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Akio Onishi,1 Yayoi Matsumura-Kimoto,1,2 Shinsuke Mizutani,1 Taku Tsukamoto,1 Takahiro Fujino,1 Akihiro Miyashita,1,3 Daichi Nishiyama,4 Kazuho Shimura,5 Hiroto Kaneko,5 Eri Kawata,6 Ryoichi Takahashi,7 Tsutomu Kobayashi,1,8 Hitoji Uchiyama,8 Nobuhiko Uoshima,3 Yoko Nukui,9 Yuji Shimura,1 Tohru Inaba,9 Junya Kuroda1 1Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan; 2Department of Hematology, Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center, Kyoto, Japan; 3Department of Hematology, Japanese Red Cross Kyoto Daini Hospital, Kyoto, Japan; 4Department of Hematology, Fukuchiyama City Hospital, Fukuchiyama, Japan; 5Department of Hematology, Aiseikai Yamashina Hospital, Kyoto, Japan; 6Department of Hematology, Matsushita Memorial Hospital, Moriguchi, Japan; 7Department of Hematology, Omihachiman Community Medical Center, Omihachiman, Japan; 8Department of Hematology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan; 9Division of Infection Control & Molecular Laboratory Medicine, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, JapanCorrespondence: Junya Kuroda, Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan, Tel +81-75-251-5740, Fax +81-75-251-5743, Email junkuro@koto.kpu-m.ac.jpBackground and Purpose: Anti-CD20 monoclonal antibodies (MoAbs), rituximab (RIT), and obinutuzumab (OBZ) are the central components of immunochemotherapy for B-cell lymphoma (BCL). However, these agents potentially cause B-cell depletion, resulting in the impairment of antibody (Ab) production. During the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, the optimal prediction of Ab response against anti–SARS-CoV-2 vaccination is critically important in patients with BCL treated by B-cell depletion therapeutics to prevent coronavirus disease 2019 (COVID-19).Patients and Methods: We investigated the effect of using RIT and/or OBZ on the Ab response in 131 patients with various types of BCL who received the second SARS-CoV-2 mRNA vaccine either after, during, or before immunochemotherapy containing B-cell–depleting moiety between June and November 2021 at seven institutes belonging to the Kyoto Clinical Hematology Study Group. The SARS-Cov-2 neutralizing Ab (nAb) was measured from 14 to 207 days after the second vaccination dose using the iFlash3000 automatic analyzer and the iFlash-2019-nCoV Nab kit.Results: Among 86 patients who received the vaccine within 12 months after B-cell depletion therapy, 8 (9.3%) were seropositive. In 30 patients who received the vaccine after 12 months from B-cell depletion therapy, 22 (73%) were seropositive. In 15 patients who were subjected to B-cell depletion therapy after vaccination, 2 (13%) were seropositive. The multivariate analysis indicated that an interval of 12 months between B-cell depletion therapy and the subsequent vaccination was significantly associated with effective Ab production. Receiver operating characteristic curve analysis identified the optimal threshold period after anti-CD20 MoAb treatment, which determines the seropositivity against SARS-CoV-2, to be 342 days.Conclusion: The use of anti-CD20 MoAb within 12 months before vaccination is a critical risk for poor Ab response against anti–SARS-CoV-2 vaccination in patients with BCL.Keywords: COVID-19, vaccine, B-cell lymphoma, anti-CD20 monoclonal antibody

