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Makoto Saito, Shinpei Harada, Reiki Ogasawara, Koh Izumiyama, Akio Mori, Masanobu Morioka, Takeshi Kondo Department of Internal Medicine and Hematology, Blood Disorders Center, Aiiku Hospital, Sapporo, JapanCorrespondence: Makoto Saito Email ikyoku@aiiku-hp.or.jpAbstract: Eculizumab has been developed as a breakthrough treatment for paroxysmal nocturnal hemoglobinuria (PNH). Not only for breakthroughs, eculizumab therapy is also known to increase the risk of invasive meningococcal infection. It has also been recently reported that, although rarely, administration of eculizumab may result in disseminated gonococcal infection (DGI). We report here a case in which a young patient who had used eculizumab for PNH developed DGI. A 22-year-old Japanese male with PNH who had been treated with eculizumab complained of high fever, mild nausea, headache and right knee joint pain. The patient was admitted and suspected to have sepsis due to meningococcal infection and began to receive ceftriaxone (CTRX). Gonococci were detected in a venous blood culture a few days later, and this case was diagnosed as DGI. CTRX was effective, and the patient was discharged. However, four weeks later, he complained of the same subjective symptoms as at the beginning and was hospitalized again. The presence of gonococcus was proven by venous blood culture, CTRX was re-administered and the patient responded. After discharge, he was counseled on safer sexual activity, including accurate and consistent use of condoms, by urologists. He has not relapsed with DGI for more than one year. When serious signs of infection occur in patients receiving eculizumab, it is recommended to consider DGI as well as invasive meningococcal infection, and CTRX should be given.Keywords: disseminated gonococcal infection, DGI, eculizumab, paroxysmal nocturnal hemoglobinuria, PNH, ceftriaxone

Makoto Saito,1 Kencho Miyashita,2 Yosuke Miura,3 Reiki Ogasawara,1 Minoru Kanaya,1 Koh Izumiyama,1 Akio Mori,1 Takeshi Kondo,1 Masanori Tanaka,1 Masanobu Morioka,1 Shinya Tanaka4 1Department of Internal Medicine and Hematology, Aiiku Hospital, Sapporo, Japan; 2Department of Gastroenterology, Aiiku Hospital, Sapporo, Japan; 3Department of Internal Medicine, Megumino Hospital, Eniwa, Japan; 4Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan Abstract: Colorectal follicular lymphoma (FL) occurs less frequently than duodenal-type FL, which is an established entity, and primary multiple FL only involving the colon is rare. Furthermore, the coexistence of lymphoma and multiple myeloma (MM) within the same patient is rare and the current study reports such a case. The patient was an asymptomatic 62-year-old man. He underwent colonoscopy screening, which revealed at least five polypoid tumors from the cecum to the rectum. Biopsy samples stained positive for CD20 and B-cell lymphoma 2 (BCL2) but stained negative for CD10, and fluorescence in situ hybridization analysis identified IGH/BCL2 in 95.2% of the tumor cells. Based on these findings, the patient was diagnosed with FL. On the bone marrow aspirate, the plasma cell count was 30% of all nucleated cells. Bence-Jones κ-type protein was detected by protein electrophoresis in serum and urine. The serum-free light chain κ/λ level was significantly elevated (484.3). Thus, the patient was also diagnosed with MM. Both FL and MM were targeted therapeutically; rituximab and bendamustine were effective for FL, and lenalidomide and low-dose dexamethasone were effective for MM. The patient was treated for 3 years and 7 months and, until now, was off-treatment for 4 years without rapid progression of the two malignancies. Although both diseases are still present, the patient has maintained stable disease. Our findings suggest that lymphoma and MM should be targeted separately as independent hematological malignancies when they occur concurrently. Keywords: follicular lymphoma, colon, multiple myeloma, coexistence, treatment

