Hiroshi Ureshino

Effector Regulatory T Cells Reflect the Equilibrium between Antitumor Immunity and Autoimmunity in Adult T-cell Leukemia.

Anti-CCR4 treatment of ATL destroys leukemic and normal Tregs, which can lead to autoimmunity. Only leukemic Tregs expressed CADM1, distinguishing the two populations. Treg depletion was associated with autoimmunity and Treg reemergence with relapse of ATL. The regulatory T cells (Treg) with the most potent immunosuppressive activity are the effector Tregs (eTreg) with a CD45RA–Foxp3++CCR4+ phenotype. Adult T-cell leukemia (ATL) cells often share the Treg phenotype and also express CCR4. Although mogamulizumab, a monoclonal antibody to CCR4, shows marked antitumor effects against ATL and peripheral T-cell lymphoma, concerns have been raised that it may induce severe autoimmune immunopathology by depleting eTregs. Here, we present case reports for two patients with ATL who responded to mogamulizumab but developed a severe skin rash and autoimmune brainstem encephalitis. Deep sequencing of the T-cell receptor revealed that ATL cells and naturally occurring Tregs within the cell population with a Treg phenotype can be clearly distinguished according to CADM1 expression. The onset of skin rash and brainstem encephalitis was coincident with eTreg depletion from the peripheral blood, whereas ATL relapses were coincident with eTreg recovery. These results imply that eTreg numbers in the peripheral blood sensitively reflect the equilibrium between antitumor immunity and autoimmunity, and that mogamulizumab might suppress ATL until the eTreg population recovers. Close monitoring of eTreg numbers is crucial if we are to provide immunomodulatory treatments that target malignancy without severe adverse events. Cancer Immunol Res; 4(8); 644–9. ©2016 AACR.

Rituximab-containing Chemotherapy (R-CHOP)-induced Kaposi's Sarcoma in an HIV-negative Patient with Diffuse Large B Cell Lymphoma

Rituximab treatment may cause or exacerbate Kaposis sarcoma (KS) in patients with human immunodeficiency virus (HIV)-associated multicentric Castlemans disease. Despite the widespread use of rituximab, rituximab-induced KS has not yet been reported in HIV-negative patients with diffuse large B cell lymphoma (DLBCL). We herein report a case of KS that developed after undergoing rituximab-containing chemotherapy in an HIV-negative patient with DLBCL. An 84-year-old man who received rituximab-containing chemotherapy for the treatment of DLBCL developed severe infection, and subsequently KS. Our observations indicate that serious infections under rituximab treatment may trigger KS. KS should therefore be considered when skin tumors appear in lymphoma patients receiving rituximab-containing chemotherapy.

Deep sequencing of the T cell receptor visualizes reconstitution of T cell immunity in mogamulizumab-treated adult T cell leukemia

ABSTRACT Although the anti-CCR4 antibody mogamulizumab (moga) shows striking antitumor activity against adult T cell leukemia (ATL), it can also cause fatal immunological pathology such as severe skin rash and graft-versus-host disease, which might be attributed to depletion of CCR4+ regulatory T cells. We previously showed that next generation sequencing enables precise analysis of the T cell receptor (TCR) repertoire, and we here used the technique to reveal the immunological dynamics in moga-treated ATL patients. Treatment with moga resulted in remarkable reduction or elimination of clonal cells, and enhanced reconstitution of non-tumor polyclonal CD4+ T cells and oligoclonal CD8+ T cells. Interestingly, cutaneous T cells infiltrating moga-related skin rashes did not share the same major clones in peripheral blood, which minimizes the possibility of cross-reaction. Thus, deep sequencing of the TCR can reveal the immune reconstitution of moga-treated ATL and provides powerful insights into its mode of action.

Rituximab-induced Acute Thrombocytopenia in High Tumor Burden Follicular Lymphoma

Rituximab-induced acute thrombocytopenia (RIAT), a rare complication of rituximab administration, has not yet been described in follicular lymphoma (FL). A 65-year-old man received rituximab for the treatment of high tumor burden follicular lymphoma in the leukemic phase. The next day, his platelet count abruptly dropped from 85,000 to 5,000/μL, which spontaneously recovered in a few days without specific treatment. We speculate that the occurrence of infusion-related cytokine release syndrome in rituximab-sensitive high tumor burden FL contributed to the development of RIAT. Frequent monitoring of the platelet count is advisable for select patients considered to be at a high risk for RIAT.

