[MYC gene amplification attributed to double minutes in a patient with atypical chronic myeloid leukemia].

A 61-year-old man was admitted to our hospital with fever and massive leukocytosis. A bone marrow smear revealed an increased density of myeloid cells in various stages of maturation as well as dysplasia in the neutrophils. There was no proliferation of blasts, eosinophils, or basophils. Genomic analysis of the bone marrow cells revealed no detectable abnormalities associated with myeloproliferative neoplasms, including BCR-ABL1. Therefore, the patient was diagnosed with atypical chronic myeloid leukemia (aCML). Chromosomal analysis revealed the presence of 1-17 double minute chromosomes (dmin) in 20 of 20 tumor cells examined. Multiple MYC signals were detected via interphase fluorescence in situ hybridization, indicating MYC gene amplification in the dmins. Three months after the oral administration of hydroxyurea, leukocytosis reoccurred. Therefore, induction therapy followed with umbilical cord blood transplantation was performed. However, MYC signals remained detectable in the bone marrow sample obtained immediately after neutrophil engraftment, indicating the presence of residual tumor cells. To the best of our knowledge, this is the first case report of aCML with dmin gene amplification, suggesting that the dmin MYC amplification exacerbated the patient's disease.

[Essential thrombocythemia correctly diagnosed through the guidance of comprehensive genomic profiling].

In 2003, a 60-year-old man presenting with thrombocytosis was referred to our hospital. Laboratory tests revealed normal white blood cell count and hemoglobin level. Bone marrow examination showed an increased number of megakaryocytes with dysplasia. G-banded karyotype analysis revealed del (5q). Initially, the patient was diagnosed with myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and it was treated with aspirin and hydroxyurea. During the treatment course, fluorescence in situ hybridization for CSF1R and EGR1 was performed to detect del (5q), which showed negative results. In 2017, the patient had increased platelet count despite receiving treatment. A comprehensive genomic profiling revealed that the deleted region in this case was present in 5q14-5q23, which was different from the common deleted region of 5q- syndrome (5q32-5q33, where CSF1R was present) and that of high-risk MDS or acute myeloid leukemia (5q31, where EGR1 was present). Moreover, a CALR mutation was also detected. This case met the diagnostic criteria of essential thrombocythemia. The platelet count decreased with the administration of anagrelide. In conclusion, comprehensive genetic profiling is very important, and it leads to accurate diagnosis and therapy.

Successful treatment with bortezomib and dexamethasone for proliferative glomerulonephritis with monoclonal IgG deposits in multiple myeloma: a case report.

BACKGROUND: Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a form of renal involvement by monoclonal IgG deposits that was found in mesangial, subendothelial or subepithelial regions. The distribution of glomerular deposits was completely different from that in monoclonal immunoglobulin deposition disease. PGNMID is reported to be rarely associated with a hematological malignancy. Previously, only five cases of PGNMID with multiple myeloma have been reported. However, the pathogenic relationship between PGNMID and multiple myeloma was unclear because a detailed description was not provided. We report that a patient with PGNMID associated with multiple myeloma was treated with bortezomib and dexamethasone and underwent the second renal biopsy after treatment, showing that chemotherapy was effective for PGNMID clinically and pathologically. CASE PRESENTATION: A 75-year-old man presented with progressive leg edema, had nephrotic range proteinuria, hypoalbuminemia, moderate renal failure, and occult blood in his urine. Electrophoresis results showed serum and urinary monoclonal spikes of IgGκ type immunoglobulin. A renal biopsy specimen showed lobular mesangial proliferation with mesangiolysis, glomerular micro-aneurysm, and endocapillary hypercellularity. Immunofluorescence results revealed strong granular capillary and mesangial staining for IgG1, C3 and κ light chain in glomeruli without tubular deposits of any immunoglobulin. Electron microscopy also showed dense granular deposits in subendothelial and mesangial areas. PGNMID associated with multiple myeloma (IgGκ type) was diagnosed on the basis of a subsequent bone marrow examination. Bortezomib and dexamethasone therapy significantly reduced proteinuria and elevated serum albumin level. Eight months later, the second renal biopsy showed no active lesions and that the IgG1 and κ light chain deposits had drastically disappeared. CONCLUSIONS: This is the first case of PGNMID with multiple myeloma successfully treated with bortezomib and dexamethasone in which comparative renal biopsies were performed before and after treatment. Our findings suggest the pathogenesis of PGNMID and therapeutic options for PGNMID.

