Fatal hemophagocytic lymphohistiocytosis with intravascular large B-cell lymphoma following coronavirus disease 2019 vaccination in a patient with systemic lupus erythematosus: an intertwined case.

Hemophagocytic lymphohistiocytosis (HLH) has been recognized as a rare adverse event following the coronavirus disease 2019 (COVID-19) vaccination. We report a case of neuropsychiatric symptoms and refractory HLH in a woman with systemic lupus erythematosus (SLE) after receiving her COVID-19 vaccine treated with belimumab, later found to have intravascular large B-cell lymphoma (IVLBCL) at autopsy. A 61-year-old woman with SLE was referred to our hospital because of impaired consciousness and fever. One month prior to consulting, she received her second COVID-19 vaccine dose. Afterward, her consciousness level decreased, and she developed a high fever. She tested negative for SARS-CoV-2. Neuropsychiatric SLE was suspected; therefore, glucocorticoid pulse therapy was initiated on day 1 and 8. She had thrombocytopenia, increased serum ferritin levels and hemophagocytosis. The patient was diagnosed with HLH and treated with etoposide, dexamethasone and cyclosporine. Despite treatment, the patient died on day 75; autopsy report findings suggested IVLBCL as the underlying cause of HLH. Differentiating comorbid conditions remains difficult; however, in the case of an atypical clinical presentation, other causes should be considered. Therefore, we speculate that the COVID-19 vaccination and her autoimmune condition may have expedited IVLBCL development.

Sporadic Late-onset Nemaline Myopathy Associated with Sjögren's Syndrome: A Case Report.

We report the case of a 46-year-old female patient who developed a subacute progression of axial and proximal muscle weakness. Laboratory findings revealed mildly elevated serum creatine kinase levels. No monoclonal gammopathy was detected. A muscle biopsy revealed that she had nemaline myopathy. Serological tests and a lip biopsy revealed Sjögren's syndrome (SjS). We diagnosed her as having sporadic late-onset nemaline myopathy without monoclonal gammopathy of undetermined significance associated with SjS. Her symptoms improved after methylprednisolone pulse therapy followed by intravenous immunoglobulin therapy. A good response to immunotherapy demonstrates the necessity of making a correct diagnosis, for which a muscle biopsy is required.

Long-term survival by surgery and adjuvant chemotherapy in a patient with perforated extranodal NK/T-cell lymphoma of the small intestine: a retrospective case study.

BACKGROUND: Extranodal natural killer/T-cell lymphoma, nasal type (ENKL) of the small intestine, is a disease with extremely poor prognosis. We describe treatment in a case which is novel in that it demonstrated long-term survival. CASE PRESENTATION: A 68-year-old man was admitted to the emergency department of our hospital with the complaint of severe umbilical pain with tenderness and muscular defense. An abdominal computed tomography scan revealed a thick-wall mass on the small intestine and intra-abdominal free air. He was suspected of perforation of a small intestinal tumor and underwent emergency surgery. The surgery revealed a perforated tumor ulcer, and ENKL was diagnosed from the postoperative pathological findings. The patient's postoperative course was uneventful. He was further treated with adjuvant chemotherapy by hematologist comprising six courses of dexamethasone, etoposide, ifosfamide, and carboplatin. The patient demonstrated long-term survival and was in remission at the time of writing, four years and five months after surgery. CONCLUSIONS: We report a rare case of long-term survival of perforated ENKL of the small intestine achieved by surgery and adjuvant chemotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin. It is essential to consult with a hematologist to determine the most appropriate chemotherapy such as DeVIC if one encounters rare postoperative pathological findings of ENKL. To elucidate the pathophysiology of this disease and to prolong survival of affected patients, accumulation of cases of long-term survival and examination of associated characteristics is necessary.

TAFRO Syndrome: A Disease Requiring Immediate Medical Attention.

