Progressive, refractory macrophage activation syndrome as the initial presentation of anti-MDA5 antibody positive juvenile dermatomyositis: a case report and literature review.

BACKGROUND: Macrophage activation syndrome (MAS) is a severe and under-recognized complication of rheumatologic diseases. We describe a patient who presented with rapidly progressive, refractory MAS found to have anti-MDA5 antibody Juvenile Dermatomyositis (JDM) as her underlying rheumatologic diagnosis. CASE PRESENTATION: We describe a 14-year-old female who at the time of admission had a history of daily fevers for 6 weeks and an unintentional sixteen-pound weight loss. Review of systems was significant for cough, shortness of breath, chest pain, headaches, sore throat, muscle aches, rash, nausea, and loss of appetite. An extensive initial workup revealed findings consistent with an autoimmune process. While awaiting results of her workup she had clinical decompensation with multi-organ system involvement including pancytopenias, interstitial lung disease, hepatitis, cardiac involvement, gastrointestinal distension and pain, feeding intolerance, extensive mucocutaneous candidiasis, and neuropsychiatric decline. Due to her decompensation, significant interstitial lung disease, and likely underlying rheumatologic condition she was started on high dose pulse steroids and mycophenolate. An MRI was performed due to her transaminitis and shoulder pain revealing significant myositis. Intravenous immunoglobulin was then initiated. The myositis antibody panel sent early in her workup was significant for anti-MDA5 and anti-SSA-52 antibodies. Despite high dose pulse steroids, mycophenolate, and IVIG, her disease progressed requiring escalating therapies. Ultimately, she responded with resolution of her MAS as well as significant and steady improvement in her feeding intolerance, interstitial lung disease, cardiac dysfunction, myositis, arthritis, and cutaneous findings. CONCLUSIONS: JDM in the pediatric patient is rare, as is MAS. In patients with complex rheumatologic conditions and lack of response to treatment, it is important to continually assess the patient's clinical status with MAS in mind, as this may change the treatment approach. Without proper recognition of this complication, patients can have a significant delay in diagnosis leading to life-threatening consequences.

Cytokine Release Syndrome in Cancer Patients Receiving Immune Checkpoint Inhibitors: A Case Series of 25 Patients and Review of the Literature.

Cytokine release syndrome (CRS) is a phenomenon of immune hyperactivation described in the setting of immunotherapy. Unlike other immune-related adverse events, CRS triggered by immune checkpoint inhibitors (ICIs) is not well described. The clinical characteristics and course of 25 patients with ICI-induced CRS from 2 tertiary hospitals were abstracted retrospectively from the medical records and analyzed. CRS events were confirmed by 2 independent reviewers and graded using the Lee et al. scale. The median duration of CRS was 15.0 days (Q1; Q3 6.3; 29.8) and 10 (40.0%) had multiple episodes of CRS flares. Comparing the clinical factors and biomarkers in Grades 1-2 and 3-5 CRS, we found that patients with Grades 3-5 CRS had following: (i) had longer time to fever onset [25.0 days (Q1; Q3 13.0; 136.5) vs. 3.0 days (Q1; Q3 0.0; 18.0), p=0.027]; (ii) more cardiovascular (p=0.002), neurologic (p=0.001), pulmonary (p=0.044) and rheumatic (p=0.037) involvement; (iii) lower platelet count (p=0.041) and higher urea (p=0.041) at presentation compared to patients with Grades 1-2 CRS. 7 patients (28.0%) with Grades 1-2 CRS were rechallenged using ICIs without event. 9 patients (36.0%) were treated with pulse methylprednisolone and 6 patients (24.0%) were treated with tocilizumab. Despite this, 3 patients (50%) who received tocilizumab had fatal (Grade 5) outcomes from ICI-induced CRS. Longer time to fever onset, lower platelet count and higher urea at presentation were associated with Grade 3-5 CRS. These parameters may be used to predict which patients are likely to develop severe CRS.

Comparison of pulse-dose and high-dose corticosteroids with no corticosteroid treatment for COVID-19 pneumonia in the intensive care unit.

