The death toll caused by COVID-19 reached 7 million in the whole world. With a better understanding of the mechanism and pathophysiology underlying COVID-19 and including late COVID, it will be possible to identify novel treatment targets that ultimately reduce or prevent disease aggravation. In previous studies, the authors have identified so-called “cytokine storm syndrome,” constituting the secretion of inflammatory cytokines driven by the coagulation/fibrinolytic system as an inflammatory cytodynamic control mechanism contributing to the aggravated pathology of COVID-19 and the cytokine storm syndrome.

 Vasculature-lining endothelial cells are bioreactors that produce or contribute to the modulation status of cytokines, coagulation, and fibrinolytic system factors using serine proteases and metalloproteases. Critical steps in the organ damage pathophysiology are the angiocrine system’s destabilization triggered by vascular endothelial damage during severe COVID-19. In addition, overproduction or imbalance of angiocrine factors and inflammatory cytokines contribute to cytokine storm syndrome. This paper outlines the significance of two protease systems in the pathophysiology of inflammatory diseases, focusing on the results of our research. Finally, we discuss the possibility of molecular targeting these proteases for inflammatory disease as novel treatment approaches for systemic inflammatory diseases.

 Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 has been shown to be highly effective in B-cell leukemias and lymphomas. Many researchers are currently trying to develop CAR-T cells for various types of cancer. B-cell maturation antigen (BCMA) has been shown to be an excellent target for multiple myeloma (MM). However, MM remains difficult to cure, and many researchers are trying to identify additional target molecules. Recently, the efficacy of CAR-T cells targeting GRPC5 was reported. We also reported that activated integrin β7 is a good target for CAR-T cell therapy against MM, and clinical trials are currently underway.

 Recently, the anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell therapy has opened a new avenue of the treatment for patients with tiple class-exposed (TCE) multiple myeloma (MM) who has been previously exposed to proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibody. In Japan, two anti-BCMA CAR-T cell therapies, i.e., Idecabtagene vicleucel (Ide-cel) and Ciltacabtagene autoleucel (Cilta-cel), have been approved for the treatment of TCE-MM in 2022, and have shown higher response rates and longer disease control periods compared with pre-existing treatment strategies with various anti-MM agents; however, it remains still difficult to provide a cure of MM by anti-BCMA CAR-T cell therapy with the currently available setting. This article will review the clinical efficacies and limitations of Ide-cel and Cilta-cel against TCE-MM, summarizes the known mechanisms of resistance to anti-BCMA CAR-T cell therapy in MM, and discuss the future perspectives for the new strategies, including the use of anti-BCMA CAR-T in the earlier line of therapy, the challenging strategies for T cell manipulation, the development of non-BCMA-targeted CAR-T cell therapy, and the strategies to manipulate immunosuppressive components in the tumor immune microenvironment in MM.

 Donor T cells strongly kill HLA-mismatched leukemia cells (graft-versus-leukemia effect, GVL effect) after haploidentical hematpoietic stem cell transplantation (haplo-HCT), resulting in leukemic clones that avoid the GVL effect. A frequent and important mechanism of relapse is the loss of mismatched HLA due to loss of heterozygosity (LOH). Approximately 20-50% of patients who relapse after haplo-HCT have LOH. Since these patients have no benefit from donor lymphocyte infusion, the identification of LOH at relapse is clinically very important. Recently, decreased expression of HLA class Ⅱ molecules has also attracted attention as an epigenetic post-transplantation immune escape mechanism after allogeneic transplantation including haplo-HCT. Successful haplo-HCT for leukemia requires strategies to prevent post-transplant immune escape.

 One hundred trillion microbes inhabit humans, with the largest population residing in the gastrointestinal tract. The intestinal microbiota forms a complex ecosystem that interacts with the host immune system. Next-generation sequencing technologies have suggested an association between intestinal dysbiosis, an abnormal microbiome structure, and graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-SCT), as well as other transplant outcomes. Moreover, basic research has clarified that, in addition to the impact of antibiotics on the microbiota, GVHD itself induces intestinal dysbiosis, which in turn contributes to the further exacerbation of GVHD. Therefore, the development of allo-SCT methods which maintain intestinal symbiotic microbes may further improve the safety and efficacy of allo-SCT. In this review, we summarize the recent findings on the mechanism of the development of dysbiosis after SCT and its effect on transplant outcomes. We also discuss our recent findings on the relationship between the alteration of gut microbiota in prolonged neutropenia and reactive granulopoiesis in the bone marrow.

 We conducted a study to investigate the impact of chimeric antigen receptor (CAR)-T cell therapy on the physical function of patients and its invasiveness, which has not been extensively reported. Our study included 58 patients who underwent CAR-T cell therapy and autologous transplantation for diffuse large B-cell lymphoma and multiple myeloma at our hospital between 2014 and 2022. Out of the 26 patients who underwent CAR-T cell therapy, 23 developed cytokine release syndrome (CRS), with a median fever duration of 6 days. Patients with prolonged fever exhibited a decline in performance status at the time of discharge. To measure physical function, we used the 6-minute walk distance (6MWD) test. Before treatment, the 6MWD was lower in patients receiving CAR-T cell therapy than in those undergoing autologous transplantation, and it did not improve significantly after discharge. However, in patients undergoing autologous transplantation, the 6MWD declined significantly from pre- to post-treatment. Our results suggested that autologous transplantation may be more invasive than CAR-T cell therapy when considering the degree of invasiveness of treatment from the perspective of physical function. However, many patients receiving CAR-T cell therapy had poor physical function before treatment, indicating the need for rehabilitation interventions to extend the indications of CAR-T cell therapy to elderly patients and those with a prolonged treatment history.