Tocilizumab for severe cytokine-release syndrome after haploidentical donor transplantation in a patient with refractory Epstein-Barr virus-positive diffuse large B-cell lymphoma

It has been well documented that patients may develop cytokine‐release syndrome (CRS) following the administration of monoclonal antibodies, such as chimeric antigen receptor‐modified T cell. Cytokine‐release syndrome is a common complication in patients who have received haploidentical donor allogeneic haematopoietic cell transplantation (haplo‐HCT). Although severe CRS after haplo‐HCT is a potentially life‐threatening toxicity, a standard treatment has not been established. Cytokine blockade with tocilizumab, an anti‐IL‐6 receptor antibody, has been effective for the treatment of patients with CRS after chimeric antigen receptor‐modified T‐cell treatment and has also improved CRS after haplo‐HCT. A 46‐year‐old man was diagnosed with haemophagocytic syndrome associated with Epstein‐Barr virus‐positive diffuse large B‐cell lymphoma. Salvage chemotherapy was unsuccessful; consequently, he received haplo‐HCT. On day +4, he developed grade 3 CRS, subsequently high‐dose corticosteroid initiated. Nevertheless, on day +6, he developed grade 4 CRS, resulting in requirement for ventilator support and multiple vasopressors. Corticosteroid could not improve severe CRS; therefore, tocilizumab was administered on day +14. Serum C‐reactive protein level transiently decreased and weaned multiple vasopressors. Although CRS improved, he developed candidaemia; consequently, he died on day +34. Tocilizumab could transiently improve severe CRS after haplo‐HCT. Although tocilizumab may have led to the improvement of CRS, a remaining concern is whether it inhibited the patients ability to mount antifungal immunity, leading to their demise.

Detection of human T-cell lymphotropic virus type I-specific cytotoxic T-cells may predict treatment responses in adult T-cell leukemia/lymphoma patients

Dear Editor, Human T-cell lymphotropic virus type I (HTLV-I) specific cytotoxic T lymphocytes (CTLs) exhibit cytotoxicity against HTLV-I infected T-cells, resulting in the regulation of HTLV-I proviral load. CTLs are rarely seen in adult T-cell leukemia/ lymphoma (ATL) patients, but are strongly activated in some ATL patients who remain in complete remission (CR) after allogenic stem cell transplantation (allo-SCT) [1]; moreover, CTLs also regulate ATL disease progression [2]. Tax peptidepulsed dendritic cell vaccination can strongly induce CTLs, yielding positive clinical responses [3]. Mogamulizumab, an anti-CCR4 monoclonal antibody, can also activate CTLs [4]. However, the clinical impact of CTLs has not been fully elucidated [5]. Here, we report on a patient with acute ATL who received mogamulizumab-containing chemotherapy and achieved extremely long-term remission, during which HTLV-I specific CTLs were detected. An 84-year-old woman was admitted due to systemic lymphadenopathy, skin eruptions, and increased abnormal lymphocytes in the peripheral blood (PB). Subsequently, a diagnosis of acute ATL was made. VP-16 monotherapy initiated, and then the abnormal lymphocytes and skin eruptions were gradually decreased, nevertheless, the number of enlarged systemic lymph nodes, levels of serum lactate dehydrogenase and soluble interleukin-2 receptor did not decrease, indicating that ATL was refractory. Subsequently, mogamulizumab and half-doses of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) were administered. After two courses of chemotherapy, the patient achieved and remained in CR >42 months. HTLV-I specific CTLs were detec ted (0.38%) in her PB at 14 months af te r mogamulizumab administration (Fig. 1). Our patient achieved extremely long-term remission after mogamulizumab-containing chemotherapy. ATL is a chemotherapy-resistant T-cell neoplasm with a poor prognosis. Although mogamulizumab improves the outcome of ATL patients, the outcome remains extremely poor, and long-term remission rarely achieved without allo-SCT [6, 7]. HTLV-I specific CTL could play a pivotal role in regulating of ATL progression [2]. A hypothesis states that CTLs against ATL cells are involved in long-term remission. CTLs are generally inactivated in ATL patients; nevertheless, CTLs were detected after the administration of mogamulizumabcontaining chemotherapy. Mogamulizumab activates CTLs through the depletion of effector regulatory T-cells (eTregs) [4, 8]. Because of the resistance of the ATL to VP-16 monotherapy, VP-16 could not yield antitumor immune responses; however, the use of mogamulizumab-containing chemotherapy led to long-term remission, indicating that mogamulizumab could yield antitumor immune responses. Activated CTLs can contribute to clinical responses in ATL patients who receive allo-SCT or tax peptide-pulsed dendritic cell vaccination [2, 3]. The number of CD4and CD25-positive T-cells, including eTregs, and ATL cells, were decreased (<1% of CD3-positive T-cells) in our patient after VP-16 monotherapy; hence, these cells were not analyzed preand post-mogamulizumab administration, and it remained uncertain whether the eTreg levels had changed. However, our clinical observation suggests mogamul izumab can ac t iva te CTLs through an * Hiroshi Ureshino m00010hu@jichi.ac.jp