Corticosteroid dosing in the range of 0.5-2 mg/kg/day of methylprednisolone equivalents has become a standard part of the management of intensive care unit (ICU) patients with COVID-19 pneumonia based on positive results of randomized trials and a meta-analysis. Alongside such conventional dosing, administration of 1 gm of methylprednisolone daily (pulse dosing) has also been reported in the literature with claims of favorable outcomes. Comparisons between such disparate approaches to corticosteroids for Coronavirus disease 2019 (COVID-19) pneumonia are lacking. In this retrospective study of patients admitted to the ICU with COVID-19 pneumonia, we compared patients treated with 0.5-2 mg/kg/day in methylprednisolone equivalents (high-dose corticosteroids) and patients treated with 1 gm of methylprednisolone (pulse-dose corticosteroids) to those who did not receive any corticosteroids. The endpoints of interest were hospital mortality, ICU-free days at Day 28, and complications potentially attributable to corticosteroids. Pulse-dose corticosteroid therapy was associated with a significant increase in ICU-free days at Day 28 compared to no receipt: adjusted relative risk (aRR): 1.45 (95% confidence interval [CI]: 1.05-2.02; p = 0.03) and compared with high-dose corticosteroid administration (p = 0.003). Nonetheless, receipt of high-dose corticosteroids-but not of pulse-dose corticosteroids-significantly reduced the odds of hospital mortality compared to no receipt: adjusted Odds ratio (aOR) 0.31 (95% CI: 0.12-0.77; p = 0.01). High-dose corticosteroids reduced mortality compared to pulse-dose corticosteroids (p = 0.04). Pulse-dose corticosteroids-but not high-dose corticosteroids-significantly increased the odds of acute kidney injury requiring renal replacement therapy compared to no receipt: aOR 3.53 (95% CI: 1.27-9.82; p = 0.02). The odds of this complication were also significantly higher in the pulse-dose group when compared to the high-dose group (p = 0.05 for the comparison). In this single-center study, pulse-dose corticosteroid therapy for COVID-19 pneumonia in the ICU was associated with an increase in ICU-free days but failed to impact hospital mortality, perhaps because of its association with development of severe renal failure. In line with existing trial data, the effect of high-dose corticosteroids on mortality was favorable.

Endoscopic trans-ethmosphenoid optic canal decompression is an optimal choice to save vision for indirect traumatic optic neuropathy.

PURPOSE: To evaluate and compare the effectiveness of endoscopic trans-ethmosphenoid optic canal decompression (ETOCD) and steroid pulse therapy (SPT) for indirect traumatic optic neuropathy (ITON). DESIGN: Prospective interventional case series. METHODS: Total 140 monocular ITON patients from January 2017 to June 2019 were recruited, including 100 patients received ETOCD (56 patients received ETOCD only and 44 patients received ETOCD combined with SPT before surgery), and 40 patients received SPT only. Their visual acuity (VA) and visual evoked potential (VEP) were analysed before and after treatments. Initial VA, lag time, causes of injuries and age were analysed for evaluating prognosis of treatment. RESULTS: In contrast with patients received SPT only (15/40 = 38%), the effective rate of patients received ETOCD only and patients received ETOCD combined with SPT were both significantly better (46/56 = 82%, p < 0.001 and 30/44 = 68%, p = 0.005). Whether with SPT before ETOCD or not, after ETOCD, patients with VA improvement showed no significant difference. And 59/76 (77.6%) patients showed improvement within 24 hours. Patients who had residual visions achieved higher effective rate than those with no light perception (56/58 = 97% and 20/42 = 48%; p < 0.001) after ETOCD. For patients with long lag time of 21-90 days, 23/32 (72%) patients presented with vision improvement. Moreover, VEP was significantly improved after ETOCD. No severe complications were observed. CONCLUSIONS: Endoscopic trans-ethmosphenoid optic canal decompression (ETOCD) is an effective and safe therapy for ITON, which is more effective than SPT. Even for patients with failure in responding to SPT, the successfully physical decompression is the most effective way to rescue optical nerve from permanent damage.

An expanded-access clinical study of thiotepa (DSP-1958) high-dose chemotherapy before autologous hematopoietic stem cell transplantation in patients with malignant lymphoma.

