[Development of classical Hodgkin lymphoma in a patient receiving tocilizumab for rheumatoid arthritis].

A 66-year-old woman was being treated with methotrexate and etanercept for rheumatoid arthritis (RA). Because her RA symptoms worsened, her medication was changed to tocilizumab (TCZ), and her symptoms improved. However, one year and six months later, she was referred to our hospital because of fever, cervical and para-aortic lymphadenopathy, and massive lesions of the liver/spleen. She was diagnosed with clinical stage IVB mixed cellularity classical Hodgkin lymphoma (cHL) on the basis of right cervical lymph node biopsy. Immunohistochemically, Hodgkin cells were positive for CD20, CD30, PAX-5, LMP-1, PD-L1, and EBER and were negative for CD5, CD15, and EBNA2. Her fever and lymphadenopathy did not improve after the discontinuation of TCZ. Therefore, she was administered ABVd therapy and achieved complete remission (CR) after six cycles of ABVd therapy. She was found to be alive and in CR on regular follow up till February 2021. To the best of our knowledge, there are limited reports of immunodeficiency-related lymphoproliferative disorders associated with TCZ in literature, and our case may be a valuable report on the association of TCZ with the development of cHL in patients with RA.

Double-Hit Primary Plasma Cell Leukemia with IGH/MYC and IGH/CCND1 Translocations.

Primary plasma cell leukemia (pPCL) is an aggressive variant of multiple myeloma (MM). Immunoglobulin heavy chain (IgH) translocations are found in a majority of pPCL cases, supporting a central relation to pathogenesis of pPCL. However, two independent IgH translocations are barely detected at the onset of pPCL, and their significance is yet to be elucidated. Here, we report a case of an aggressive pPCL with simultaneous IGH/MYC and IGH/CCND1 translocations. A 73-year-old man was referred to our hospital with back pain and diagnosed as having pPCL with more than 50% circulating plasma cells. Cytogenetic analysis revealed 47, Y, t (X; 8;14) (q24; q24; q32), t (11; 14) (q13; q32), and +18. IGH/MYC and IGH/CCND1 translocations were confirmed by fluorescence in situ hybridization analysis. Bortezomib and dexamethasone treatment achieved rapid elimination of peripheral malignant plasma cells, and the patient maintained a partial response for 18 months. After biological relapse, he received salvage therapy with ixazomib, lenalidomide, and dexamethasone, followed by pomalidomide and dexamethasone, and exhibited stable disease for an additional 14 months. Although IGH/MYC translocation in association with dysregulation of antiapoptotic pathway leads to worse prognosis in lymphomas, the novel agent-based regimen showed good efficacy, suggesting that IGH/MYC plays a different role in the pathogenesis of MM. IGH/CCND1 and IGH/MYC translocations may have contributed to abrupt onset of pPCL in this case.

[Sustained Complete Remission after Eradication Therapy in A Helicobacter pylori-Negative Cecum Mucosa-Associated Lymphoid Tissue Lymphoma].

Most primary gastric mucosa-associated lymphoid tissue(MALT)lymphomas are associated with a chronic Helicobacter pylori(H. pylori)infection. The eradication of H. pylori is the first-line treatment for H. pylori-positive cases with early-stage disease. In addition, successful treatment of H. pylori-negative early stage MALT lymphomas by eradication has been reported in several small cases series. However, the association of primary gastrointestinal MALT lymphomas with H. pylori in areas other than the stomach is not clear, and the efficacy of eradication therapy for these patients has not been established. We performed H. pylori eradication therapy for H. pylori-negative cecum MALT lymphoma. Three months later, a histopathological examination showed no evidence of MALT lymphoma, and the patient was classified as being in remission. So far, the patient has been in remission for 1 year and 6 months. Our case is the first report of successfully treating H. pylori- negative cecum MALT lymphoma with eradication therapy.

[Leucovorin Administration Allows Continued Pralatrexate Treatment in a Patient with Angioimmunoblastic T-Cell Lymphoma].

Pralatrexate(PDX)has been approved for the treatment of relapsed/refractory peripheral T-cell lymphoma(PTCL), including angioimmunoblastic T-cell lymphoma(AITL). Oral mucositis is the most common and severe adverse effect of PDX that often leads to dose reduction or omission. Herein, we report a 65-year-old man with AITL, who received PDX treatment after a second relapse. This drug was effective; however, the adverse effects, such as oral mucositis, were severe. Therefore, leucovorin(LV)was administered to prevent the adverse effect, resulting in continuation of the PDX treatment for 8 months. LV administration minimizes adverse effects for patients receiving high-dose methotrexate. However, the optimal dose and schedule of LV in PDX treatment has not yet been established. In the future, clinical trials on the use of LV for PDX-induced oral mucositis are needed.