Makoto Saito,1 Minoru Kanaya,1 Koh Izumiyama,1 Akio Mori,1 Tatsuro Irie,1 Masanori Tanaka,1 Masanobu Morioka,1 Masahiro Ieko2 1Department of Internal Medicine and Hematology, Aiiku Hospital, Japan; 2Department of Internal Medicine, Health Sciences University of Hokkaido, Japan Abstract: Recombinant activated factor VII (rFVIIa) is the bypassing agent used in the first-line hemostatic therapy for acquired hemophilia A (AHA); however, the occurrence of thrombotic complications in rFVIIa-treated AHA patients was recently reported to be 2.9–6.5%. Therefore, the investigation of the proper administration of rFVIIa for AHA is needed. In the present study, we retrospectively investigated the clinical features of AHA with regards to the use of rFVIIa (presence or absence of use and total amount) in 7 AHA patients encountered in our department for 7 years between January 2008 and December 2014. Ages were 63–89 years old (median: 79 years old), and there were 5 male and 2 female patients. The coexistence of cardiovascular risk factors and arteriosclerotic diseases, such as hypertension, diabetes mellitus, and cerebral infarction were present in 6 patients. Anemia progressed to less than 7 g/dL of hemoglobin and required red blood cell transfusion in 5 patients, showing “severe” hemorrhage. Factor VIII inhibitors were removed by immunological treatments in 6 patients. As a hemostatic therapy, rFVIIa was used in 4 patients. rFVIIa was not administered or was administered at a very low dose (20 mg) to 3 and 1 patient, respectively, and bleeding stopped as inhibitor titers decreased and disappeared in these patients. Inhibitors did not disappear in 1 patient and the control of hemostasis became poor and was accompanied by intestinal hemorrhage. Although a large amount of rFVIIa (265 mg in total) was administered, the patient bled to death. Therefore, bleeding may be stopped without the administration of rFVIIa in some AHA cases, while the dose of rFVIIa is not necessarily related to hemostatic effects in other cases. Since the main aim of AHA treatments is the removal of inhibitors, caution is needed to ensure that more than the necessary amount of rFVIIa is not administered. Keywords: acquired hemophilia A, recombinant activated factor VII, thrombotic complications

Makoto Saito,1 Masanobu Morioka,1 Ko Izumiyama,1 Akio Mori,1 Tatsuro Irie,1 Masanori Tanaka,1 Yoshihiro Matsuno21Department of Internal Medicine and Hematology, Aiiku Hospital, Sapporo, Japan; 2Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, JapanAbstract: We report a case of Epstein–Barr virus (EBV)-positive ileal extraosseous plasmacytoma containing plasmablastic lymphoma components with CD20-positive lymph node involvement. A 34-year-old healthy Japanese male developed intussusception due to an ileal plasmacytoma. The lesion was positive for EBV-encoded small nuclear RNA in in situ hybridization, with the surrounding lymph nodes showing the expression of CD20. Tumor cells in the ileal and lymph node lesions contained high-grade malignant features compatible with plasmablastic lymphoma. Because his abdominal lymph nodes recurred 6 months after resection, he received six cycles of R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), and had a complete remission. Although his case was complicated by acute promyelocytic leukemia, he has so far survived, recurrence-free, for more than 7.5 years after chemotherapy for extraosseous plasmacytoma.Keywords: ileal extraosseous plasmacytoma, plasmablastic lymphoma, Epstein–Barr virus (EBV), lymph node involvement, CD20, R-CHOP

Objectives: Patients with myeloproliferative neoplasms (MPNs) are at higher risk of developing secondary malignancies. In this study, we focused on patients with MPNs that complicated lymphoid neoplasms. To analyze the real-world status of lymphoid neoplasm treatment in patients with pre-existing MPNs in Japan, we conducted a multicenter retrospective study., Methods: Questionnaires were sent to collect the data on patients who were first diagnosed with either polycythemia vera, essential thrombocythemia or myelofibrosis and who later were complicated with lymphoid neoplasms defined as malignant lymphoma, multiple myeloma, or chronic lymphocytic leukemia/small cell lymphoma., Results: Twenty-four patients with MPNs complicated by lymphoid neoplasms were enrolled (polycythemia vera, n  = 8; essential thrombocythemia, n  = 14; and primary myelofibrosis, n  = 2). Among these, diffuse large B-cell lymphoma (DLBCL) was the most frequently observed ( n  = 13, 54.1%). Twelve (92.3%) of the patients with DLBCL received conventional chemotherapy. Among these 12 patients, regarding cytoreductive therapy for MPNs, 8 patients stopped treatment, one continued treatment, and two received a reduced dose. Consequently, most patients were able to receive conventional chemotherapy for DLBCL with a slightly higher dose of granulocyte colony-stimulating factor support than usual without worse outcomes. All 3 patients with multiple myeloma received a standard dose of chemotherapy., Conclusion: Our data indicate that if aggressive lymphoid neoplasms develop during the course of treatment in patients with MPNs, it is acceptable to prioritize chemotherapy for lymphoma.