Thiotepa, an antineoplastic ethylenimine alkylating agent that can penetrate the central nervous system, was recently approved in Japan as high-dose chemotherapy prior to autologous hematopoietic stem cell transplantation (HSCT) for patients with malignant lymphoma. To further evaluate the safety and efficacy of thiotepa, a multicenter, open-label, non-comparative, expanded access program was undertaken in Japan, including a larger population of Asian patients with malignant lymphoma. Intravenous thiotepa (200 mg/m2/day) was administered over 2 h on days -4 and -3 before scheduled HSCT, plus intravenous busulfan (0.8 mg/kg) over 2 h every 6 h on days -8, -7, -6 and -5. In the safety analysis population (N = 51), 25 patients (49.0%) had primary central nervous system lymphomas. The most common treatment-emergent adverse event was febrile neutropenia (49/51 [96.1%]). No unexpected safety events were observed, and no event resulted in death or treatment modification. Forty-seven patients (92.2%) had engraftment (neutrophil count ≥ 500/mm3 for three consecutive days after bone-marrow suppression and HSCT). The survival rate at day 100 post-transplantation was 100%. These data confirm the safety of thiotepa prior to autologous HSCT for patients with malignant lymphoma.Trial registration: JapicCTI-173654.

Comparison of administration of single- and triple-course steroid pulse therapy combined with tonsillectomy for immunoglobulin A nephropathy.

ABSTRACT: Immunoglobulin A nephropathy (IgAN) is a form of chronic glomerulonephritis that can cause end-stage renal disease. Recently, tonsillectomy combined with corticosteroid pulse (TSP) has been shown to be effective for achieving clinical remission and favorable renal outcome in patients with IgAN. However, the standard regimen of corticosteroid use in TSP has not been established. Herein, we compared the effect of single- or triple-course steroid pulse therapy combined with tonsillectomy in patients with IgAN.This retrospective, observational cohort study included 122 patients with IgAN enrolled from January 2004 to December 2018 at 2 independent institutions. We divided the patients into 2 groups; single-course (TSP1: n = 70) and triple-course (TSP3: n = 52) of corticosteroid pulse therapy (1 course comprised 3 consecutive days' infusion of 0.5 g methylprednisolone) combined with tonsillectomy. The primary outcome for renal survival was defined as the first occurrence of ≧30% decrease in estimated glomerular filtration rate from baseline. Secondary outcomes included the incidence of clinical remission and recurrence of the disease.Regarding clinical parameters and findings at baseline, there were no significant differences between the 2 groups. The 8-years renal survival in the 2 groups was not significantly different according to Kaplan-Meier curves (TSP1; 82.5% vs TSP3; 69.2%, log-rank test P = .39). The cumulative incidence rates of remission of hematuria (94.4% vs 85.4%, P = .56) and clinical remission (85.0% vs 64.8%, P = .07) were comparable in both groups, while those of proteinuria showed higher rates in TSP1 than TSP3 (88.4% vs 65.4%, P = .02). The cumulative incidence of relapse of hematuria (5.6% vs 2.3%, P = .42) and proteinuria (7.1% vs 3.3%, P = .41) showed no significant differences in the 2 groups. Cox regression analyses showed that the number of courses of corticosteroid pulse therapy was not significantly associated with renal outcome (TSP1 vs TSP3; Hazard ratios 0.69, 95% confidence intervals 0.29-1.64, P = .39).The effect of single-course corticosteroid pulse therapy is not statistically, significantly different from triple-course in TSP protocol for improving renal outcome and preventing relapse in patients with IgAN. Single-course corticosteroid pulse therapy may become a treatment option for patients with IgAN.

Early steroid pulse therapy for children with suspected acute encephalopathy: An observational study.

