Dural Arteriovenous Fistula Treated with Transvenous Embolization via the Upper Limb Cutaneous Vein.

Objective: In recent years, the transradial artery approach has gained prominence and is increasingly employed in neurovascular angiography and therapy due to its safety, reduced complications, and minimal invasiveness. While various venous approaches, including the conventional transfemoral vein approach, exist for procedures such as transvenous embolization, recent reports have highlighted methods involving upper extremity cutaneous veins. However, the practicality and efficacy of these approaches remain unclear. Case Presentations: This study presents our experience with three cases of dural arteriovenous fistulas, where transvenous embolization was performed via upper limb cutaneous veins. In all instances, the arteriovenous approach was successfully executed using a single upper extremity, leading to the successful completion of treatment. Conclusion: This technique demonstrates significant advantages, not only in terms of its minimal invasiveness but also due to its simplicity and safety. Anticipating broader acceptance in the future, this approach offers a promising avenue for further exploration in neurovascular interventions.

A single-institution pre-post comparison of subcutaneous immunoglobulin replacement therapy in allogeneic haematopoietic cell transplantation recipients.

Immunoglobulin replacement therapy (IgRT) reduces the risk of infection in hypogammaglobulinaemia secondary to chronic lymphocytic leukaemia and multiple myeloma. However, the benefit of IgRT, especially subcutaneous IgRT (ScIgRT), has not been assessed in hypogammaglobulinaemia after allogeneic haematopoietic cell transplantation (allo-HCT). We performed a pre-post comparison of the clinical impact of ScIgRT after allo-HCT in a retrospective analysis of 209 patients who underwent allogeneic HCT at our institution from 2011 to 2019. Since ScIgRT became available at our institution in April 2017, we categorized patients treated from January 2011 to March 2017 as the Pre-ScIgRT group (n = 118) and those treated from April 2017 to December 2019 as the Post-ScIgRT group (n = 91). The 2-year overall survival rate was 65% in the Pre-ScIgRT group and 81% in the Post-ScIgRT group (p = 0.02). The cumulative incidence (CI) of non-relapse mortality at 2 years was 18% and 7% (p = 0.02). There were 78 infectious events in 44 patients in the Pre-ScIgRT group and 28 such events in 19 patients in the Post-ScIgRT group. The CI of the documented infection during the observation period was between 38% and 21% (p = 0.01). Our study suggests that ScIgRT may reduce infection rates and improve prognosis after allo-HCT.

Gilteritinib in peritransplant period for relapsed or refractory FLT3-mutated acute myeloid leukemia: A case report of three patients.

Patients with relapsed or refractory acute myeloid leukemia (RR-AML) with mutations of FMS-like tyrosine kinase 3 (FLT3) have a poor prognosis even after allogeneic hematopoietic cell transplantation (allo-HCT). Multiple FLT3 inhibitors, including gilteritinib, have been developed and serve as treatment options for RR-AML. Here, we describe three cases of FLT3 mutated RR-AML that were successfully treated with gilteritinib administration before and after allo-HCT. Gilteritinib treatment before HCT was helpful in achieving remission. However, HCT often resulted in mild liver damage, and careful introduction of gilteritinib after HCT at a lower dose may be helpful for its safe usage. The three cases discussed had a successful clinical outcome in terms of disease control as well as the management of side effects associated with gilteritinib treatment.

