Refractory immune thrombocytopenic purpura associated with IgM monoclonal gammopathy of undetermined significance: Successful treatment with tirabrutinib plus conventional therapies.

When immune thrombocytopenia (ITP) is secondary to malignant diseases, chemotherapy is expected to improve the platelet count (PC) as well. Herein, we report a case of a 72-year-old man with ITP refractory to standard therapies. IgM monoclonal gammopathy of undetermined significance (MGUS) was determined as an underlying disease. After bendamustine and rituximab (BR) therapy was found inadequately effective, tirabrutinib, a novel Bruton's tyrosine kinase inhibitor, was initiated, and the PC normalised subsequently. Surveillance of underlying diseases with which effective therapies are available may help manage refractory ITP, and IgM-MGUS is potentially a targetable underlying disease with this newly available drug.

Chronic GVHD complicated with polymyositis and cardiomyopathy after myeloablative hematopoietic stem cell transplantation.

A 50-year-old woman presented with leukocytosis, anemia, and thrombocytopenia in June 2013. She was diagnosed with de novo acute myeloid leukemia with the t(16;21)(q24;q22) translocation. She received an allogeneic hematopoietic stem cell transplant from an HLA-DRB1 locus-mismatched unrelated donor in June 2014. The myeloablative preparative regimen consisted of cyclophosphamide at 60 mg/kg for 2 days and total body irradiation at 12 Gy. On Day 55, she was treated with prednisolone at 20 mg/day for acute GVHD (Grade III; Skin Stage 2, Gut Stage 2, Liver Stage 0) and gradually improved. She had fever, myalgia in the upper limbs, and asymptomatic sinus tachycardia on Day 145. Laboratory tests showed elevated CK, CKMB, aldolase, and troponin I. Electromyographic examination revealed myopathic abnormalities compatible with the diagnosis of myositis. Electrocardiography showed tachycardia and anteroseptal ST elevation, and echocardiography showed hypokinesia of the left interventricular septal wall without evidence of infection or leukemia relapse. She was immediately treated with 40 mg/day prednisolone after the diagnosis of polymyositis and cardiomyopathy, associated with chronic GVHD. The polymyositis and cardiomyopathy improved promptly after the administration of prednisolone and the patient remains in remission with a current maintenance program of prednisolone at 5 mg/day.

Ratio of peripheral blood absolute lymphocyte count to absolute monocyte count at diagnosis is associated with progression-free survival in follicular lymphoma.

The prognosis of follicular lymphoma (FL) is significantly associated with host immunity and tumor microenvironment. Lymphopenia has been identified as a negative prognostic factor for FL. The association between monocytosis and progression-free survival (PFS) in FL remains controversial. It is unknown whether the ratio of peripheral blood absolute lymphocyte count to absolute monocyte count (ALC/AMC) at diagnosis is associated with FL prognosis. We studied 99 consecutive patients with FL who were treated with rituximab-containing chemotherapy at Kitano Hospital or Kyoto University Hospital between 2000 and 2012. We analyzed individual variables associated with the ALC/AMC ratio before treatment, as well as known prognostic factors of FL, and found that an ALC/AMC ratio of 4.7 was the best cut-off value for PFS. Kaplan-Meier analysis showed that a decreased ALC/AMC ratio was associated with inferior PFS (P = 0.022). Multivariate analysis showed that a decreased ALC/AMC ratio was a significant poor prognostic factor independent of other variables (hazard ratio, 2.714; 95 % confidence interval, 1.060-6.948; P = 0.037). The ALC/AMC ratio before treatment may be a significant prognostic factor predicting PFS of FL.

Primary peripheral T-cell lymphoma, not otherwise specified of the thyroid with autoimmune thyroiditis.

Primary peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) of the thyroid is an extremely rare neoplasm. Six cases of primary PTCL-NOS of the thyroid were analysed for clinicopathological features and genomic alteration patterns using oligo-array comparative genomic hybridization. All patients had a diffusely enlarged thyroid and three cases showed leukaemic manifestation. Five of the six cases had anti-thyroid antibodies and the remaining case showed hypothyroidism, suggesting that all cases had autoimmune thyroiditis. Except for one early relapsed case, the remaining five patients are alive and three of these five individuals have survived for 70 months or more. Interestingly, two cases showed spontaneous regressions after partial thyroid biopsy without any therapy. Leukaemic manifestation disappeared after irradiation of the thyroid mass in another two cases. The tumour cells were positive for CD3, CD4 and CXCR3 in all cases, suggesting that the tumour cells are of a type 1 helper T-cell origin. All six cases showed genomic alterations that were different from those previously reported for PTCL-NOS. The loss of 6q24·2 was characteristic and was detected in four of the six cases. These results suggest that primary PTCL-NOS of the thyroid arising from autoimmune thyroiditis is a distinct disease entity among heterogeneous PTCL-NOS.

