[Successful treatment with tucidinostat in a patient with relapsed adult T-cell leukemia/lymphoma following allogeneic hematopoietic stem cell transplantation].

Aggressive types of adult T-cell leukemia-lymphoma (ATL), namely, the acute type, lymphoma type, and chronic type with poor prognostic factors, have a poor prognosis. Although allogeneic hematopoietic stem cell transplantation (HSCT) may improve prognosis, relapse is common. In June 2021, tucidinostat was approved for relapsed or refractory ATL in Japan. We report a case of a 62-year-old man with relapsed ATL after allogeneic HSCT. In March 2017, he was diagnosed with ATL (acute type) and received two courses of mLSG-15 therapy. ATL cells reappeared in his peripheral blood, so he underwent allogeneic bone marrow transplantation in September 2017. In June 2021, his soluble interleukin-2 receptor (sIL-2R) level increased, and he began experiencing sensory abnormalities in his face and legs. In September, he developed respiratory failure and was diagnosed with relapse of ATL. He was again treated with mLSG-15. His sIL-2R normalized and the sensory abnormalities decreased, but sIL-2R rose again in February 2022. After tucidinostat treatment was initiated, sIL-2R normalized and the patient's general condition improved. Tucidinostat shows promise as an effective treatment for ATL that has relapsed after allogeneic HSCT.

Real-world clinical characteristics of post-essential thrombocythemia and post-polycythemia vera myelofibrosis.

There are few prospective studies on patients with post-essential thrombocythemia myelofibrosis (PET-MF) and post-polycythemia vera myelofibrosis (PPV-MF). Therefore, we conducted a nationwide longitudinal prospective survey to clarify the clinical characteristics of these diseases. A total of 197 PET-MF and 117 PPV-MF patients diagnosed between 2012 and 2021 were analyzed. The median age at diagnosis was 70.0 years for both diseases. The time from diagnosis of ET or PV to that of MF was 9.6 and 10.4 years, respectively, with no significant difference. Patients with PPV-MF had higher hemoglobin levels and white blood cell counts than those with PET-MF, whereas those with PET-MF had higher platelet counts than those with PPV-MF. Although splenomegaly was more frequent in patients with PPV-MF at diagnosis, there was no difference in the frequency of constitutional symptoms. Ruxolitinib was the most common treatment administered to 74.6% and 83.8% of patients with PET-MF and PPV-MF, respectively. Patients with PET-MF and PPV-MF had similar prognoses, with 3-year overall survival (OS) of 0.742 in PET-MF and 0.768 in PPV-MF patients. In both diseases, leukemic transformation was the leading cause of death, followed by infection. The 3-year OS for patients with PET/PPV-MF and primary MF diagnosed during the same period was 0.754 and 0.626, respectively, with no significant difference. This survey provides real-world clinical features and prognostic data on secondary myelofibrosis in the ruxolitinib era.

Pathogenicity chromosome of Fusarium oxysporum f. sp. cepae.

Fusarium oxysporum f. sp. cepae (Foc) is the causative agent of Fusarium basal rot disease in onions, which leads to catastrophic global crop production losses. Therefore, the interaction of Foc with its host has been actively investigated, and the pathogen-specific (PS) regions of the British strain Foc_FUS2 have been identified. However, it has not been experimentally determined whether the identified PS region plays a role in pathogenicity. To identify the pathogenicity chromosome in the Japanese strain Foc_TA, we initially screened effector candidates, defined as small proteins with a signal peptide that contain two or more cysteines, from genome sequence data. Twenty-one candidate effectors were identified, five of which were expressed during infection. Of the expressed effector candidates, four were located on the 4-Mb-sized chromosome in Foc_TA. To clarify the relationship between pathogenicity and the 4-Mb-sized chromosome in Foc_TA, nine putative 4-Mb-sized chromosome loss strains were generated by treatment with benomyl (a mitotic inhibitor drug). A pathogenicity test with putative 4-Mb-sized chromosome loss strains showed that these strains were impaired in their pathogenicity toward onions. Genome analysis of three putative 4-Mb-sized chromosome loss strains revealed that two strains lost a 4-Mb-sized chromosome in common, and another strain maintained a 0.9-Mb region of the 4-Mb-sized chromosome. Our findings show that the 4-Mb-sized chromosome is the pathogenicity chromosome in Foc_TA, and the 3.1-Mb region within the 4-Mb-sized chromosome is required for full pathogenicity toward onion.

