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Background/aim: To evaluate the association between prophylactic administration of clarithromycin (CAM) and the development of radiation pneumonitis (RP) in patients treated with intensity modulated radiation therapy (IMRT) for lung cancer., Patients and Methods: A total of 89 patients who underwent definitive or salvage IMRT for lung cancer were retrospectively evaluated. The median total and daily doses were 60 Gy and 2 Gy, respectively. A total of 39 patients (44%) received CAM for a median of three months after the start of IMRT. The relationship between the development of RP and certain clinical factors was analyzed., Results: RP of Grade ≥2 was recognized in 10 (11%) patients; Grade 2 in six patients and Grade 3 in four patients. The incidence of Grade ≥2 RP was 3% (1/39) in patients treated with CAM, which was significantly lower than that of 18% (9/50) in patients without CAM. The median lung V20 and V5 in the 10 patients with RP Grade ≥2 were 24% and 46%, respectively, compared with 18% and 37% in the 79 patients with RP Grade 0-1, and the differences were significant. Durvalumab administration after IMRT was also a significant factor for RP Grade ≥2., Conclusion: Prophylactic administration of CAM may reduce Grade ≥2 RP in patients treated with IMRT for lung cancer. Therefore, further clinical trials are warranted., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Secondary central nervous system involvement (sCNSi) in diffuse large B-cell lymphoma (DLBCL) is fatal. However, its features in patients with sCNSi who are categorized as lower risk by international prognostic index (IPI) or CNS-IPI are not yet fully understood. In the present analysis, we evaluated DLBCL patients who developed sCNSi at their first progression and who participated in JCOG0601, most of whom were lower risk by IPI. Of 409 patients, 21 (5.1%) developed sCNSi during a median follow-up of 4.9 years. Five-year cumulative incidence of sCNSi were 5.1%; and 4.0%, 5.3%, and 11.5% at low, intermediate, and high risk of CNS-IPI, respectively. The most common locations of extranodal lesions at the time of registration in patients with sCNSi were the stomach (n = 4), paranasal cavity (n = 3), and bone marrow (n = 2). In univariable analysis, paranasal cavity lesion was a high-risk factor for sCNSi (subdistribution hazard ratio, 4.34 [95% confidence interval 1.28-14.73]). Median overall survival after sCNSi was 1.3 years, with a 2-year overall survival rate of 39.3%. The incidence of sCNSi in DLBCL patients at lower risk of CNS-IPI was low, as previously reported, but paranasal cavity lesion might indicate high risk for organ involvement. CLINICAL TRIAL REGISTRATION: JCOG0601 was registered in the UMIN Clinical Trials Registry (UMIN000000929, date of registration; December 04, 2007) and the Japan Registry of Clinical Trials (jRCTs031180139, date of registration; February 20, 2019)., (© 2024. The Author(s).)

Viral cell-free DNA (cfDNA) in plasma has been widely evaluated for detecting cancer and monitoring disease in virus-associated tumors. We investigated whether the amount of cfDNA of human T-cell leukemia virus type 1 (HTLV-1) correlates with disease state in adult T-cell leukemia-lymphoma (ATL). HTLV-1 cfDNA in aggressive ATL was significantly higher than that in indolent ATL and asymptomatic carriers. Notably, patients with lymphoma type represented higher HTLV-1 cfDNA amount than chronic and smoldering subtypes, though they had no abnormal lymphocytes in the peripheral blood. HTLV-1 cfDNA can be a universal biomarker that reflects the expansion of ATL clones., Competing Interests: The authors declare they have no conflicts of interest., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

A 67-year-old man complained of lower limb edema with a purpuric skin rash. Laboratory tests revealed proteinuria, elevated serum creatinine levels, and low serum albumin levels. The patient was also positive for cryoglobulin in serum, immunoglobulin (Ig) M gammopathy, hypocomplementemia, and rheumatoid factor. He was negative for anti-hepatitis C virus antibodies. A pathological analysis of the renal tissue revealed membranoproliferative glomerulonephritis, common histological features of cryoglobulinemic vasculitis (CV), and mucosa-associated lymphoid tissue lymphoma invasion. Although hematologic malignancy is a rare cause of type II CV, these clinical findings suggest that mucosa-associated lymphoid tissue lymphoma (MALT) lymphoma may have been the cause in the present case.