Chika Maekura,1 Ayako Muramatsu,1 Hiroaki Nagata,1 Haruya Okamoto,1 Akio Onishi,1 Daishi Kato,1 Reiko Isa,1 Takahiro Fujino,1 Taku Tsukamoto,1 Shinsuke Mizutani,1 Yuji Shimura,1,2 Tsutomu Kobayashi,1 Keita Okumura,3 Tohru Inaba,4 Yoko Nukui,4 Junya Kuroda1 1Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan; 2Department of Blood Transfusion, University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan; 3Faculty of Clinical Laboratory, University Hospital, Kyoto Prefectural University of Medicine, Kyoto, Japan; 4Department of Infection Control & Laboratory Medicine, Kyoto Prefectural University of Medicine, Kyoto, JapanCorrespondence: Junya Kuroda, Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto, 602-8566, Japan, Tel +81 75 251 5740, Fax +81 75 251 5743, Email junkuro@koto.kpu-m.ac.jpAbstract: Previous studies have demonstrated that the appropriate production of serum anti-severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) neutralizing antibody (nAb) plays a critical role in the recovery from coronavirus disease 2019 (COVID-19); however, the role of nAb production in the recovery from a flare-up of chronic immune thrombocytopenia (ITP) has been unknown. We here report the first retrospectively investigated case of serum anti-SARS-Cov-2 nAb production during chronic ITP flare-up triggered by COVID-19. A 79-year-old woman with a history of corticosteroid-refractory ITP visited our hospital complaining of fever, cough, and sore throat for 4 days. Although chronic ITP was controlled by 12.5 mg of eltrombopag (EPAG) every other day, laboratory tests showed a decreased peripheral blood platelet count of 15.0 × 109/L, which indicated worsening thrombocytopenia. Meanwhile, PCR testing of a nasopharyngeal swab revealed that the patient was positive for SARS-Cov-2, and a computed tomography scan revealed bilateral pneumonia. On the basis of the flare-up of chronic ITP associated with COVID-19 pneumonia which was determined as a moderately severe status according to the WHO clinical progression scale, intravenous immunoglobulin therapy for 5 days (days 0– 4) and antiviral therapy were added on top of EPAG, which only resulted in a transient increase in the platelet count for several days. After decreasing to 8.0 × 109/L on day 13, the platelet count increased from day 16, coinciding with a positive detection for serum nAb against SARS-Cov-2. Although the increased dose up to 50 mg/day of EPAG was challenged during the clinical course, rapid dose reduction did not cause another relapse. In addition, no thrombotic or bleeding event was seen. These collectively suggest the vital role of the production of anti-SARS-Cov-2 nAb and improvement of clinical symptoms for recovery from a flare-up of chronic ITP in our case.Keywords: chronic immune thrombocytopenia, COVID-19, flare, neutralizing antibody

Yuka Kawaji-Kanayama,1 Ayako Nishimura,2 Makoto Yasuda,3 Emiko Sakiyama,1,4 Yuji Shimura,1 Taku Tsukamoto,1 Tsutomu Kobayashi,1 Shinsuke Mizutani,1 Shota Okamoto,3 Gaku Ohmura,3 Shigeru Hirano,3 Eiichi Konishi,2 Kazutoshi Shibuya,5 Junya Kuroda1 1Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan; 2Division of Surgical Pathology, Department of Pathology, Kyoto Prefectural University of Medicine, Kyoto, Japan; 3Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan; 4Department of Hematology, Matsushita Memorial Hospital, Moriguchi, Japan; 5Department of Surgical Pathology, Toho University Graduate School of Medicine, Tokyo, JapanCorrespondence: Junya KurodaDivision of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-Cho, Kamigyo-Ku, Kyoto 602-8566, JapanTel +81 75 251 5740Fax +81 75 251 5743Email junkuro@koto.kpu-m.ac.jpAbstract: Invasive fungal rhinosinusitis (FRS) is a rare but intractable infectious disease of the sinonasal region with destructive direct infiltration into surrounding tissues, such as the bone, orbit and brain, and potential dissemination to systemic organs. Symptomatic assessments and imaging are frequently not sufficiently diagnostic, and histopathological examination is essential for definite diagnosis of FRS. We herein report a case of chronic invasive FRS (CIFRS) in a 58-year-old Japanese male with end-stage diabetic nephropathy that required maintenance dialysis after graft rejection of living kidney transplantation. His initial main clinical presentation was sinus gangrene, which gradually progressed from the paranasal sinus to the nasal septum and oral palate, but not towards the intracranial or orbital region, for two months. The patient was first strongly suspected to have extranodal natural killer/T cell lymphoma (ENKTL), nasal type, a subtype of malignant lymphoma, based on the macroscopic appearance of the gangrene, expansion pattern and high serum soluble interleukin-2 level; however, repeated biopsies and eventual resection led to diagnosis of CIFRS due to Aspergillus niger and Mucor. The disease was improved by surgical resection in combination with antifungal pharmacologic treatment with liposomal amphotericin B and voriconazole. CIFRS typically occurs in immunocompetent patients and shows intracranial progression, but this case shows that atypical CIFRS with an uncommon expansion pattern can occur in an immunodeficient patient.Keywords: chronic invasive fungal rhinosinusitis, diabetes mellitus, maintenance dialysis, extranodal natural killer/T cell lymphoma, nasal type

