Prognostic factors of idiopathic hypereosinophilic syndrome: A nationwide survey in Japan.

Idiopathic hypereosinophilic syndrome (iHES) is a condition wherein persistent hypereosinophilia associated with end-organ damage occurs without any known causes. Due to the rarity of the disease, insufficient knowledge has been accumulated. We therefore conducted a retrospective, multicentre, nationwide survey on iHES in Japan. A total of 57 patients were identified. For 43 patients who received any treatment, all cases were first treated with corticosteroids. An eosinophil percentage of less than 30% in the bone marrow and the absence of oedema were identified as factors associated with steroid dependency. The 5-year overall survival was 88.2%, and five patients died during follow-up; factors associated with worse overall survival were age >50, haemoglobin <12 g/dL, activated partial thromboplastin time >34 s, the presence of dyspnoea, the presence of thrombotic tendency and the presence of renal failure. Given the rarity of fatalities in our cohort, time-to-next-treatment (TTNT) was further analysed; the presence of renal failure, splenomegaly and lung abnormalities were associated with worse TTNT. Our nationwide study not only demonstrated clinical characteristics and the outcome of patients with iHES but also for the first time revealed clinical factors associated with steroid dependency and duration of first-line corticosteroid efficacy.

Erdheim-Chester disease: consensus recommendations for evaluation, diagnosis, and treatment in the molecular era.

Erdheim-Chester disease (ECD) is a rare histiocytosis that was recently recognized as a neoplastic disorder owing to the discovery of recurrent activating MAPK (RAS-RAF-MEK-ERK) pathway mutations. Typical findings of ECD include central diabetes insipidus, restrictive pericarditis, perinephric fibrosis, and sclerotic bone lesions. The histopathologic diagnosis of ECD is often challenging due to nonspecific inflammatory and fibrotic findings on histopathologic review of tissue specimens. Additionally, the association of ECD with unusual tissue tropism and an insidious onset often results in diagnostic errors and delays. Most patients with ECD require treatment, except for a minority of patients with minimally symptomatic single-organ disease. The first ECD consensus guidelines were published in 2014 on behalf of the physicians and researchers within the Erdheim-Chester Disease Global Alliance. With the recent molecular discoveries and the approval of the first targeted therapy (vemurafenib) for BRAF-V600-mutant ECD, there is a need for updated clinical practice guidelines to optimize the diagnosis and treatment of this disease. This document presents consensus recommendations that resulted from the International Medical Symposia on ECD in 2017 and 2019. Herein, we include the guidelines for the clinical, laboratory, histologic, and radiographic evaluation of ECD patients along with treatment recommendations based on our clinical experience and review of literature in the molecular era.

Clinical usefulness of a novel classification of T cell distribution patterns in the tumor microenvironment of follicular lymphoma to detect transformation.

The clinical course of follicular lymphoma (FL) is thought to be influenced by the infiltrating immune cells in the tumor microenvironment. Focusing on the distribution patterns of T cells may be a promising approach to estimate the prognosis of FL, especially histological transformation. This study was a retrospectively cohort study in the relationship between the pathological distribution pattern of T cells in the tumor microenvironment and clinical course of FL. One hundred twenty-eight patients with FL initially diagnosed at the University of Tokyo Hospital from January 2008 to January 2017 were evaluated. We classified each patient's specimen at initial diagnosis by the distribution pattern of tumor infiltrating CD3-positive cells, intra-follicle focal (IFF), intra-follicle diffuse (IFD), extra-follicle marginal (EFM), and extra-follicle diffuse (EFD). We analyzed the distribution pattern's correlation with other prognostic factors including overall survival (OS), progression free survival (PFS), and transformation. Among 128 cases, 81 had evaluable pathological specimen. Based on our criteria, in the intra-follicle,17 cases (21%) were classified as IFF. Sixty-four cases (79%) were classified as IFD. In the extra follicle, 25 cases (31%) were classified as EFM. Fifty-six cases (69%) were classified as EFD. There was significant difference in risk of transformation between the EFM and EFD around extra-follicle area in the adjusted model (p < 0.05). Also, cases with IFF and EFM had significantly higher risk of transformation compared to cases with other T cell distribution patterns (p < 0.01). We proposed a new classification of CD3-positive T cell distribution patterns around the follicle lesions in FL and demonstrated its clinical significance.