TAFRO syndrome was first described in 2010, standing for thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly. Because the lymph node histopathology of TAFRO syndrome mimics idiopathic multicentric Castleman disease (iMCD), some researchers consider TAFRO syndrome to be a subtype of iMCD. However, the clinical features of TAFRO syndrome considerably differ from those of iMCD without TAFRO. The clinical features of patients with TAFRO syndrome with or without iMCD-histopathology are similar, and these patients require an accurate diagnosis and urgent treatment. Although a histological diagnosis, including a differential diagnosis, is important, lymph node involvement in patients with TAFRO syndrome is usually modest or sometimes absent. Furthermore, a bleeding tendency due to thrombocytopenia and severe anasarca hampers performing a biopsy. Nonetheless, patients with various other disorders may manifest TAFRO syndrome-like symptoms, making the differential diagnosis in borderline cases difficult. Therefore, the establishment of precise and specific biomarkers is important.

Prognostic impacts of serum levels of C-reactive protein, albumin, and total cholesterol in patients with myelodysplastic syndromes.

Various systems for predicting the prognosis of patients with myelodysplastic syndromes (MDS) have been developed. However, associations between performance status (PS) and prognosis of MDS require further investigation. To objectively assess the impact of PS on survival, we examined laboratory findings associated with PS, including serum levels of C-reactive protein (CRP), albumin (ALB), and total cholesterol (CHOL). Patients (n = 123; male 86, female 37; median age 74 yrs.) diagnosed with MDS or myelodysplastic/myeloproliferative neoplasms at Kanazawa Medical University Hospital between 2010 and 2020 were enrolled and grouped by cutoff values determined by receiver operating characteristic analysis: 0.44 mg/dL for CRP, 4.0 g/dL for ALB, and 120 mg/dL for CHOL. The median follow-up period was 17.6 months. Kaplan-Meier analysis revealed that overall survival (OS) in the high CRP, low ALB, and low CHOL groups was significantly shorter than in the low CRP, high ALB, and high CHOL groups, respectively. Multivariable analysis revealed that elevated serum CRP was an independent prognostic risk factor independent of gender, bone marrow blast percentage, and cytogenetics.

Castleman disease and TAFRO syndrome.

Although Castleman disease was first described in 1956, this disease includes various conditions, including unicentric Castleman disease with hyaline vascular histology, human herpesvirus-8 (HHV-8) related multicentric Castleman disease, idiopathic multicentric Castleman disease, and mimics of Castleman disease associated with other conditions. To date, Castleman disease remains incompletely understood due to its rareness and difficulties in clinical and pathological diagnosis. TAFRO syndrome was reported in Japan in 2010. Because lymph node histology is similar in patients with TAFRO syndrome and Castleman disease, TAFRO syndrome is described as a related disorder of Castleman disease. Clinically, however, these conditions differ markedly. Although elevated interleukin-6 (IL-6) expression is characteristic of Castleman disease, increased expression of IL-6 may occur in patients with other diseases, making elevated IL-6 unsuitable for differential diagnosis. Further understanding of these disorders requires the identification of novel disease-specific biomarkers. This review article therefore outlines the characteristics of Castleman disease and TAFRO syndrome.

Comparison of inulin clearance with 2-h creatinine clearance in Japanese pediatric patients with renal disease: open-label phase 3 study of inulin.

BACKGROUND: There is no approved dosage and administration of inulin for children. Therefore, we measured inulin clearance (Cin) in pediatric patients with renal disease using the pediatric dosage and administration formulated by the Japanese Society for Pediatric Nephrology, and compared Cin with creatinine clearance (Ccr) measured at the same time. We examined to what degree Ccr overestimates Cin, using the clearance ratio (Ccr/Cin), and confirmed the safety of inulin in pediatric patients. METHODS: Pediatric renal disease patients aged 18 years or younger were enrolled. Inulin (1.0 g/dL) was administered intravenously at a priming rate of 8 mL/kg/hr (max 300 mL/hr) for 30 min. Next, patients received inulin at a maintenance rate of 0.7 × eGFR mL/min/1.73 m2 × body surface area (max 100 mL/hr) for 120 min. With the time the maintenance rate was initiated as a starting point, blood was collected at 30 and 90 min, while urine was collected twice at 60-min intervals. The primary endpoint was the ratio of Ccr to Cin (Ccr/Cin). RESULTS: Inulin was administered to 60 pediatric patients with renal disease; 1 patient was discontinued and 59 completed. The primary endpoint, Ccr/Cin, was 1.78 ± 0.52 (mean ± standard deviation). Regarding safety, five adverse events were observed in four patients (6.7%); all were non-serious. No adverse reactions were observed in this study. CONCLUSIONS: The results in this study on the dosage and administration of inulin showed that inulin can safely and accurately determine GFR in pediatric patients with renal disease. CLINICALTRIALS. GOV IDENTIFIER: NCT03345316.