Objective: Treatment-free remission (TFR) after tyrosine kinase inhibitor (TKI) discontinuation at the first attempt is a therapeutic goal for patients with chronic phase chronic myeloid leukemia (CML-CP). However, it remains unclear whether discontinuation of TKIs at a second or subsequent attempt can be performed safely., Patients and Method: Here, we report a 72-year-old man diagnosed with CML-CP. He achieved TFR successfully after TKI discontinuation at the third attempt. Before discontinuation, the patient received imatinib, nilotinib, and finally nilotinib. His neutrophil count at the third attempt was higher than after the second attempt. We also performed a retrospective investigation of 53 patients who discontinued TKIs on the first or subsequent attempts., Results: Overall, 64 TKI discontinuations were documented (first, 53; second, ten; third, one). We found that a higher neutrophil count at the time of TKI discontinuation (>2439/μL; hazard ratio, 0.325; 95% confidence interval, 0.137-0.772; p  = 0.011) was associated independently with lower rates of molecular relapse., Conclusion: We report a case of a patient who successfully achieved third attempt TKI discontinuation and, an increased neutrophil percentage may reflect stronger antitumor immune responses in patients with CML-CP.

Background: The purpose of this study was to evaluate the efficacy and toxicity of adding regional hyperthermia to intensity-modulated radiotherapy (IMRT) plus neoadjuvant androgen deprivation therapy (ADT) for high-risk localized prostate carcinoma., Methods: Data from 121 consecutive patients with high-risk prostate carcinoma who were treated with IMRT were retrospectively analyzed. The total planned dose of IMRT was 76 Gy in 38 fractions for all patients; hyperthermia was used in 70 of 121 patients. Intra-rectal temperatures at the prostate level were measured to evaluate thermal dose., Results: Median number of heating sessions was five and the median total thermal dose of CEM43T90 was 7.5 min. Median follow-up duration was 64 months. Addition of hyperthermia to IMRT predicted better clinical relapse-free survival. Higher thermal dose with CEM43T90 (>7 min) predicted improved biochemical disease-free survival. The occurrence of acute and delayed toxicity ≥Grade 2 was not significantly different between patients with or without hyperthermia., Conclusions: IMRT plus regional hyperthermia represents a promising approach with acceptable toxicity for high-risk localized prostate carcinoma. Further studies are needed to verify the efficacy of this combined treatment.

Recently, allogeneic peripheral blood stem cell transplantation from human leukocyte antigen (HLA)-haploidentical donors using post-transplantation cyclophosphamide (PTCY-haploPBSCT) has become available in clinical practice. However, the efficacy of PTCY in adult T-cell leukemia (ATL) is not fully established yet. In this study, we retrospectively examined data of seven patients who underwent PTCY-haploPBSCT. The overall survival rate at 100 days after transplantation was 85.7%, and the 1-year overall survival rate was 68.6%. The cumulative incidence of relapse at 1 year was 31.4%, whereas the 1-year nonrelapse mortality was 17.1%. The cumulative incidence of grade III-IV acute graft-versus-host disease (GVHD) on day 100 was 14.3%, and the incidence of chronic GVHD at 1 year was 33.3%. These results suggest that PTCY-haploPBSCT can be a viable option even in patients with ATL. Further accumulation of knowledge and improvement of transplantation outcomes are warranted in the future.

Rapid immune reconstitution without developing graft-versus-host disease (GVHD) is required for the success of allogeneic hematopoietic stem cell transplantation. Here, we analyzed the effects of pharmacological MEK inhibition on human polyclonal T-cell reconstitution in a humanized mouse GVHD model utilizing deep sequencing-based T-cell receptor (TCR) repertoire analysis. GVHD mice exhibited a skewed TCR repertoire with a common clone within target organs. The MEK inhibitor trametinib ameliorated GVHD and enabled engraftment of diverse T-cell clones. Furthermore, trametinib also ameliorated GVHD sparing diverse T cell repertoire, even when it was given from day 15 through 28. Although tacrolimus also reduced development of GVHD, it disturbed diverse T cell reconstitution and resulted in skewed TCR repertoire. Thus, trametinib not only suppresses GVHD-inducing T cells but also promotes human T cell reconstitution in vivo, providing a novel rationale for translational studies targeting human GVHD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to evaluate the effectiveness of the clinical setting for deep regional hyperthermia of an 8 MHz radiofrequency (RF) capacitively coupled device in the pelvis by using numerical simulations of the electromagnetic field. Methods: A three-dimensional patient model of cervical cancer of the uterus in an obese patient was reconstructed with computed tomography data. The specific absorption rate (SAR) and temperature distributions among the various heating settings were evaluated using numerical simulations. Results: The averaged SAR value of the deep target tumor was similar between with or without overlay boluses (OBs), and that of the subcutaneous fat (SF) at the edges of cooling boluses with OBs was lower than that of the SF without OBs. The use of OBs reduced the overheating of the SF. The 0.5% salt solution in the OB produced the least overheated areas outside the deep target tumor compared with the other concentrations. The insertion of the intergluteal cleft (IGC) bolus could improve the temperature concentration of the deep target tumor. Conclusions: The use of OBs and the salt solution concentration in the OB were important to optimize the temperature distribution. IGC bolus might contribute to temperature optimization. Further studies with individualized numerical simulations in each patient are expected.