Successful treatment of pneumonia caused by multidrug-resistant Pseudomonas aeruginosa after allogeneic hematopoietic stem cell transplantation with colistin and amikacin inhalation therapy.

Pseudomonas aeruginosa is a Gram-negative bacillus that often causes severe infections during immunosuppression in patients with hematologic malignancies. P. aeruginosa can easily acquire drug resistance, and often develops into multidrug-resistant P. aeruginosa (MDRP). Although many antibiotics are used in combination to treat MDRP infections, colistin and amikacin are less likely to be transferred to the lungs, and inhalation therapy may be used. Herein, we report a Case of pneumonia caused by MDRP after allogeneic hematopoietic stem cell transplantation (HSCT) treated with inhaled colistin and amikacin. This 61-year-old female patient was diagnosed with myelodysplastic syndromes and underwent allogeneic HSCT from an 8/8 HLA-matched unrelated donor after reduced-intensity conditioning. On the day of the stem cell infusion, the patient's sputum culture was found to be positive for MDRP. The patient subsequently developed bacteremia, pneumonia, and lung abscess caused by MDRP, and we administered multidrug antibiotic therapy including colistin and amikacin inhalation therapy. The patient's blood cultures were subsequently turned negative, and the lung abscess disappeared. To our knowledge, this is the first case of MDRP pneumonia after HSCT in which colistin and amikacin inhalation therapy was effective.

Reduction of cycles of bendamustine plus rituximab therapy in the cases with good response for indolent B-cell lymphomas.

Bendamusutine plus rituximab (BR) regimen is one of the standard regimens for indolent B-cell lymphomas, yet the possibility of reduction of cycles of BR therapy without compromising therapeutic effects is not still uncovered. We retrospectively surveyed 57 cases including 40 follicular lymphoma cases who underwent BR regimen in our institute. The overall response (OR) rate and complete response (CR) rate were 86.0% (95% confidential interval (CI), 74.2-93.7) and 54.4% (40.7-67.6), respectively. Five-year overall survival (OS) and 5-years progression-free survival (PFS) were 76.8% and 45.7%, respectively. We then grouped the patients by the number of administered cycles of BR regimen. PFS was significantly longer in 41 cases of the later cessation group (cycle 4-6) than in 16 cases of the earlier cessation group (cycle 1-3) (p = 0.012, 5-years PFS; 46.8% vs. 35.2%, respectively), and both of OR and CR rate of the former was better than the latter (OR rate; 95.1% vs. 62.5%, p < 0.01, CR rate; 61.4% vs. 31.3%, p = 0.04). Interestingly PFS of twenty-one (36.8%) cases receiving just 4 cycles was longer than that of 20 cases who received five or 6 cycles (p < 0.01, 5-years PFS; 71.8% vs. 23.2%, respectively). Focusing on the group of four cycles, the 12 case with CR revealed longer PFS than seven cases with partial response (PR), and median PFS was not reached in CR cases and 16.9 months in the PR cases (p < 0.01). These results suggest that four cycles at least should be administered if possible, and the outcome of the patients who discontinued BR after four cycles was not inferior to that of the cases who received five or six cycles. In conclusion, discontinuation after four cycles may be permissible in some cases with complete response to BR regimen.

Risk factors for early in-hospital death in patients who developed coagulopathy during induction therapy for acute promyelocytic leukemia: a nationwide analysis in Japan.