Comprehensive analysis of protein-expression changes specific to immunoglobulin G4-related disease.

BACKGROUND AND AIMS: Immunoglobulin 4 (IgG4)-related disease (IgG4-RD) is a lymphoproliferative disorder characterized by elevated serum IgG4 levels and tissue infiltration of IgG4-positive plasma cells. We analyzed the serum proteins, whose levels varied based on the disease state and treatment. MATERIALS AND METHODS: Serum proteins from patients with IgG4-related disease and healthy subjects were resolved using two-dimensional electrophoresis, silver-stained, and scanned. Alternatively, the proteins were labeled with Cy2, Cy3, and Cy5 before electrophoresis. The proteins, whose expression differed significantly between patients and healthy individuals, and between before and after steroid treatment, were identified and validated using enzyme-linked immunosorbent assays. RESULTS: Pre-treatment sera from patients with IgG4-related disease was characterized by increased levels of immunoglobulins such as IgG1, IgG4; inflammatory factors such as α-1 antitrypsin (A1AT); and proteins associated with immune system regulation such as clusterin and leucine-rich α-2-glycoprotein (LRG-1). The serum levels of A1AT, LRG-1 and clusterin, during treatment with prednisolone for up to 12 months revealed that LRG-1 levels were halved after 1 month of treatment, comparable to those in healthy subjects; LRG-1 levels remained normal until the end of treatment. CONCLUSION: LRG-1 could serve as a novel biomarker of IgG4-related diseases.

Mean of creatinine clearance and urea clearance examined over 1 h estimates glomerular filtration rate accurately and precisely in children.

AIM: Accurate and precise estimation of glomerular filtration rate (GFR) is essential in kidney disease. We evaluated the usefulness of the mean of creatinine clearance (CCr ) and urea clearance (CUN ) examined over a 1-h urine collection period (1-h (CCr + CUN )/2) in a retrospective, cross-sectional study across two centres, as a relatively simple method for estimating GFR in children. METHODS: Children aged ≤18 years who underwent inulin clearance (CIn ) tests were eligible. Two clearance values were obtained during a 2-h test consisting of two periods of 1 h each. The mean clearance in two periods was defined as 1-h clearance. 1-h (CCr + CUN )/2, 1-h CCr , 1-h CUN and GFR estimated by Cr-based and cystatin C (CysC)-based formulas for Japanese children were compared with CIn . Bland-Altman plots were used to evaluate correlations. The primary outcome measure was the correlation between 1-h (CCr + CUN )/2 and CIn . RESULTS: Fifty-three children were analysed. Their median age was 10.9 (interquartile range [IQR] 5.3-14.2) years, and median CIn and 1-h (CCr + CUN )/2 were 77.0 (IQR: 51.5-95.1) and 81.0 (IQR: 64.1-97.7) ml/min/1.73 m2 , respectively. Percentage difference of CIn and 1-h (CCr + CUN )/2 in the Bland-Altman plot was -11.2% (95% confidence interval - 15.3% - -7.1%), with 95% lower and upper limits of agreement of -40.3% and 18.0%, respectively. Thus, 1-h (CCr + CUN )/2 was 1.12 times CIn . CONCLUSION: 1 h (CCr + CUN )/2 was almost concordant with CIn . 1-h (CCr + CUN )/2 can estimate GFR accurately and precisely, making it a simple and speedy test for use in clinical practice.

Patient's age and D-dimer levels predict the prognosis in patients with TAFRO syndrome.