ABSTRACT: Steroid pulse therapy is widely used to treat virus-associated acute encephalopathy, especially the cytokine storm type; however, its effectiveness remains unknown. We sought to investigate the effectiveness of early steroid pulse therapy for suspected acute encephalopathy in the presence of elevated aspartate aminotransferase (AST) levels.We enrolled children admitted to Hyogo Children's Hospital between 2003 and 2017 with convulsions or impaired consciousness accompanied by fever (temperature >38°C). The inclusion criteria were: refractory status epilepticus or prolonged neurological abnormality or hemiplegia at 6 hours from onset, and AST elevation >90 IU/L within 6 hours of onset. We excluded patients with a neurological history. We compared the prognosis between the groups with or without steroid pulse therapy within 24 hours. A good prognosis was defined as a Pediatric Cerebral Performance Category Scale (PCPC) score of 1-2 at the last evaluation, within 30 months of onset. Moreover, we analyzed the relationship between prognosis and time from onset to steroid pulse therapy.Fifteen patients with acute encephalopathy and 5 patients with febrile seizures were included in this study. Thirteen patients received steroid pulse therapy within 24 hours. There was no between-group difference in the proportion with a good prognosis. There was no significant correlation between PCPC and timing of steroid pulse therapy (rs = 0.253, P = .405). Even after excluding 2 patients with brainstem lesions, no significant correlation between PCPC and steroid pulse therapy timing (rs = 0.583, P = .060) was noted. However, the prognosis tended to be better in patients who received steroid pulse therapy earlier.Steroid pulse therapy within 24 hours did not improve the prognosis in children with suspected acute encephalopathy associated with elevated AST. Still, even earlier administration of treatment could prevent the possible neurological sequelae of this condition.

Effect of systemic steroid therapy in Graves' orbitopathy on regulatory T cells and Th17/Treg ratio.

PURPOSE: Glucocorticoids are a mainstay treatment for Graves' orbitopathy, yet their exact mechanisms of action remain unclear. We aimed to determine whether the therapeutic effects of systemic steroid therapy in Graves' orbitopathy are mediated by changes in regulatory T lymphocytes (Tregs) and T helper 17 lymphocytes (Th17). METHODS: We assessed Treg and Th17 levels in the peripheral blood of 32 patients with active, moderate-to-severe Graves' orbitopathy who received 12 weekly pulses of methylprednisolone, and determined their association with disease severity, disease activity, and treatment outcomes. The acute orbitopathy phase was confirmed based on clinical evaluation and magnetic resonance imaging, and assessed using the clinical activity score (CAS). The severity of the disease was classified according to ETA/EUGOGO guidelines, and quantified based on the total eye score. Treatment response was determined based on specific criteria (e.g., changes in CAS score, diplopia grade, visual acuity, etc.). Treg and Th17 cells were identified using flow cytometry. RESULTS: Methylprednisolone treatment improved the activity of the disease and altered the Th17/Treg balance (i.e., the percentage of Tregs decreased while the number of Th17 cells remained unchanged). There was no association between the Treg/Th17 ratio and the activity and severity of the disease or the treatment response. CONCLUSIONS: Therapeutic effects of steroid therapy in Graves' orbitopathy are not mediated by Treg and Th17 alterations in the peripheral blood. The decrease in peripheral Treg percentage is likely a consequence of the non-specific effects of steroids and does not impact clinical outcome.

Effect of Early High-Dose Vitamin D3 Repletion on Cognitive Outcomes in Critically Ill Adults.

BACKGROUND: Long-term cognitive impairment frequently occurs after critical illness; no treatments are known to improve long-term cognition. RESEARCH QUESTION: Does a single high-dose (540,000 International Units) enteral treatment of vitamin D3 given shortly after hospital admission in critically ill patients who are vitamin D deficient improve long-term global cognition or executive function? STUDY DESIGN AND METHODS: This study evaluated long-term cognitive outcomes among patients enrolled in a multicenter, blinded, randomized clinical trial comparing vitamin D3 treatment vs placebo in critically ill adults with vitamin D deficiency. Global cognition was measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Executive function was measured with a composite score derived from three Delis-Kaplan Executive Function System subscales. Outcomes were assessed at a median of 443 days (interquartile range, 390-482 days) after randomization and were compared using multivariate proportional odds regression. Adjusted ORs of > 1.0 would indicate better outcomes in the vitamin D3 group compared with the placebo group. RESULTS: Ninety-five patients were enrolled, including 47 patients randomized to vitamin D3 treatment and 48 patients randomized to placebo. The adjusted median RBANS score at follow-up was 79.6 (95% CI, 73.0-84.0) in the vitamin D3 group and 82.1 (95% CI, 74.7-84.6) in the placebo group (adjusted OR, 0.83; 95% CI, 0.50-1.38). The adjusted median executive function composite scores were 8.1 (95% CI, 6.8-9.0) and 8.7 (95% CI, 7.4-9.3), respectively (adjusted OR, 0.72; 95% CI, 0.36-1.42). INTERPRETATION: In vitamin D-deficient, critically-ill adults, a large dose of enteral vitamin D3 did not improve long-term global cognition or executive function. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03733418; URL: www.clinicaltrials.gov.