COVID­19 antibody production by vaccination in chemotherapy with CD20 antibody for B­cell lymphoma.

Most hematologic diseases are immunosuppressed, either by the disease itself or by treatment. As such, the implementation of vaccination is largely at the discretion of the attending physician. In this context, an objective measure is needed, therefore the index of vaccination against coronavirus disease 2019 (COVID-19) in B-cell lymphomas treated with antibody therapy against CD20 (including after the completion of therapy) was examined. A total of 40 patients with B-cell lymphoma during or after antibody therapy against CD20 were vaccinated twice with the BNT162b2 messenger RNA (mRNA) COVID-19 vaccine (Pfizer, Inc. and BioNTech SE.) at 3-week intervals and then again six months later with the same vaccine or mRNA-1273 (Moderna, Inc.). Antibody testing was conducted ~1 month after the third vaccination. Analysis was performed using the antibody titers to the anti-spike immunoglobulin assay, with a titer of 0.8 U/ml or higher (considered positive) and a titer of 264 U/ml or higher (considered the value at which the efficacy of the vaccine can be fully expected). Significant factors of antibody acquisition were identified when i) antibody titers were 0.8 U/ml or higher (CD4 ≥400/µl), ii) no anti-CD20 antibody maintenance therapy was undertaken (CD19 ≥100/µl), iii) patients were not on treatment (CD4 ≥400/µl), or 4) at least six months had passed since treatment ended (CD19 ≥100/µl). When antibody titers were 264 U/ml or higher, the treatment method, the stage of the primary disease and other factors related to the condition treatment method of the patient were relevant. When these were analyzed by multivariate analysis, the significant factor when antibody titers were set to 0.8 U/ml was CD19 ≥100/µl. In contrast, when setting them to 264 U/ml or higher, CD4 ≥400/µl was not significant, but there was a tendency for it to be related. The findings of the present study on vaccine-induced antibody acquisition in patients with B-cell lymphoma indicated that it is desirable to have a CD19 titer of at least 100/µl and a CD4 titer of at least 400/µl (both conditions should be met), and that no maintenance therapy with anti-CD20 antibody should be administered for at least six months after the last treatment or completion of the treatment. Interestingly, when the criteria for antibody titers were compared between 0.8 U/ml, where antibody titer is detected, and 264 U/ml, where vaccine efficacy is expected, several key factors were different. It is possible that these key factors may change depending on the antibody titer used as a criterion.

Hepatitis C Virus (HCV)-Ribonucleic Acid (RNA) As a Biomarker for Lymphoid Malignancy with HCV Infection.

The hepatitis C virus (HCV) is potentially associated with liver cancer, and advances in various drugs have led to progress in the treatment of hepatitis C and attempts to prevent its transition to liver cancer. Furthermore, reactivation of HCV has been observed in the treatment of lymphoma, during which the immortalization and proliferation of lymphocytes occur, which leads to the possibility of further stimulating cytokines and the like and possibly to the development of lymphoid malignancy. There are also cases in which the disappearance of lymphoid malignancy has been observed by treating HCV and suppressing HCV-Ribonucleic acid (RNA), as well as cases of recurrence with an increase in HCV-RNA. While HCV-associated lymphoma has a poor prognosis, improving the prognosis with Direct Acting Antivirals (DAA) has recently been reported. The reduction and eradication of HCV-RNA by means of DAA is thus important for the treatment of lymphoid malignancy associated with HCV infection, and HCV-RNA can presumably play a role as a biomarker. This review provides an overview of what is currently known about HCV-associated lymphoma, its epidemiology, the mechanisms underlying the progression to lymphoma, its treatment, the potential and limits of HCV-RNA as a therapeutic biomarker, and biomarkers that are expected now that DAA therapy has been developed.