Emiko Sakiyama, Yoshiaki Chinen, Taku Tsukamoto, Tomoko Takimoto-Shimomura, Saeko Kuwahara-Ota, Yayoi Matsumura-Kimoto, Yuji Shimura, Tsutomu Kobayashi, Shigeo Horiike, Junya Kuroda Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, JapanCorrespondence: Junya Kuroda Email junkuro@koto.kpu-m.ac.jpAbstract: Ruxolitinib is a selective JAK1/2 inhibitor that is widely used for the treatment of myeloproliferative neoplasms (MPNs), including myelofibrosis and polycythemia vera (PV). Despite its clinical efficacy for MPNs, ruxolitinib possesses immunosuppressive properties that potentially increase the risks for opportunistic infection, such as mycobacterium tuberculosis (MTB) infection, and reactivation of occult viral infection. Herein, we report the case of a 76-year-old male with PV who developed tuberculosis peritonitis under ruxolitinib therapy for 28 weeks. While previous studies and case reports have suggested an increased risk of MTB infection of various organs during ruxolitinib treatment of MPNs, this case is apparently the first of tuberculosis peritonitis in a patient with MPN treated with ruxolitinib. A review of previous case reports suggests the need for careful observation for MTB from the relatively early phase of ruxolitinib treatment, given that the median duration from the start of ruxolitinib treatment to the emergence of MTB was 20 weeks (range: 3– 88 weeks). Clinicians should consider tuberculosis peritonitis as a differential diagnosis when patients with MPN treated with ruxolitinib develop infectious abdominal symptoms.Keywords: ruxolitinib, tuberculosis peritonitis, polycythemia vera

Shuji Suzuki,1 Mitsugi Shimoda,1 Jiro Shimazaki,1 Tsunehiko Maruyama,1 Yukio Oshiro,1 Kiyotaka Nishida,1 Jun Kuroda,1 Kenta Miyoshi,1 Nobusada Koike,2 Nobuhiko Harada21Department of Gastroenterological Surgery, Ibaraki Medical Center, Tokyo Medical University, Ibaraki 300-0395, Japan; 2Department of Surgery, Hachioji Digestive Disease Hospital, Tokyo 192-0903, JapanBackground: Early recurrence of distal cholangiocarcinoma (DCC) may result in a poorer prognosis. This study aimed to evaluate the clinicopathological factors that predict survival and recurrence in patients with DCC.Methods: Fifty-five patients with DCC who underwent pancreaticoduodenectomy between 2005 and 2015 were studied retrospectively. The following clinicopathological parameters were analyzed as predictors of disease-free survival (DFS) and overall survival (OS): sex, age, body mass index, presence of biliary tract decompression, macroscopic type, histological type, tumor size, TNM classification, lymph node metastasis ratio, number of positive lymph nodes (PLNs), lymphatic invasion, venous invasion, perineural invasion, proximal bile duct margin, dissected margin, portal system invasion, arterial system invasion, stage, and residual tumor.Results: Univariate analysis showed that contiguous extension of the primary tumor, PLN, lymphatic invasion, venous invasion, perineural invasion, and stage were significant prognostic factors for DFS and OS. Multivariate analysis revealed that PLN and lymphatic invasion were prognostic for DFS and OS (P

Saeko Kuwahara-Ota, Yoshiaki Chinen, Yoshimi Mizuno, Tomoko Takimoto-Shimomura, Yayoi Matsumura-Kimoto, Kazuna Tanba, Taku Tsukamoto, Shinsuke Mizutani, Yuji Shimura, Tsutomu Kobayashi, Shigeo Horiike, Junya Kuroda Department of Medicine, Division of Hematology and Oncology, Kyoto Prefectural University of Medicine, Kyoto, Japan Abstract: Primary infection with human herpesvirus-6 (HHV-6) commonly occurs at an early age in children, most often at 3 years of age, and is associated with childhood diseases, such as exanthema subitum, hepatitis, febrile convulsions, or encephalitis. However, the virus occasionally reactivates from its latent state in immunosuppressed adults, especially posttransplant, resulting in serious disseminated, sometimes life-threatening end-organ complications. Herein, we report a case of a 68-year-old man with relapsed follicular lymphoma who developed HHV-6 pneumonitis. Eighteen months after achieving second complete remission by salvage immunochemotherapy with rituximab, the patient was complicated by pneumonia, with chest computed tomography finding showing disseminated nodular shadows with ground-glass opacity in both lungs. While empiric antibiotic and antifungal therapies did not improve the pneumonia, polymerase chain reaction–based viral screening tests on his bronchoalveolar lavage fluid detected the presence of HHV-6 DNA, and ganciclovir treatment quickly resolved the pneumonia, indicating that he suffered from HHV-6 pneumonitis. He had no other HHV-6–related end-organ damage, such as encephalitis. This case suggests that, although extremely rare, HHV-6 reactivation should be considered as one of the candidate pathogens for pulmonary complications of uncertain etiology in patients who have been treated with intensive immunosuppressive chemotherapy, even without hematopoietic stem cell transplantation. Furthermore, polymerase chain reaction–based viral screening testing on bronchoalveolar lavage fluid is a powerful diagnostic tool for pneumonitis due to viral reactivation, including HHV-6 reactivation. Keywords: human herpesvirus-6, pneumonitis, viral reactivation, lymphoma