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Background As desmoid-type fibromatosis (DF) exhibits a high recurrence rate after surgery, initial active surveillance followed by medical therapy is the mainstay of the treatment. However, there are few effective drugs with acceptable side effects. Methodology Among drugs that have been used for a long period and possess a known safety profile, auranofin was observed to be effective in suppressing DF using the drug repositioning method in our laboratory. This clinical study has been designed to examine the efficacy and safety of auranofin, an approved anti-rheumatic drug, in patients with progressive DF. Results This study is conducted as a single-center, single-arm, open-label study. Auranofin 3 mg tablets will be administered twice daily to DF patients with progressive disease. The primary endpoint is progression-free survival at 26 weeks after starting treatment. Secondary endpoints include response rate, T2-weighted MRI evaluation, pain intensity, quality of life (QOL), and safety assessment. Conclusions This is the first clinical trial of auranofin in patients with aggressive DF. The study will allow an in-depth understanding of the efficacy of auranofin for response rate as well as for changes in MRI findings, pain, and QOL in patients with aggressive DF., Competing Interests: Human subjects: All authors have confirmed that this study did not involve human participants or tissue. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: Yoshihiro Nishida declare(s) a grant from Nagoya University Hospital. This research is supported by Nagoya University Hospital Funding for Clinical Development. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Nishida et al.)

Background: Umbilical cord blood transplant (UCBT) improves access to transplant for patients lacking a fully matched donor. Previous Center for International Blood and Marrow Transplant Research (CIBMTR) showed that Black patients had a lower overall survival (OS) than White patients following single UCBT. The current study draws on a larger modern cohort and compares outcomes among White, Latinx, Black, and Asian patients., Objective: To compare outcomes by social determinants of health., Study Design: We designed a retrospective study using CIBMTR data. US patients were between ages 1 and 80; 983 received single and 1529 double UCBT as reported to CIBMTR, following either a myeloablative (N = 1752) or reduced intensity conditioning (N = 759) for acute myeloid leukemia, acute lymphoid leukemia, or myelodysplasia. The primary outcome was 2-year OS. Secondary outcomes included disease free survival, transplant related mortality (TRM), acute and chronic graft vs host disease (GVHD), and GVHD free, relapse free survival (GRFS)., Results: For 1705 adults, in univariate analysis, 2-year OS was 41.5% (99% CI, 37.6 to 45.3) for Whites, 36.1% (99% CI, 28.2 to 44.5) for Latinx, 45.8% (99% CI, 36.7 to 55.1) for Blacks, and 44.5% (99% CI, 33.6 to 55.6) for Asians. In multivariate analysis of adults, Latinx patients had inferior OS compared to black patients (p = .0005, HR 1.45, 99% CI 1.18 to 1.79). OS improved over time for all racial/ethnic groups. GVHD rates were comparable among the different racial/ethnic groups. In the 807 children, the 2-year OS in univariate analysis was 66.1% (99% CI, 59.7 to 72.2) for Whites, 57.1% (99%CI, 49 to 64.9) for Latinx, 46.8% (99%CI, 35.3 to 58.4) for Blacks, and 53.8% (99%CI, 32.7 to 74.2) for Asians. In multivariate analysis, no difference in OS was observed among racial/ethnic groups (p = .051). Grade III/IV acute GVHD was higher in Blacks compared with Whites (p = .0016, HR 2.25, 99% CI 1.36 to 3.74) and Latinx (p = .0016, HR 2.17, 99% CI 1.43 to 3.30). There was no survival advantage to receiving a UCB unit from a donor of similar race and ethnicity, for any racial/ethnic groups, for both children and adults. Black and Latinx adult patients were more likely to live in areas defined as high poverty. Patients from high poverty level areas had worse OS (p = .03), due to a higher rate of TRM (p=0.04). Educational level, and type of insurance did not impact overall survival, GVHD, TRM or other transplant outcomes. Children from areas with a higher poverty level had higher TRM, regardless of race and ethnicity (p = .02). Public health insurance, such as Medicaid, was also associated with a higher TRM (p = .02). However, poverty did not impact pediatric OS, DFS, or other post-transplant outcomes., Conclusions: OS for UCBT has improved over time. In adults, OS is comparable among Whites, Blacks, and Asians and lower for Latinx patients. In children, OS is comparable among Whites, Blacks, Latinx, and Asians, but Grade III/IV acute GVHD was higher in Black patients. There was no survival benefit to matching UCB unit and patient by race and ethnicity for adults and children., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Prognosis for patients undergoing hematopoietic cell transplantation (HCT) has been improving. Short-term survival information, such as crude survival rates that consider deaths immediately after the transplantation, may not be sufficiently useful for assessing long-term survival. Using the data of the Japanese HCT registry, the net survival rate of patients who survived for a given period was determined according to age, disease, and type of transplant. We included a total of 41,716 patients who received their first allogeneic hematopoietic cell transplantation between 1991 and 2015. For each disease, age group, graft source subcategory, net survival was calculated using the Pohar-Perme method, and 5-year conditional net survival (CS) was calculated. Ten-year net survivals of total patient cohort were 41.5% and 47.4% for males and females, respectively. Except for myelodysplastic syndrome, multiple myeloma, and adult T-cell leukemia/lymphoma, 5-year CS for 5-year transplant survivors exceeded 90%. CS was especially high for aplastic anemia, of which was over 100% for children and younger adults receiving cord blood, suggesting that these patients have similar longevity to an equivalent group from the general population. These findings provide useful information for long-term survival, and can serve as benchmark for comparisons among registries, including other cancers., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: No efficient treatment has yet been established for epidermolytic ichthyosis (EI), which is caused by pathogenic variants of KRT1 or KRT10. Patients with ichthyosis with confetti (IWC) have multiple normal-appearing spots, caused by the revertant somatic recombination of pathogenic variants that occurs at each spot independently. Additionally, some patients with EI have large areas of normal skin due to revertant postzygotic mosaicism., Objectives: To assess the feasibility of transplanting cultured epidermal autografts (CEAs) produced from revertant epidermal keratinocytes in patients with EI and IWC., Methods: We performed a clinical trial of treatment with CEAs produced from each patient's own revertant epidermal keratinocytes as a proof-of-concept study. This was a single-arm, open, unmasked, uncontrolled, single-assignment, treatment-purpose study. The primary outcome was the percentage area that lacked recurrence of ichthyosis lesions 4 weeks after