Convulsive Seizure Due to Hypomagnesemia Caused by Short-term Vonoprazan Intake.

A 71-year-old woman was admitted for the treatment of diffuse large B-cell lymphoma of the ileum. She had been taking lansoprazole but was switched to vonoprazan due to epigastric discomfort. Three weeks after starting vonoprazan intake, she had a convulsive seizure, and a blood test showed hypomagnesiemia. The cause of hypomagnesemia was considered to be malabsorption of magnesium from the intestinal tract associated with vonoprazan. After discontinuation of vonoprazan, the magnesium level quickly recovered, and the seizures did not relapse. It is important to consider the risk of hypomagnesemia in patients taking vonoprazan, even for a short period of time.

Patients with marginal zone dural lymphoma successfully treated with rituximab and bendamustine: A report of two cases.

Primary dural low-grade marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) is a rare disease whose main treatment has been local surgery or radiotherapy. Until now, there have been no cases of dural MALT lymphoma treatment of a patient with several relapses or systemic disease. The present study included two patients with dural MALT lymphoma who had several relapses or systemic disease. Since local therapy was not enough to control the disease for these patients, they were treated with systemic chemotherapy. The patients were administered rituximab (375 mg/m2) and two days of bendamustine (90 mg/m2). Both patients recovered from their clinical symptoms immediately, and their tumors were reduced. During and after rituximab and bendamustine therapy, no central nervous system (CNS) metastasis or cerebrospinal fluid invasion of MALT were observed. The current approach using rituximab and bendamustine treatment was effective against dural MALT lymphoma and may prevent its invasion of the CNS.

Correcting anemia and native vitamin D supplementation in kidney transplant recipients: a multicenter, 2 × 2 factorial, open-label, randomized clinical trial.

Anemia and vitamin D deficiency are associated with allograft failure, and hence, are potential therapeutic targets among kidney transplant recipients (KTRs). We conducted a multicenter, two-by-two factorial, open-label, randomized clinical trial to examine the effects of anemia correction and vitamin D supplementation on 2-year change in eGFR among KTRs (CANDLE-KIT). We enrolled 153 patients with anemia and >1-year history of transplantation across 23 facilities in Japan, and randomly assigned them to either a high or low hemoglobin target (>12.5 vs. <10.5 g/dl) and to either cholecalciferol 1000 IU/day or control. This trial was terminated early based on the planned interim intention-to-treat analyses (α = 0.034). Among 125 patients who completed the study, 2-year decline in eGFR was smaller in the high vs. low hemoglobin group (i.e., -1.6 ± 4.5 vs. -4.0 ± 6.9 ml/min/1.73 m2 ; P = 0.021), but did not differ between the cholecalciferol and control groups. These findings were supported by the fully adjusted mixed effects model evaluating the rate of eGFR decline among all 153 participants. There were no significant between-group differences in all-cause death or the renal composite outcome in either arm. In conclusion, aggressive anemia correction showed a potential to preserve allograft kidney function.

Ethanol-ethylene conversion mechanism on hydrogen boride sheets probed by in situ infrared absorption spectroscopy.

Two-dimensional hydrogen boride (HB) sheets were recently demonstrated to act as a solid acid catalyst in their hydrogen-deficient state. However, both the active sites and the mechanism of the catalytic process require further elucidation. In this study, we analyzed the conversion of ethanol adsorbed on HB sheets under vacuum during heating using in situ Fourier transform infrared (FT-IR) absorption spectroscopy with isotope labelling. Up to 450 K, the FT-IR peak associated with the OH group of the adsorbed ethanol molecule disappeared from the spectrum, which was attributed to a dehydration reaction with a hydrogen atom from the HB sheet, resulting in the formation of an ethyl species. At temperatures above 440 K, the number of BD bonds markedly increased in CD3CH2OH, compared to CH3CD2OH; the temperature dependence of the formation rate of BD bonds was similar to that of the dehydration reaction rate of ethanol on HB sheets under steady-state conditions. The rate-determining step of the dehydration of ethanol on HB was thus ascribed to the dehydrogenation of the methyl group of the ethyl species on the HB sheets, followed by the immediate desorption of ethylene. These results show that the catalytic ethanol dehydration process on HB involves the hydrogen atoms of the HB sheets. The obtained mechanistic insights are expected to promote the practical application of HB sheets as catalysts.