Aim: We examined the relationship between the degree of sufficiency of each estimated energy requirement and weight loss in allogeneic hematopoietic stem cell transplantation (HSCT) .

Subjects and Methods: Patients with standard body mass index (BMI) who underwent HSCT (transplantation day=day 0) at the Division of Stem Cell Transplantation, Shizuoka Cancer Center, between April, 2015 and March, 2017, were evaluated of clinical indices from the day before pretreatment to the day 42. We evaluated the relationship between the weight loss during the period and the degree of sufficiency obtained by dividing the total calorie supply by each required energy amount.

Results: There were 40 cases (52 years old, 20 males) in total. The sensitivity (specificity) of the estimated energy requirement sufficiency for predicting the weight loss on the day 42 (29 cases) were 72% (91%) with the Harris-Benedict equation for the basal metabolic energy, and 58% (91%) with the standard basal metabolic value for the Japanese dietary intake, and 58% (82%) with the Cunningham equation for the basal metabolic rate.

Conclusion: The degree of sufficiency of each estimated energy requirement and weight loss were related in HSCT.

 In this study, we retrospectively analyzed 42 patients who received tisa-cel at our institution to identify pre-infusion factors for predicting early (within 3 months) disease progression or relapse. The median follow-up period was 8.2 (range, 0.2-36.5) months, and 16 patients (38.1%) had early disease progression/relapse after tisa-cel infusion. Primary refractory cases before leukapheresis and a high lactate dehydrogenase level (>1.5×upper limit of normal) and extranodal involvement ≥2 before lymphodepleting chemotherapy were the significant factors predicting early disease progression or relapse after tisa-cel infusion. In particular, 9 out of 10 (90%) patients with de novo DLBCL and primary refractory course developed disease progression within 4 months after tisa-cel infusion, suggesting the importance of considering new treatment strategies in these patients.

 Since allogeneic hematopoietic stem cell transplantation (allo-SCT) is not performed in the East Hokkaido region where our hospital is located, patients receive allo-SCT at other hospitals. Patients are usually followed up at our hospital after allo-SCT, but long-term follow-up (LTFU) data has not been reported from non-transplantation centers. We performed a retrospective analysis of patients who underwent allo-SCT at other hospitals between 2015 and 2022 and are being followed up at our LTFU clinic. Forty-eight patients were identified, and the median follow-up period was 2.4 years. Estimated OS and EFS rates at 2 years were respectively 65.9% and 57.6%. The cumulative incidence of chronic graft versus host disease (GVHD) was 38.3% at 2 years. Sixteen patients died, of which 5 were relapse-related mortality and 11 were non-relapse mortality (NRM). Of the 11 NRMs, 8 were complicated by chronic GVHD, and all required systemic treatment with corticosteroids. To deal with post-transplant physical and social problems, an LTFU system should be established at non-transplant centers in cooperation with multiple professions and transplant centers.

 This study aimed to identify factors that affect the decline in endurance during allogeneic hematopoietic stem cell transplantation. Seventy-one individuals who were over 20 years old and had received this type of transplantation were enrolled in the study. The six-minute walking distance (6MWD) ―the index of endurance―was treated as the dependent variable, while independent variables included the effects of basic characteristics (physique, length of hospital stays, and the severity of comorbidities), physiological function (cardiac function, and respiratory function), and physical function (fatigue, grip, muscle strength of knee extension, and 30-s chair stand test [CS-30]). Multiple regression analysis showed that young age and the lower CS-30 affected the fewer 6MWD at discharge. Furthermore, path analysis indicated that the total irradiation dose and carbon monoxide diffusion capacity also indirectly affected the decline in endurance at discharge. These results suggest that even young people must strengthen their lower extremity muscles and endurance during the transplantation procedure. As young patients are often treated with high doses of total irradiation, information on those doses and lung function was shown to be important during their rehabilitation.

 A 58-year-old male who was diagnosed with myelodysplastic syndrome underwent a haploidentical stem cell transplantation using posttransplant cyclophosphamide. He developed congestive heart failure 2 days after the first administration of cyclophosphamide as the prophylaxis of graft-versus host disease. The patient was urgently intubated and mechanically ventilated. His congestive heart failure gradually improved with conventional supportive care including vasodilator, angiotensin-converting enzyme inhibitor, beta-blocker, and diuretics, and the patient was weaned from the ventilator on day 11. Cyclophosphamide-induced cardiomyopathy is serious complication and should be taken into consideration in haploidentical transplantation with posttransplant cyclophosphamide to enable early recognition of this rare complication and prompt intervention.