A Case of Spontaneous Regression of Adult Multi-system Langerhans Cell Histiocytosis Presenting as Liver Tumor Rupture.

Adult multisystem Langerhans cell histiocytosis (MS-LCH) is rare and has a poor prognosis. A 67-year-old man with MS-LCH presented with a hepatic tumor rupture and multiple masses in the lungs, liver, and pancreas. Despite the initial aggressive disease course and involvement of organs at risk, the patient experienced spontaneous regression and lesion disappearance following smoking cessation without chemotherapy. A literature review revealed a distinct subset of MS-LCH that can be managed by smoking cessation and careful observation through follow-up imaging. This suggests that careful observation through follow-up imaging may be a reasonable alternative to chemotherapy in select adult cases of MS-LCH.

Epstein-Barr-Virus-Related Lymphoproliferative Disorder in a Patient With Primary Myelofibrosis: A Case Report and Literature Review.

Primary myelofibrosis (PMF) is a rare myeloproliferative neoplasm characterized by elevated platelet counts and fibrous tissues in the bone marrow. The JAK1/2 inhibitor (JAKi), ruxolitinib, has demonstrated efficacy in reducing splenic size, alleviating myelofibrosis-related symptoms, and improving overall survival. While an increased risk of lymphoproliferative disease (LPD) is suggested in patients with PMF, particularly those treated with JAKi, the involvement of Epstein-Barr virus (EBV) in such cases remains poorly documented. Here, we present the case of a 69-year-old woman with PMF who developed multiple lymphadenopathies and elevated soluble interleukin-2 receptor (sIL-2R) levels. Ruxolitinib and steroid therapy improved the symptoms for a short period; however, the lymphadenopathies and ascites eventually worsened. A biopsy confirmed EBV-positive diffuse large B-cell lymphoma, but the patient died of severe tumor lysis syndrome. Additionally, we conducted a literature review on EBV-related LPD in patients with primary and secondary myelofibrosis. Our report and literature review shed light on the occurrence of EBV-related LPD in MF, especially in those treated with JAKi, emphasizing the need to consider lymphoma as a potential diagnosis and monitor the EBV-DNA viral load in patients displaying lymphadenopathies or increased sIL-2R levels.

NK-cell post-transplant lymphoproliferative disease successfully treated by second allogenic hematopoietic stem cell transplantation in chronic active Epstein-Barr virus infection.

Chronic active Epstein-Barr virus infection (CAEBV) is a systemic T- or NK-lymphoproliferative disorder (LPD) caused by EBV. Allogenic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for CAEBV, but relapse sometimes occurs. Relapse is generally attributed to proliferation of recipient-derived CAEBV cells. We herein report a case of donor-derived CAEBV-like NK-cell post-transplant lymphoproliferative disease (PTLD) in a 41-year-old female after the first allogenic HSCT for CAEBV from an HLA-matched sibling donor. A second HSCT from an HLA-matched unrelated donor successfully controlled the disease, but EBV infection of cells derived from the second donor continued to be detected. Although the mechanisms underlying CAEBV and CAEBV-like NK-cell PTLD have not yet been elucidated in detail, the findings of the present case imply that host genetic factors, including familial factors, may be important in disease development.

Identification of an asymptomatic Shwachman-Bodian-Diamond syndrome mutation in a patient with acute myeloid leukemia.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive inherited disorder characterized by bone marrow failure, exocrine pancreatic dysfunction, and skeletal abnormalities. SDS is typically caused by a pathogenic mutation in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene. Patients with SDS have an increased risk of developing acute myeloid leukemia (AML) and myelodysplastic syndromes. We identified germline biallelic SBDS mutations (p.K62X and p.I167M) in a 50-year-old AML patient who had never experienced the typical symptoms of SDS. The K62X mutation is one of the most common pathogenic mutations, whereas the significance of the I167M mutation was unclear. Based on cellular experiments, we concluded that the I167M mutation contributed to the development of AML, and chemotherapy including topoisomerase inhibitors, which induce DNA double-strand breaks, may have been toxic to this patient. Our experience indicates that some asymptomatic Shwachman-Bodian-Diamond syndrome mutations contribute to the development of leukemia, and that careful treatment selection may be warranted for patients harboring these mutations.

Acquired hypofibrinogenemia in a patient with multiple myeloma.

