A Case Report on Dysgraphia in a Patient Receiving Blinatumomab: Complex Characters Are Easy to Find in a Handwriting Test.

Recent advances in chemotherapy have led to the emergence of new types of anticancer agents. With these advances, cases of side effects that have not been witnessed in the past have emerged. The systems of side effect evaluation and their grading have been based on the existing knowledge, such as the CTCAE (Common Terminology Standard for Adverse Events) for evaluating adverse drug reactions in cancer chemotherapy clinical trials. Therefore, new types of side effects may be overlooked or underestimated. Blinatumomab is a bispecific T-cell-engager (BiTE) antibody with specificity for CD19 on B cells and CD3 on T cells. Neurological events, such as neuropathy and encephalopathy, are serious side effects of BiTE antibodies. We encountered a case of a 62-year-old woman who experienced short-term memory impairment and dysgraphia after the first blinatumomab administration for Philadelphia chromosome negative (Ph-) B-cell acute lymphoblastic leukemia (ALL). The CTCAE does not include dysgraphia as a classifier for antibody therapies, such as blinatumomab, and immune effector cell-associated neurotoxicity syndrome, which is defined as a Chimeric antigen receptor T cell therapy-related toxicity; dysgraphia is included in the list of symptoms but is not graded. In this case, the severity of dysgraphia differed depending on the complexity of the letters examined. There is no report that the severity of dysgraphia depends on the letters' complexity, and therefore, it may be overlooked when using simple letters. We have reported the characteristics of dysgraphia in this case and the differences observed when judging different letters.

Association between health-related hope and adherence to prescribed treatment in CKD patients: multicenter cross-sectional study.

BACKGROUND: In chronic kidney disease (CKD), patients' adherence to prescriptions for diet and for medications might depend on the degree to which they have hope that they will enjoy life, and that hope could vary with the stage of CKD. The aims of this study were to quantify both the association of CKD stage with health-related hope (HR-Hope), and the association of that hope with psychological and physiological manifestations of adherence. METHODS: This was a cross-sectional study involving 461 adult CKD patients, some of whom were receiving dialysis. The main exposure was HR-Hope, measured using a recently-developed 18-item scale. The outcomes were perceived burden of fluid restriction and of diet restriction, measured using the KDQOL, and physiological manifestations of adherence (systolic and diastolic blood pressure [BP], and serum phosphorus and potassium levels). General linear models and generalized ordered logit models were fit. RESULTS: Participants at non-dialysis stage 4 and those at stage 5 had lower HR-Hope scores than did those at stage 2 or 3 (combined). Those at non-dialysis stage 5 had the lowest scores. HR-Hope scores of participants at stage 5D were similar to those of participants at stage 4, but they were lower than the scores of participants at stage 2 or 3 (combined). Higher HR-Hope scores were associated with lower perceived burdens of fluid restriction and of diet restriction (adjusted ORs per ten-point difference were 0.82 and 0.84, respectively). Higher HR-Hope scores were associated with lower systolic BP (adjusted mean difference in systolic BP per ten-point difference in HR-Hope scores was - 1.87 mmHg). In contrast, HR-Hope scores were not associated with diastolic BP, serum phosphorus levels, or serum potassium levels. CONCLUSIONS: Among CKD patients, HR-Hope is associated with disease stage, with psychological burden, and with some physiological manifestations of adherence.

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.

Changing clinical and molecular characteristics of hepatitis E virus infection in Mie Prefecture, Japan: Disappearance of indigenous subtype 3e strains.

AIM: To evaluate the clinical and molecular characteristics of hepatitis E virus (HEV) infection in Mie Prefecture, Japan, from 2004 through 2018. METHODS: The clinical information of hepatitis E cases was collected from 21 medical institutions in Mie Prefecture. The nucleotide sequences of infecting HEV strains were determined for cases with available serum samples. The origins or transmission routes were inferred from phylogenetic analyses of the nucleotide sequences. RESULTS: Fifty-three patients were diagnosed with HEV infection. The number of cases increased each year through 2012 and then decreased. Analyses of the clinical characteristics of the cases indicated that even mild cases were detected in the latter 10 years of the study. Nucleotide sequence analyses were undertaken on 38 of the 53 cases. The HEV subtype 3e (HEV-3e) strains identified for 13 cases were closely related to a swine HEV-3e strain that was isolated from the liver of a pig bred in Mie Prefecture. The number of cases infected with the indigenous Mie HEV-3e strains increased until 2012 but have not been reported since 2014. In the latter half of the study, cases involving various HEV strains of different genotypes and subtypes emerged. CONCLUSIONS: The disappearance of indigenous Mie HEV-3e strains appeared to be the primary cause for the decrease in hepatitis E cases in Mie Prefecture. The disappearance might have been associated with improved hygienic conditions on pig farms or the closure of contaminated farms. The results suggest that indigenous HEV strains can be eradicated by appropriate management.