To prevent early death, management of coagulopathy is important in patients with untreated acute promyelocytic leukemia (APL). This study aimed to clarify factors associated with in-hospital death in patients with coagulopathy during induction therapy for APL. We retrospectively identified patients with newly diagnosed APL who received induction therapy including all-trans retinoic acid (ATRA) and developed coagulopathy, using a nationwide inpatient database in Japan. Of 1115 eligible patients, 175 (15%) died at a median of 13 days (interquartile range, 7-30) after admission. In the multivariable analysis, compared with younger patients (aged < 40 years), the occurrence of in-hospital death was significantly more common among older patients (aged ≥ 40 and < 60 years: odds ratio = 2.58 [95% confidence interval: 1.29-5.19]; aged ≥ 60 and < 80 years: 7.66 [3.89-15.10]; aged ≥ 80 years: 16.83 [7.41-38.21]). Delayed initiation of ATRA and no conventional chemotherapy were significantly associated with in-hospital death (1.79 [1.16-2.76] and 2.40 [1.47-3.92], respectively). A total of 699 patients (63%) received anticoagulant therapies, but none of these was significantly associated with lower mortality. Although the present study was constrained by a lack of laboratory findings because of database limitations, the results showed that untreated patients with APL, especially the elderly, had a poor prognosis. Immediate administration of ATRA may reduce in-hospital mortality.

Difference of preventing effects of G-CSF according to age in patients with malignant lymphoma: A nation-wide analysis in Japan.

INTRODUCTION: There has been no comprehensive analysis of the age-specific efficacy of G-CSF to prevent febrile neutropenia (FN). We evaluated factors associated with FN occurrence according to patient age in rituximab-cyclophosphamide-doxorubicin-vincristine-prednisolone (R-CHOP) treatment. METHODS: We retrospectively reviewed diffuse large B-cell lymphoma (DLBCL) patients aged ≥50 years, who underwent the first R-CHOP cycle between July 2010 and March 2017, using a Japanese inpatient database. Multivariable logistic regression analysis was performed to identify the factors associated with FN. RESULTS: A total of 16,399 patients with untreated DLBCL were identified. Primary prophylaxis with pegfilgrastim was significantly associated with the lower occurrence of FN (odds ratio: 0.71 [95% confidence interval: 0.51-0.99]). Subgroup analysis according to age was then performed. Although there was no significance, primary prophylaxis with pegfilgrastim tended to have a lower odds ratio for the occurrence of FN in patients aged 50-60 years (0.86 [0.39-1.89]) and 61-70 years (0.64 [0.36-1.13]). In patients aged 71-80 years, primary prophylaxis with pegfilgrastim was significantly associated with reduced FN occurrence (0.46 [0.26-0.80]). Notably, in patients aged >80 years, the use of pegfilgrastim tended to be associated with a rather higher occurrence of FN (1.55 [0.84-2.87]). CONCLUSIONS: Preventing effect of G-CSF may be limited in patients aged >80 years.

Posterior reversible encephalopathy syndrome concurrent with human herpesvirus-6B encephalitis after allogeneic hematopoietic stem cell transplantation.

Posterior reversible encephalopathy syndrome (PRES) and human herpesvirus (HHV)-6 encephalitis are both serious neurological complications post hematopoietic stem cell transplantation. Although infection is one of the important causes of PRES, only few cases have reported the relation between PRES and viral infection. Herein, we report the first adult case of PRES concurrent with HHV-6 encephalitis after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia. This case suggests that HHV-6 reactivation is associated with the pathogenesis of PRES. Also, PRES and HHV-6 encephalitis cause similar symptoms, and switching the immunosuppressant from calcineurin inhibitor to prednisolone for treating PRES may worsen HHV-6 encephalitis. Therefore, we should pay attention to the complication of HHV-6 encephalitis even after PRES is diagnosed.

Development and internal validation of a risk scoring system for gastrointestinal events requiring surgery in gastrointestinal lymphoma patients.

BACKGROUND AND AIM: The predictors of severe gastrointestinal (GI) events in GI lymphoma patients are unclear. We aimed to develop a risk scoring system for GI events requiring surgery. METHODS: In this retrospective study of 192 patients with GI lymphoma, the state of lymphoma, macroscopic findings, examination results, and International Prognostic Index were assessed. We developed a risk score for GI events that required surgery and assessed its accuracy by calculating the area under the receiver operating characteristic curve (AUC). Internal validation was performed using bootstrap resampling. RESULTS: Severe GI events occurred in 21 (11%) patients. We developed a 4-point scoring system (the FLASH score) comprising the following three independent predictors (weighted by regression coefficients): (i) focal appearance and large size (≥ 40 mm), 1 point; (ii) aggressive lymphoma of the small bowel, 2 points; and (iii) high (18)F-fluorodeoxyglucose positron emission tomography uptake, 1 point. The score predicted severe GI events with an AUC value of 0.91 (internal validation; AUC, 0.86). Risk was classified into three categories: the GI event rate was 0% in the low-risk group (0 points), 9% in the intermediate-risk group (1-2 points), and 61% in the high-risk group (3-4 points) (AUC, 0.89). CONCLUSIONS: We developed and internally validated a risk scoring system (the FLASH score) that included macroscopic findings to predict severe GI events in GI lymphoma patients. Patients with high scores are candidates for elective surgery to prevent GI events.