OBJECTIVES: To identify prognostic factors for TAFRO syndrome, a rare inflammatory disorder of unknown etiology characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. METHODS: Data of patients with TAFRO syndrome were extracted from a Japanese patient registry. Patients were divided into groups according to the clinical and laboratory parameters at initial presentation. Cut-off values for the laboratory parameters were determined using receiver operating characteristic curve analysis and by clinical relevance. Patient survival was analyzed by the Kaplan-Meier method. Univariable analysis was performed using log-rank tests. Multivariable analyses were performed with the logistic regression model and the Cox proportional hazards model. RESULTS: We extracted the data of 83 patients with TAFRO syndrome from the registry. Univariable analysis identified several potential prognostic factors. Of these factors, age ≥60 years and D-dimer ≥18 µg/dL remained significant predictors of poor overall survival in the multivariable Cox proportional hazards model. Based on these results, we developed a simple prognostic scoring system for TAFRO syndrome (TS-PSS). CONCLUSION: Patients in our cohort were stratified into low, intermediate, and high-risk groups by the TS-PSS. This system should be verified with independent patient cohorts in future studies.

Optimal treatments for TAFRO syndrome: a retrospective surveillance study in Japan.

TAFRO syndrome is a systemic inflammatory disorder of unknown etiology characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. Mortality in patients with this syndrome is high; however, an optimal treatment strategy has not been established. To explore the strategy, we retrospectively analyzed 81 patients with TAFRO syndrome registered in the Multicenter Collaborative Retrospective Study for Establishing the Concept of TAFRO Syndrome in Japan by December 2019. Sixty-eight patients received corticosteroid therapy as the first-line treatment, and as the second-line treatment, 21 received tocilizumab (Toc), 14 received cyclosporine A (CsA), and 8 received rituximab (Rit) in addition to corticosteroids. We compared these second-line treatment groups by setting the primary endpoint as time to next treatment or death (TTNT). Kaplan-Meier analysis showed that the median TTNT in the Toc, CsA, and Rit groups were 2.8 months, 9.2 months, and not reached, respectively. The TTNT of the Rit group was significantly longer than that of the Toc group. In contrast, there were no significant differences in overall survival between groups, indicating that subsequent salvage therapies rescued a large proportion of patients who failed the second-line treatments. Further studies are warranted to establish the optimal treatment strategies for this syndrome.

Uptake of further investigations following universal urinary screening among elementary and junior high school students in Shiga Prefecture, Japan: A retrospective cohort study.

AIM: This study aimed to investigate the current progression status from screening phase to further investigation phase in the Japanese school urine mass screening (SUS) project. METHODS: This retrospective cohort study on the SUS project across the Shiga Prefecture during 2012 to 2017 analysed data from school life instruction sheets, which are principal documents in the SUS project, regarding urinalysis, attendance at follow-up and diagnoses. RESULTS: Between the years 2012 to 2017, a median of 107 out of 83 749 elementary school students (aged 6-11 years) and 215 out of 42 870 junior high students (aged 12-14 years) had urine abnormalities identified for the first time in the SUS project. Among those with urine abnormalities, a mean of 4.2% of elementary school and 1.8% of junior high school students, respectively, were diagnosed with suspected glomerulonephritis for the first time. Overall, 5.9% (95% confidence interval [CI] 4.1, 7.7) and 23.6% (95% CI 21.3, 25.9) of proteinuria-positive elementary and junior high school students, respectively, did not undergo further investigations. The probability of a student undergoing further investigations was not affected by the local availability of medical care benefits. CONCLUSION: In the current SUS project, screening frequently does not lead to further investigation, especially among junior high school students. To maintain the integrity of the SUS project and to prevent the progression of renal disease in young students, efforts including elucidation of barriers to further investigations should be made to reduce the proportions of students not undergoing further investigations for abnormal urinalysis findings.

Enhancing Wettability of Radio Frequency Magnetron-Sputtered Glass Films by Exploiting Structural Defects.

