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Hematopoietic stem cell transplantation (HSCT) is a useful tool for the treatment of hematologic malignancies. However, transplantation-related complications are the main cause of non-relapse mortality. Previous reports suggest that endothelial damage is related to early complications after HSCT. Non-invasive reactive hyperemia peripheral arterial tonometry (RH-PAT) was performed to evaluate endothelial function as a predictive marker for these complications.The reactive hyperemia index (RHI) obtained from RH-PAT was evaluated before the conditioning regimen. The relationship between the RHI and the appearance of engraftment syndrome, thrombotic microangiopathy, and acute graft-versus-host disease (aGVHD) was assessed. Receiver operating characteristic curve analysis showed that an RHI value of 1.58 was the optimal cut-off for predicting transplantation-related complications.In total, 49 patients (22 acute myelogenous leukemia, 7 acute lymphocytic leukemia, 6 myelodysplastic syndrome, 6 adult T-cell leukemia, 6 non-Hodgkin lymphoma, and 2 others) were enrolled; 34 had a normal RHI (≥ 1.59), and 15 had an abnormally low RHI (≤ 1.58). Thrombotic microangiopathy (20.2% vs 0.0%, P = 0.025) and aGVHD (80.0% vs 41.2%, P = 0.015) were significantly more frequent in patients with a low RHI.Endothelial dysfunction assessed by RH-PAT before HSCT was able to predict transplantation-related complications.

研究グループは、白血病マウスモデルを使用した実験において、ロペグインターフェロンが生体内でがん細胞に作用するメカニズムを明らかにしました。ロペグインターフェロンが血液がんの治療で有望な結果が出ているとの報告が近年増加しています。しかし、そのメカニズムは明らかではありませんでした。本研究では、ロペグインターフェロンが腫瘍細胞に対して、直接的な細胞傷害作用をもたらしているのか、もしくは細胞そのものではなく間接的に免疫調整作用をもたらしているのかを検証しました。その結果、優れた抗腫瘍免疫作用を確認し、中でもT細胞の活性化が重要な役割を担っていることが分かりました。これは、幅広いがん種での応用の可能性も示唆しています。加えて、白血病細胞が体内から消失したマウスに再び白血病細胞株を注入しても再発しなかったことから、免疫記憶が獲得され、再発率の低下につながる可能性があると考えられます。, Although ropeginterferon alfa-2b has recently been clinically applied to myeloproliferative neoplasms with promising results, its antitumor mechanism has not been thoroughly investigated. Using a leukemia model developed in immunocompetent mice, we evaluated the direct cytotoxic effects and indirect effects induced by ropeginterferon alfa-2b in tumor cells. ...

For successful chimeric antigen receptor T (CAR-T) cell therapy, CAR-T cells must be manufactured without failure caused by suboptimal expansion. In order to determine risk factors for CAR-T cell manufacturing failure, we performed a nationwide cohort study in Japan and analysed patients with diffuse large B-cell lymphoma (DLBCL) who underwent tisagenlecleucel production. We compared clinical factors between 30 cases that failed (7.4%) with those that succeeded (n = 378). Among the failures, the proportion of patients previously treated with bendamustine (43.3% vs. 14.8%; p, CAR-T細胞製造を成功させるためのレシピ --アフェレーシス前の下ごしらえでの工夫--. 京都大学プレスリリース. 2023-04-27.

CD19-directed chimeric antigen receptor (CAR) T-cell therapy has been widely used and highly effective for B-cell lymphoid malignancies. Immune-mediated adverse effects such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) occur in the acute phase and are monophasic after CAR T-cell therapy. However, late-onset inflammatory and neurological toxicities have not been well studied. We encountered a patient with recurrent late-onset inflammatory toxicities and progressive dysautonomia after CD19-directed CAR T-cell therapy. A 69-year-old man was treated with CD19-directed CAR T-cell therapy for transformed follicular lymphoma. Triphasic inflammation with stomatitis, cytopenia, and non-infectious pneumonia was first observed 7 months after CAR T-cell infusion. Progressive dysautonomia was also observed and eventually fatal. Residual CAR T cells, predominantly central memory CD4+ cells, were detectable in peripheral blood approximately one year after CAR T-cell infusion. The cytokine profile with the lack of tumor necrosis factor-α, interferon-γ, and interleukin-1β elevation in the peripheral blood and cerebrospinal fluid was inconsistent with that of typical CRS or ICANS. The persistence of central memory CD4+ CAR T cells might be associated with unique manifestations of late-onset immune-mediated adverse effects. More cases should be accumulated to elucidate the mechanism and establish the optimal management strategy of late-onset immune-mediated toxicities previously unrecognized.