Relationship between muscle thickness measured by ultrasound and physical functions: A 2-year follow-up study of allogeneic hematopoietic stem cell transplantation recipients.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for hematological malignancies. Several complications following allo-HSCT, such as graft-versus-host disease, infection, and malnutrition, often cause physical dysfunction, and the assessment of physical function and evaluation of muscle mass are incompletely performed. Use of ultrasound (US) allows muscle mass measurement in patients with poor general conditions. In allo-HSCT recipients, the correlation between physical function and muscle thickness, as measured by US, remains unclear. OBJECTIVE: To clarify whether muscle thickness measured by US correlated with physical function in allo-HSCT recipients. DESIGN: A single-center prospective cohort study. SETTING: Hospital. PATIENTS: Ninety-two patients underwent allo-HSCT at our hospital from April 2017 to March 2019. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE(S): Biceps and quadriceps muscle thickness measured by US, grip strength, isometric muscle strength (elbow flexion and knee extension), and 6-minute walking test (6MWT) before allo-HSCT and on days 30, 90, 180, 1 year, and 2 years after allo-HSCT. The implementation rates of these assessments were also investigated. RESULTS: Correlations were observed between biceps thickness and elbow flexion muscle strength/grip strength before allo-HSCT, on days 30, 90, 180, 1 year, and 2 years after allo-HSCT (r = 0.71/0.74, 0.73/0.72, 0.70/0.79, 0.67/0.75, 0.72/0.75, and 0.85/0.79, respectively, all p < .001). At the same time points, quadriceps thickness moderately correlated with knee extensor strength (r = 0.49, 0.50, 0.45, 0.64, 0.61, and 0.58, all p < .001). However, biceps and quadriceps thicknesses did not correlate with the 6MWT. The percentages of patients measured with US and 6MWT were 93.4% and 82.4% (p = .01) on day 30 and 97.5% and 87.8% (p = .02) on day 90, respectively. CONCLUSIONS: US assessment may be a useful alternative method for estimating muscle strength in fragile allo-HSCT recipients, particularly when physical function assessment is difficult to quantify.

A case of severe oral mucosal GVHD induced by heterologous SARS-CoV-2 vaccination after cord blood transplantation.

Patients who have undergone hematopoietic cell transplantation (HCT) are at a higher risk of severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) infection than the general population. Therefore, early vaccination is recommended for post-transplant patients. Although exacerbation of chronic graft-versus-host disease (cGVHD) after the initial vaccination has been reported, it is unknown whether severe cGVHD occurs when different RNA vaccines are combined. We treated a patient who developed severe oral mucosal cGVHD after receiving two different RNA vaccines. Visual inspection showed that the patient presented with typical mucocutaneous cGVHD, and cGVHD in this case responded well to low-dose steroids compared to common oral GVHD exacerbations. Histopathological findings revealed T cell, B cell, and conspicuous neutrophil infiltration. Multiple doses of SARS-Cov2 vaccination are required in post-transplant recipients. In conclusion, it is essential to obtain the vaccination history of allo-HSCT recipients with cGVHD exacerbation. Furthermore, reviewing the pathological findings may help treat patients with lower doses of steroids.

Risk factors for CAR-T cell manufacturing failure among DLBCL patients: A nationwide survey in Japan.

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 < 0.001) was significantly higher, and their platelet counts (12.0 vs. 17.0 × 104 /µL; p = 0.01) and CD4/CD8 T-cell ratio (0.30 vs. 0.56; p < 0.01) in peripheral blood at apheresis were significantly lower than in the successful group. Multivariate analysis revealed that repeated bendamustine use with short washout periods prior to apheresis (odds ratio [OR], 5.52; p = 0.013 for ≥6 cycles with washout period of 3-24 months; OR, 57.09; p = 0.005 for ≥3 cycles with washout period of <3 months), low platelet counts (OR, 0.495 per 105 /µL; p = 0.022) or low CD4/CD8 ratios (

Novel risk assessment for the intensity of conditioning regimen in older patients.

Reduced-intensity conditioning (RIC) regimens have long-term outcomes that are generally comparable with those of myeloablative conditioning (MAC) because of a lower risk of nonrelapse mortality (NRM) but a higher risk of relapse. However, it is unclear how we should select the conditioning intensity in individual cases. We propose the risk assessment for the intensity of conditioning regimen in elderly patients (RICE) score. We retrospectively analyzed 6147 recipients aged 50 to 69 years using a Japanese registry database. Based on the interaction analyses, advanced age (≥60 years), hematopoietic cell transplantation-specific comorbidity index (≥2), and umbilical cord blood were used to design a scoring system to predict the difference in an individual patient's risk of NRM between MAC and RIC: the RICE score, which is the sum of the 3 factors. Zero or 1 implies low RICE score and 2 or 3, high RICE score. In multivariate analyses, RIC was significantly associated with a decreased risk of NRM in patients with a high RICE score (training cohort: hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.60-0.90; P = .003; validation cohort: HR, 0.57; 95% CI, 0.43-0.77; P < .001). In contrast, we found no significant differences in NRM between MAC and RIC in patients with a low RICE score (training cohort: HR, 0.99; 95% CI, 0.85-1.15; P = .860; validation cohort: HR, 0.81; 95% CI, 0.66-1.01; P = .061). In summary, a new and simple scoring system, the RICE score, appears to be useful for personalizing the conditioning intensity and could improve transplant outcomes in older patients.