Information regarding follow-up duration after treatment for newly diagnosed diffuse large B-cell lymphoma (DLBCL) is important. However, a clear endpoint has yet to be established. We totally enrolled 2182 patients newly diagnosed with DLBCL between 2008 and 2018. The median age of the patients was 71 years. All patients were treated with rituximab- and anthracycline-based chemotherapies. Each overall survival (OS) was compared with the age- and sex-matched Japanese general population (GP) data. At a median follow-up of 3.4 years, 985 patients experienced an event and 657 patients died. Patients who achieved an event-free survival (EFS) at 36 months (EFS36) had an OS equivalent to that of the matched GP (standard mortality ratio [SMR], 1.17; P=0.1324), whereas those who achieved an EFS24 did not have an OS comparable to that of the matched GP (SMR, 1.26; P=0.0095). Subgroup analysis revealed that relatively old patients (>60 years), male patients, those with limited-stage disease, those with a good performance status, and those with low levels of soluble interleukin 2 receptor already had a comparable life expectancy to the matched GP at an EFS24. In contrast, relatively young patients had a shorter life expectancy than matched GP, even with an EFS36. In conclusion, an EFS36 was shown to be a more suitable endpoint for newly diagnosed DLBCL patients than an EFS24. Of note, younger patients require a longer EFS period than older patients in order to obtain an equivalent life expectancy to the matched GP.

It has been suggested that the effect of coronavirus disease 2019 (COVID-19) booster vaccination in patients with B-cell non-Hodgkin's lymphoma (B-NHL) is inferior to that in healthy individuals. However, differences according to histological subtype or treatment status are unclear. In addition, there has been less research on patients who subsequently develop breakthrough infections. We investigated the effects of the first COVID-19 booster vaccination for patients with B-NHL and the clinical features of breakthrough infections in the Omicron variant era. In this study, B-NHL was classified into two histological subtypes: aggressive lymphoma and indolent lymphoma. Next, patients were subdivided according to treatment with anticancer drugs at the start of the first vaccination. We also examined the clinical characteristics and outcomes of patients who had breakthrough infections after a booster vaccination. The booster effect of the COVID-19 mRNA vaccine in patients with B-NHL varied considerably depending on treatment status at the initial vaccination. In the patient group at more than 1 year after the last anticancer drug treatment, regardless of the histological subtype, the booster effect was comparable to that in the healthy control group. In contrast, the booster effect was significantly poorer in the other patient groups. However, of the 213 patients who received the booster vaccine, 22 patients (10.3%) were infected with COVID-19, and 18 patients (81.8%) had mild disease; these cases included the patients who remained seronegative. Thus, we believe that booster vaccinations may help in reducing the severity of Omicron variant COVID-19 infection in patients with B-NHL.

Vaccination with a coronavirus disease-2019 (COVID-19) vaccine is an effective public health measure for reducing the risk of infection and severe complications from COVID-19. However, serious hematological complications after COVID-19 vaccination have been reported. Here, we report a case of new-onset hypomegakaryocytic thrombocytopenia (HMT) with the potential for progression to aplastic anemia (AA) that developed in a 46-year-old man 4 days after the fourth mRNA COVID-19 vaccination. Platelet count rapidly decreased after vaccination and white blood cell count declined subsequently. Bone marrow examination immediately after disease onset showed severely hypocellular marrow (cellularity of almost 0%) in the absence of fibrosis, findings that were consistent with AA. Since the severity of pancytopenia did not meet the diagnostic criteria for AA, the patient was diagnosed with HMT that could progress to AA. Treatment with eltrombopag and cyclosporine was started immediately after diagnosis and cytopenia improved. Although it is difficult to determine whether the post-vaccination cytopenia was vaccine induced or accidental because the association was chronological, vaccination with an mRNA-based COVID-19 vaccine may be associated with development of HMT/AA. Therefore, physicians should be aware of this rare, but serious adverse event and promptly provide appropriate treatment., (© 2023. The Author(s).)