Distinctive cell properties of B cells carrying the BCL2 translocation and their potential roles in the development of lymphoma of germinal center type.

The BCL2/IGH translocation is a hallmark of follicular lymphoma and germinal center B-cell type diffuse large B-cell lymphoma. Although a strong determinant of these histological subtypes, this translocation is insufficient by itself for lymphomagenesis, so that other genetic alterations are required. To clarify how the BCL2 translocation contributes to the development of specific lymphoma subtypes, we used chimeric mouse models and a bone marrow transplantation system to examine the biological features of BCL2-overexpressing B cells. These cells showed a cell-autonomous differentiation preference for follicular B cells. Their cell cycle progression was enhanced in wild-type but not in Emu-BCL2 transgenic mice, indicating that the low proliferative activity of B cells in Emu-BCL2 transgenic mice is partly due to their specific microenvironment, which is caused by the abnormal B cells themselves. Moreover, in vitro experiments demonstrated that Emu-BCL2(+) B cells have reduced responsiveness to terminal differentiation stimulation. According to these results, we hypothesize that B cells that have undergone BCL2/IGH translocation might possibly be forced to localize in follicles, and accumulate genetic abnormalities by being subjected to recurrent stimulation. Our findings lead us to propose that B cells carrying the BCL2/IGH translocation comprise a distinctive cell population that leads to the development of germinal center B-cell type lymphoma.

B7-H1 expression is regulated by MEK/ERK signaling pathway in anaplastic large cell lymphoma and Hodgkin lymphoma.

B7-H1 is a member of the B7 family that inhibits the function of T-cells through its receptor programmed death-1 (PD-1). We examined B7-H1 expression in anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma (HL) and found that it was constitutively expressed in both clinical samples and cell lines. In anaplastic lymphoma kinase-positive (ALK(+)) ALCL cells, B7-H1 expression was suppressed by the blocking of extracellular signal-regulated kinase (ERK) signaling and upregulated by the augmentation of ERK activity by phorbol 13-myristate 12-acetate stimulation, suggesting that B7-H1 expression is regulated by ERK signaling pathway in ALCL. ERK is one of the downstream mediators of nucleophosmin (NPM)/ALK signaling in ALK(+)ALCL, and pharmacological inhibition of ALK was shown to dephosphorylate ERK and down-regulate B7-H1. The involvement of NPM/ALK in B7-H1 expression was also demonstrated by introducing the construct into human non-ALCL lymphoid cell lines, which resulted in B7-H1 expression. In the case of HL, B7-H1 expression was shown to be dependent on the ERK and p38 mitogen-activated protein kinase (MAPK) signaling pathways. These results suggest that B7-H1 expression is controlled by common ERK signaling pathways in ALCL and HL cells. Our findings provide a potentially effective immunotherapeutic strategy for these B7-H1-expressing tumors.

Successful treatment with intravenous colistin for sinusitis, orbital cellulites, and pneumonia caused by multidrug-resistant metallo-beta-lactamase-producing Pseudomonas aeruginosa in a patient with acute myeloid leukemia.

The incidence of multidrug-resistant Pseudomonas aeruginosa (MDRPA) and metallo-beta-lactamase (MBL)-producing P. aeruginosa has increased worldwide. The treatment options are limited for infectious diseases caused by these two organisms. The use of colistin has been of recent interest in cases involving both types. We report the case of a 74-year-old man with acute myeloid leukemia who was successfully treated with intravenous colistin for maxillary sinusitis and orbital cellulites due to MBL-producing MDRPA during neutropenia, and then for pneumonia caused by the bacteria after the recovery of neutrophil counts.

[Epstein-Barr virus-associated B cell lymphoproliferative disorder complicated in adult T-cell leukemia].