Silica-based films were prepared by radio-frequency magnetron sputtering to investigate the influence of the chemical compositions of the target glass on the structure and wettability of the sputtered films. The sputtered films were more hydrophilic than the untreated glasses. Oxygen defects formed in the silica units of the sputtered films and resulted in the formation of hydroxyl groups, regardless of the chemical composition of the glass. The three-phase contact lines were distorted by chemical heterogeneities on the surfaces of the sputtered films.

Osteosarcoma Manifesting Systemic Inflammation and Histological Features Mimicking Plasma Cell-type Castleman Disease.

A 73-year-old man was referred to our hospital with a persistent fever, anemia, and a mass in the left pubic region. The findings of biopsy evaluations of the mass and a left inguinal lymph node were consistent with Castleman disease (CD) of plasma cell type. His serum interleukin 6 (IL-6) level was remarkably elevated, supporting the diagnosis of CD. However, imaging analyses revealed destruction of the pubic bone by the mass, which was atypical for CD. Therefore, another deeper biopsy was performed, which finally led to the diagnosis of IL-6-producing osteosarcoma. We conclude that clinicians should carefully exclude malignancies prior to making a CD diagnosis.

Is TAFRO syndrome a subtype of idiopathic multicentric Castleman disease?

Castleman disease (CD) is a rare lymphoproliferative disorder that can be unicentric or multicentric. Multicentric CD (MCD) is further subdivided into human herpesvirus type-8-associated, POEMS syndrome-associated, and idiopathic (iMCD). TAFRO syndrome is a newly identified disorder of unknown etiology characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, renal dysfunction, and organomegaly. The TAFRO syndrome is sometimes regarded as a subtype of iMCD (TAFRO-iMCD), whereas iMCD without TAFRO syndrome is considered "not otherwise specified" (iMCD-NOS). However, a proportion of patients with TAFRO syndrome have been diagnosed without lymph node biopsies (TAFRO syndrome without proven iMCD; TAFRO-w/op-iMCD). To clarify the clinical features of iMCD-NOS, TAFRO-iMCD, and TAFRO-w/op-iMCD, we retrospectively analyzed 220 patients extracted from the database of the Multicenter Collaborative Retrospective Study for Establishing the Concept of TAFRO Syndrome. The patients included 87 with iMCD-NOS, 63 with TAFRO-iMCD, and 19 with TAFRO-w/op-iMCD. Patients in all three groups exhibited anemia, hypoalbuminemia, and elevated serum C-reactive protein and interleukin-6 levels. No significant differences in clinical, laboratory, and prognostic features were noted between the TAFRO-iMCD, and TAFRO-w/op-iMCD groups. However, the iMCD-NOS group exhibited polyclonal hyper-γ-globulinemia. The five-year survival rates of patients in the iMCD-NOS and TAFRO-involved groups were 100% and 66.5%, respectively (dropping markedly during the first few months in the latter). The iMCD-NOS and the TAFRO-iMCD samples typically showed plasma cell and mixed-type histologies, respectively. Thus, iMCD can be classified into two distinct subtypes, iMCD-NOS and TAFRO-iMCD. As such, TAFRO-iMCD and TAFRO-w/op-iMCD may be considered the same entity, requiring prompt diagnosis and intensive care.

High-Dose Chemotherapy with Autologous Stem Cell Transplantation in Primary Central Nervous System Lymphoma: Data From the Japan Society for Hematopoietic Cell Transplantation Registry.

High-dose chemotherapy (HDT) with autologous stem cell transplantation (ASCT) has been shown to improve the prognosis of patients with central nervous system (CNS) lymphoma. We queried the Japan Society for Hematopoietic Cell Transplantation Registry for 2006 to 2015 to analyze the outcomes of 102 patients with primary CNS lymphoma (PCNSL) who underwent first HDT/ASCT. The median patient age was 54 years (range, 20 to 74 years), and 65 patients were treated in an upfront setting. With a median duration of follow-up of 44 months, the 5-year overall survival (OS) and progession-free survival (PFS) were 54.9% and 38.4%, respectively. There were no significant differences in OS and PFS between upfront and salvage HDT/ASCT. Because thiotepa, a key agent in HDT/ASCT for PCNSL, has been unavailable since 2011 in Japan, the HDT regimens used were not uniform. Thiotepa-containing HDT was received by 16 out of 32 patients before 2010, but by only 2 of 70 patients after 2011. Thiotepa-containing HDT was associated with better PFS (P = .019), lower relapse (P = .042), and a trend toward a survival benefit. In multivariate analysis, noncomplete remission at HDT/ASCT was an independent predictor for OS (hazard ratio [HR], 2.40; 95% confidence interval [CI], 1.25 to 4.58; P = .008) and thiotepa-containing HDT remained significant for PFS (HR, .42; 95% CI, .19 to .95; P = .038). These results confirm the activity of thiotepa-containing regimens.