We report a case of acquired hypofibrinogenemia with multiple myeloma presenting λ-type IgG monoclonal protein. The patient had anemia and renal deficiency, and also developed bleeding tendency due to severe coagulopathy. Her fibrinogen level was under the detectable limits in a functional assay. Enzyme-linked immunosorbent assay (ELISA) and immunoblotting analysis results were consistent with functional assay results, and deficiency patterns observed in cross-mixing tests for PT and aPTT confirmed the diagnosis of hypofibrinogenemia. To determine the cause of hypofibrinogenemia, we purified the patient's immunoglobulin via protein A agarose, and confirmed that fibrinogen was included in the bound fraction, strongly indicating paraprotein interference with fibrinogen. As accelerated removal of fibrinogen was indicated, we incubated the patient's plasma up to 48 h, but did not observe significant loss of fibrinogen. In sharp contrast, fibrinogen returned to below the detection level 12 h after infusion of fresh frozen plasma. These findings support leukocyte-mediated fibrinogen removal, rather than paraprotein-triggered fibrinogen instability. Surprisingly, the patient's paraprotein was IgG2, but we speculate the amount of paraprotein (IgG 5346 mg/dL) compensated for lower affinity to Fcγ receptors.

Borderline Case of TAFRO Syndrome and POEMS Syndrome.

TAFRO syndrome and POEMS syndrome are lymphoproliferative disorders with elevated interleukin-6 and vascular endothelial growth factor (VEGF) levels; however, their underlying pathogenic mechanisms remain unclear. Similarities have been reported in the pathological findings of the lymph nodes of TAFRO syndrome, Multicentric Castleman disease (MCD), and some cases of POEMS syndrome. However, there is no consensus on the relationship among them. We encountered a case of lymphoproliferative disorder that presented with manifestations of both TAFRO syndrome and POEMS syndrome. This case may be a subtype of idiopathic MCD and will be very important for establishing the disease concept of TAFRO syndrome and POEMS syndrome.

Efficacy of salvage therapy with MTX-HOPE for elderly patients with heavily pretreated non-Hodgkin's lymphoma.

Methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide (MTX-HOPE) chemotherapy was originally reported in 2007 as a salvage regimen for relapsed or refractory non-Hodgkin's lymphoma. To clarify the safety and efficacy of this regimen, we retrospectively analyzed patients at our institute. We analyzed 18 patients, including 16 with diffuse large B-cell lymphoma (DLBCL), one with follicular lymphoma (FL), and one with T-cell lymphoma. The median age at MTX-HOPE therapy was 79 (range: 68-87). Ten patients received more than 3 previous chemotherapy regimens. The median period from the initial treatment to the first MTX-HOPE administration was 53 months. No patient had severe renal dysfunction. The overall response rate was 78%, with 39% achieving CR and 39% achieving PR. The median OS and PFS after the initiation of MTX-HOPE were 10 months (range: 0.5-86 months) and 7 months (range: 0.2-86 months), respectively. The one-year OS rate was 44% and the two-year OS rate was 22%. The median number of treatment cycles was 7 (range: 1-46), and 6 patients received more than 10 cycles. Among eight patients who were over 80 years of age, 7 responded to the therapy, and the median OS and PFS of this subgroup were 19 months and 11 months, respectively. All patients tolerated the treatment well, mostly on an outpatient basis, except for one who died from infection and one who developed intracranial hemorrhage. MTX-HOPE may be a promising treatment option for elderly patients with refractory or relapsed malignant lymphoma.

Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia.

The WD40-containing E3 ubiquitin ligase RFWD3 has been recently linked to the repair of DNA damage by homologous recombination (HR). Here we have shown that an RFWD3 mutation within the WD40 domain is connected to the genetic disease Fanconi anemia (FA). An individual presented with congenital abnormalities characteristic of FA. Cells from the patient carrying the compound heterozygous mutations c.205_206dupCC and c.1916T>A in RFWD3 showed increased sensitivity to DNA interstrand cross-linking agents in terms of increased chromosomal breakage, reduced survival, and cell cycle arrest in G2 phase. The cellular phenotype was mirrored in genetically engineered human and avian cells by inactivation of RFWD3 or introduction of the patient-derived missense mutation, and the phenotype was rescued by expression of wild-type RFWD3 protein. HR was disrupted in RFWD3-mutant cells as a result of impaired relocation of mutant RFWD3 to chromatin and defective physical interaction with replication protein A. Rfwd3 knockout mice appear to have increased embryonic lethality, are subfertile, show ovarian and testicular atrophy, and have a reduced lifespan resembling that of other FA mouse models. Although RFWD3 mutations have thus far been detected in a single child with FA, we propose RFWD3 as an FA gene, FANCW, supported by cellular paradigm systems and an animal model.