Adult T-cell leukemia (ATL) is accompanied by remarkably impaired cellular immune responses. Reports on the simultaneous development of ATL and Epstein-Barr virus-associated lymphoproliferative disorders (EBV-LPD) are, however, quite rare. A 53-years-old man was admitted to our hospital because of multiple bilateral pulmonary nodules, skin rash, lymphadenopathy, and hypercalcemia. The smear preparation of peripheral blood demonstrated pathological lymphocytes with lobulated nuclei. They expressed CD2, CD3, and CD25, but did not express either CD4 or CD8. In addition, he was positive for Human T-cell leukemic virus type-I (HTLV-I), and monoclonal integration of HTLV-I provirus was detected in peripheral blood. Unexpectedly, inguinal lymph node biopsy showed polyclonal proliferation of EBV-positive large and bizarre-shaped B cells, and monoclonal growth of large abnormal T cells. He was diagnosed as having acute type ATL complicated by EBV-LPD. Chemotherapy for ATL effectively decreased the tumor burden of ATL, but persistent high fever developed suddenly on the 68th day after admission, and he died of multi-organ failure with severe metabolic acidosis. At the time of multi-organ failure, viral load had increased strikingly, suggesting that the progression of EBV-LPD might have been responsible for multi-organ failure in this case.

PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma.

Programmed death-1 (PD-1)-PD-1 ligand (PD-L) signaling system is involved in the functional impairment of T cells such as in chronic viral infection or tumor immune evasion. We examined PD-L expression in lymphoid cell lines and found that they were up-regulated on Hodgkin lymphoma (HL) and several T-cell lymphomas but not on B-cell lymphomas. PD-L expression was also demonstrated in primary Hodgkin/Reed-Sternberg (H/RS) cells. On the other hand, PD-1 was elevated markedly in tumor-infiltrating T cells of HL, and was high in the peripheral T cells of HL patients as well. Blockade of the PD-1 signaling pathway inhibited SHP-2 phosphorylation and restored the IFN-gamma-producing function of HL-infiltrating T cells. According to these results, deficient cellular immunity observed in HL patients can be explained by "T-cell exhaustion," which is led by the activation of PD-1-PD-L signaling pathway. Our finding provides a potentially effective immunologic strategy for the treatment of HL.

[Two cases of intramedullary spinal cord metastasis of lung cancer detected with MRI].

We report two cases of intramedullary spinal cord metastasis of lung cancer detected by MRI. Case 1: A 77-year-old man underwent chemotherapy and left lower lung lobectomy for squamous cell carcinoma of the lung (T2N0M0). About one year later, he complained of paresthesia of the lower extremities and claudication on walking, and then of weakness of the lower limbs and bladder dysfunction. Magnetic resonance imaging (MRI) revealed an enhanced mass in the dural sac at the level of the spines of L1-2. Volume reduction surgery was promptly performed. The pathological diagnosis was squamous cell carcinoma. Case 2: A small cell carcinoma of lung with metastasis to bone, kidney and cerebellum (T4 N3 M1) in a 73-year-old man was diagnosed. He showed a partial response to chemotherapies and to whole brain radiation (45 Gy). Three months later, he presented sudden onset paraplegia, paraesthesia and bladder dysfunction. MRI demonstrated an enhancing intramedullary lesion that delineated the conus of the cauda equina, and T 2-weighted MRI images showed multiple nodules in sacs.

[A case of paraneoplastic syndrome improved following chemoradiotherapy for lung cancer].

Paraneoplastic neurosyndrome (PNS) is a group of neurological disorders caused by or associated with neoplasms that are not direct effects of the primary tumor or of a metastasis to the involved organs. Chemotherapy, radiotherapy, immunosuppressive therapy, and plasmapheresis have been performed to treat PNS, but improvement of the neurological disorder is rather rare. A 64-year-old man was referred to our hospital with dysesthesia of the extremities and ataxic gait. Small cell lung cancer was diagnosed in another hospital and chemotherapy (CDDP 80 mg/m2 + VP-16 100 mg/m2) was performed. A partial response was obtained with this treatment, but the neurological dysfunction was exacerbated. Three months later, the patient was admitted to our hospital. On treatment with CDDP 80 mg/m2 (day 1) and CPT-11 80 mg/m2 (days 1, 8 and 15) and subsequent radiation therapy (60 Gy), his neurological disorder improved. We consider that neurological symptoms are important signs of malignancy in PNS and that a full course of treatment could improve the neurological disorders.