Validation of estimated glomerular filtration rate equations for Japanese children.

BACKGROUND: The gold standard for evaluation of kidney function is renal inulin clearance (Cin). However, the methodology for Cin is complicated and difficult, especially for younger children and/or patients with bladder dysfunction. Therefore, we developed a simple and easier method for obtaining the estimated glomerular filtration rate (eGFR) using equations and values for several biomarkers, i.e., serum creatinine (Cr), serum cystatin C (cystC), serum beta-2 microglobulin (ß2MG), and creatinine clearance (Ccr). The purpose of the present study was to validate these equations with a new data set. METHODS: To validate each equation, we used data of 140 patients with CKD with clinical need for Cin, using the measured GFR (mGFR). We compared the results for each eGFR equation with the mGFR using mean error (ME), root mean square error (RMSE), P30, and Bland-Altman analysis. RESULTS: The ME of Cr, cystC, ß2MG, and Ccr based on eGFR was 15.8 ± 13.0, 17.2 ± 16.5, 15.4 ± 14.3, and 10.6 ± 13.0 ml/min/1.73 m2, respectively. The RMSE was 29.5, 23.8, 20.9, and 16.7, respectively. The P30 was 79.4, 71.1, 69.5, and 92.9%, respectively. The Bland-Altman bias analysis showed values of 4.0 ± 18.6, 5.3 ± 16.8, 12.7 ± 17.0, and 2.5 ± 17.2 ml/min/1.73 m2, respectively, for these parameters. CONCLUSION: The bias of each eGFR equation was not large. Therefore, each eGFR equation could be used.

Nephrotoxicity in children with frequently relapsing nephrotic syndrome receiving long-term cyclosporine treatment.

BACKGROUND: Steroid-sparing drugs, such as cyclosporine, are recommended as treatment for children with frequently relapsing nephrotic syndrome (FRNS) and steroid-related toxicities. We recently reported a high rate of relapsing nephrotic syndrome 2 years after discontinuation of cyclosporine treatment, suggesting that long-term treatment is necessary. Cyclosporine-associated nephrotoxicity (CAN) is a potential side effect of long-term cyclosporine treatment. METHODS: We retrospectively reviewed pediatric patients with FRNS treated with cyclosporine for ≥3 years at a single center between 1999 and 2012. The cyclosporine dose was adjusted to maintain the whole-blood cyclosporine trough level at 80-100 ng/ml for 6 months, at 60-80 ng/ml for 18 months, and then at around 50-60 ng/ml thereafter. Maintenance dose of prednisolone was not prescribed. CAN was graded in terms of arteriolar hyalinosis and the degree of interstitial fibrosis. RESULTS: Thirty-six children (28 males) were enrolled in the study. The median age at the start of long-term cyclosporine treatment was 9.4 years. The median duration of the longest period of cyclosporine treatment was 4.5 years. Most CAN cases were characterized by arteriolar hyalinosis. The frequency of CAN was positively correlated with the duration of cyclosporine treatment, with an odds ratio (95% confidence interval) for CAN of 3.84 (0.79-18.74) after 2-5 years and 6.60 (1.18-36.94) after >5 years of cyclosporine treatment (vs. 0-2 years). CONCLUSIONS: Although the frequency of CAN was correlated with the duration of cyclosporine treatment in our pediatric patient population, most cases of CAN involved arteriolar hyalinosis. We conclude that long-term cyclosporine treatment is useful for treating FRNS in children, providing its dose is controlled and kidney biopsies are regularly performed.