the final transplant. The secondary outcome was the percentage area lacking recurrence of ichthyosis lesions 24 weeks after the initial transplantation. The trial was registered with the Japan Registry of Clinical Trials (jRCTb041190097)., Results: We successfully produced CEAs from genetically confirmed revertant skin from two patients with mosaic EI and from one patient with IWC and confirmed by amplicon sequencing and droplet digital polymerase chain reaction analysis that the CEAs mainly consisted of revertant wild-type cells. Single-cell RNA sequencing analysis confirmed the normal proliferation and safety profiling of CEAs. CEAs were transplanted onto desquamated lesional sites in the patients. Four weeks post-transplantation, the percentage area lacking recurrence of ichthyosis lesions in the three patients was 40%, 100% and 100% respectively, although recurrence of ichthyosis lesions was seen at the site of CEA transplantation in all three patients at 24 weeks post-transplantation., Conclusions: CEAs from normal skin have the potential to be a safe and local treatment option for EI and IWC., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: Awake craniotomy is performed to resect brain tumors in eloquent brain areas to maximize tumor reduction and minimize neurological damage. Evidence suggests that intraoperative anesthetic management of awake craniotomy with remimazolam is safe. We compared the time to arousal and efficacy of anesthetic management with remimazolam and propofol during awake craniotomy., Methods: In a single-institution randomized, prospective study, patients who underwent elective awake craniotomy were randomized to receive remimazolam and reversal with flumazenil (group R) or propofol (group P). The primary end point was time to awaken. Secondary end points were time to loss of consciousness during induction of anesthesia, the frequency of intraoperative complications (pain, hypertension, seizures, nausea, vomiting, and delayed arousal), and postoperative nausea and vomiting. Intraoperative task performance was assessed using a numerical rating scale (NRS) score., Results: Fifty-eight patients were recruited, of which 52 (26 in each group) were available for the efficacy analysis. Patients in group R had faster mean (±SD) arousal times than those in the P group (890.8±239.8 vs. 1075.4±317.5 s; P=0.013)and higher and more reliable intraoperative task performance (NRS score 8.81±1.50 vs. 7.69±2.36; P=0.043). There were no significant intraoperative complications., Conclusions: Compared with propofol, remimazolam was associated with more rapid loss of consciousness and, after administration of flumazenil, with faster arousal times and improved intraoperative task performance., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Mitochondrial dysfunction has been suggested to play a role in depression pathogenesis. This clinical trial (jRCTs042220011) was conducted to evaluate whether depression symptoms could be alleviated by an Extremely Low Frequency, Extremely Low Magnetic Environment (ELF-ELME), which has been found in basic research studies to enhance mitochondrial membrane potential. Participants were exposed to the ELF-ELME via a head-mounted magnetic field device (10 μTesla, 4 ms, 1-8 Hz/8 s) worn for 2 h per day for 8 consecutive weeks. Four male patients with treatment-resistant depression were enrolled. Significant reductions from baseline in the average total Montgomery-Åsberg Depression Rating Scale (MADRS) score were observed at 4, 6, and 8 weeks. ELF-ELME appears to ameliorate depressive symptoms in patients with major depressive disorder safely and effectively, suggesting that it could be used as an alternative treatment for depressive patients who do not prefer to take antidepressants and in combination with antidepressant therapy for patients who only partially respond to pharmacotherapy., Competing Interests: Declaration of Competing Interest The authors affirm that they have no conflicts of interest with any subject matter discussed in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study aimed to address the prognostic impact of center experience based on the data of 7821 adults with acute myeloid leukemia who underwent allogeneic hematopoietic cell transplantation (HCT) from 2010 to 2019 in Japan, where medical care was provided within a uniform healthcare system. Center experience was defined based on the number of allogeneic HCTs performed for any indication during the study period, by which centers were divided into low-, intermediate-, and high-volume centers. After adjusting for known confounding factors, the risk of overall mortality was lowest for the high-volume centers and highest for the low-volume centers, with the difference between the center categories attributed primarily to the risk of relapse. Patients transplanted at high-volume centers had higher risks of acute and chronic graft-versus-host diseases but without an increased risk of non-relapse mortality (NRM). These findings reveal the presence of a center effect in allogeneic HCT conducted during the past decade in Japan, highlighting the difference in relapse based on center experience. The weaker effect on NRM compared with that on relapse suggests that the transplantation care quality is becoming equalized across the country., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Delayed neutrophil recovery is an important limitation to the administration of cord blood transplantation (CBT) and leaves the recipient vulnerable to life-threatening infection and increases the risk of other complications. A predictive model for neutrophil recovery after single-unit CBT was developed by using a machine learning method, which can handle large and complex datasets, allowing for the analysis of massive amounts of information to uncover patterns and make accurate predictions. Japanese registry data, the largest real-world dataset of CBT, was selected as the data source. Ninety-eight variables with observed values for >80% of the subjects known at the time of CBT were selected. Model building was performed with a competing risk regression model with lasso penalty. Prediction accuracy of the models was evaluated by calculating the area under the receiver operating characteristic curve (AUC) using a test dataset. The primary outcome was neutrophil recovery at day (D) 28, with recovery at D14 and D42 analyzed as secondary outcomes. The final cord blood engraftment prediction (CBEP) models included 2991 single-unit CBT recipients with acute leukemia. The median AUC of a D28-CBEP lasso regression model run 100 times was .74, and those for D14 and D42 were .88 and .68, respectively. The predictivity of the D28-CBEP model was higher than that of 4 different legacy models constructed separately. A highly predictive model for neutrophil recovery by 28 days after CBT was constructed using machine learning techniques; however, identification of significant risk factors was insufficient for outcome prediction for an individual patient, which is necessary for improving therapeutic outcomes. Notably, the prediction accuracy for post-transplantation D14, D28, and D42 decreased, and the model became more complex with more associated factors with increased time after transplantation., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: As the Japanese population may have less genetic diversity than other ethnic groups, treatment outcomes may be affected when allogeneic hematopoietic cell transplantation is performed in other races. However, evidence explaining the effect of racial differences is limited., Methods: We used the Japanese National Database to examine the outcomes of first allogeneic bone marrow transplantations (BMTs) performed between Japanese and non-Japanese patients from 1996 to 2021. We performed propensity score matching using sex, age group, underlying disease group, HLA mismatch, conditioning regimen intensity, and BMT implementation age to select Japanese-to-Japanese BMT patients as the controls., Results: The numbers of non-Japanese-to-Japanese and Japanese-to-non-Japanese BMT cases included in the analysis were 48 and 75, respectively, and the following outcomes were compared: overall survival, non-relapse mortality, acute graft-vs-host disease (GVHD) ≥ grade II, chronic GVHD, and engraftment of neutrophils and platelets. Most parameters did not differ when comparing BMTs according to ethnicity; only platelet engraftment was delayed in Japanese-to-non-Japanese BMT but not in non-Japanese-to-Japanese BMT., Conclusions: The results of this study suggested that BMT performed in Japanese and non-Japanese patients has little effect on treatment outcomes. The results of this study may be useful for donor selection in Japan, where internationalization has progressed in recent years., Competing Interests: Declaration of competing interest All the authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In Japan, systemic chemotherapy is the standard treatment for unresectable, advanced, or recurrent gastric cancer. However, numerous patients with gastric cancer do not receive late-line treatment because of the rapid progression of gastric cancer. Additionally, late-line treatments, such as nivolumab, trifluridine tipiracil (FTD/TPI), or irinotecan, have limited effects on improving clinical symptoms and delaying the onset of symptoms associated with cancer progression. Recently, a combination of FTD/TPI and ramucirumab was reported to have a high response rate in late-line treatment; however, owing to patient selection bias and a high rate of hematologic toxicity in that previous study, this regimen may not be feasible in real-world clinical applications. Our objective is to conduct a single-arm phase II study to assess the safety and efficacy of FTD/TPI plus ramucirumab combination therapy for gastric cancer after third-line treatment under real-world clinical conditions. This study will recruit 32 patients according to eligibility criteria and administer FTD/TPI (35 mg/m 2 ) and intravenous ramucirumab (8 mg/kg). The primary endpoint will be the time to treatment failure. The secondary endpoints will include the overall survival time, progression-free survival time, overall response rate, disease control rate, relative dose intensity, and incidence of adverse events. The results will add new insights for improving the late-line treatment of advanced gastric cancer., Competing Interests: The authors declare the following financial interests/personal relationships that may be considered potential competing interests: Dr Nakanishi reports personal fees from Taiho Pharmaceutical Co, Ltd, Ono Pharmaceutical Co, Ltd, and Daiichi Sankyo Company, Ltd, outside the scope of the submitted work. Dr Kodera reports grants and personal fees from Taiho Pharmaceutical Co, Ltd, Chugai Pharma, MSD, Nihon Kayaku, Yakult, Lilly Japan, Ono Pharmaceutical Co, Ltd, Covidien, Daiichi Sankyo Company, Ltd, Tsumura, Johnson & Johnson, and Abbvie; grants from Takeda, Kaken Pharma, EA Pharma, Otsuka, Sanofi, Abbot, Bayer, and Pfizer; and personal fees from Miyarisan, Amgen, and Olympus, outside the scope of the submitted work. Dr Ando reports grants and personal fees from Chugai Pharmaceutical Co, Ltd, Kyowa Kirin Co, Ltd, Nippon Kayaku Co, Ltd, Yakult Honsha Co, Ltd, Ono Pharmaceutical Co, Ltd, Taiho Pharmaceutical Co, Ltd, Novartis Pharma KK, Daiichi Sankyo Company, Ltd, and Eisai Co, Ltd; personal fees from Eli Lilly Japan KK, Bayer Holding Ltd, Sawai Pharmaceutical Co, Ltd, MSD KK, Astellas Pharma Inc., Otsuka Holdings Co, Ltd, Sanwa Kagaku Kenkyusho Co, Ltd, Hisamitsu Pharmaceutical Co, Inc., SymBio Pharmaceuticals, Aptitude Health, and Alfresa Pharma Corporation; and grants from BeiGene, Ltd, outside the scope of the submitted work. Dr Murotani reports personal fees from Taiho Pharmaceutical Co, Ltd, outside the scope of the submitted work. The other authors declare that no financial or material support was received for this study.

Background: In recent years, technologies promoting the digitization of self-monitoring of blood glucose (SMBG) records including app-cloud cooperation systems have emerged. Studies combining these technological interventions with support from remote health care professionals have reported improvements in glycemic control., Objective: To assess the use of an app-cloud cooperation system linked with SMBG devices in clinical settings, we evaluated its effects on outpatient management of diabetes without remote health care professional support., Methods: In this multicenter, open-label, and single-armed prospective study, 48 patients with diabetes (including type 1 and type 2) at 3 hospitals in Japan treated with insulin or glucagon-like peptide 1 receptor agonists and performing SMBG used the app-cloud cooperation system for 24 weeks. The SMBG data were automatically uploaded to the cloud via the app. The patients could check their data, and their attending physicians reviewed the data through the cloud prior to the patients' regular visits. The primary outcome was changes in glycated hemoglobin (HbA 1c ) levels., Results: Although HbA 1c levels did not significantly change in all patients, the frequency of daily SMBG following applying the system was significantly increased before induction at 12 (0.60 per day, 95% CI 0.19-1.00; P=.002) and 24 weeks (0.43 per day, 95% CI 0.02-0.84; P=.04). In the subset of 21 patients whose antidiabetic medication had not been adjusted during the intervention period, a decrease in HbA 1c level was observed at 12 weeks (P=.02); however, this significant change disappeared at 24 weeks (P=.49). The Diabetes Treatment Satisfaction Questionnaire total score and "Q4: convenience" and "Q5: flexibility" scores significantly improved after using the system (all P<.05), and 72% (33/46) patients and 76% (35/46) physicians reported that the app-cloud cooperation system helped them adjust insulin doses., Conclusions: The digitization of SMBG records and sharing of the data by patients and attending physicians during face-to-face visits improved self-management in patients with diabetes., Trial Registration: Japan Registry of Clinical Trials (jRCT) jRCTs042190057; https://jrct.niph.go.jp/en-latest-detail/jRCTs042190057., (©Tomoko Handa, Takeshi Onoue, Tomoko Kobayashi, Ryutaro Maeda, Keigo Mizutani, Ayana Yamagami, Tamaki Kinoshita, Yoshinori Yasuda, Shintaro Iwama, Takashi Miyata, Mariko Sugiyama, Hiroshi Takagi, Daisuke Hagiwara, Hidetaka Suga, Ryoichi Banno, Yoshinori Azuma, Takatoshi Kasai, Shuko Yoshioka, Yachiyo Kuwatsuka, Hiroshi Arima. Originally published in JMIR Diabetes (https://diabetes.jmir.org), 19.01.2024.)