A sufficient dose of radiation is difficult to administer in re-irradiation for local recurrence of cancer after radiotherapy because of the dose limitation to organs at risk. Re-irradiation cases also include radioresistant tumors that are difficult to control locally, and their prognosis is poor in general. The effect of re-irradiation using intensity-modulated radiotherapy (IMRT) has recently been reported to significantly reduce the dose to organs at risk, and the efficacy of hyperthermia has been reported for radioresistant tumors. We report a case of local recurrence after concurrent chemoradiotherapy treated with salvage re-irradiation using IMRT and chemotherapy combined with hyperthermia in a patient with nasopharyngeal carcinoma, and include a discussion of the literature.

Although the prognosis of chronic myeloid leukemia (CML) in blastic crisis remains poor, some patients achieve long-term remission after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This may be attributable to graft-versus-leukemia (GVL) effects by donor lymphocytes, but their regulating mechanisms are unclear. Antitumor natural killer (NK) cell immunity is assumed to be important in CML, and we have previously shown that allelic polymorphisms of killer immunoglobulin-like receptors (KIRs) and histocompatibility leukocyte antigens (HLAs) are associated with the response of CML to tyrosine kinase inhibitors. Here, we report a case of CML in blastic phase who received HLA-matched but KIR3DL1 allelic-mismatched allo-HSCT. After transplant, decreased BCR-ABL transcript levels and enhanced NK cell activity were transiently observed. However, reconstitution of KIR3DL1-expressing NK cells occurred, which was associated with diminished NK cell activity and increased BCR-ABL. This case indicates the potential significance of KIR3DL1 in NK cell-mediated GVL activity following allo-HSCT. To the best of our knowledge, this is the first report to analyze the association between sequential KIR3DL1 expression and activity of NK cells after allo-HSCT. Selecting donors with KIR3DL1-null alleles may maintain competent GVL effects and provide improved outcomes in allo-HSCT for CML.

To diagnose graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is sometimes difficult. We showed previously that MEK inhibitors selectively suppress murine GVHD while retaining antiviral and antitumor immunity. Here, we asked whether the RAS/MEK/ERK pathway is activated in human allo-HSCT recipients with GVHD, and whether the phosphorylated ERK1/2 can be a biomarker of GVHD. Peripheral blood was sequentially collected from 20 allo-HSCT recipients: 1 bone marrow transplant, 7 peripheral blood stem cell transplants (PBSCT), and 12 cord blood transplants. Ten of the 20 allo-HSCT recipients developed GVHD, and phosphorylation of ERK1/2 in T and B cells was analyzed by flow cytometry. Occurrence of acute GVHD was associated with phosphorylation of ERK1/2 in CD4+ T cells at day 30 (P < .001), which was suppressed by ex vivo exposure to a MEK inhibitor trametinib at clinically achievable concentrations. In particular, ERK1/2 was phosphorylated preferentially in naive/central memory CD4+ T cells. Notably, phosphorylation of ERK1/2 fell as GVHD improved. These results suggest that phosphorylation status of ERK1/2 in peripheral blood CD4+ T cells may be a future biomarker for diagnosing human GVHD, and the potential efficacy of MEK inhibitors against human GVHD., (© 2020 by The American Society of Hematology.)

Radiation recall pneumonitis is a phenomenon in which a recall-triggering drug induces an acute inflammatory reaction in the lungs, corresponding to a previously irradiated area. Radiation recall reactions have been reported to occur following treatments with various cytotoxic anticancer agents and molecular-targeting drugs; however, only a few reports have described immune checkpoint inhibitor-induced radiation recall pneumonitis. We report a case of radiation recall pneumonitis induced by pembrolizumab in a patient with the postoperative local recurrence of non-small cell lung cancer. This case demonstrated that pembrolizumab might cause severe radiation recall pneumonitis, even after typical radiation pneumonitis has been resolved.