Spontaneous Regression of Methotrexate-related Lymphoproliferative Disorder with T-cell Large Granular Lymphocytosis

Spontaneous regression of methotrexate-related lymphoproliferative disorders (MTX-LPDs) occurs in some patients after withdrawal of MTX. However, the mechanisms by which MTX withdrawal contributes to the spontaneous regression of MTX-LPDs have not been fully elucidated. We herein show that spontaneous regression of MTX-LPDs is associated with the development of significant and transient T-cell large granular lymphocyte (T-LGL) lymphocytosis induced by MTX withdrawal. Since T-LGLs show strong cytotoxicity, their expansion may contribute to the spontaneous regression of lymphoma. Therefore, the development of T-LGL lymphocytosis maybe associated with a favorable prognosis in MTX-LPD patients.

Three coexisting lymphomas in a single patient: composite lymphoma derived from a common germinal center B-cell precursor and unrelated discordant lymphoma

Composite lymphoma (CL) is a rare disorder defined as the coexistence of two or more distinct lymphoma subtypes at a single anatomic site. Discordant lymphoma (DL), which is the simultaneous occurrence of two or more distinct lymphoma subtypes at different sites, is also rare. CL complicated with DL involving three distinct subtypes of lymphoma in the same patient is an extremely rare disease. Clonal relationships in CL and DL are commonly investigated by molecular analysis using mutational status with t(14;18)BCL2/IgH translocation and immunoglobulin heavy chain variable-region (IgVH) gene rearrangement. A 73-year-old woman was admitted to our hospital with systemic lymphadenopathy and was initially diagnosed with diffuse large B-cell lymphoma based on pathological features of the biopsied esophageal tumor. However, the results of inguinal lymph node biopsy led to a revised pathological diagnosis CL consisting of Hodgkin lymphoma and follicular lymphoma. Three distinct coexisting lymphomas were identified in this individual patient. Molecular analysis revealed CL derived from common germinal center B-cell precursors, while clonal relationship between CL and DL was not clarified. This case suggests a mechanism underlying B-cell lymphoma pathogenesis involving two pivotal somatic mutations, t(14;18)BCL2/IgH translocation and IgVH rearrangement.

Sustained ventricular tachycardia caused by subacute thyroiditis: Letters to the Editor

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Oral ulceration: an unusual manifestation of lymphomatoid granulomatosis

Dear Editor, Lymphomatoid granulomatosis (LYG) is a rare angiocentric and angiodestructive lymphoproliferative disorder (LPD) caused by latent Epstein-Barr virus (EBV) reactivation in immunosuppressed individuals [1]. Methotrexate (MTX) has been associated with the development of LPDs. In contrast to pulmonary involvement occurring in > 90% patients with LYG, involvement of oral cavity is extremely rare [2, 3]. We report two cases of oral cavity ulceration as an initial clinical manifestation of LYG.