Tentative diagnostic criteria and disease severity classification for Castleman disease: A report of the research group on Castleman disease in Japan.

OBJECTIVES: To determine the tentative diagnostic criteria and disease severity classification for Castleman disease (CD) and describe the clinical and pathologic features among human herpesvirus 8 (HHV-8) negative idiopathic multicentric CD (iMCD) in the Japanese population. METHODS: We established the working groups for the research of CD in Japan and had meetings to discuss and define the tentative diagnostic criteria and disease severity classification for CD. We subsequently analyzed 142 patients classified into iMCD by using the nationwide Japanese patient registry. RESULTS: We proposed the preliminary diagnostic criteria and disease severity classification for CD based on our discussion. In addition, we made a proposal for the disease activity score. We identified clinical and pathological features of patients with iMCD diagnosed by these diagnostic criteria. In the disease severity classification, 37, 33 and 30% patients were categorized into mild, moderate and severe diseases, respectively. CONCLUSION: This is the first proposal for diagnosis and classification of CD by the Japanese group. Further studies are required to validate whether they can distinguish CD from other inflammatory diseases and to determine their sensitivity and specificity.

Investigating the origin and global dispersal history of hepatitis E virus genotype 4 using phylogeographical analysis.

BACKGROUND & AIMS: Hepatitis E virus (HEV) genotype 4 has mainly been isolated from sporadic hepatitis cases and swine in Asian countries. We analysed the origin and global dispersal history of genotype 4 using a Bayesian phylogeographical approach. METHODS: The 412-nucleotide sequences of open reading frame 2 of genotype 4 (47 Japanese, 40 Chinese, 1 Indian, 8 Indonesian, 1 Korean, 1 Taiwanese, 2 Danish and 2 Italian), of which sampling date and location were known, were collected. Evolutionary rate, divergence time, demographic growth and phylogeography were co-estimated in the Bayesian statistical inference framework implemented in the BEAST package to model spatial dispersal on a time-scaled genealogy. RESULTS: The most probable origin of genotype 4 was Japan and the time of origin was 1909 (95% highest posterior density, 1871-1940). Seven lineages of genotype 4 migrated from Japan to China. The analysis also showed the migration of genotype 4 from Japan or China to India and Indonesia and from China to Indonesia, Taiwan, Korea and a few European countries. CONCLUSIONS: Swine trade between countries coincided with the migration time and direction of genotype 4 in some cases and was considered the primary cause of dispersal. However, there was no clear cause of dispersal for some cases, for which no records of pig trade were found. Future research should analyse additional nucleotide sequences paired with epidemiological data from various countries to improve our understanding of HEV dispersal.

Proposed diagnostic criteria, disease severity classification, and treatment strategy for a novel disorder; TAFRO syndrome.

TAFRO syndrome is a systemic inflammatory disorder manifesting as thrombocytopenia; anasarca including pleural effusion and ascites; fever; renal insufficiency; and organomegaly including hepatosplenomegaly and lymphadenopathy. Its onset may be acute or sub-acute, but its etiology remains unknown. Although several clinical and pathological characteristics of TAFRO syndrome resemble those of Castleman's disease, other specific features can differentiate between the two. Some patients have been successfully treated with glucocorticoids and/or immunosuppressants including cyclosporin A, tocilizumab and rituximab, whereas others are refractory to treatment, eventually succumbing to the disease. Early and reliable diagnoses and early treatments with appropriate agents are essential to enhancing patient survival. The 2015 updated diagnostic criteria, disease severity classification and treatment strategy for TAFRO syndrome, as formulated by Japanese research teams, are presented herein. Furthermore, clinicopathological data on 28 patients with this condition and similar symptoms (e.g., MCD with serositis and thrombocytopenia) were analyzed retrospectively.

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.

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.

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.

Enzymatic synthesis of γ-glutamylglutamine, a stable glutamine analogue, by γ-glutamyltranspeptidase from Escherichia coli K-12.