Renal pathological analysis using galactose-deficient IgA1-specific monoclonal antibody is a strong tool for differentiation of primary IgA nephropathy from secondary IgA nephropathy.

In several cases with IgA nephropathy (IgAN), differential diagnosis is difficult due to the complication with other systemic diseases which can induce secondary IgAN. Recently, we demonstrated that immunostaining with galactose-deficient IgA1-specific monoclonal antibody (KM55 mAb) specifically showed positive in primary IgAN cases. Here, we report four cases which we could make definitive diagnosis by immunohistological analysis using KM55 mAb. The underlying systemic diseases are rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), hepatitis C (HCV) and Crohn's disease (CD). Renal pathological findings in the four cases revealed mesangial proliferative glomerulonephritis with IgA and C3 deposits. Immunostaining with KM55 mAb was positive for three cases complicated with RA, SLE and CD, respectively. Thus, these three cases were diagnosed as primary IgAN and treated with tonsillectomy and steroid pulse therapy. These three cases finally achieved clinical remission. On the other hand, the case with HCV showed negative for KM55. Finally, we diagnosed as HCV-related nephropathy and successfully treated by antiviral agents. These cases suggested KM55 mAb is a strong tool to differentiate primary IgAN from secondary IgAN.

Vogt-Koyanagi-Harada syndrome: a discussion about resistance to corticotherapy / Vogt-Koyanagi-Harada: uma discussão sobre resistência à corticoterapia

ABSTRACT Vogt-Koyanagi-Harada (VKH) syndrome is an inflammatory condition of unknown etiology that can affect the eye. The most common ocular manifestation related to VKH is bilateral diffuse uveitis associated to exudative retinal detachment. Although these patients respond well to steroid pulse therapy, we report a case of a 44-year-old female patient presenting bilateral exudative retinal detachment and clinical diagnosis of VKH, who did not respond to the first cycle of 3-day pulse therapy with methylprednisolone. The exudation was reabsorbed only after a second cycle of steroid therapy.

RESUMO A doença de Vogt-Koyanagi-Harada é inflamatória e de etiologia desconhecida, podendo afetar o olho. A manifestação ocular mais comum relacionada à doença de Vogt-Koyanagi-Harada é a uveíte difusa bilateral associada ao descolamento exsudativo da retina. Embora esses pacientes respondam bem à pulsoterapia com esteroides, relatamos um caso de paciente de 44 anos que apresentou descolamento exsudativo bilateral da retina com diagnóstico clínico de doença de Vogt-Koyanagi-Harada que não respondeu ao primeiro ciclo de pulsoterapia de 3 dias com metilprednisolona. A exsudação apenas reabsorveu após uma segunda rodada de terapia com esteroides.

Successful Induction Treatment With Rituximab of Isolated Pauci-Immune Pulmonary Capillaritis Presenting as Diffuse Alveolar Hemorrhage in a Pediatric Patient.

Diffuse alveolar hemorrhage often presents as dyspnea, cough, or hemoptysis, and it is mediated by both immune and nonimmune processes. Isolated pauci-immune capillaritis (IPPC) is a rare diagnosis in which capillaritis, small-vessel vasculitis of the lung, is found on biopsy in the absence of an underlying systemic disorder. Traditionally, IPPC has been treated similarly to anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis with cyclophosphamide and glucocorticoids. However, few cases describing management options are available in the literature, especially among pediatric patients. Our report of successful induction of remission in an adolescent girl suggests that the combination of IV rituximab and pulse methylprednisolone may be a viable option for disease control in pediatric patients with IPPC.