[Durable remission attained by long-term brentuximab vedotin administration in a relapsed post-allogeneic bone marrow transplant Hodgkin lymphoma patient].

The prognosis for relapsed Hodgkin lymphoma after allogeneic hematopoietic cell transplantation (HSCT) is poor, partly because of limited treatment options. Here we present a case of a Hodgkin lymphoma patient who relapsed after allogeneic HSCT but remains in complete remission (CR) at 38 months from the start of extended brentuximab vedotin (BV) dosing. A 33-year-old man with refractory and relapsed nodular sclerosis classical Hodgkin lymphoma who underwent previous treatments, including adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) ; seven combination regimens; and autologous HSCT, prior to allogeneic HSCT achieved CR after three cycles of BV. BV was continued for 26 cycles and then discontinued because of a neurogenic bladder. The other adverse effects were mild paresthesia in the fingers, mild dysgeusia, and fatigue. The patient still remains in CR at 38 months from the start of BV. Thus, extended BV dosing may be a treatment option for relapsed and refractory Hodgkin lymphoma after allogeneic HSCT.

Long-term follow-up results of a phase I/II study of melphalan, prednisolone and bortezomib in Japanese transplant-ineligible multiple myeloma patients (JPN-102).

The phase I/II study of melphalan-prednisolone-bortezomib (MPB) therapy in Japanese patients with previously untreated multiple myeloma (MM) who are ineligible for hematopoietic stem cell transplantation (JPN-102 trial) (registered between July 2008 and March 2011) showed an overall response rate in the MPB arm equivalent to that of the VISTA trial. In this study, we followed up the clinical data of 92 of the 101 patients registered in the JPN-102 trial to clarify the long-term outcomes of MPB therapy. The median follow-up period was 50.8 (0.9-66.1) months. The median age of this cohort was 72 (48-84) years. The median progression-free survival was 25.7 (95%CI: 21.3-33.9) months and the overall survival rates at 1, 3 and 5 years were 98, 86 and 76%, respectively. There was no significant difference in either progression-free survival or overall survival when comparing a total bortezomib amount of 39 mg/m2 or more being administered versus less than 39 mg/m2. The outcomes of the JPN-102 cohort appeared, at a minimum, to not be inferior to those of the MPB cohort in the VISTA trial. A prospective trial is needed to establish the MPB regimen as being suitable for Japanese patients with multiple myeloma.

Serum IgA level, monocyte count, and international prognostic index are independently associated with overall survival in patients with HTLV-I-negative nodal peripheral T cell lymphoma.

Peripheral T cell lymphomas (PTCL) account for 10-15 % of non-Hodgkin's lymphomas and are associated with poor prognosis. Although many prognostic factors for PTCL have been proposed, the heterogeneity of PTCL seems to be an obstacle in the establishment of clinically useful prognostic system, such as the International Prognostic Index (IPI) in diffuse large B cell lymphoma. PTCL with nodal manifestation include the HTLV-I-negative histologic subtypes of PTCL not otherwise specified (PTCL-NOS), angioimmunoblastic T cell lymphoma (AITL), and anaplastic large cell lymphoma (ALCL). As PTCL-NOS encompasses a group of similar tumors and mostly shares their clinical pictures, we retrospectively analyzed clinical data from 77 patients diagnosed with ALCL, AITL, and PTCL-NOS at Kobe City Medical Center General Hospital from May 1994 to February 2012 to identify the prognostic factor for nodal PTCL. The median age of patients was 64 years, ranging from 23 to 83 years. With a median follow-up of 50 months, 5-year overall survival (OS) was 43 %. Multivariate analysis identified high-risk IPI (hazard ratio (HR), 4.04; P = 0.015), absolute monocyte count > 0.8 × 10(9)/L (HR, 3.44; P = 0.001), and serum concentration of IgA > 410 mg/dL (HR, 2.31; P = 0.013) as poor prognostic factors for OS. Thus, we have identified novel prognostic factors of monocyte count and serum IgA level for nodal PTCL. Although conventional prognostic models mainly reflect both tumor characteristics and host factors, the present model indicates the importance of host immune response as the unfavorable prognosis.

IP-10/CXCL10 and MIG/CXCL9 as novel markers for the diagnosis of lymphoma-associated hemophagocytic syndrome.

