24 weeks, TcO2 (28.4 ± 8.4 vs. 46.2 ± 13.0 mmHg for pretreatment vs after 24 weeks, p

Anti-neutrophil cytoplasmic autoantibodies (ANCA) are useful diagnostic markers in systemic vasculitic disorders with small-vessel involvement, but depending on the particular test used, the myeloperoxidase (MPO)-ANCA results are variable. In the present study, we performed a comparative analysis between our originally developed nMPO-ANCA assay that targets the native MPO antigen and other commercially available assays using sera of patients with clinical features of ANCA-associated vasculitis (AAV).Sera of 24 patients strongly suspected of having AAV were examined for the presence of MPO-ANCAs by our nMPO-ANCA assay and by other commercial-based MPO-ANCA assays. These results were correlated to indirect immunofluorescence microscopy staining patterns and patient clinical parameters.Eighteen out of 24 patients (75 %) were positive for nMPO-ANCA, compared with 13 out of 24 patients (54 %) by one of the most frequently used commercial-based MPO-ANCA enzyme-linked immunosorbent assays (ELISAs) in Japan. Interestingly, the patients who tested positive with our nMPO-ANCA assay alone showed clinical features of AAV marked by continuous fever, polyarthritis, and mild nephritis. The titers of nMPO-ANCA decreased in association with clinical improvement after treatment.Our data suggest that a positive nMPO-ANCA result, which identifies antibodies to human native MPO antigen, correlates with AAV disease activity. Moreover, the nMPO-ANCA test has clinical utility in detecting AAV-affected patients who have tested negative using commercially available assays.

ObjectivesTumour necrosis factor alpha (TNFα) blockade is an effective therapy for rheumatoid arthritis (RA). The immunomodulatory effects of TNFα antagonists are thought to contribute to their therapeutic action. This study investigated whether anti-TNFα therapeutics exerted their immunoregulatory effects through modulation of dendritic cell (DC) function.MethodsTwo complementary approaches were taken: in the first ‘in vitro’ approach monocyte-derived DC from healthy donors were matured with lipopolysaccharide and treated with TNFα antagonists in vitro for 48 h. In the second ‘ex vivo’ approach monocyte-derived DC were generated from RA patients before and 8–12 weeks into anti-TNFα treatment. DC were analysed for survival, phenotype, cytokine production and T-cell stimulatory capacity.ResultsTNFα blockade during DC maturation in vitro induced approximately 40% of DC to undergo apoptosis. Importantly, the surviving DC displayed a semimature phenotype with reduced levels of HLA-DR, CD80, CD83, CD86 and CCR7, and their production of IL-10 was enhanced compared with DC matured without TNFα antagonists. Furthermore, anti-TNFα-treated DC were poor stimulators of T-cell proliferation and polarised T-cell development towards a higher IL-10/lower IFNγ cytokine profile. Similarly, DC derived from RA patients after anti-TNFα treatment showed impaired upregulation of CD80 and CD86 upon lipopolysaccharide activation and displayed poor T-cell stimulatory activity.ConclusionsThe data show that TNFα blockade has profound effects on DC function with downstream, potentially immunoregulatory, effects on T cells. These data provide an interesting new insight into the potential mechanism by which anti-TNFα drugs contribute to the restoration of immunoregulation in RA patients.

In systemic vasculitis, the serum level of myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic autoantibodies (MPO-ANCA) is significantly elevated with the progression of disease. We have established a model of murine systemic vasculitis by administration of MPO-ANCA and fungal mannoprotein to C57BL/6 mice. We examined the role of MPO and MPO-ANCA in the pathogenesis of glomerulonephritis and systemic vasculitis in this model using quantum dots (QDs). We demonstrated that QD-conjugated MPO-ANCA (ANCA-QD) visualized the translocation of MPO on the neutrophil membrane surface after stimulation with proinflammatory cytokines. We also observed that MPO translocation on neutrophils in both patients with rapid progressive glomerulonephritis and these model mice without any stimulation, suggesting that MPO translocation is certain to contribute to the development of glomerular lesion. In addition, blood flow on the kidney surface vessel was significantly decelerated in both SCG/Kj mice and this model, suggesting that ANCA induces the damage of blood vessel. These results indicate that MPO-ANCA and surface-translocated MPO on the activated neutrophils coordinately plays essential roles in the initial steps of the glomerulonephritis.