Background: The surgical techniques for treatment of chronic subdural hematoma (CSDH), a common neurosurgical condition, have been discussed in a lot of clinical literature. However, the recurrence proportion after CSDH surgery remains high, ranging from 10 to 20%. The standard surgical procedure for CSDH involves a craniostomy to evacuate the hematoma, but irrigating the hematoma cavity during the procedure is debatable. The authors hypothesized that the choice of irrigation fluid might be a key factor affecting the outcomes of surgery. This multicenter randomized controlled trial aims to investigate whether intraoperative irrigation using artificial cerebrospinal fluid (ACF) followed by the placement of a subdural drain would yield superior results compared to the placement of a subdural drain alone for CSDH., Methods: The study will be conducted across 19 neurosurgical departments in Japan. The 1186 eligible patients will be randomly allocated to two groups: irrigation using ACF or not. In either group, a subdural drain is to be placed for at least 12 h postoperatively. Similar to what was done in previous studies, we set the proportion of patients that meet the criteria for ipsilateral reoperation at 7% in the irrigation group and 12% in the non-irrigation group. The primary endpoint is the proportion of patients who meet the criteria for ipsilateral reoperation within 6 months of surgery (clinical worsening of symptoms and increased hematoma on imaging compared with the postoperative state). The secondary endpoints are the proportion of reoperations within 6 months, the proportion being stratified by preoperative hematoma architecture by computed tomography (CT) scan, neurological symptoms, patient condition, mortality at 6 months, complications associated with surgery, length of hospital stay from surgery to discharge, and time of the surgical procedure., Discussion: We present the study protocol for a multicenter randomized controlled trial to investigate our hypothesis that intraoperative irrigation with ACF reduces the recurrence proportion after the removal of chronic subdural hematomas compared with no irrigation., Trial Registration: ClinicalTrials.gov jRCT1041220124. Registered on January 13, 2023., (© 2023. The Author(s).)

Background: Fluorodeoxyglucose positron emission tomography ( 18 F-FDG-PET) can noninvasively assess active inflammatory myocardium in patients with cardiac sarcoidosis (CS). Prednisolone (PSL) is the initial drug of choice for active CS; however, its efficacy has not been prospectively evaluated. Moreover, there are no alternative systematic treatment strategies., Objectives: The goal of this study was to evaluate the efficacy of methotrexate (MTX) in patients refractory to PSL assessed by using cardiac metabolic activity (CMA) in 18 F-FDG-PET., Methods: A total of 59 patients with active CS were prospectively enrolled. CMA (standardized uptake value × accumulation area) was used as an indicator of active inflammation, and a 6-month regimen of PSL therapy was introduced, followed by a second FDG scan. Poor responders to PSL therapy (CMA reduction rate <70%) and patients with recurrent CS (CMA reduction rate ≥70% after initial PSL therapy but CMA recurred after an additional 6 months of therapy) were randomly assigned to the MTX or repeat PSL (re-PSL) therapy groups for another 6 months., Results: Fifty-six patients completed the initial 6-month PSL therapy regimen. Median CMA reduced from 203.3 to 1.0 (P < 0.001), and 47 patients were allocated to the response group, 9 to the poor response group, and 2 to the recurrent group. Accordingly, 11 patients were randomly assigned to the MTX (n = 5) or re-PSL (n = 6) groups. After 6 months, neither group showed a significant reduction in CMA values. MTX was comparable to re-PSL in reducing CMA., Conclusions: The 6-month regimen of PSL was a potent therapeutic tool for active CS. When MTX was added to low-dose PSL in patients refractory to the initial PSL therapy, there was no significant difference compared with re-PSL. Further studies are needed to evaluate the therapeutic potential of MTX for active CS, including how MTX works when it is administered in higher doses or for longer periods., Competing Interests: Funding Support and Author Disclosures This work was supported by the Japan Society for the Promotion of Science KAKENHI grants JP18K15387 and JP22K08178 (to Dr Morimoto). Dr Okumura has received lecture fees from Ono Pharma Co Ltd, Novartis Pharma KK, Otsuka Pharma Co Ltd, and AstraZeneca Co Ltd; and research grants from Ono Pharma Co Ltd, Amgen Astellas BioPharma KK, Pfizer Japan Inc, Alnylam, and Alexion (not in connection with the submitted work). Dr Ishii has received lecture fees from AstraZeneca Inc, Bayer Pharmaceutical Co Ltd, Boehringer Ingelheim Japan, Bristol Myers Squibb Inc, Daiichi Sankyo Pharma Inc, MSD KK, Mitsubishi Tanabe Pharma Co Ltd, Mochida Pharmaceutical Co Ltd, Novartis Japan, and Pfizer Japan Inc; and has received scholarship funds or donations from Boehringer Ingelheim Japan and Bristol Myers Squibb Inc. Dr Murohara has received lecture fees and unrestricted research grants from Bayer Pharma Co Ltd, Daiichi Sankyo Co, Ltd, Dainippon Sumitomo Pharma Co Ltd, Kowa Co Ltd, MSD KK, Mitsubishi Tanabe Pharma Co, Boehringer Ingelheim Co Ltd, Novartis Pharma KK, Pfizer Japan Inc, Sanofi, Takeda Pharma Co Ltd, Astellas Pharma Inc, Otsuka Pharma Ltd, and Teijin Pharma Ltd. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: In our previously reported randomized controlled trial in patients with noninsulin-treated type 2 diabetes, the use of flash glucose monitoring (FGM) improved glycated hemoglobin (HbA1c), and the improvement was sustained after the cessation of glucose monitoring. In this post-hoc analysis, we examined data from our trial to identify the factors that influenced FGM efficacy., Methods: We analyzed data for 48 of 49 participants of the FGM group who completed the trial to clarify the changes in various parameters and factors related to HbA1c improvement with the use of FGM., Results: Analyses of the FGM data during the 12-week FGM provision period showed that the weekly mean blood glucose levels considerably decreased as early as at 1 week compared with the baseline values, and this decline continued for 12 weeks. An enhancement in the Diabetes Treatment Satisfaction Questionnaire regarding "willingness to continue the current treatment" score was significantly associated with the improvement in HbA1c at 12 (p = 0.009) and 24 weeks (p = 0.012)., Conclusions: Glycemic control was improved soon after FGM initiation, accompanied by improved satisfaction with continuation of the current treatment in patients with noninsulin-treated type 2 diabetes., Competing Interests: Declaration of Competing Interest HA reports grants and speakers’ honoraria from Abbott Japan outside the submitted work. No other potential conflicts of interest relevant to this article were reported., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes., (Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Immune checkpoint inhibitors (ICI) plus platinum-based chemotherapy has been recognized as a standard first-line therapy in non-small cell lung cancer (NSCLC); however, no prospective clinical trials of docetaxel (DTX) plus ramucirumab (RAM) following first-line ICI plus platinum-based chemotherapy has been reported., Methods: In this multicentre, open-label, single-arm, phase 2 trial, we enrolled patients with NSCLC from eight centres in Japan. Patients with metastatic NSCLC with disease progression after platinum-based chemotherapy plus ICI were eligible for the study. Patients were intravenously treated with 60 mg/m 2 of DTX and 10 mg/kg of RAM on day 1 with a strong recommendation of pegfilgrastim administration on day 2 every 3 weeks. The primary end point was objective response rate (ORR) in efficacy analysis population. Safety was assessed in all patients treated at least one dose. The ORR of the null and alternative hypotheses were 10% and 30%, with α error of 0.1 and β error of 0.1. This trial is registered with the Japan Registry for Clinical Trials, jCRTs041190077., Findings: Between 16 January, 2020, and 24 August, 2021, 33 patients (median age 66 [range 42-79] years) were enrolled. Thirteen patients (41%) had Eastern Cooperative Oncology Group performance status of 1. Twenty-five patients (78%) had an interval of <60 days after the last administration of ICI. In the efficacy analysis population (n = 32), the primary endpoint was met as 11 patients achieved partial response (PR), with ORR of 34.4% (80% CI, 23.1-47.2). Grade ≥3 anaemia and febrile neutropenia were observed in 2 (6%) and 3 (9%) patients, respectively. No treatment-related deaths and no new safety signals were observed., Interpretation: DTX plus RAM demonstrated encouraging antitumor activity with a manageable safety profile in patients who have progressed on front-line ICIs plus platinum-based chemotherapy. The results of this trial can be a helpful reference in conducting further phase III trials of new second-line treatment options., Funding: Eli Lilly Japan K.K., Competing Interests: RM received personal fees from Boehringer Ingelheim, AstraZeneca, Pfizer, Eli Lilly, Chugai Pharmaceutical, Merk Sharp & Dohme (MSD), Ono Pharmaceutical, and Taiho Pharmaceutical. MM received grants from Boehringer Ingelheim and Eli Lilly; personal fees from Eli Lilly, Chugai, Astra Zeneca, Ono, Pfizer, and MSD; non-financial support from F. Hoffmann-La Roche; others from Chugai, Astra Zeneca, Pfizer, Merk Serono, Kissei, Taiho, and Novartis. KI received personal fees from Boehringer Ingelheim, AstraZeneca, Pfizer, Eli Lilly, Chugai, MSD, Ono, Taiho, Takeda, and Daiichi Sankyo. OH received grants from AstraZeneca, Novartis, MSD, Daiichi Sankyo, Bayer Yakuhin, AbbVie, Eli Lilly, Janssen, and Ono; personal fees from AstraZeneca, Chugai, Takeda, MSD, Merck, Daiichi Sankyo, Eli Lilly, AbbVie, Boehringer Ingelheim, Nippon Kayaku, and Taiho. KT received personal fees from AstraZeneca, Boehringer Ingelheim, Chugai, Eli Lilly, GlaxoSmithKline (GSK), MSD, Nippon Kayaku, Novartis, Pfizer, Taiho, and Takeda. YG received personal fees from Taiho, Boehringer Ingelheim, Chugai, MSD, GSK, Pfizer, Takeda, Nippon Kayaku, Novartis, Bristol-Meyers Squibb, Kyowa Hakko Bio, and Eli Lilly. HI received personal fees from Eli Lilly. TY received personal fees from Ono, Chugai, Eli Lilly, Taiho, AstraZeneca, MSD, and Bristol-Meyers Squibb. YZ received grants from AstraZeneca, MSD, Daiichi-Sankyo, Merck and Amgen; personal fees from AstraZeneca, Eli Lilly, Chugai, Ono, Bristol-Meyers Squibb, Takeda, Boehringer-Ingelheim, Taiho, MSD, Novartis, Pfizer, Nihon Kayaku, Kyowa Kirin, and Amgen. MO received grants from AbbVie, Chugai, GSK, MSD, Parexel, Sanofi, AstraZeneca, Fujifilm Toyama Chemical, Janssen, Ono and Pfizer; personal fees from AMCO, Canon Medical Systems, Fujifilm Toyama Chemical, Merit Medical Japan, Olympus, AstraZeneca, Chugai, Kaneka Medix, Novartis, and Sanofi. MI received personal fees from AstraZeneca, GlaxoSmithKline, Pfizer, Shionogi, Sanofi, Insmed, Asahi Kasei Pharma, Kyorin pharmaceutical, Chugai pharmaceutical, Boehringer Ingelheim, Eli Lilly, Daiichi Sankyo, MSD, Abbott, Taiho pharmaceutical, Amgen, and Novartis., (© 2023 The Authors.)