Lay abstract This case report describes a 72-year-old man with non-small-cell lung cancer who received four cycles of pembrolizumab-containing chemotherapy. He developed multiple immune-related adverse events (irAEs), which are significant side effects of immune checkpoint inhibitors (ICIs). Despite the discontinuation of pembrolizumab due to multiple irAEs, he developed immune-related hepatitis and neutropenia at 92 days and 118 days, respectively, after the final pembrolizumab dose. He received supportive care and immunosuppressive therapy and recovered from neutropenia. Recently, delayed development of irAEs was reported even in patients that discontinued ICIs; this is referred to as a delayed immune-related event (DIRE). This case developed strikingly delayed immune-related neutropenia as a DIRE. Clinicians should pay close attention to neutropenia as a possible life-threatening DIRE after ICI treatment.

Introduction: The safety and efficacy of blinatumomab, a CD19/CD3 bispecific T-cell engager (BiTE®) molecule, was evaluated in an expansion cohort of the phase 1b/2 study (NCT02412306) in Japanese adult (n = 14) and pediatric (n = 17) patients with relapsed/refractory Philadelphia-negative B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). Materials and methods: Globally recommended blinatumomab doses were administered to adult (9–28 μg/day) and pediatric (5–15 μg/m2/day) patients. Primary endpoint was the incidence of treatment-emergent adverse events (TEAEs) and treatment-related AEs. Results: All adult and pediatric patients experienced ≥1 TEAE. Grade ≥3 TEAEs were observed in 11 (79%) adult and 15 (88%) pediatric patients. Blinatumomab was discontinued in 1 (6%) pediatric patient due to treatment-related grade 4 cytokine release syndrome. Fatal AEs such as disease progression and multiple-organ dysfunction syndrome, which were not treatment-related, were reported in 2 (12%) pediatric patients. Eleven (79%) adults achieved complete remission (CR)/CR with partial hematological recovery (CRh) within the first two blinatumomab cycles. Nine of 10 adult patients with CR/CRh and evaluable minimal residual disease (MRD) achieved MRD response. CR/CRh was achieved by 5 (29%) pediatric patients, of which two had MRD response. Conclusion: In conclusion, blinatumomab was safe and efficacious in Japanese patients with relapsed/refractory BCP ALL.

A 46-year-old woman with a sore throat was diagnosed with anaplastic lymphoma kinase-negative anaplastic large cell lymphoma that had spread from the piriform fossa to the cervical esophagus. Tracheoesophageal fistula developed after induction chemotherapy. Because conservative repair was not applicable, intensified chemotherapy, including autologous stem cell transplantation was performed with the fistula remaining open. Laryngopharyngectomy and cervical esophagectomy were performed 6 months after transplantation. The optimal strategy for refractory lymphoma with active tracheoesophageal fistula remains undetermined. To the best of our knowledge, this is the first report describing the successful treatment of a patient with tracheoesophageal fistula who received high-dose chemotherapy supported by autologous stem cell transplantation.

There is currently no evidence that a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine might be associated with the development of autoimmune hemolytic anemia or disease progression in patients with mature B-cell neoplasm. Our patient was a 71-year-old man with indolent mature B-cell neoplasm who had been monitored for many years without treatment. After receiving the second dose of the BNT162b2 mRNA COVID-19 vaccine, he developed severe warm autoimmune hemolytic anemia. Although steroid therapy improved his anemia, he continued to develop IgM-monoclonal gammopathy, renal insufficiency, and splenomegaly. He was diagnosed with splenic marginal zone lymphoma after undergoing splenectomy. The splenectomy improved the patient's symptoms. We assessed his SARS-CoV-2 specific antibody response, but the patient's serologic response to the vaccine was impaired. In patients with mature B-cell neoplasm, a non-specific immune response after vaccination might be associated with paraneoplastic syndromes.