Background: Previously we observed that the coagulation system promotes matrix protein accumulation through transforming growth factor (TGF)-β and connective tissue growth factor (CTGF) expression in rat mesangioproliferative glomerulonephritis (MsPGN). Angiotensin II receptor blockers (ARBs) are known to suppress matrix accumulation in experimental MsPGN. In the present study, we investigated whether ARB suppresses MsPGN through inhibition of these profibrotic cytokines, and in relation to coagulation and fibrinolytic systems. Methods: MsPGN was induced in Wistar rats by intravenous injection of anti-Thy-1.1 monoclonal antibody, OX-7. As an ARB, olmesartan was orally administered in rat feed from the day of OX-7 injection (day 0) to day 8, when rats were sacrificed and kidney specimens were collected. The degrees of cellular proliferation, matrix production, coagulation factors, and inhibitory factor of fibrinolysis were evaluated. Results: Although blood pressure did not change in the normal, disease control, or treatment groups, the amount of urinary protein was significantly decreased in the ARB-treated groups, compared with the disease control group (p < 0.05). α-Smooth muscle actin expression was suppressed significantly in the treatment groups (p < 0.001). Blue-staining areas of trichrome, the number of proliferating cell nuclear antigen (PCNA)- or ED-1-positive cells, fibronectin and plasminogen activator inhibitor type 1 in glomeruli significantly decreased in the treatment groups (p < 0.05, respectively); however, fibrin-related antigen and factor V depositions were not suppressed in the treatment groups. Conclusions: These results suggest that the ARB drug would ameliorate MsPGN in vivo, at least partly through CTGF and plasminogen activator inhibitor type 1 suppression, and independently of the local coagulation system in glomeruli.

Background: To determinewhether intravenous immunoglobulin (IVIg) cancontrol disease activity in patients with myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA)-associated rapidly progressive glomerulonephritis (RPGN). Methods: Twelve patients with serologically and histologically confirmed MPO-ANCA-associated RPGN (7 men, 5 women; mean age 71 ± 3 years) received IVIg (400 mg/kg/day) alone for 5 days. The effects of IVIg were evaluated by white blood cell counts, serum C-reactive protein levels, Birmingham Vasculitis Activity Score, rate of change in reciprocal creatinine (1/Cre), and plasma tumor necrosis factor-α levels after IVIg administration. Corticosteroids with or without cyclophosphamide were commenced after IVIg. Results:After IVIg treatment, a significant decrease was observed in white blood cell count (p < 0.05), C-reactive protein values (p < 0.001), and Birmingham Vasculitis Activity Score (p < 0.001) concomitant with the amelioration of systemic symptoms. The rate of change in 1/Cre significantly improved (p < 0.05). Plasma tumor necrosis factor-α levels that were significantly elevated in patients before IVIg compared with normal controls (p < 0.0001), rapidly declined after IVIg with a significant reduction(p < 0.05). Three months post-treatment with IVIg, all patients showed improvement of disease without serious infectious complications. Conclusion: IVIg is a potential component of remission induction therapy for patients with MPO-ANCA-associated RPGN.

For 30 myeloperoxidase (MPO) antineutrophil cytoplasmic antibody (ANCA) related rapidly progressive glomerulonephritis patients (male 17, female 13, average age of 68 +/- 11.8 years old), intravenous immunoglobulin (IVIg) (400 mg/kg/day) was administered for 5 consecutive days before or along with conventional immunosuppressive therapy in Japan. Twenty patients were treated with IVIg before the start or newly increase of conventional therapy and evaluated the independent effect of this therapy. In these patients, just after IVIg, significant decrease of CRP from 8.61 +/- 5.77 to 5.47 +/- 4.50 mg/dl (P0.001) was noted with improvement of elevated serum creatinine in 12 out of 19 patients (63%). In the analysis of the overall outcome of 30 patients, at 3 months after IVIg and following conventional therapy, no patients showed renal death except 4 for whom hemodialysis had been started before IVIg. At 6 months, renal survival rate were 92% (newly renal death 2 out of 26) and 2 patients died due to cerebral bleeding (survival rate was 93%). No fatal infection was noted. IVIg might be the potent inducible therapy which can be promoted before the beginning of conventional immunosuppressant treatment for relatively aged and lower immunopotent MPO-ANCA patients in Japan.