The number of hematopoietic stem cell transplantations (HCTs) is increasing annually worldwide, and the Asia-Pacific (AP) region is no exception. We report on the absolute number of HCTs in 2018 and 2019 and the trends in graft selection and disease indication in the past few decades. In 2018, 24,292 HCTs were performed in the AP region, of which 8,754 (36.0%) were autologous and 15,538 (64.0%) were allogeneic. Among the allogeneic HCTs, 10,552 (67.9%) of the recipients were related to their donors, whereas 4,986 (32.1%) were unrelated. In 2019, 27,583 HCTs were reported, of which 17,613 (63.9%) were allogeneic and 9,970 (36.1%) were autologous. Although, in 2010, there was a nearly equal number of related and unrelated HCTs, the difference has shown an annual increase, with more than double (2.05) the number of related than unrelated HCTs in 2019. Recent trends in the AP region show that peripheral blood has overwhelmingly surpassed the bone marrow as a graft source for both related and unrelated HCTs, with the haploidentical donor type being preferred; however, their trends in each country/region were quite different among countries/regions. In 2019, the main conditions requiring HCT were acute myelogenous leukemia (n=6,629 [24.0%]), plasma cell disorders (PCD) (n=4,935 [17.9%]), malignant lymphoma (ML) (n=4,106 [14.9%]), acute lymphoblastic leukemia (AML) (n=3,777 [13.7%]), myelodysplastic syndrome or myelodysplastic/myeloproliferative neoplasm (n=1,913 [6.9%]), severe aplastic anemia (n=1,671 [6.1%]), and hemoglobinopathy (n=910 [3.3%]). PCD and ML were the main indications for autologous HCT, and the number of PCD cases has grown more prominent than the corresponding of ML. The increased number of allogeneic transplants for hemoglobinopathy remains prominent, as well as that of AML and acute lymphocytic leukemia for the past 5 years. There was a significant regional variation in the number of facilities performing HCTs, ranging from one in Mongolia and Nepal to 313 in Japan, and differing regional densities varying from 0.1 in Indonesia and Pakistan to 24.7 in Japan. The total transplant density per 10 million population in each country/region also differed (0.2 in Indonesia and 627 in New Zealand). This annual Activity Survey aims to help all participating countries/regions understand the changes in HCT, serve as an asset in promoting HCT activities in the AP region, and be used as a reference for comparison with other registries from Europe and the United States., Competing Interests: The authors declare no conflict of interest. Disclosure forms provided by the authors are available on the website. MI, AS, MB, AAH, and SO are editors of Blood Cell Therapy. They were not involved in the editorial evaluation and the decision to accept this article for publication., (Copyright Ⓒ2023 Asia-Pacific Blood and Marrow Transplantation Group (APBMT).)

Background: Spinal cord stimulation (SCS) is one of the neuromodulation therapies for chronic neuropathic pain. The conventional paresthesia-based SCS involves the application of tonic stimulation that induces a sense of paresthesia. Recently, new SCS stimulation patterns without paresthesia have been developed. Differential target multiplexed (DTM) stimulation and fast-acting subperception therapy (FAST) stimulation are the latest paresthesia-free SCS patterns., Methods: A single-center, open-label, crossover, randomized clinical trial to investigate the superiority of SCS using the latest new stimulation patterns over conventional tonic stimulation for neuropathic pain is planned. This study consists of two steps: SCS trial (first step) and SCS system implantation (second step). In the SCS trial, participants will be randomly assigned to 4 groups receiving stimulation, including tonic, DTM, and FAST. Each stimulation will then be performed for 2 days, and a visual analog scale (VAS) for pain will be evaluated before and after each stimulation pattern. A stimulation-off period for 1 day is set between each stimulation pattern to wash out the residual previous stimulation effects. Pain improvement is defined as more than 33% reduction in the pain VAS. The primary analysis will compare pain improvement between the new stimulation patterns and the conventional tonic stimulation pattern in the SCS trial. The secondary outcomes will be evaluated as follows: (1) the relationships between causative disease and improvement rate by each stimulation pattern; (2) comparison of pain improvement between the DTM and FAST stimulation patterns in all cases and by causative disease; (3) changes in assessment items preoperatively to 24 months after the implantation; (4) preoperative factors associated with long-term effects defined as continuing for more than 12 months; and (5) adverse events related to this study 3 months after the implantation., Discussion: This study aims to clarify the effectiveness of the latest new stimulation patterns compared to the conventional tonic stimulation. In addition, which stimulation pattern is most effective for which kind of causative disease will be clarified., Trial Registration: Japan Registry of Clinical Trials (jRCT) 1,042,220,094. Registered on 21 November 2022, and last modified on 6 January 2023. jRCT is an approved member of the Primary Registry Network of WHO ICTRP., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Pancreatic fistula after gastrectomy with lymph node dissection is associated with prolonged hospital stay and critical complications such as intra-abdominal bleeding and sepsis. Polyglycolic acid (PGA) sheets are absorbable suture reinforcement materials. A randomized Phase II trial has been planned to evaluate the effect of PGA sheets on preventing postoperative pancreatic fistula. A total of 320 patients will be recruited from thirteen institutions. Patients who are scheduled to undergo distal or total gastrectomy will be randomly allocated into the PGA group or control group, and the dissected area around the pancreas will be covered by the PGA sheet in the PGA group. The primary endpoint will be the maximum value of drain amylase concentration up to 5 days after surgery. The secondary endpoints will be as follows: transition of value of amylases of drain discharge, incidence of pancreatic fistula, incidence of intra-abdominal abscess, white blood cell count, value of C-reactive protein, incidence of postoperative complication, duration of antibiotic agents administration, duration of abdominal drainage, usage of octreotide, duration of hospital stay, incidence of bleeding in abdominal cavity, mortality, and incidence of reoperation., Competing Interests: Professor Masahiko Ando reports grants from Kyowa Kirin, Co. Ltd., outside the submitted work. The authors report no other conflicts of interest in this work., (© 2023 Shimizu et al.)