Background: Unlike the already established effect of Helicobacter pylori ( H. pylori ) eradication on gastric mucosa-associated lymphoid tissue (MALT) lymphoma, its therapeutic effect on primary gastric diffuse large B-cell lymphoma (DLBCL) is still unclear., Aim: To clarify the efficacy of H. pylori eradication treatment for primary gastric DLBCL., Methods: We reported on 3 new cases, and added them to 3 previously reported cases. We analyzed the usefulness of H. pylori eradication treatment for gastric DLBCL for a total of 6 cases at our center., Results: Of the 6 patients (27-90 years old, 3 males and 3 females), all 3 patients with single lesions (one transformed from MALT lymphoma) achieved complete remission (CR) after H. pylori eradication. Regarding the 2 newly reported cases, CR was maintained for more than 6 years with eradication treatment alone. In contrast, none of the 3 patients with 2 lesions achieved CR. In 1 newly reported case, endoscopic CR was achieved in one lesion, while stable disease was obtained in the other lesion. Two patients with progressive disease responded to standard chemotherapy ± radiation and remained in CR for more than 6 years., Conclusion: We believe it is worthwhile to attempt H. pylori eradication for elderly patients with primary gastric DLBCL in a single lesion with a small tumor burden., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objectives: The aim of this study was to investigate the influences of hemodialysis (HD) on activities of daily living (ADL) in patients with hip fracture., Methods: This study included 28 patients (14 HD and 14 non-HD patients) with acute hip fracture. The effects of variables such as age, sex, surgical procedure, length of hospital stay, serum albumin, C-reactive protein (CRP), number of physical therapy units, and functional independence measure (FIM) were assessed. For each factor, a two-group comparison was conducted between the HD and non-HD groups. Multiple regression analysis was used to examine the factors affecting FIM efficacy (E-FIM)., Results: For HD patients, total and motor FIM at discharge, E-FIM, and albumin level were significantly lower than in non-HD patients. Length of hospital stay was significantly longer for HD patients. Multiple regression analysis showed that HD had a negative effect on E-FIM., Conclusions: The results suggest that rehabilitation for HD patients with hip fractures require intervention that not only provides standard rehabilitation but also addresses aspects of renal rehabilitation., Competing Interests: CONFLICTS OF INTEREST: The authors declare no conflict of interest., (2023 The Japanese Association of Rehabilitation Medicine.)

The JSH Practical Guidelines for Hematological Malignancies, 2018 expanded edition, newly adopted brentuximab vedotin, doxorubicin, vinblastine, dacarbazine(A+AVD)protocol as a standard treatment for advanced-stage classical Hodgkin lymphoma(CHL). Therefore, this retrospective analysis compared 15 patients who received A+AVD therapy with 21 patients who received doxorubicin, bleomycin, vinblastine, dacarbazine(ABVD)therapy. All patients were newly diagnosed with CHL and received induction therapy between April 2015 and June 2022 in our hospital. All except 1 patient of the A+AVD group had advanced-stage CHL. The median age was 63(23-85)years. The estimated 2-year overall survival of the A+AVD group was better than that of the ABVD group which included 6 patients with clinical stage Ⅲ or higher CHL (100% vs 66.7%, p=0.047). In contrast, there was no significant difference in the complete response rate(53.8% vs 100%, p=0.109)between the 2 groups. The overall response rate after first-line treatment(69.2% vs 100%, p=0.255), and the estimated 2-year progression-free survival(70.1% vs 66.7%, p=0.321)between the A+AVD and the ABVD groups were similar.

Background: We have reported that seroconversion rates after the second dose of mRNA-based COVID-19 vaccines for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) were 100% and 95% respectively, with no significant difference from healthy controls (HCs).However, there are very limited data for the response to a third vaccine dose in those patients., Aims: In this complementary study, we investigated the booster effect of a third mRNA-based COVID-19 vaccine dose in patients with myeloid malignancies., Materials & Methods: A total 58 patients including 20 patients with MDS and 38 patients with AML were enrolled. Anti-SARS-CoV-2S immunoassays were performed at 3, 6, and 9 months after the second vaccine dose., Results: Seventy-five percent of the MDS patients and 37% of the AML patients were receiving active treatment at the time of the third vaccination. Both the initial and third vaccine response in AML patients were comparable to those in HCs. In MDS patients, although the initial vaccine immunogenicity was inferior to that in HCs and AML patients, the third vaccine improved the response to a level not inferior to those in HCs and AML patients. Of note, the third vaccine resulted in a significant increase of antibodies in actively treated MDS patients who had shown a response inferior to that in untreated patients after two doses of vaccination., Discussion: In patients with myeloid malignancies, the third vaccine dose showed a booster effect, and disease- and therapy-related factors associated with the booster response have been identified., Conclusion: The third dose of an mRNA-based COVID-19 vaccine showed a booster effect in patients with myeloid malignancies. Such a good booster response has not been reported in other haematological malignancies., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Neurolymphomatosis (NL) is a rare clinical entity characterized by lymphomatous infiltration of the peripheral nervous system. According to recent retrospective data, consolidative high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) may be beneficial for NL. However, few reports to date have discussed optimal conditioning regimens. Herein, we report two cases of NL in patients with relapsed intravascular large B-cell lymphoma who received consolidative thiotepa-containing HDC-ASCT. Case 1: A 56-year-old woman who relapsed 2 months after the first complete remission (CR) and underwent ASCT. Case 2: A 65-year-old woman who relapsed 8 months after the first CR and underwent ASCT. Both patients engrafted. Time to neutrophil engraftment was 10 and 12 days after HDC-ASCT, and CR was sustained for 26 and 18 months, respectively, as of the last follow-up. Although there is little evidence supporting the utility of thiotepa-based HDC-ASCT in patients with NL, the results of this case report suggest that further studies are warranted to determine its efficacy in this setting., (© 2023. Japanese Society of Hematology.)