RFWD3-Mediated Ubiquitination Promotes Timely Removal of Both RPA and RAD51 from DNA Damage Sites to Facilitate Homologous Recombination.

RFWD3 is a recently identified Fanconi anemia protein FANCW whose E3 ligase activity toward RPA is essential in homologous recombination (HR) repair. However, how RPA ubiquitination promotes HR remained unknown. Here, we identified RAD51, the central HR protein, as another target of RFWD3. We show that RFWD3 polyubiquitinates both RPA and RAD51 in vitro and in vivo. Phosphorylation by ATR and ATM kinases is required for this activity in vivo. RFWD3 inhibits persistent mitomycin C (MMC)-induced RAD51 and RPA foci by promoting VCP/p97-mediated protein dynamics and subsequent degradation. Furthermore, MMC-induced chromatin loading of MCM8 and RAD54 is defective in cells with inactivated RFWD3 or expressing a ubiquitination-deficient mutant RAD51. Collectively, our data reveal a mechanism that facilitates timely removal of RPA and RAD51 from DNA damage sites, which is crucial for progression to the late-phase HR and suppression of the FA phenotype.

Impact of high-dose chemotherapy and autologous transplantation as first-line therapy on the survival of high-risk diffuse large B cell lymphoma patients: a single-center study in Japan.

High-dose chemotherapy (HDT), together with autologous stem cell transplantation (ASCT), plays an important role in the treatment of diffuse large B cell lymphoma (DLBCL), especially as second-line therapy. However, its significance in up-front settings remains to be elucidated. In our institute, patients with DLBCL in both the high-intermediate and high international prognostic index (IPI) groups initially underwent CHOP/R-CHOP treatment followed by HDT/ASCT at upfront settings between 2002 and 2011. We retrospectively analyzed 25 patients who were all treated with upfront HDT/ASCT. We excluded one patient who failed to undergo transplantation because of primary refractory disease from the analysis. The median follow-up was 77 months (range 17-110 months). Five-year overall survival (OS) and progression-free survival (PFS) were 91.7 and 79.2 %, respectively, which were higher than the equivalents in previous studies. The OS and PFS in the high-risk group were lower than those in the high-intermediate group. Treatment-related mortalities or fatal complication were not observed. Our results confirm that HDT/ASCT for high-risk aggressive lymphoma is a feasible and promising therapy, but patients with high IPI continued to have poor prognoses; improvements in treatment strategy are clearly needed. Since HDT/ASCT is an aggressive treatment option associated with long-term complications, we need to identify patient groups that will gain the maximum benefit from HDT/ASCT in the upfront setting.

Immune reconstitution inflammatory syndrome mimics a relapse of AIDS-related Burkitt lymphoma.

Immune reconstitution inflammatory syndrome (IRIS) is associated with clinical manifestations that can overlap with the patients with acquired immunodeficiency disease (AIDS)-related non-Hodgkin's lymphoma. We herein report a case of AIDS-related Burkitt lymphoma which was successfully treated with dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, and prednisone (EPOCH). However, the patient developed a lymphoma-like clinical presentation shortly after the conclusion of chemotherapy. The patient's symptoms were identical to the initial symptoms characteristic of lymphoma; however, the laboratory data revealed no evidence of a relapse of Burkitt lymphoma. A bone marrow examination showed T-cell clonality, even though there were no signs of any progression of the lymphoma. The patient was diagnosed with IRIS, and the clinical manifestations rapidly improved following treatment.

Male gonadotroph adenoma: report of three cases and a review of the literature.