The optimal reaction conditions for the synthesis of γ-glutamylglutamine using γ-glutamyltranspeptidase from Escherichia coli were determined. The maximum yield of γ-glutamylglutamine (110 mM) was obtained using 250 mM L: -glutamine and 1.1 U γ-glutamyltranspeptidase/ml at pH 10.5 and at 37°C for 7 h; the conversion of glutamine to γ-glutamylglutamine was 88%.

Psychological Flexibility and Depression in Advanced CKD and Dialysis.

RATIONALE & OBJECTIVE: Depression is prevalent and highly associated with mortality among patients with chronic kidney disease (CKD). Psychological flexibility can be captured as acceptance in psychology, and its improvement by behavioral therapy is associated with reduced depression in some clinical settings. However, no study has been reported on patients with CKD. This study aimed to examine the association between psychological flexibility and depression in patients with CKD. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: This multicenter study of 5 hospitals in Japan included patients with nondialysis stage 3-5 CKD or stage 5D CKD receiving hemodialysis or peritoneal dialysis. PREDICTOR: Psychological flexibility measured using the 7-item Acceptance and Action Questionnaire (AAQ-II). OUTCOMES: The prevalence and incidence of depression after 1 year, which was defined by a score ≥ 16 points on the Center for Epidemiologic Studies Depression (CES-D) questionnaire. ANALYTICAL APPROACH: Gamma regression was used in the examination of correlates of the psychological flexibility value. Modified Poisson regression models were fit for the prevalence and incidence of depression. RESULTS: The cross-sectional and longitudinal analyses included 433 and 191 patients, respectively. Lower (ie, worse) psychological flexibility levels were associated with hemodialysis and peritoneal dialysis. Higher (ie, better) psychological flexibility levels were associated with lower prevalence of depression (per 5-point increase; adjusted prevalence ratio, 0.75; 95% CI, 0.70-0.80) and lower incidence of depression (per 5-point increase; adjusted risk ratio, 0.72; 95% CI, 0.61-0.85). LIMITATIONS: Depression was assessed using the CES-D questionnaire. Cultural differences may exist in the interpretation of AAQ-II scores. CONCLUSIONS: Better psychological flexibility was associated with lower prevalence and incidence of depression in patients with CKD. Further studies are warranted to determine the possible prevention and treatment of depression by the development of behavioral interventions to improve psychological flexibility.

The potential role of follicular helper T cells in idiopathic multicentric Castleman disease with and without TAFRO syndrome.

Idiopathic multicentric Castleman disease (iMCD) is a systemic inflammatory disease of unknown etiology caused by hypercytokinemia. Recently, TAFRO (thrombocytopenia, anasarca, fever, renal failure or reticulin fibrosis, and organomegaly) syndrome has been reported, which shows similar histopathological findings to iMCD and factors associated with a poor prognosis. iMCD shows no plasma cell infiltration in the germinal center (GC), but CD38-positive (CD38+)-plasma cells are observed in the interfollicular area. Our previous report revealed that atrophic change of GC, glomeruloid vascular proliferation, and abnormal proliferation of follicular dendritic cells are more prominent in iMCD with TAFRO (TAFRO+) in comparison to iMCD without TAFRO (TAFRO-). In addition, the numbers of CD38+ and immunoglobulin G4-positive (IgG4+) plasma cells were decreased in the interfollicular area. The roles of T follicular helper cells (Tfh) are well-known to assist B-cell proliferation, maturation, and differentiation．It maintains the formation of GC and is also related in the class switching of IgG isotypes, including IgG4. Thus, we immunohistochemically examined the number of Tfh in GCs in both TAFRO- and TAFRO+ iMCD. The number of Tfh was significantly decreased in TAFRO- iMCD (n = 9) and was further decreased in TAFRO+ iMCD (n = 18) in comparison to non-specific lymphadenopathy (n = 6) and IgG4-related disease (n = 4). These results suggest that decreased Tfh may be one etiology of iMCD.

Epidemiological analysis of multicentric and unicentric Castleman disease and TAFRO syndrome in Japan.

Castleman disease is a polyclonal lymphoproliferative disease which is clinically classified into unicentric (UCD) and multicentric (MCD). TAFRO syndrome is a relatively new concept that partly overlaps with MCD. Due to their rarity, their incidence remains unknown. This study investigated the incidence and prevalence of UCD, MCD, and TAFRO syndrome in Japan using a fixed-point observation method based on their incidence in Ishikawa prefecture. The annual incidences of MCD, UCD, and TAFRO syndrome in Japan were 309-731, 71-542, and 110-502, respectively, yielding annual incidence rates per million individuals of 2.4-5.8, 0.6-4.3, and 0.9-4.9, respectively, and nationwide prevalence of 4,180-14,900, 1,350-10,300, and 860-7,240, respectively. In conclusion, MCD, UCD and TAFRO syndrome may not be as rare as previously estimated in Japan.