Current Status and Issues of the Japan Oncofertility Registry.

Purpose: Fertility preservation (FP) is becoming increasingly common among child, adolescent, and young-adult (CAYA) patients with cancer. However, Japan has long lacked definite estimates of utilization rates for FP services among CAYA patients with cancer, and little is known about disease/FP outcomes among users. Therefore, the Japan Society for Fertility Preservation (JSFP) launched the Japan Oncofertility Registry (JOFR) in 2018 and started the online registration of information regarding primary disease, FP, and data on prognosis and pregnancy outcomes. This study reports the analytical results of FP data registered in the JOFR as of 2021. Methods: Data about patients' primary disease(s), treatment courses, cancer and pregnancy outcomes, and specific procedures were extracted from the JOFR and analyzed. Results: In 2021, 1244 patients received counseling or treatment related to FP (540 males, 704 females). While the numbers of males in each age group were approximately equal, most females were aged between 31 and 40 years. In total, 490 male and 540 female patients underwent FP procedures. Leukemia, testicular cancer, and malignant lymphoma accounted for the majority of male cases seeking treatment, whereas breast cancer was the primary disease in two-thirds of the females. Since 1999, 395 patients have accumulatively experienced subsequent pregnancy. Conclusions: As of January 2022, >7000 cases from >100 fertility facilities have been registered in the JOFR. In the future, maintaining JOFR to disseminate information on cancer prognoses, pregnancy rates, and other oncofertility outcomes is expected to drive further expansion of oncofertility services in Japan.

Leucine retention in lysosomes is regulated by starvation.

Cells acquire essential nutrients from the environment and utilize adaptive mechanisms to survive when nutrients are scarce. How nutrients are trafficked and compartmentalized within cells and whether they are stored in response to stress remain poorly understood. Here, we investigate amino acid trafficking and uncover evidence for the lysosomal transit of numerous essential amino acids. We find that starvation induces the lysosomal retention of leucine in a manner requiring RAG-GTPases and the lysosomal protein complex Ragulator, but that this process occurs independently of mechanistic target of rapamycin complex 1 activity. We further find that stored leucine is utilized in protein synthesis and that inhibition of protein synthesis releases lysosomal stores. These findings identify a regulated starvation response that involves the lysosomal storage of leucine.

Reliability and validity of ultrasound to measure of muscle mass following allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients frequently show physical dysfunction due to loss of muscle mass. This study aimed to clarify the reliability and validity of ultrasound in evaluating muscle mass and to analyze the patterns of change in muscle mass before and after allo-HSCT. We conducted a prospective observational study using data from 68 patients who had undergone their first allo-HSCT. We evaluated the thickness of the quadriceps, biceps, and suprahyoid muscle. Three individual evaluators underwent this examination for each muscle before transplantation and on days 30, 90, and 180 after allo-HSCT. Inter-rater reliability was calculated using the interclass correlation (ICC), and the level of correlation between muscle mass measured by ultrasound and psoas muscle mass assessed using computed tomography (CT) was assessed using Pearson correlation. ICC values ranged from 0.897 to 0.977 in the measurement. The correlation scores were 0.730, 0.546 and 0.579 between psoas muscle and the biceps, quadriceps, and suprahyoid muscle. The thickness of the biceps and quadriceps muscle were both significantly decreased after allo-HSCT from baseline. These results showed that the ultrasound technique was a reliable tool for evaluating muscle mass and detecting changes in muscle mass following allo-HSCT.