Lymphoma-associated hemophagocytic syndrome (LAHS) is a serious disorder, and its early diagnosis and treatment with appropriate chemotherapy are very important. However, reliable markers for early diagnosis of LAHS have not been identified. We screened serum cytokines using a newly introduced assay system, cytometric bead array (CBA), and identified interferon-inducible protein 10 (IP-10)/CXCL10 and monokine induced by interferon gamma (MIG)/CXCL9 as useful markers. Serum concentrations of IP-10 and MIG at the time of LAHS diagnosis were greater than 500 and 5,000 pg/ml, respectively. The sensitivity and specificity for LAHS diagnosis were 100 and 95 %, respectively, when we set the above values as the cut-off levels. Serum levels of these two chemokines were already elevated at the time of admission and significantly decreased after successful treatment, indicating their usefulness for both the diagnosis and therapeutic outcomes for LAHS. IP-10 and MIG were also useful in distinguishing severe from moderate/mild LAHS, and B-cell-type LAHS from T-cell/natural killer cell-type LAHS. Furthermore, IP-10 and MIG were of use to distinguish LAHS from sepsis in patients with hematologic malignancies. Rapid measurement of IP-10 and MIG by CBA appeared to be important for early diagnosis and treatment of LAHS.

Simultaneous thrombosis of the mesenteric artery and vein as a novel clinical manifestation of intravascular large B-cell lymphoma.

A 79-year-old man with a 2-month history of fever and weight loss was admitted to our hospital because of an acute abdomen. Abdominal CT scans showed marked sectional thickening and edema of the small intestine. On laparotomy, a 16-cm section of the small intestine was ischemic and necrotic; therefore, segmentectomy of the intestine was performed. A thrombus was noted at the stump of the mesenteric artery branch. Histopathological analysis of the resected intestine revealed fibrin thrombi in both mesenteric arteries and veins. Furthermore, a cluster of large, abnormal lymphoid cells bordering the intima of most branches of the mesenteric veins and small vessels was observed. Immunohistochemical analysis revealed that these abnormal cells were positive for CD20, leading to a diagnosis of intravascular large B-cell lymphoma (IVLBCL). The patient was successfully treated with standard R-CHOP chemotherapy; however, the lymphoma recurred in the central nervous system 18 months after the initial diagnosis, and the patient died. Simultaneous thrombosis of the mesenteric artery and vein is unusual as a clinical manifestation of IVLBCL. However, IVLBCL should be taken into consideration when ischemic disorders of unknown cause, accompanied by fever of unknown origin, are encountered.

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.

The prognostic impact of absolute lymphocyte and monocyte counts at diagnosis of diffuse large B-cell lymphoma in the rituximab era.

BACKGROUND: A recent report showed that the combination of the absolute lymphocyte count (ALC) and the absolute monocyte count (AMC) at diagnosis gave a prognostic score in diffuse large B-cell lymphoma (DLBCL). However, this model requires validation in other patient cohorts. METHODS: We retrospectively evaluated the prognostic impact of the combination of the ALC and the AMC at diagnosis in a cohort of 299 DLBCL patients who were treated in the rituximab era at a single institution. RESULTS: In univariate analyses, an ALC ≤1.0 × 10(9)/l [4-year overall survival (OS) rate 47.0 vs. 79.4%; p < 0.001] and an AMC ≥0.63 × 10(9)/l (4-year OS rate 52.4 vs. 75.6%; p < 0.001) were associated with inferior OS, respectively. In multivariate analyses, an ALC ≤1.0 × 10(9)/l and an AMC ≥0.63 × 10(9)/l were significantly associated with inferior OS independently of the International Prognostic Index. Furthermore, the combination of ALC and AMC could identify patients with the dismal prognosis; the 4-year OS rates for patients with ALC ≤1.0 × 10(9)/l and AMC ≥0.63 × 10(9)/l were 18.8%. CONCLUSIONS: The combination of ALC and AMC at diagnosis may be useful for the prognostic stratification of patients with DLBCL.

Successful treatment of γ-heavy-chain disease with rituximab and fludarabine.