OBJECTIVES The short-term efficacy of virtual-assisted lung mapping (VAL-MAP), a preoperative bronchoscopic multi-spot lung-marking technique, has been confirmed in 2 prospective multicentre studies. The objectives of this study were to analyse the local recurrence and survival of patients enrolled in these studies, long-term. METHODS Of the 663 patients enrolled in the 2 studies, 559 patients’ follow-up data were collected. After excluding those who did not undergo VAL-MAP, whose resection was not for curative intent, who underwent concurrent resection without VAL-MAP, or who eventually underwent lobectomy instead of sublobar resection (i.e. wedge resection or segmentectomy), 422 patients were further analysed. RESULTS Among 264 patients with primary lung cancer, the 5-year local recurrence-free rate was 98.4%, and the 5-year overall survival (OS) rate was 94.5%. Limited to stage IA2 or less (≤2 cm in diameter; n = 238, 90.1%), the 5-year local recurrence-free and OS rates were 98.7% and 94.8%, respectively. Among 102 patients with metastatic lung tumours, the 5-year local recurrence-free rate was 93.8% and the 5-year OS rate was 81.8%. Limited to the most common (colorectal) cancer (n = 53), the 5-year local recurrence-free and OS rates were 94.9% and 82.3%, respectively. CONCLUSIONS VAL-MAP, which is beneficial in localizing small barely palpable pulmonary lesions and determining the appropriate resection lines, was associated with reasonable long-term outcomes. Subj collection 152, 1542

A combination of three post-transplant drugs, cyclophosphamide (PTCy), a calcineurin inhibitor, and mycophenolate mofetil, has long been used for prophylaxis of graft-versus-host-disease (GVHD) after HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT). Recently, this combination has been used following HLA-matched allo-HCT as well, but the optimal combination of drugs for GVHD prophylaxis in an HLA-matched setting remains unclear. This prospective phase II study evaluated the safety and efficacy of PTCy plus tacrolimus (TAC) for GVHD prophylaxis after allo-HCT from HLA-matched related donors (MRD) or HLA-matched unrelated donors (MUD). The cumulative incidences of grades II-IV and III-IV acute GVHD at 100 days post-transplantation were 18% and 5.9%, respectively, in the MRD group, and 18% and 9.1%, respectively, in the MUD group. The cumulative incidences of moderate to severe chronic GVHD at 1 year were 12% and 9.1% in the MRD and MUD groups, respectively. The 1-year overall survival rates in the MRD and MUD groups were 88% and 64%, respectively, and the 1-year GVHD-free, relapse free survival rates were 59% and 50%, respectively. These results suggest that GVHD prophylaxis with a less intensive double drug combination (PT/Cy and TAC) might be feasible after HLA-matched allo-HCT.Clinical Trial Notation This trial was a prospective single-center trial registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; identification number: UMIN000023890) and the Japan Registry of Clinical Trials (jRCTs051180143).

Collection of CD3+ lymphocytes via lymphapheresis is essential for manufacturing autologous chimeric antigen receptor (CAR) T cells. Optimization of timing and procedures for lymphapheresis for each patient is critical because patients often have progressive diseases and receive medications that could reduce T cell counts. We conducted a retrospective study of clinical data from 28 patients who underwent lymphapheresis for CD19-directed CAR-T therapy with tisagenlecleucel to identify factors that could affect CD3+ lymphocyte yields. The numbers of CD3+ cells in peripheral blood were significantly correlated with CD3+ cell yields (correlation coefficient r = 0.84), which enabled us to estimate the volume of blood to process before apheresis. We also found that small cell ratio (SCR) at the apheresis site precisely reflected the proportion of lymphocytes, especially in patients without circulating blasts (coefficient of determination: r2 = 0.9). We were able to predict the CD3+ cell yield and prevent excessive apheresis by measuring pre-apheresis circulating CD3+ cell counts and monitoring SCR. Collectively, these results will help us to establish a strategy for optimization of lymphapheresis procedures for CAR-T cell production on a patient-by-patient basis.

We described and compared the mating behavior and morphology of the reproductive system in chromodorid nudibranchs, then, examined how extensively the unique usage of the penis (autotomy and sperm removal) evolved among Chromodorids. In addition to Ardeadoris egretta, all of examined five species in Glossodoris autotomized their penises at the last stage of copulation. An interspecific difference was seen in penis autotomy in Noumea and Goniobranchus. A spiral structure was recognized in the vas deferens of autotomized species. This structure is supposed to be undifferentiated “next penises” stored in the vas deferens, which ensure successive copulation in autotomized species. Though the basic mechanism of penis replenishment was consistent, the reason to autotomize their penises may not be the same. Goniobranchus reticulatus is reported to remove sperm already stored in the mating partner’s sperm storage organ(s) with backward-pointing spines on the surface of its penis. Contrary to G. reticulatus, all of ten species that autotomized their penises in the present study did not have thorny but smooth penises. When they autotomized their penises, the tip of the penises still remained in the vagina of the partners. This suggests that autotomized penises in these nudibranchs function as a kind of copulatory plugs.