Magnesium oxide induces immunity against Fusarium wilt by triggering the jasmonic acid signaling pathway in tomato.

Fusarium wilt, caused by Fusarium oxysporum f. sp. lycopersici (FOL), is a worldwide tomato disease. Although Fusarium wilt management remains unsuccessful, enhancing host FOL resistance using magnesium oxide to activate plant immunity may enable effective control. We demonstrated that MgO-pretreatment of roots induced FOL resistance in susceptible tomato plants. Resistance was not induced in tomato mutants deficient in the jasmonic acid (JA) signaling pathway, whereas the opposite trend was observed in mutants deficient in the salicylic acid and ethylene signaling pathways, suggesting that JA signaling activation is essential for MgO-induced FOL immunity. Quantitative real-time polymerase chain reaction analysis of MgO-pretreated tomato plants, and challenge-inoculated with FOL, revealed that MYELOCYTOMATOSIS ONCOGENE HOMOLOG 2 (MYC2), the master regulator of JA signaling, as well as MYC2-targeted transcription factors that directly regulate the JA-induced transcription of late defense genes and their downstream wound-responsive genes were preferentially upregulated in both roots and stems. Moreover, in MgO-pretreated tomato plants challenge-inoculated with FOL, the late wound-responsive THREONINE DEAMINASE 2 (TD) gene was expressed earlier than its upstream genes, including MYC2, suggesting that a primed state for defense was established in MgO-pretreated plants. We conclude that MgO is a promising agent for the control of Fusarium wilt.

Lymphocyte-monocyte ratio (LMR) can predict bendamustine therapeutic efficacy in low-grade B-cell lymphoma.

INTRODUCTION: Bendamustine has been reported to be effective against low-grade B-cell lymphoma. We examined the effect of bendamustine on the lymphocyte-monocyte ratio (LMR) in low-grade B-cell lymphoma patients. METHODS: We retrospectively reviewed 127 cases of first line or relapse/refractory low-grade B-cell lymphoma in three individual institutions (Asahikawa Municipal Hospital, Aiiku Hospital, and Hakodate Municipal Hospital). Only patients who had received at least three courses of bendamustine therapy were selected; the LMR was evaluated at starting the initial course of bendamustine therapy. Time to next treatment (TTNT) was used to ascertain the efficacy of bendamustine therapy. RESULTS: Follicular lymphoma (FL), at 68.5% (87/127), is the most common histological subtype of low-grade B-cell lymphoma. The receiver operating characteristic (ROC) curve for the LMR showed a cutoff value of 2.0, and 33 cases (26.0%) had an LMR ≤2.0. Cases with LMR ≤2.0 had a significantly earlier progression than those with LMR > 2.0, based on the TTNT (P = .0007). Additionally, LMR ≤2.0 indicates earlier progression in TTNT when comparing only FL and low-grade B-cell lymphoma cases without FL (P = .007, 0.002). For multivariate analysis, the factors associated with an LMR ≤2.0 (HR, 2.741; 95% CI, 1.4330-5.245; P = .002) were considered as early progression factors with regard to the TTNT. CONCLUSION: Lymphocyte-monocyte ratio effectively predicts the efficacy of bendamustine therapy for low-grade B-cell lymphoma, particularly FL; its application may improve treatment strategies for this disease.

Extracellular calcium stimulates osteogenic differentiation of human adipose-derived stem cells by enhancing bone morphogenetic protein-2 expression.