Prognostic factors of Erdheim-Chester disease: a nationwide survey in Japan.

Erdheim-Chester disease is a rare histiocytosis with insufficient clinical data. To clarify the clinical features and prognostic factors of Erdheim-Chester disease, we conducted a nationwide survey to collect the detailed data of 44 patients with Erdheim-Chester disease in Japan. The median age of onset of the participants was 51 (range: 23-76) years, and the median number of involved organs per patient was 4 (range: 1-11). The existence of central nervous system disease was correlated with older age (P=0.033), the presence of cardiovascular lesions (P=0.015), and an increased number of involved organs (P=0.0042). The median survival from the onset was 10.4 years, and >3.0 mg/dL C-reactive protein level at onset was associated with worse outcome (median survival, 14.6 vs. 7.4 years; P=0.0016). In a multivariate analysis, age >60 years (hazard ratio, 25.9; 95% confidence interval, 2.82-237; P=0.0040) and the presence of digestive organ involvement (hazard ratio, 4.74; 95% confidence interval, 1.05-21.4; P=0.043) were correlated with worse survival. Fourteen patients had available histological samples of Erdheim- Chester disease lesions. BRAFV600E mutation was detected in 11 patients (78%) by Sanger sequencing. A correlation between BRAF mutation status and clinical factors was not observed. Our study revealed that age and digestive organ involvement influence the outcome of Erdheim-Chester disease patients, and an inflammatory marker, such as C-reactive protein, might reflect the activity of this inflammatory myeloid neoplasm.

Three cases of Candida fermentati fungemia following hematopoietic stem cell transplantation.

Bloodstream infection with non-Candida albicans Candida species is one of the serious complications among patients with hematological malignancies who receive long-term prophylactic antifungal agents. Here we describe three cases of Candida fermentati (C. fermentati) candidemia after allogeneic stem cell transplantation for hematological malignancies. Case 1 is fluconazole-breakthrough C. fermentati fungemia, which was well controlled with liposomal amphotericin B. Case 2 and 3 were caspofungin-breakthrough C. fermentati fungemia. In case 2, blood culture turned negative for Candida responding to liposomal amphotericin B. Although in vitro susceptibility data for the isolated pathogen suggested the efficacy of both caspofungin and liposomal amphotericin B in all three cases, clinically liposomal amphotericin B seemed to have been more effective for eradication of the pathogen from blood stream. C. fermentati needs to be considered as a possible cause for breakthrough candidemia among post-transplant patients with prolonged antifungal prophylaxis. Discrepancy between in vitro and in vivo susceptibility to antifungals, especially to echinocandins, might provide a clue for the optimal choice of antifungals for C. fermentati infections.

A therapeutic benefit of daptomycin against glycopeptide-resistant gram-positive cocci bloodstream infections under neutropenia.

Antibiotic-resistant infections remain to be a major issue for all over the world. Although appropriate diagnosis and rapid treatment initiation are crucially important particularly in immunocompromised patients, selection of antibiotics without identification of causative bacteria is often challenging. A 44-year-old woman with acute myeloid leukemia (AML) under myelosuppression suffered from teicoplanin-resistant gram-positive cocci bacteremia. Taking severe neutropenia due to chemotherapy and glycopeptide-resistance into account, teicoplanin was empirically substituted with daptomycin, which led to prompt defervescence. This microorganism later turned out to be Leuconostoc lactis (L. Lactis), and daptmycin was continued to use based on antimicrobial susceptibility tests. As a result, empiric use of daptomycin successfully controlled glycopeptide-resistant gram-positive cocci bacteremia under neutropenia. This is the first report of daptomycin treatment for L. lactis bacteremia in a patient with AML under neutropenia. Our findings suggest that daptomycin would be a suitable treatment option for glycopeptide-resistant gram-positive cocci bloodstream infections, especially in myelosuppressive patients.