A rare entity of acquired idiopathic generalised anhidrosis which has been successfully treated with pulse steroid therapy: Does the histopathology predict the treatment response?

Acquired idiopathic generalised anhidrosis is an uncommon sweating disorder characterized by loss of sweating in the absence of any neurologic, metabolic or sweat gland abnormalities. Although some possible immunological and structural mechanisms have been proposed for this rare entity, the definitive pathophysiology is still un-clear. Despite some successfully treated cases with systemic corticosteroid application, the dose and route of steroid application are controversial. Here, we present a 41-year-old man with lack of genera-lised sweating who has been successfully treated with high dose pulse intravenous prednisolone. We have discussed his clinical and histopathological findings as well as the treatment options in view of the current literature.

Diverse echocardiographic changes in the course of hypoxia due to acute exacerbation of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive parenchymal disease. Pulmonary hypertension (PH) is a potentially lethal complication in the course of IPF. In almost all cases of IPF-PH there is gradual deterioration, but patients can also decline suddenly due to hypoxia. This case report describes the different echocardiographic changes observed in 2 episodes of hypoxic attack in a 73-year-old man. On admission, the tricuspid regurgitation peak gradient (TRPG) was 21 mmHg and the oxygen saturation rate was 94% (O2: 4 L/min). Five days after admission, the TRPG and oxygen saturation rate deteriorated [TRPG: 85 mmHg, oxygen saturation: 72% (O2; 4 L/min)]. He was diagnosed with IPF-PH due to hypoxic pulmonary vasoconstriction. Oxygen therapy and methylprednisolone pulse therapy (MPT) were administered. Five days after the MPT treatment, the hypoxia and PH improved [TRPG: 21 mmHg, oxygen saturation: 95% (O2: 4 L/min)]. Acute exacerbation of IPF (IPF-AE) occurred 20 days after the MPT, and a second dose of MPT was administered. The TRPG and oxygen saturation rate did not decline [TRPG: 27 mmHg, oxygen saturation: 94% (O2: 4 L/min)]. The patient died 10 days after the second dose of MPT. Divergent echocardiographic findings were observed during the deterioration of IPF-AE in the presence of IPF-PH.

Methylprednisolone pulse therapy in 31 patients with refractory epilepsy: A single-center retrospective analysis.

PURPOSE: We investigated the efficacy of methylprednisolone pulse therapy (MP) and responder characteristics in patients with refractory epilepsy. METHODS: We reviewed medical records of our center to identify patients with refractory epilepsy treated with MP other than continuous spikes and waves during slow sleep (CSWS), Landau-Kleffner syndrome (LKS), or Rasmussen's syndrome (RS) between 2004 and 2015. A course of MP consisted of intravenous methylprednisolone (30 mg/kg/day) on three consecutive days. Patients received multiple courses at intervals of four weeks. We examined seizure outcome, developmental outcome, antibodies to N-methyl-d-aspartate (NMDA)-type glutamate receptors (GluRs), cerebral spinal fluid (CSF)-albumin/serum-albumin ratio, and interictal electroencephalograms (EEGs). Responder to MP was defined as maintaining seizure reduction rate (SRR) ≥50% for three months after the first course of MP. RESULTS: Thirty-one consecutive patients treated with MP at our center were studied. Seizure types were focal onset impaired awareness seizure (FIAS) only (n = 23), FIAS with epileptic spasms (ES) (n = 7), and ES only (n = 1). Responder rate was 32.2% (10/31 patients), and seizure-free rate was 9.7% (3/31). Responders constituted 43.5% of patients without ES. No patient with ES was responder. Behavior and cognition also improved in 6 of 10 responders. History of seizure aggravation after inactivated vaccine before MP was found significantly higher rate in responder patients, comparing with nonresponder patients (p = 0.01). CONCLUSION: Methylprednisolone pulse therapy may be considered for possible treatment in patients with focal epilepsy with drug-resistant seizures without ES, and it may improve cognitive function and behavioral comorbidities.

Early tonsillectomy for severe immunoglobulin A nephropathy significantly reduces proteinuria.