Bone morphogenetic protein-2 (BMP-2) promotes the differentiation of non-osteogenic mesenchymal cells to osteogenic cells. In this study, we isolated human adipose-derived stem cells (hASCs) and investigated the effects of recombinant human BMP-2 (rhBMP-2) and extracellular Ca2+ concentration ([Ca2+]out) on the osteogenic differentiation of hASCs. rhBMP-2 promoted calcium deposition in hASCs and stimulated the mRNA expressions of six proteins known to be involved in the osteogenic differentiation of hASCs: Runx2, osterix, alkaline phosphatase, osteonectin, bone sialoprotein and osteocalcin. Elevation of [Ca2+]out enhanced the level of alkaline phosphatase enzyme, increased the mRNA expressions of Runx2 and osteocalcin and induced the expressions of BMP-2 mRNA and protein in hASCs. Elevation of [Ca2+]out transiently increased the intracellular Ca2+ concentration ([Ca2+]in) due to activation of the calcium-sensing receptor (CaSR). The Ca2+-induced expressions of BMP-2 mRNA and protein were inhibited by the calmodulin antagonist, W-7. Furthermore, elevation of [Ca2+]out decreased the cytoplasmic level of phosphorylated nuclear factor of activated T-cell-2 (NFAT-2) and increased the nuclear level of dephosphorylated NFAT2. Taken together, these results suggest that rhBMP-2 promotes the osteogenic differentiation of hASCs. Furthermore, an increase in [Ca2+]out enhances the expression of BMP-2 via activation of the CaSR, elevation of [Ca2+]in and stimulation of Ca2+/calmodulin-dependent NFAT-signaling pathways.

Ibrutinib Caused Mediastinal Emphysema and Pneumothorax in the Treatment of a Patient with Mantle Cell Lymphoma.

A 70-year-old Japanese man with mantle cell lymphoma underwent extensive chemotherapy and radiation because of the relapse of mantle cell lymphoma. He developed mediastinal emphysema and a pneumothorax 14 days after treatment with 560 mg of ibrutinib. The mediastinal emphysema and the right pneumothorax disappeared after the ibrutinib treatment was tapered off. The patient developed interstitial pneumonia without any infection and new lesions of mantle cell lymphoma in the lungs after restarting treatment with 560 mg of ibrutinib. In this case, the patient developed pneumonia after retreatment with ibrutinib, suggesting the small lung fibrosis that penetrated the mediastinum might have caused the emphysema and pneumothorax.

Myasthenia gravis after allogeneic bone marrow transplantation: A case report and literature review.

A 52-year-old man with acute myeloid leukemia underwent allogeneic hematopoietic stem cell transplantation and developed extensive chronic graft-versus-host disease and myasthenia gravis (MG), which became involved with oculobulbar and proximal upper and lower limb weakness in 677days. In the literature, we identified 24 cases where MG developed after allo-SCT. Graft-versus-host disease development and male recipients of female donors might be prone to the development of posttransplant MG (odds ratio, 3.75).

[Thrombotic microangiopathy developing subsequent to tocilizumab therapy in a patient with TAFRO syndrome].

We report a case of a 60-year-old male who presented with fever and anasarca as well as hepatosplenomegaly, general lymphadenopathy, and disseminated intravascular coagulation (DIC), and was, therefore, admitted to our hospital. In addition, the patient suffered from respiratory failure and renal dysfunction and had pleural effusion and ascites. The pathological diagnosis from lymph node biopsy suggested multicentric Castleman's disease of the plasma cell type; however, the presence of high IL-6 levels, myelofibrosis, thrombocytopenia, anasarca, renal dysfunction, and hepatosplenomegaly led to a definitive diagnosis of TAFRO syndrome. Tocilizumab was administered on day 15 of disease diagnosis, resulting in the improvement in DIC but not other symptoms. As schizocytes were detected in the peripheral blood, he also experienced disturbance of consciousness and thrombotic microangiopathy (TMA) was considered. Following plasma exchange (PE) and continuous hemodiafiltration (CHDF), his symptoms temporarily improved. However, his condition worsened again, and he eventually died on day 33. Pathological autopsy revealed that although the lymph nodes were not enlarged, he had organomegaly, gastrointestinal and omental hemorrhage, and acute necrotizing pancreatitis. Since TMA developed after the administration of tocilizumab, the possibility of drug-induced secondary TMA cannot be ruled out.