Serologic responses of COVID-19 vaccine are impaired in patients with B-cell lymphoma, especially those who had recently been treated with anti-CD20 monoclonal antibodies. However, it is still unclear whether those patients develop an immune response following vaccination. We investigated the efficacy of vaccination against SARS-CoV-2 in 171 patients with B-cell non-Hodgkin lymphoma (B-NHL) who received two doses of an mRNA-based COVID-19 vaccine and we compared the efficacy of vaccination to that in 166 healthy controls. Antibody titers were measured 3 months after administration of the second vaccine dose. Patients with B-NHL showed a significantly lower seroconversion rate and a lower median antibody titer than those in healthy controls. The antibody titers showed correlations with the period from the last anti-CD20 antibody treatment to vaccination, the period from the last bendamustine treatment to vaccination and serum IgM level. The serologic response rates and median antibody titers were significantly different between diffuse large B-cell lymphoma (DLBCL) patients in whom anti-CD20 antibody treatment was completed within 9 months before vaccination and follicular lymphoma (FL) patients in whom anti-CD20 antibody treatment was completed within 15 months before vaccination. Moreover, the serologic response rates and median antibody titers were significantly different among FL patients in whom bendamustine treatment was completed within 33 months before vaccination. We demonstrated that B-NHL patients who were recently treated with anti-CD20 antibodies and bendamustine had a diminished humoral response to COVID-19 vaccination. UMIN 000,045,267., (© 2023. The Author(s).)

Patients with lymphoid malignancies have impaired humoral immunity caused by the disease itself and its treatment, placing them at risk for severe coronavirus disease-19 (COVID-19) and reduced response to vaccination. However, data for COVID-19 vaccine responses in patients with mature T cell and NK-cell neoplasms are very limited. In this study of 19 patients with mature T/NK-cell neoplasms, anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike antibodies were measured at 3 months, 6 months, and 9 months after the second mRNA-based vaccination. At the time of the second and third vaccinations, 31.6% and 15.4% of the patients were receiving active treatment. All patients received the primary vaccine dose and the third vaccination rate was 68.4%. In patients with mature T/NK-cell neoplasms, both seroconversion rate (p < 0.01) and antibody titers (p < 0.01) after the second vaccination were significantly lower than those in healthy controls (HC). In individuals who received the booster dose, patients had significantly lower antibody titers than those in HC (p < 0.01); however, the seroconversion rate in patients was 100%, which was the same as that in HC. The booster vaccine resulted in a significant increase of antibodies in elderly patients who had shown a response that was inferior to that in younger patients after two doses of vaccination. Since higher antibody titers and higher seroconversion rate reduced the incidence of infection and mortality, vaccination more than three times may have the advantage for patients with mature T/NK-cell neoplasms, especially in elderly patients. Clinical trial registration number: UMIN 000,045,267 (August 26th, 2021), 000,048,764 (August 26th, 2022)., (© 2023. The Author(s).)

Data for COVID-19 vaccine response in patients with immune thrombocytopenia (ITP) are very limited. In a study of 28 patients with ITP, anti-severe acute respiratory syndrome coronavirus 2 spike antibody titres were measured after vaccination. The seroconversion rate for ITP patients was 91.3%, comparable to that in healthy controls (HCs). However, the antibody titre in ITP patients was significantly lower than that in HCs and declined with ageing. Furthermore, the antibody titre in ITP patients who received a minimum prednisolone dose of at least 5 mg/day at any time-point at or after initial vaccination was lower than that in other patients., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)