Background: Anti-programmed cell death protein 1 (PD-1) monotherapy is one of the standard systemic therapies for advanced melanoma; however, the efficacy of salvage systemic therapies after PD-1 monotherapy failure (PD-1 MF), particularly in acral melanoma (AM), the main clinical melanoma type in Japanese patients, is unclear. This study aimed to investigate the efficacy of salvage systemic therapies in Japanese patients with AM after PD-1 MF., Patients and Methods: The study included 108 patients with advanced AM (palm and sole, 72; nail apparatus, 36) who underwent salvage systemic therapy at 24 Japanese institutions. We mainly assessed the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)., Results: Thirty-six (33%) patients received ipilimumab, 23 (21%) received nivolumab and ipilimumab (nivo/ipi), 10 (9%) received cytotoxic chemotherapy, 4 (4%) received BRAF and MEK inhibitors (BRAFi/MEKi), and the remaining 35 (32%) continued with PD-1 monotherapy after disease progression. The ORRs in the ipilimumab, nivo/ipi, cytotoxic chemotherapy, and BRAFi/MEKi groups were 8, 17, 0, and 100%, respectively. The nivo/ipi group showed the longest OS (median, 18.9 months); however, differences in ORR, PFS, and OS between the groups were insignificant. The OS in the nivo/ipi group was higher in the palm and sole groups than in the nail apparatus group (median: not reached vs. 8.7 months, p  < 0.001). Cox multivariate analysis demonstrated that nail apparatus melanoma independently predicted unfavorable PFS and OS ( p  = 0.006 and 0.001). The total OS (from PD-1 monotherapy initiation to death/last follow-up) was insignificant between the groups., Conclusion: Nivo/ipi was not more effective than cytotoxic chemotherapy and ipilimumab after PD-1 MF in patients with advanced AM. The prognosis after PD-1 MF would be poorer for nail apparatus melanoma than for palm and sole melanoma., Competing Interests: TMo and SS have received honoraria from Ono Pharma. KeN has served as a consultant and/or received honoraria from Novartis, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Novartis, and Ono Pharma. NY has received research funding from BMS, MSD, Novartis, Ono Pharma, and Takara Bio, and has served as a consultant and/or received honoraria from BMS, MSD, Novartis, and Ono Pharma. YKi, SY, HK, and NF have received honoraria from Novartis and Ono Pharma. OY has received research funding and/or honoraria from Ono Pharma. TIn has received honoraria from BMS, MSD, and Ono Pharma. SF has received research funding from Ono Pharma and honoraria from BMS, MSD, and Novartis. TT, TMae, and SM have received honoraria from BMS, MSD, Novartis, and Ono Pharma. AO has served as a consultant and/or received honoraria from BMS, MSD, Novartis, and Ono Pharma, and has received research funding from Eisai. TIs has served as a consultant and/or received honoraria from Ono Pharma, Pfizer, BMS, and Novartis. YNakamura has served as a consultant and/or received honoraria from BMS, MSD, Maruho, Ono Pharma, Sanofi, Sun Pharma, Tanabe Mitsubishi Pharma, and Torii. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mori, Namikawa, Yamazaki, Kiniwa, Yamasaki, Yoshikawa, Inozume, Kato, Nakai, Fukushima, Takenouchi, Maekawa, Matsushita, Otsuka, Nomura, Baba, Isei, Saito, Fujimoto, Tanaka, Kaneko, Kuwatsuka, Matsuya, Nagase, Onishi, Onuma and Nakamura.)

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are considered to have the potential to maintain renal function by correcting glomerular hypertension in patients with diabetic kidney disease (DKD). The aim of this study is to demonstrate the renoprotective effect of SGLT2i by measuring renal hemodynamics, including glomerular filtration fraction (FF), in type 2 diabetic patients with moderate renal dysfunction., Methods: Renoprotective effect of canagliflozin derived from test of renal hemodynamics in diabetic kidney disease (FAGOTTO) study is a 12-week multicenter, open-label, randomized (1:1), parallel-group trial of type 2 diabetic patients with diabetic kidney disease (30 ≤ estimated glomerular filtration rate [eGFR] ≤ 60 mL/min/1.73 m 2 ). A total of 110 patients are to be randomly allocated to receive once-daily canagliflozin 100 mg or control (standard therapy). FF will be calculated by dividing the measured GFR (mGFR) by the effective renal plasma flow (eRPF). mGFR and eRPF will be measured by the clearance of inulin and para-aminohippuric acid (PAH), respectively. The primary endpoint of this trial is the percentage change in FF after 4 weeks of treatment in the canagliflozin and control groups., Discussion: The FAGOTTO study will elucidate the mechanism of the renoprotective action of SGLT2i. The background, rationale, and study design of this trial are presented. To date, > 80 patients have been enrolled in this trial. The study will end in 2025., Trial Registration: jRCT (Japan Registry Of Clinical Trials) jRCTs041200069. Date of registration: November 27, 2020., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Neuropathic pain after spinal cord injury (SCI), both traumatic and non-traumatic, is refractory to various treatments. Spinal cord stimulation (SCS) is one of the neuromodulation therapies for neuropathic pain, although SCS has insufficient efficacy for neuropathic pain after SCI. The reasons are presumed to be inappropriate locations of SCS leads and conventional tonic stimulation itself does not have a sufficient analgesic effect for the pain. In patients with past spinal surgical histories, the cylinder-type leads are likely to be placed on the caudal side of the SCI because of surgical adhesions. Differential target multiplexed (DTM) stimulation is one of the latest new stimulation patterns that is superior to conventional stimulation., Methods: A single-center, open-label, randomized, two-way crossover trial is planned to investigate the efficacy of SCS using DTM stimulation placing a paddle lead at the appropriate site for neuropathic pain after SCI in patients with spinal surgical histories. The paddle-type lead delivers energy more efficiently than a cylinder-type lead. This study consists of two steps: SCS trial (first step) and SCS system implantation (second step). The primary outcome is rates of achieving pain improvement with more than 33% reduction 3 months after SCS system implantation. The secondary outcomes are to be evaluated as follows: (1) effectiveness of DTM and tonic stimulations during the SCS trial; (2) changes of assessment items from 1 to 24 months; (3) relationships between the result of the SCS trial and the effects 3 months after SCS system implantation; (4) preoperative factors associated with a long-term effect, defined as continuing for more than 12 months; and (5) whether gait function improves from 1 to 24 months., Discussion: A paddle-type lead placed on the rostral side of SCI and using DTM stimulation may provide significant pain relief for patients with intractable neuropathic pain after SCI in patients with past spinal surgical histories., Trial Registration: Japan Registry of Clinical Trials (jRCT) jRCT 1042220093. Registered on 21 November 2022, and last modified on 6 January 2023. jRCT is approved as a member of the Primary Registry Network of WHO ICTRP., (© 2023. The Author(s).)