An 84-year-old Japanese man was admitted because of pancytopenia. The bone marrow was hypoplastic with a predominance of abnormal small lymphocytes and grape cells, which were positive for CD19 and CD20, and partially for the surface ĸ-light chain. Systemic CT scanning showed neither lymph node swelling nor hepatosplenomegaly. Serum immunoelectrophoresis and rocket immunoselection assays showed the presence of monoclonal IgG protein without a corresponding light chain and faint IgMĸ monoclonal protein. Histologic analysis of the clot preparation of the bone marrow aspirate facilitated a diagnosis of lymphoplasmacytic lymphoma (LPL). PCR analysis of the marrow cells demonstrated a clonal rearrangement of the immunoglobulin heavy-chain gene. From these results, we made a final diagnosis of γ-heavy-chain disease (γ-HCD) with underlying LPL localized in the bone marrow. We performed only a single course of immunochemotherapy (rituximab and fludarabine) in view of severely impaired hematopoiesis, which resulted in marked reduction of lymphoma cells and improvement of hematopoiesis. This report suggests the efficacy of rituximab plus fludarabine therapy for LPL-associated γ-HCD.

[Fatal hepatic failure due to AL amyloidosis in a patient with multiple myeloma].

Although about 10 to 15% of patients with multiple myeloma (MM) develop AL amyloidosis, liver-restricted fatal amyloidosis is rare. We encountered such an MM patient. A 73-year-old female without a history of carpal tunnel syndrome was diagnosed with IgG-κ MM (Stage I by Durie & Salmon) in January, 2005. Because MM was exacerbated to Stage III in May, 2007, VAD (vincristine, adriamycin, dexamethasone) chemotherapy was performed with minor response, despite 3 courses of this regimen. Three courses of salvage chemotherapy (cyclophosphamide+melphalan; CM) were then performed with near partial response. In March, 2008, just before the 4th cycle of CM chemotherapy, she was slightly icteric with elevated biliary tract enzymes; therefore, treatment was switched to oral cyclophosphamide and prednisolone. At this time, she did not have macroglossia, skin eruption, gastrointestinal dysfunction, or bleeding. Echocardiography was also non-specific. One month later, she developed a marked bleeding tendency and leg edema. Laboratory tests showed a severe deterioration in liver function. In the middle of May, 2008, she progressed to hepatic coma and died of intracranial hemorrhage several days later. Autopsy showed that the liver was almost substituted by AL amyloid substance.

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.

[Exacerbation of autoimmune neutropenia to agranulocytosis in association with severe autoimmune thrombocytopenia and hemolytic anemia in a patient with Sjögren's syndrome].

A 73-year-old woman with Sjögren's syndrome and autoimmune neutropenia (AIN) associated with large granular lymphocytosis of the polyclonal T cell type, demonstrated autoimmune thrombocytopenia (AIT) at diagnosis of sigmoid colon cancer. Ten months later, both AIN and AIT had exacerbated to agranulocytosis and severe thrombocytopenia below 10×10(9)/L, respectively. There were no dysplastic features of bone marrow hematopoietic cells. Furthermore, an in vitro assay of hematopoietic progenitors showed normal granuloid and erythroid colony formation. Although we serially treated her with prednisolone (oral), filgrastim, intravenous high-dose immunoglobulin infusion, cyclophosphamide (oral), danazol, cyclosporine A (oral), and rituximab, number of neutrophils and platelets elevated only temporarily. During the course of agranulocytosis and severe thrombocytopenia, the patient also developed autoimmune hemolytic anemia (AIHA). She died of pneumonia 5 months after the onset of agranulocytosis. This case is very unique and novel in terms of autoimmune phenomena simultaneously directed to granulocytes, platelets, and red blood cells under the background of Sjögren's syndrome.

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.

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.

Successful living donor liver transplantation for severe hepatic GVHD histologically resembling autoimmune hepatitis after bone marrow transplantation from the same sibling donor.

A 30-year-old woman developed severe liver dysfunction 1 year after bone marrow transplantation (BMT) from an HLA-identical sibling donor for B lymphoblastic leukemia (B-ALL) during the tapering of cyclosporin A. The histologic picture resembled autoimmune hepatitis (AIH), although neither autoantibody nor hypergammaglobulinemia was detected. She entered hepatic coma, and underwent living donor liver transplantation from the same donor on day 421 after BMT. She is well 18 months after the procedure, showing normal liver function and hematopoiesis. AIH-like hepatic graft-versus-host disease (GVHD) has not been documented. This patient is the second case of living donor liver transplantation for hepatic GVHD from the same donor.