Cancer in adolescents and young adults in Japan: epidemiology and cancer strategy.

According to national cancer registry data in Japan, approximately 20,000 adolescents and young adults (AYAs, age 15-39 years) are newly diagnosed with cancer each year. Improvements in treatment and care for AYAs with cancer are included in the Phase Three Basic Plan to Promote Cancer Control Programs in Japan. This article reviews current cancer incidence and survival for AYAs with cancer in Japan using population-based cancer registry data. Mortality data through 2019 from the Vital Statistics of Japan are also described. Encouragingly, the 5-year survival probability for AYA cancers has continued to improve, in parallel with childhood cancers, and the mortality rate has decreased. There has been increasing attention to these vulnerable patients and improved partnerships and collaboration between adult and pediatric oncology; however, obstacles to the care of this population still exist at multiple levels. These obstacles relate to specific areas: research efforts and enrollment in clinical trials on AYA malignancies, AYA-specific psychosocial support such as education, financial support, and oncofertility care, and cancer care systems. It is important for Japanese oncologists, health care providers, and health policy makers to recognize that the AYA population remains vulnerable and still have unmet needs.

Cytomegalovirus gastroenteritis in patients with acute graft-versus-host disease.

A preemptive strategy has successfully decreased cytomegalovirus (CMV) disease after allogeneic hematopoietic cell transplantation (HCT). However, some recipients still develop CMV gastroenteritis, especially after acute graft-versus-host disease (aGVHD), and its incidence, risk factors, and prognostic impact remain to be elucidated. We retrospectively analyzed 3759 consecutive adult patients who developed grade II-IV aGVHD using a Japanese registry database. The cumulative incidence of CMV gastroenteritis was 5.7% by day 365 from the development of grade II-IV aGVHD. Advanced age (hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.16-2.22; P = .004), GVHD prophylaxis with mycophenolate mofetil and calcineurin inhibitor (HR, 1.73; 95% CI, 1.08-2.77; P = .024), lower-gut aGVHD (HR, 2.17; 95% CI, 1.58-2.98; P < .001), and the use of systemic steroids (HR, 1.78; 95% CI, 1.16-2.74; P = .008) were independent risk factors for CMV gastroenteritis. Development of CMV gastroenteritis was associated with an increased risk of nonrelapse mortality (HR, 1.89; 95% CI, 1.50-2.39; P < .001). Moreover, letermovir prophylaxis significantly reduced both the incidence of CMV gastroenteritis (HR, 0.50; 95% CI, 0.25-0.99; P = .047) and the risk of nonrelapse mortality (HR, 0.72; 95% CI, 0.52-0.99; P = .043). In summary, CMV gastroenteritis is a life-threatening complication that sets the need for preventive strategies with letermovir and targeted surveillance.

Serial Changes in Cardiac Strain and Contractility After Hematopoietic Stem Cell Transplantation in Patients with Hematologic Malignancies.

Hematopoietic stem cell transplantation (HSCT) is occasionally associated with cardiac dysfunction during long-term follow-up. Global longitudinal strain (GLS) has emerged as an early predictor of cardiotoxicity associated with cancer therapy; however, the serial changes in GLS before and after HSCT have not been elucidated. To clarify the association between HSCT and GLS, we investigated serial changes in GLS before and after HSCT. We evaluated cardiac function before and 1, 3, and 6 months after HSCT in 38 consecutive HSCT patients enrolled in this study. Overall, GLS and left ventricular (LV) ejection fraction (EF) temporally decreased 1 month post-HSCT. LVEF completely recovered to baseline at 3 months after HSCT, whereas GLS partially recovered 6 months after HSCT. Except for five patients who died within 6 months, GLS values in the low EF group (LVEF ≤ 55% at 6 months post-HSCT, n = 6) were significantly and consistently lower than those in the normal EF group (LVEF > 55% at 6 months post-HSCT, n = 27) at any time during follow-up. These findings suggest that GLS before HSCT might be associated with a decrease in LVEF after HSCT in patients with hematologic malignancies. Further prospective and long-term data will be important for understanding the management of HSCT-associated cardiac dysfunction.