Novel anti-myeloma drugs have significantly improved the overall survival (OS) of patients with multiple myeloma (MM). However, not all MM patients treated with these drugs show survival benefits, and biologic and genetic prognostic factors are insufficient to predict the response to treatment. Decreasing treatment-related complications is important to improve the efficacy of treatment in patients with MM. The Controlling Nutritional Status (CONUT) score is a screening method for poor nutritional status, which is associated with poor prognosis in several cancers because it increases the rate of treatment-related complications. We retrospectively analyzed the OS of 64 patients with symptomatic MM and evaluated the correlation between the CONUT score and patient prognosis in MM. The median age at diagnosis was 66 years, and multivariate analysis showed that a high CONUT score (≥ 5; hazard ratio, 3.937; 95% confidence interval, 1.214-12.658; P = 0.022) was an independent prognostic risk factor. Subgroup analysis was performed according to patient age because the choice of treatment strategy, particularly autologous peripheral blood stem cell transplantation (auto-PBSCT), can vary depending on age in MM patients. Younger patients (< 65 years old) who received auto-PBSCT and had a lower CONUT score (0-3) showed a significantly better survival outcome than those with a higher CONUT score (≥ 4) (median OS, not reached vs. 64.1 months; P = 0.011). The CONUT score is simple to calculate and provides a useful prognostic indicator in patients with MM, especially transplant-eligible patients.

Accurate risk assessment to determine the eligibility for allogeneic hematopoietic stem cell transplantation (allo-HCT) in patients with adult T cell leukemia (ATL) is necessary to improve survival outcomes. The controlling nutritional status (CONUT) score predicts prognosis in several tumors; however, the prognostic significance of the CONUT score in ATL remains unclear. The present study investigated the correlation between the CONUT score and the survival outcomes of transplant-eligible ATL patients. Mogamulizumab, a humanized monoclonal antibody against C-C chemokine receptor 4, was recently identified as a promising salvage chemotherapy agent for transplant-ineligible ATL patients. We therefore evaluated the efficacy of mogamulizumab in transplant-ineligible ATL patients. Patients diagnosed with aggressive ATL (acute lymphoma of unfavorable chronic type) between January 2008 and March 2017 at Saga University Hospital, Japan, were retrospectively enrolled. Of 54 patients, 25 were < 70 years of age and 14 received allo-HCT. The median overall survival (OS) and non-relapse mortality (NRM) rate at 1 year among patients receiving allo-HCT were 1685.5 days and 30% in those with a CONUT score 0-3 (n = 10) and 184.5 days and 100% in those with a score ≥ 4 (n = 4) (p = 0.017, OS; p = 0.064, NRM). Older patients who received mogamulizumab had a significantly longer OS (n = 12, median 432 days) than those who did not receive mogamulizumab (n = 17, median 199 days) (p = 0.018). The CONUT score was identified as a prognostic tool for transplant-eligible ATL patients, and mogamulizumab improved OS in transplant-ineligible ATL patients.

Hairy cell leukemia (HCL) is a rare B-cell lymphoid malignancy that is difficult to distinguish from other morphological variants. The frequency of HCL has not been determined accurately in Japan. Recent studies revealed that the BRAF V600E mutation is the causal genetic event in HCL. We assessed the BRAF mutation in Japanese patients with HCL and related diseases using the quenching probe (QP) method, a single-nucleotide polymorphism detection system, and evaluated the incidence rate of HCL among Japanese patients with chronic lymphocytic leukemia, and related diseases. We identified 18 cases (33.3%) harboring the BRAF mutation among 54 patients diagnosed with, or suspected of having HCL. Of BRAF V600E-positive patients, 7 were only detected using the QP method, not by direct sequencing, whereas 11 were positive using both tests. In a larger cohort of Japanese patients diagnosed with chronic lymphoid leukemia or related diseases, the frequency of HCL was 4%. Patients with the BRAF V600E mutation had a significantly higher frequency of neutropenia, thrombocytopenia, and elevated soluble interleukin-2 receptor and common B-cell surface markers than patients without the mutation. Our results confirm that BRAF V600E-positive HCL is a relatively rare disorder in the Japanese leukemia patient population.

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 (IgV H ) 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 IgV H rearrangement.

Polyphenol oxidases (PPOs) catalyze browning reactions in various plant organs, therefore controlling the reactions is important for the food industry. PPOs have been assumed to be involved in skin browning of white grape cultivars; however, the molecular mechanism underlying PPO-mediated browning process remains elusive. We have recently identified a new PPO gene named VvPPO2 from "Shine Muscat" (Vitis labruscana Bailey × V. vinifera L.), and have shown that the gene is transcribed at a higher level than the previously identified VvPPO1 in browning, physiologically disordered berry skins at the maturation stage. In this study, we expressed VvPPO2 in Escherichia coli and, using the purified preparation, revealed unique physicochemical characteristics of the enzyme. Our study opens up a way to not only understand the berry skin browning process but also to elucidate the enzymatic maturation process of grape PPOs.