BACKGROUND: This feasibility study aimed to detect respiratory waveforms from thoracic movements and evaluate if postoperative complications could be predicted using a carbon nanotube sensor. METHODS: Fifty patients who underwent lung resection for lung tumors were enrolled. The lung monitoring system of the carbon nanotube sensor was placed on bilateral chest walls across the 6(th)–9(th) ribs to measure chest wall motion. We examined the respiratory waveform in relation to surgical findings, postoperative course, and complications using Hilbert transform and Fast Fourier Transform (FFT). RESULTS: Of 50 patients (37 males, 13 females), 22 were included in the normal lung function group and 28 were included in the low lung function group. The respiratory rate and waveform indicated a regular pattern in the normal lung function group and the respiratory rate could be detected. Conversely, irregular respiratory pattern was detected in 70% of patients in the low lung function group. There was no significant different overall envelope peak value between operated side and non-operated side (0.195±0.05 and 0.18±0.06). In contrast, there was significantly high peak value in the presence of postoperative complications (P

Due to the COVID-19 pandemic, the 84thAnnual Meeting of the Japanese Circulation Society (JCS) was held in a web-based format for the first time in its history as "The Week for JCS 2020" from Monday, July 27 to Sunday, August 2, 2020. All sessions, including general abstracts, were streamed live or on-demand. The main theme of the meeting was "Change Practice!" and the aim was to organize the latest findings in the field of cardiovascular medicine and discuss how to change practice. The total number of registered attendees was over 16,800, far exceeding our expectations, and many of the sessions were viewed by far more people than at conventional face-to-face scientific meetings. At this conference, the power of online information dissemination was fully demonstrated, and the evolution of online academic meetings will be a direction that cannot be reversed in the future. The meeting was completed with great success, and we express our heartfelt gratitude to all affiliates for their enormous amount of work, cooperation, and support.