Trends in survival of leukemia among children, adolescents, and young adults: A population-based study in Osaka, Japan.

This study focused on children as well as adolescents and young adults (AYAs) and aimed to examine trends in survival of leukemia over time using population-based cancer registry data from Osaka, Japan. The study subjects comprised 2254 children (0-14 years) and 2,905 AYAs (15-39 years) who were diagnosed with leukemia during 1975-2011. Leukemia was divided into four types: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and other leukemias. We analyzed 5-year overall survival probability (5y-OS), using the Kaplan-Meier method and expressed time trends using the joinpoint regression model. For recently diagnosed (2006-2011) patients, a Cox proportional hazards model was applied to determine predictors of 5y-OS, using age group, gender, and treatment hospital as covariates. Over the 37-year period, 5y-OS greatly improved among both children and AYAs, for each leukemia type. Among AYAs, 5y-OS of ALL improved, especially after 2000 (65% in 2006-2011), when the pediatric regimen was introduced but was still lower than that among children (87% in 2006-2011, P < .001). Survival improvement was most remarkable in CML, and its 5y-OS was over 90% among both children and AYAs after the introduction of molecularly targeted therapy with tyrosine kinase inhibitors. Among patients with recently diagnosed AML, the risk of death was significantly higher for patients treated at nondesignated hospitals than those treated at designated cancer care hospitals. The changes in survival improvement coincided with the introduction of treatment regimens or molecularly targeted therapies. Patient centralization might be one option which would improve survival.

A multi-center retrospective analysis of patients with relapsed/refractory follicular lymphoma after third-line chemotherapy.

The overall outcome of patients with advanced-stage follicular lymphoma (FL) has improved significantly. However, some patients still develop multiple relapsed/refractory FL (RRFL). To address the still-limited data on this population, we performed this multi-center retrospective study. We analyzed 41 patients who received third-line treatment for RRFL at 8 institutes. The median age at diagnosis was 59 years (range, 38-70). The median progression-free survival (PFS) and probability of PFS at 2 years were 1.61 years and 39.4%, respectively, after third-line chemotherapy, and 0.45 years and 19.0%, respectively, after fourth-line chemotherapy. Objective response (OR) after third-line chemotherapy was achieved in 24 patients (53.7%). Bendamustine (Ben)-based regimens were associated with a significantly higher OR rate than other regimens (77.8% vs. 40.0%, respectively, P = 0.025). The median overall survival (OS) and probability of OS at 2 years were 4.71 years and 65.9%, respectively, after third-line chemotherapy, and 1.01 year and 45.1%, respectively, after fourth-line chemotherapy. In conclusion, this study had a small sample size and retrospective design, but it was able to demonstrate poor response rate and duration in patients with multiple RRFL, particularly after fourth-line chemotherapy. The optimal treatment strategy in this population should be clarified, including possibly hematopoietic stem cell transplantation.

Pretreatment serum soluble interleukin-2 receptor level predicts survival in patients with newly diagnosed follicular lymphoma.

This retrospective, multicenter observational study investigated the prognostic value of pretreatment serum soluble interleukin-2 receptor (sIL-2R) level for outcomes of newly diagnosed follicular lymphoma (FL) grade 1-3a who required treatment at diagnosis. A total of 628 patients were recorded, and 502 of these were eligible for analysis. Patients were divided into four quartiles, based on their serum sIL-2R levels as follows: Q1 (sIL-2R < 520 IU/mL), Q2 (520 ≤ sIL-2R < 1030 IU/mL), Q3 (1030 ≤ sIL-2R < 2530 IU/mL) and Q4 (sIL-2R ≥ 2530 IU/mL). Using a multivariable Cox proportional-hazards model, we showed the adjusted probability of overall survival (OS) decreased with increasing serum sIL-2R levels (p for trend = .007). Similar trends were observed for disease-specific survival (DSS) and progression-free survival (PFS). In conclusion, pretreatment serum sIL-2R levels significantly and dose-dependently associate with worse outcomes (OS, DSS and PFS) of patients with newly diagnosed FL.