BACKGROUND: Early multiple-drug therapy for severe childhood immunoglobulin A (IgA) nephropathy prevents the progression of nephritis and improves the long-term prognosis. Recent studies have focused on the relationship between the pathophysiology of IgA nephropathy and tonsillar focal infection, and the efficacy of tonsillectomy with methylprednisolone pulse therapy in children has been demonstrated. However, no study has reported on the relationship between the period from diagnosis to tonsillectomy and the long-term prognosis of IgA nephropathy. METHODS: To clarify the long-term effects of an early tonsillectomy, 40 patients who were diagnosed with severe IgA nephropathy in childhood and underwent a tonsillectomy were divided into two groups based on the period from diagnosis to undergoing tonsillectomy: Group A, less than 3 years; and Group B, more than 3 years. The primary endpoint of this study was the change in the amount of proteinuria. Renal prognosis was evaluated 10 years after the diagnosis. RESULTS: This study enrolled 40 patients diagnosed with severe IgA nephropathy in childhood who underwent tonsillectomy after multiple-drug therapy with/without methylprednisolone pulse therapy at Kindai University Hospital; eight patients were excluded based on the exclusion criteria. Group A consisted of 18 patients and Group B, 14 patients. Proteinuria and hematuria levels were significantly reduced in the early surgery group (P < 0.01). No significant differences were found in serum creatinine, uric acid, and IgA/C3 ratio. CONCLUSIONS: High proteinuria levels worsen the renal prognosis in IgA nephropathy. Tonsillectomy in less than 3 years combined with multiple-drug therapy after the initial diagnosis could improve long-term prognosis.

Sorafenib administered using a high-dose, pulsatile regimen in patients with advanced solid malignancies: a phase I exposure escalation study.

BACKGROUND: (Pre)clinical evidence is accumulating that intermittent exposure to increased doses of protein kinase inhibitors may improve their treatment benefit. In this phase I trial, the safety of high-dose, pulsatile sorafenib was studied. PATIENTS AND METHODS: High-dose sorafenib was administered once weekly in exposure escalation cohorts according to a 3 + 3 design. Drug monitoring was performed in weeks 1-3 and doses were adjusted to achieve a predefined target plasma area under the curve (AUC)(0-12 h). The effect of low gastric pH on improving sorafenib exposure was investigated by intake of the acidic beverage cola. RESULTS: Seventeen patients with advanced malignancies without standard treatment options were included. Once weekly, high-dose sorafenib exposure was escalated up to a target AUC(0-12 h) of 125-150 mg/L/h, achieving a twofold higher Cmax compared to standard continuous dosing. Dose-limiting toxicity was observed in three patients: grade 3 duodenal perforation (2800 mg sorafenib), grade 5 multiorgan failure (2800 mg sorafenib) and grade 5 biliary tract perforation (3600 mg sorafenib). The mean difference between observed and target AUC(0-12 h) was 45% (SD ± 56%) in week 1 using a fixed starting dose of sorafenib compared to 2% (SD ± 32%) in week 3 as a result of drug monitoring (P = 0.06). Dissolving sorafenib in cola, instead of water, did not improve sorafenib exposure. Clinical benefit with stable disease as the best response was observed in two patients. CONCLUSION: Treatment with high-dose, once weekly sorafenib administration resulted in dose-limiting toxicity precluding dose escalation above the exposure cohort of 125-150 mg/L/h. Drug monitoring was a successful strategy to pursue a target exposure.

Sudden Cardiac Arrest as the First Manifestation in a Patient with Catastrophic Antiphospholipid Syndrome.

We herein report a 26-year-old woman with sudden cardiac arrest who had no remarkable medical history. While resuscitation was successfully performed with adrenalin administration and extracorporeal membrane oxygenation, the cause of cardiac arrest could not be determined for over two weeks. Given the presence of autoimmune disease along with the findings of refractory renal insufficiency and thrombocytopenia, a kidney biopsy and blood examinations, including lupus anticoagulant testing, were performed, which proved the presence of antiphospholipid syndrome. The patient was successfully treated with steroid pulse therapy. This drastic case scenario highlighted the fact that autoimmune disease can be the cause of sudden cardiac arrest.