Invasive candidiasis leading to gastric perforation in an immunocompromised patient.

Invasive candidiasis remains an important cause of mortality and morbidity in patients with underlying diseases. Here, we report a case of gastric perforation due to Candia glabrata infection in a 74-year-old-male with Paroxysmal nocturnal hemoglobinuria (PNH) who received long-term corticosteroid treatment of hemophagocytic syndrome associated with acute cholecystitis. Total gastrectomy was performed, and he was treated liposomal amphotericin B. The patient was extubated successfully on the 2nd postoperative day, but the patient died of Pneumocystis jirovecii pneumonia (PJP). An autopsy revealed that there was a small amount of the cystic form of Pneumocystic jirovecii, but there was not the presence of Candida spp. Concerning the prophylaxis of invasive candidiasis, there is no strong evidence-based data in clinical practice in immunocompromised patients, such as those receiving long-term immunomodulatory therapy or corticosteroids. Our present case suggests the importance of fungal management and may indicate the need for a new approach to the fungal prophylaxis in such patients.

[Diffuse large B-cell lymphoma occurring in a Waldenström macroglobulinemia patient with central nervous system infiltration].

The rare central nervous system (CNS) infiltration of Waldenström macroglobulinemia (WM) is known as Bing-Neel syndrome (BNS). Furthermore, the transformation of WM into diffuse large B-cell lymphoma (DLBCL) is also unusual. Herein, we report a 69-year-old male with DLBCL transformed from BNS. In November 2008, the patient visited a prior hospital because of anemia and was diagnosed with WM. After receiving chemotherapy (R-CHOP), his serum immunoglobulin M (IgM) level decreased and then remained at approximately 2000 mg/dl for 3 years. In November 2011, he complained of visual impairment and photophobia in his left eye. Magnetic resonance imaging showed enlargement of the left optic nerve and cerebrospinal fluid examination indicated CNS infiltration of WM cells. Consequently, he was diagnosed with BNS. He thus received CNS targeted chemotherapy (R-MPV) and achieved a partial response. In May 2014, IgM was elevated and swelling of systemic lymph nodes was detected. Inguinal lymph node biopsy yielded a pathological diagnosis of DLBCL and the clonality of tumor cells between WM and DLBCL was confirmed by the allele-specific oligonucleotide polymerase chain reaction (ASO-PCR).

Quantitative polymerase chain reaction analysis with allele-specific oligonucleotide primers for individual IgH VDJ regions to evaluate tumor burden in myeloma patients.

Quantitative polymerase chain reaction (PCR) with patient-specific, allele-specific oligonucleotide (ASO) primers for individual immunoglobulin H VDJ region (ASO-PCR) amplification was performed using several sources of clinical material, including mRNA from peripheral blood cells (PBMNCs), whole bone marrow cells (BMMNCs), and the CD20+ CD38- B-cell population in bone marrow, as well as cell-free DNA from the sera of patients with multiple myeloma (MM). We designed the ASO primers and produced sufficient PCR fragments to evaluate tumor burden in 20 of 30 bone marrow samples at diagnosis. Polymerase chain reaction amplification efficiency depended on primer sequences because the production of ASO-PCR fragments did not correlate with serum M-protein levels. However, the ASO-PCR levels in BMMNCs showed statistically significant correlations with those in PBMNCs and CD20+ CD38- B-cells. The good association between the BMMNC and PBMNC data indicated that PBMNCs could be a suitable source for monitoring minimal residual disease (MRD). In the case of cell-free DNA, ASO-PCR levels showed a unique pattern and remained high even after treatment. Because the sequence information for each ASO-PCR product was identical to the original, the cell-free DNA might also be useful for evaluating MRD. Moreover, the ASO-PCR products were clearly detected in 17 of 22 mRNA samples from CD20+ CD38- populations, suggesting that MM clones might exist in relatively earlier stages of B cells than in plasma cells. Thus, ASO-PCR analysis using various clinical materials is useful for detecting MRD in MM patients as well as for clarifying MM pathogenesis.

[Hemophagocytic lymphohistiocytosis as an initial manifestation in an HIV-infected patient].

A 48-year old man was admitted with idiopathic fever, and subsequently diagnosed as having hemophagocytic lymphohistiocytosis (HLH). Though an extensive series of laboratory examinations failed to demonstrate an apparent etiology, empirical use of steroids achieved remission. About two years later, the patient developed Pneumocystis Jiroveci pneumonia and was diagnosed as HIV-positive. Based on this case, HIV-screening tests would be performed whenever we encounter HLH in Japan, where the number of HIV-positive patients is increasing.