An extranodal histopathological analysis of idiopathic multicentric Castleman disease with and without TAFRO syndrome.

Thrombocytopenia, anasarca, fever, renal failure or reticulin fibrosis, and organomegaly (TAFRO) syndrome, a poor prognostic clinical condition showing similar histopathological findings to idiopathic multicentric Castleman disease (iMCD), has been reported in Japan. In our previous report, a clinicopathological analysis was performed on 70 nodal cases of iMCD with/without TAFRO. iMCD is classified into three types based on histopathology: (i) plasmacytic (PC), (ii) mixed, and (iii) hypervascular (hyperV). In this report, extranodal histopathological changes of iMCD with/without TAFRO were analyzed. Regarding the kidney pathology, we observed the proliferation of mesangial cells with positive staining of interleukin-6 (IL-6), consistent with membranoproliferative glomerulonephritis, in two cases of iMCD with TAFRO. The number of megakaryocytes per high-powered fields was not significantly different between iMCD cases with and without TAFRO. In conclusion, extranodal lesions of iMCD with/without TAFRO showed various interesting histopathological findings. These lesions may therefore be related to the clinical condition of TAFRO. Obtaining further knowledge about TAFRO will require the observation of nodal as well as extranodal lesions.

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.

Total Renal Care Approach for Patients with End-Stage Renal Disease.

BACKGROUND: Advances in dialysis medicine have enabled end-stage renal disease (ESRD) patients to live longer. ESRD patients and their family members experience the illness in everyday life, and patients are required to manage their own disease to live longer. Psychological flexibility benefits a person and leads to healthier outcomes. Constructing an independent-minded attitude toward their lives with ESRD is preferably needed. SUMMARY: Holistic care is needed to see patients with ESRD and their families because they are faced with life-long illness. From the scholastic standpoint, integration of natural science and humanities is needed. After some collaboration with philosophers, sociologists, and cognitive behavioral therapists, we propose a practical method which we call the total renal care (TRC) approach. With the TRC approach, we help patients and their families by adopting a psychosocial educational approach according to the stage of attitude toward their life with ESRD. In the predialysis care and even in the end-of-life process, selection of therapy based on the individual patient's life and their viewpoints on family care burden are important. This enables patients and their families to make selections for renal replacement therapy including home dialysis, renal transplantation, and dialysis discontinuation, as well as hemodialysis and peritoneal dialysis. Key Messages: ESRD is a lifelong disease, and acquiring psychological flexibility would benefit patients and lead to healthier outcomes. Sharing the notion of TRC with their caregivers would strengthen this.

Association between keeping home records of catheter exit-site and incidence of peritoneal dialysis-related infections.

PURPOSE: To prevent peritoneal dialysis (PD)-related infection, components of self-catheter care have been emphasized. However, studies on the effectiveness of home recording for the prevention of PD-related infections are limited. This study aimed to examine the association between keeping home records of catheter exit site and incidence of PD-related infections. METHODS: Home record books were submitted by patients undergoing PD. The proportion of days on which exit-site home recording was carried out for 120 days (0-100%) was obtained. The patients were divided into the frequent home recording group (≥ 40.5%; median value) and the infrequent home recording group (< 40.5%). The associations between the recording group and the incidence rate ratios (IRRs) of PD-related infections were estimated via negative binomial regression models. RESULTS: A total of 67 patients participated in this study (mean age, 66.7 years). The incidence rates for exit-site infection, tunnel infection, and peritonitis were 0.42, 0.22, and 0.06 times/patient-year, respectively. The IRRs of the frequent versus infrequent home recording groups for PD-related infection were 1.58 (95% confidence interval [CI], 0.72-3.46) in the univariate analysis and 1.49 (95% CI, 0.65-3.42) in the multivariate analysis. The IRRs of the frequent versus infrequent home recording groups for composite of surgery to create a new exit site and removal of PD catheter were 0.55 (95% CI, 0.78-3.88) and 0.35 (95% CI, 0.06-1.99), respectively. CONCLUSIONS: This study could not prove that keeping home records of patients' catheter exit site is associated with a lower incidence of PD-related infections.