Background. Myeloperoxidase-specific anti-neutrophil cytoplasmic auto-antibody (MPO-ANCA) has been a useful diagnostic marker in systemic vasculitis with crescentic glomerulonephritis (CrGN). It is highly suspected that the antigenic enzyme MPO released from activated neutrophils is involved in these lesions. We evaluated the relationship between neutrophil functions including peripheral neutrophil counts and renal lesions in SCG/Kj mice as a model of ANCAassociated CrGN and vasculitis. Methods. Peripheral neutrophil counts, the plasma levels of MPO-ANCA and tumour necrosis factor alpha (TNF-a) were measured. The capacity of MPO release and superoxide generation were evaluated as neutrophil activity. The renal lesions were estimated by grade of proteinuria, histopathological lesion, such as glomerular neutrophil infiltration and active or chronic renal injury scores with crescent formation. Results. MPO-ANCA and TNF-a levels were higher than those of normal mice C57BL/6 even before overt proteinuria; subsequently, peripheral neutrophils increased. In the phase of nephritis with low grade proteinuria, the spontaneous release of MPO from peripheral neutrophils increased, while superoxide generation increased before spontaneous MPO release occurred. In addition, the renal lesion in histological observations was aggravated with ageing and the glomerular neutrophil infiltration was positively correlated with MPO-ANCA levels, as well as with histological indices of nephritis, active renal injury score; in particular, crescent formation was correlated with spontaneous MPO release. In contrast, superoxide generation was negatively correlated with the severity of this lesion during the progression. Conclusions. These findings indicate that neutrophils are activated and contribute to the development of the active crescentic lesion in SCG/Kj mice.

A 28-year-old Japanese woman developed fever, leg edema, purpura, and abdominal pain during the puerperal period, showing nephrotic syndrome with microscopic hematuria. At first she was thought to have Henoch-Shonlein purpura nephritis and was given steroids at another hospital. Because anasarca and massive urinary protein excretion developed, she was referred to our hospital. Renal biopsy specimens showed endocapillary proliferative glomerulonephritis with massive IgA and C3d deposition along the capillary loops and in the mesangium. A bacteriological study detected methicillin-resistant Staphylococcus aureus (MRSA) in cultures of vaginal secretions, urine, stool, and pharyngeal mucus samples. Based on the diagnosis of MRSA nephritis, anti-MRSA therapy with antibiotics was started, and MRSA became negative for each culture, and urinary protein decreased. Two months after the first renal biopsy, a second renal biopsy was performed, which revealed feeble endocapillary proliferation with mild IgA and C3d deposition in the mesangium. This case showed that the delivery procedure can cause MRSA nephritis after MRSA infection, and that steroid therapy should be avoided in the early phase of this type of nephritis.

We evaluated the safety and clinical outcomes of a single local administration of gelatin hydrogel impregnated with recombinant human fibroblast growth factor (rhFGF)-2 for the treatment of the precollapse stage of osteonecrosis of the femoral head (ONFH)., 特発性大腿骨頭壊死症に対する再生医療の良好な結果. 京都大学プレスリリース. 2016-02-02.

[Background]To date, no therapeutic option has been established for sudden deafness refractory to systemic corticosteroids. This study aimed to examine the efficacy and safety of topical insulin-like growth factor-1 (IGF-1) therapy in comparison to intratympanic corticosteroid therapy. [Methods]We randomly assigned patients with sudden deafness refractory to systemic corticosteroids to receive either gelatin hydrogels impregnated with IGF-1 in the middle ear (62 patients) or four intratympanic injections with dexamethasone (Dex; 58 patients). The primary outcome was the proportion of patients showing hearing improvement (10 decibels or greater in pure-tone average hearing thresholds) 8 weeks after treatment. The secondary outcomes included the change in pure-tone average hearing thresholds over time and the incidence of adverse events. [Results]In the IGF-1 group, 66.7% (95% confidence interval [CI], 52.9–78.6%) of the patients showed hearing improvement compared to 53.6% (95% CI, 39.7–67.0%) of the patients in the Dex group (P = 0.109). The difference in changes in pure-tone average hearing thresholds over time between the two treatments was statistically significant (P = 0.003). No serious adverse events were observed in either treatment group. Tympanic membrane perforation did not persist in any patient in the IGF-1 group, but did persist in 15.5% (95% CI, 7.3–27.4%) of the patients in the Dex group (P = 0.001). [Conclusions]The positive effect of topical IGF-1 application on hearing levels and its favorable safety profile suggest utility for topical IGF-1 therapy in patients with sudden deafness., 突発性難聴に対する新規治療法の有効性を報告. 京都大学プレスリリース. 2014-12-10.