Rare Co-occurrence of Spinal Cord Hemorrhage from Radiation-induced Cavernous Hemangioma and Classical Hodgkin Lymphoma Post-transplant Lymphoproliferative Disorder.

Post-transplant lymphoproliferative disorders (PTLDs) are lymphoproliferative diseases that occur after solid organ transplantation or hematopoietic stem cell transplantation (HSCT). The development of PTLD is often associated with reactivation of Epstein-Barr virus (EBV). A 26-year-old woman with a history of HSCT and total-body irradiation developed spinal cord hemorrhage from a radiation-induced cavernous hemangioma (RICH) shortly after the development of classical Hodgkin lymphoma PTLD with EBV reactivation. Although little is known about the factors leading to hemorrhagic events from spinal cord RICH, we suspect that EBV reactivation may have been a factor contributing to the hemorrhage in the present case.

A case of thymoma showing significant tumor reduction after anti-thymocyte globulin.

A 71-year-old female with type B3 thymoma developed severe aplastic anemia. Anti-thymocyte globulin was administered with glucocorticoids and cyclosporin A as the treatment for aplastic anemia. Computed tomography scan revealed that thymoma apparently shrank and remained without regrowth for at least 7 months. As previously reported, glucocorticoid has therapeutic effects on thymoma especially with abundant lymphocytes. Anti-thymocyte globulin also depletes peripheral lymphocytes, but its efficacy in the treatment of thymoma is unknown. Anti-thymocyte globulin and glucocorticoids may have cooperated with each other in reducing thymoma in our case. More cases should be accumulated to elucidate the effects of anti-thymocyte globulin on thymoma.

Treatment of Secondary Immune Thrombocytopenia with Non-Hodgkin Lymphoma: A Case Report and Literature Review.

Secondary immune thrombocytopenic purpura (ITP) with non-Hodgkin lymphoma (NHL) is a rare disease. Although some treatment regimens are available for primary ITP, the treatment strategy for secondary ITP remains unconfirmed. We herein report a 79-year-old man who was diagnosed with secondary ITP with mantle cell lymphoma. Although intravenous immunoglobulin (IVIG) has been considered an effective option for secondary ITP, similar to the treatment of primary ITP, our patient did not benefit from IVIG. A literature review including the current report revealed that IVIG was ineffective in all treated patients. Secondary ITP with NHL should be treated differently from primary ITP.

Serial assessments of anterior pituitary hormones in a case of mixed histiocytosis representing Langerhans cell histiocytosis overlapping with Erdheim-Chester disease.

SUMMARY: A 61-year-old man developed central diabetes insipidus caused by mixed histiocytosis (MH) representing Langerhans cell histiocytosis overlapping with Erdheim-Chester disease. Bone, skin, vascular, and retroperitoneal involvements were also observed. Dynamic hormonal testing showed normal responses for anterior pituitary hormones, except for impaired secretion of growth hormone (GH). MRI of the brain showed thickening of the pituitary stalk with slightly reduced signal hyperintensity in the posterior pituitary lobe on T1-weighted imaging. During 2 years of follow-up without radical treatment for MH, imaging studies suggested extension of vascular and retroperitoneal involvements. In contrast, brain MRI did not show any particular interval changes, except for the disappearance of hyperintense signalling in the posterior pituitary lobe. Moreover, no other anterior pituitary dysfunctions beyond GH deficiency emerged during the 2 years of follow-up. The natural history of MH in this case is described, focusing on serial assessments of pituitary functions using dynamic tests. LEARNING POINTS: Erdheim-Chester disease and Langerhans cell histiocytosis overlapping as MH was described, focusing on pituitary functions. MH caused both GH deficiency and central diabetes insipidus. Despite a lack of radical therapy for MH, no other anterior pituitary dysfunctions emerged for 2 years. Radiological images showed no particular interval changes in pituitary stalk lesions, while vascular and retroperitoneal involvements extended.