Severe adverse events by tyrosine kinase inhibitors decrease survival rates in patients with newly diagnosed chronic-phase chronic myeloid leukemia.

OBJECTIVE: This multicenter cooperative study aimed to analyze the adverse events (AEs) associated with tyrosine kinase inhibitors (TKIs) used as initial treatment for chronic-phase chronic myeloid leukemia (CML-CP) and their impact on outcome. METHODS: We retrospectively evaluated 450 patients with CML-CP who received TKIs between 2004 and 2014. RESULTS: The 5-year overall survival (OS) and event-free survival (EFS) rates were 95.1% and 89.0%, respectively. Patients with comorbidities (46.4%) and aged ≥60 years (50.4%) at diagnosis had significantly inferior OS to those without comorbidities and aged <60. Patients achieved higher rates of major molecular response (MMR) at 6 and 12 months after initial treatment with dasatinib or nilotinib compared to imatinib, but final MMR rates were almost the same. Sixty-six percent of patients required treatment modifications from first-line TKI therapy; the main reasons were AEs (48.4%) and failure (18%). Grade III-IV AEs in first-line TKI therapy were significantly correlated to inferior OS/EFS compared to grade 0-II AEs. CONCLUSION: Although long-term outcomes were similar in CML-CP patients treated with each TKI regardless of first-line TKI selection, severe AEs in first-line TKI therapy decreased their survival rates. Early change in TKIs is recommended, when faced with severe AEs of specific TKIs.

Anesthetic Management of a Patient With a History of Rhabdomyolysis for Dental Treatment.

When general anesthesia is administered for patients considered at high risk for rhabdomyolysis, appropriate precautions are warranted. The use of suitable anesthetics, with attention to intravenous fluid management, electrolyte balance, respiration, and metabolism, should be addressed. We performed general anesthesia for dental treatment and biopsy for fibrous hyperplasia of the buccal mucosa in a patient with a history of rhabdomyolysis. We utilized thiamylal sodium, midazolam, rocuronium bromide, nitrous oxide, fentanyl, and remifentanil without using volatile anesthetics and propofol for this case. No complications of rhabdomyolysis were noted.

Comparative investigation of the anti-emetic effects of granisetron and palonosetron during the treatment of acute myeloid leukemia.

Chemotherapy-induced nausea and vomiting has a considerable negative impact on the quality of life of patients with cancer. Unfortunately, there has been little progress in the development of supportive therapies for the anti-emetic treatment of patients with hematopoietic tumors. This lack of supportive treatments motivated the present retrospective comparison between two groups of anti-emetic drugs. The current study aimed to compare granisetron and palonosetron in order to determine which is more effective, based on cases of patients undergoing remission induction therapy and consolidation therapy for the treatment of acute myeloid leukemia. Granisetron or palonosetron were administered in Japanese-approved dosages (3 mg granisetron once per day for 5 or 7 days, or one administration of 0.75 mg palonosetron). Patients were randomly selected, and their clinical information was acquired from medical records. The data represent the doctors' and nurses' records. The results demonstrated that palonosetron treatment (in which the drug was administered alone or in combination with aprepitant) was more effective than granisetron treatment for the complete control of acute vomiting. Therefore, in the treatment of hematopoietic malignancies, palonosetron is an effective regimen to be administered alongside more than 5 continuous days of anti-cancer agents. Furthermore, the combination of palonosetron and aprepitant was found to be the optimal combination. In conclusion, palonosetron is superior to granisetron for the prevention of nausea and vomiting induced by chemotherapy for hematological cancers. In Japan, the standard dose of palonosetron is 0.75 mg; a dose of 0.25 mg of palonosetron must be compared with 0.75 mg in future studies.