Background: There are several prognosis prediction models about allogeneic hematopoietic cell transplantation (allo-HCT) such as the hematopoietic cell transplantation specific comorbidity index (HCT-CI) and the refined disease risk index (R-DRI). Although HCT-CI and R-DRI are valuable and commonly used, further improvement of these models is desirable because the prognostic predictive abilities for post-allo-HCT survival remain suboptimal. Both brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP), are released from the ventricular and atrial walls, in response to the walls stretch into the blood. Plasma BNP and NT-proBNP levels are well-known biomarkers of the predictors of death in patients with cancer and heart disease. However, it is unclear whether these biomarkers are useful predictors for prognosis after allo-HCT. The main aim of our study was to evaluate the potential role of plasma BNP and NT-proBNP levels in predicting the mortality in allo-HCT patients. Methods: We retrospectively registered consecutive patients who underwent allo-HCT from January 2011 to December 2018. Plasma BNP and NT-proBNP examinations and echocardiography within 1 month from the start of conditioning regimen were performed in all transplant candidates as pretransplant work-up in our institution. Cox regression models were used to estimate the hazard ratios (HRs) with 95% confidence intervals (95% CI) in the univariate and multivariate analyses. Relapse/progression (Rel/Prog) and non-relapse mortality (NRM) were considered competing events. The Fine-Gray proportional hazard regression model was used for the univariate and multivariate analyses with competing risks. A p value < 0.050 was considered statistically significant. We estimated the two models using c-statistics on the basis of time to event, using the total follow-up period to compare the predictive accuracy of R-DRI or HCT-CI with BNP or NT-proBNP added models. Standard errors (SEs) for the c-statistics were estimated by applying a bootstrap procedure using 1000 bootstrap samples to confirm the reproducibility. The SEs for the difference in c-statistics between these two models were compared with the above bootstrap samples and used to compute a z-score and a p value for the difference, similar to that in several previous studies. Results: We enrolled 174 consecutive patients. The median age was 49 (range: 16-68) years. During the follow-up period, 64 patients died (36.8%). Both plasma BNP and NT-proBNP levels showed a significant association with OS and NRM, but not Rel/Prog in the univariate analysis. Next, we conducted multivariable analysis to evaluate the independence of plasma BNP and NT-proBNP levels by adjusting for not only those variables that were reported as prognostic factors in the previous research for OS, but also diastolic dysfunction that can be associated with plasma BNP and NT-proBNP levels. We constructed each two and three multivariable model, including either BNP or NT-proBNP to assess the effects of these biomarkers on OS and NRM according to the one-in-ten rule 6 to avoid overfitting (Table 1). The adjusted models for OS showed that higher plasma BNP and NT-proBNP levels were significantly associated with poorer outcomes. Moreover, the adjusted models for NRM showed that a higher plasma BNP level was significantly associated with the outcome. We also evaluated the prognostic significance of BNP, NT-proBNP, HCT-CI, or echocardiographic parameters, including ejection fraction (EF) and diastolic dysfunction, by adding to R-DRI via computation of the c-statistic. BNP or NT-proBNP showed significantly higher c-statistic estimates for OS as compared with R-DRI alone (c-statistic estimate 0.741, 0.759, and 0.674, respectively), but not EF or diastolic dysfunction (Table 2). Both plasma BNP and NT-proBNP levels had higher HRs for OS [HR per standard deviation (SD) 2.57 (95% CI: 1.75-3.76), p < 0.001, and HR per SD 1.95 (95% CI: 1.39-2.73), p < 0.001] and NRM [HR per SD 2.10 (95% CI: 1.11-3.97), p < 0.024, and HR per SD 2.57 (95% CI: 1.92-3.44), p < 0.001] even in the normal heart function group. Conclusion: Plasma BNP and NT-proBNP levels are easy to perform and cost-effective; thus, these could be useful independent biomarkers for predicting allo-HCT prognosis than echocardiography. They enable clinical decision regarding allo-HCT. Disclosures Okamura: NIPPON SHINYAKU CO.,LTD: Honoraria. Nakane:Pfizer Japan Inc.: Research Funding; Janssen Pharmaceutical K.K.: Research Funding; Bayer Yakuhin, Ltd: Research Funding; Novartis: Honoraria, Research Funding; DAIICHI SANKYO COMPANY, LIMITED: Honoraria; Mundipharma K.K: Honoraria. Nanno:Otsuka Pharmaceutical Co., Ltd: Honoraria. Nishimoto:Bayer Yakuhin, Ltd:: Research Funding; Janssen Pharmaceutical K.K.:: Research Funding. Nakamae:Shire Japan KK: Honoraria; Celgene Corporation: Honoraria; DAIICHI SANKYO COMPANY, LIMITED: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Chugai Pharmaceutical Co., Ltd: Honoraria; Japan Blood Products Organization: Honoraria; NIPPON SHINYAKU CO.,LTD: Honoraria; Novartis: Honoraria; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb: Honoraria; Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Amgen Astellas BioPharma K.K: Honoraria; Astellas Pharma Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria. Nakashima:Amgen Astellas BioPharma K.K: Honoraria; Novartis: Honoraria, Research Funding; Eisai Co., Ltd: Honoraria, Research Funding; Amgen Inc: Honoraria; Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; JCR Pharmaceuticals Co., Ltd: Honoraria; Pfizer Japan Inc: Honoraria; Astellas Pharma Inc: Research Funding; SymBio Pharmaceuticals Limited: Research Funding; Celgene Corporation: Research Funding; AbbVie GK: Research Funding; M S D K. K: Research Funding. Koh:Takeda Pharmaceutical Company Limited: Honoraria, Research Funding; Sumitomo Dainippon Pharma Co., Ltd: Honoraria; M S D K. K: Honoraria; NIHON PHARMACEUTICAL CO., LTD: Honoraria; Chugai Pharmaceutical Co., Ltd: Research Funding; Asahi Kasei Corporation: Research Funding; Amgen Astellas BioPharma K.K: Research Funding; IQVIA Services Japan K.K.: Research Funding; Takeda Science Foundation: Research Funding. Hino:Kyowa-Kirin: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Astellas: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Taiho: Research Funding; Teijin: Research Funding; MSD: Honoraria, Research Funding; Sumitomo Dainippon: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Daiichisankyo: Honoraria, Research Funding; Eisai: Research Funding; Jansenn: Honoraria; Celgene: Honoraria; Mochida: Honoraria; Ono: Honoraria; Sanofi: Honoraria; Japan Blood Products Organization: Research Funding; Nippon Shinyaku: Honoraria; Nihon Pharmaceutical: Research Funding; Mundi Pharma: Honoraria; Alexion: Honoraria. Nakamae:Pfizer Japan Inc: Honoraria, Research Funding; Astellas Pharma Inc: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Amgen Astellas BioPharma K.K: Honoraria; ONO PHARMACEUTICAL CO., LTD: Honoraria; Kyowa-Hakko Kirin Co.,Ltd: Honoraria; Shire Japan KK: Honoraria; Celgene Corporation: Honoraria; DAIICHI SANKYO COMPANY, LIMITED: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Chugai Pharmaceutical Co., Ltd: Honoraria; Japan Blood Products Organization: Honoraria; NIPPON SHINYAKU CO.,LTD: Honoraria; Novartis: Honoraria; PPD-SNBL K.K: Research Funding.