We herein report three cases of gonadotroph adenoma in men (36-72 years of age) presenting with visual impairment and suprasellar masses measuring approximately 20 to 30 mm in diameter. Endocrinological examinations were normal, except for slightly increased follicle stimulating hormone (FSH) levels in two cases. Based on the tentative diagnosis of non-functioning pituitary adenoma, transsphenoidal surgery was performed, which revealed that the tumors consisted of FSH- and LH-positive cells. As gonadotroph adenoma is very common among patients with clinically silent pituitary adenoma, it should be diagnosed using pathological examinations.

Combination therapy of voriconazole and terbinafine for disseminated fusariosis: case report and literature review.

Fusarium spp. cause a broad spectrum of infection and are relatively resistant to most antifungal agents, leading to unfavorable prognosis, especially in immunocompromised patients. Several reports have shown synergism among amphotericin B, voriconazole (VRC), terbinafine (TRB), and other antifungal agents in vitro, but the most efficacious combination remains to be elucidated. We report the first case of disseminated Fusarium solani infection successfully treated by combination therapy of VRC and TRB accompanied by surgical resection of endocardial lesions. We also review 15 case reports of combination antifungal therapy for fusariosis and 6 case reports of Fusarium endocarditis.

Abrupt evolution of Philadelphia chromosome-positive acute myeloid leukemia in myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) is a clonal disorder arising from an alteration in multipotent stem cells, which lose the ability of normal proliferation and differentiation. Disease progression occurs in approximately 30% MDS cases. Specific chromosomal alterations seem responsible for each step in the evolution of acute myeloid leukemia (AML). Multiple genetic aberrations occur during the clonal evolution of MDS; however, few studies report the presence of the Philadelphia (Ph) chromosome. We report a rare case of Ph-positive AML, which evolved during the course of low-risk MDS. The patient, a 76-year-old man with mild leukocytopenia, was diagnosed with MDS, refractory neutropenia (RN). After 1.5 yr, his peripheral blood and bone marrow were suddenly occupied by immature basophils and myeloblasts, indicating the onset of AML. A bone marrow smear showed multilineage dysplasia, consistent with MDS evolution. Chromosomal analysis showed an additional t(9;22)(q34;q11) translocation. Because progression occurred concurrently with emergence of the Ph chromosome, we diagnosed this case as Ph-positive AML with basophilia arising from the clonal evolution of MDS. The patient was initially treated with nilotinib. A hematological response was soon achieved with disappearance of the Ph chromosome in the bone marrow. Emergence of Ph-positive AML in the course of low-risk MDS has rarely been reported. We report this case as a rare clinical course of MDS.

[Serial FDG-PET evaluation of a patchy pattern of hematopoiesis at diagnosis in aplastic anemia].

We investigated the hematopoietic status of aplastic anemia with FDG-PET before and after immunosuppressive therapy. FDG-PET showed a patchy uptake pattern before treatment, indicating residual compensatory hypercellular marrow. Three years after successful treatment with ATG plus CsA, the heterogeneity of bone marrow uptake persisted, suggesting that expanded reconstitution of hematopoiesis may require a long time even after the achievement of hematological remission.

Successful treatment with combined chemotherapy of two adult cases of hemophagocytic lymphohistiocytosis in recipients of umbilical cord blood cell transplantation.

Hemophagocytic lymphohistiocytosis (HLH), which occurs during the early period following allogeneic hematopoietic stem cell transplantation (HSCT), is often difficult to diagnose. It is characterized by severe clinical manifestations and high mortality. Despite current therapeutic approaches, outcomes remain poor. Here, we summarize the cases of two patients who experienced engraftment failure and subsequently developed hematopoietic stem cell transplantation-hemophagocytic lymphohistiocytosis (HSCT-HLH). Both patients had high-risk hematological malignancies for which they underwent umbilical cord blood transplantation (UCBT) at our institution. Based on the presence of massive hemophagocytosis in their bone marrow specimens and the results of chimerism analysis, diagnosis of HSCT-HLH was made in both cases. A single infusion of low-dose etoposide was administered immediately to each patient. Four days after the injection, therapeutic efficacy was evaluated. As both cases showed an insufficient response to etoposide, we added vincristine and a medium dose of prednisolone. Clinical symptoms rapidly improved and stable engraftments were observed within a week. The first and second patients were alive 1008 and 232 days after UCBT, respectively. The combined use of low-dose etoposide and vincristine plus prednisolone appears to be a promising treatment option for HSCT-HLH, without serious adverse side effects.