Different Immune Reconstitution between Cord Blood and Unrelated Bone Marrow Transplantation with Relation to Chronic Graft-versus-Host Disease.

Background: Advances of allogeneic hematopoietic cell transplantation (allo-HCT) have brought long-term survival to the patients with hematologic malignancies. Chronic graft-versus-host disease (GVHD) is one of major problems for the long- term survivors after allo-HCT. Dysregulation of immune reconstitution has been reported to be involved in the pathogenesis of chronic GVHD. Differences of immune reconstitution between cord blood transplantation (CBT) and unrelated bone marrow transplantation (UBMT) remain unclear in long-term survivors. We investigated immune reconstitution in patients surviving for more than 2 years after CBT (n=21) or UBMT (n=20) without relapse of underlying disease. Materials and Methods: Using flow cytometric analysis of peripheral blood, we investigated immune reconstitution of T cells, B cells, and NK cells between CBT and UBMT patients. We collected clinical data regarding allo-HCT and examined the relation of immune reconstitution to the development of chronic GVHD. Results: Between CBT and UBMT patients, we found significant differences in absolute cell number of CD8+ as well as CD19+ cell and CD4/CD8 ratio even more than 2 years after allo-HCT. Among UBMT patients, absolute cell number of naive CD4+ cell was significantly lower in patients with chronic GVHD. In addition, we found significant differences in absolute cell number of CD19+ cell, especially naive B cell between patients with and without chronic GVHD in both CBT and UBMT patients. Conclusion: These results suggest that differences of immune recovery between CBT and UBMT patients may exist even in patients surviving for more than 2 years and might be related to the development of chronic GVHD.

Tumor-Derived Retinoic Acid Regulates Intratumoral Monocyte Differentiation to Promote Immune Suppression.

The immunosuppressive tumor microenvironment (TME) is a major barrier to immunotherapy. Within solid tumors, why monocytes preferentially differentiate into immunosuppressive tumor-associated macrophages (TAMs) rather than immunostimulatory dendritic cells (DCs) remains unclear. Using multiple murine sarcoma models, we find that the TME induces tumor cells to produce retinoic acid (RA), which polarizes intratumoral monocyte differentiation toward TAMs and away from DCs via suppression of DC-promoting transcription factor Irf4. Genetic inhibition of RA production in tumor cells or pharmacologic inhibition of RA signaling within TME increases stimulatory monocyte-derived cells, enhances T cell-dependent anti-tumor immunity, and synergizes with immune checkpoint blockade. Furthermore, an RA-responsive gene signature in human monocytes correlates with an immunosuppressive TME in multiple human tumors. RA has been considered as an anti-cancer agent, whereas our work demonstrates its tumorigenic capability via myeloid-mediated immune suppression and provides proof of concept for targeting this pathway for tumor immunotherapy.

Successful treatment strategy in corporating mogamulizumab and cord blood transplantation in aggressive adult T-cell leukemia-lymphoma: a case report.

Adult T-cell leukemia-lymphoma (ATL) is a rare type of mature T cell lymphoma caused by human T-lymphotropic virus type 1 (HTLV-1) with dismal outcome with conventional chemotherapy. A humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, mogamulizumab (MOG), has been shown to be effective for CCR4-positive ATL. However, MOG administration before allogeneic hematopoietic stem cell transplantation (allo-HSCT) was reported to be associated with an increased risk of severe acute graft-versus-host disease (aGVHD) after allo-HSCT due to reduction of donor-derived regulatory T cells (Tregs). We herein present a patient with ATL who underwent allo-HSCT after MOG administration without developing severe GVHD while referring to serum MOG concentration. The clinical course of our case suggests that it might be possible to determine the appropriate timing of allo-HSCT with monitoring of residual MOG level while avoiding the detrimental effect of MOG on post-transplant clinical outcome without increasing the risk of relapse/progression.