Autologous hematopoietic stem cell transplantation (SCT) is not a standard treatment option for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL); however, its position has been reassessed since the introduction of tyrosine kinase inhibitors (TKIs). We prospectively analyzed the efficacy and safety of autologous peripheral blood SCT (auto-PBSCT) for Ph+ALL patients aged between 55 and 70 years who had achieved complete molecular remission. Melphalan, cyclophosphamide, etoposide, and dexamethasone were used for conditioning. A total of 12 courses of maintenance therapy, including dasatinib, were performed. The required number of CD34 + cells was harvested in all five patients. No patient died within 100 days after auto-PBSCT, and no unexpected serious adverse events were observed. Although 1-year event-free survival was 100%, hematological relapse was observed in three patients at a median of 801 days (range, 389-1088 days) after auto-PBSCT. Molecular progressive disease was observed in the other two patients, although they maintained their first hematological remission at the last visit. Auto-PBSCT can be safely performed for Ph+ALL with TKIs. A limitation of auto-PBSCT was suggested, despite the increase in the intensity of a single treatment. The development of long-term therapeutic strategies by including new molecular targeted drugs is warranted to maintain long-term molecular remission., Competing Interests: M.S. received honoraria from Kyowa Kirin Co., Ltd., Chugai Pharmaceutical Co., Pfizer Inc., Astellas Pharma Inc., Nippon Shinyaku, Ono Pharmaceutical, MSD, Bristol‐Myers Squibb, Asahi Kasei, Novartis Pharma K.K., Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Sanofi S.A., Takeda Pharmaceutical Co., Ltd., Celgene, Mochida Pharmaceutical Co., Ltd., Shire plc, Mundipharma K.K., AbbVie Inc., CSL Behring, SymBio, Janssen Pharmaceutical K.K., AstraZeneca plc, Daiichi Sankyo Co., and GlaxoSmithKline plc outside of this study. H.I. received research funding from Chugai Pharmaceutical Co. and honoraria from Astellas Pharma Inc., Novartis Pharma K.K., AbbVie Inc., and Janssen outside of this study. H.N. received research funding and honoraria from Ono Pharmaceutical, MSD, Bristol‐Myers Squibb, and Chugai Pharmaceutical, and research funding from Taiho Pharmaceutical, Daiichi Sankyo, Kyowa Kirin Co., Ltd., Zenyaku Kogyo, BioPharma Inc., Debiopharm, Asahi Kasei, Sysmex, FUJIFILM Corporation, SRL, Astellas Pharma Inc., Sumitomo Dainippon Pharma Co., and BD Japan outside of this study. H.K. received research funding from FUJIFILM Corporation, Kyowa Hakko Kirin Co., Ltd., Bristol‐Myers Squibb, Otsuka Pharmaceutical Co., Ltd., Perseus Proteomics Inc., Daiichi Sankyo Co., Ltd., AbbVie Inc., CURED, Inc., Astellas Pharma Inc., Chugai Pharmaceutical Co., Ltd., Zenyaku Kogyo Co., Ltd., Nippon Shinyaku Co., Ltd., Eisai Co., Ltd., Takeda Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Novartis Pharma K.K., and Sanofi K.K., and honoraria from Astellas Pharma Inc., AbbVie Inc., Chugai Pharmaceutical Co., Ltd., and Novartis Pharma K.K. outside of this study. The remaining authors declare no competing financial interests., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: Tranexamic acid (TXA) may reduce intraoperative blood loss, but it has not been investigated in pancreaticoduodenectomy (PD)., Methods: A pragmatic, multicentre, randomized, blinded, placebo-controlled trial was conducted. Adult patients undergoing planned PD for biliary, duodenal, or pancreatic diseases were randomly assigned to TXA or placebo groups. Patients in the TXA group were administered 1 g TXA before incision, followed by a maintenance infusion of 125 mg/h TXA. Patients in the placebo group were administered the same volume of saline as those in the placebo group. The primary outcome was blood loss during PD. The secondary outcomes included perioperative blood transfusions, operating time, morbidity, and mortality., Results: Between September 2019 and May 2021, 218 patients were randomly assigned and underwent surgery (108 in the TXA group and 110 in the placebo group). Mean intraoperative blood loss was 659 ml in the TXA group and 701 ml in the placebo group (mean difference -42 ml, 95 per cent c.i. -191 to 106). Of the 218 patients, 202 received the intervention and underwent PD, and the mean blood loss during PD was 667 ml in the TXA group and 744 ml in the placebo group (mean difference -77 ml, 95 per cent c.i. -226 to 72). The secondary outcomes were comparable between the two groups., Conclusion: Perioperative TXA use did not reduce blood loss during PD., Registration Number: jRCTs041190062 (https://jrct.niph.go.jp)., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: This study aimed to evaluate the correlation and diagnostic agreement between diastolic pressure ratio (dPR) and fractional flow reserve (FFR) in a Japanese real-world setting., Design: Prospective multicenter observational study., Methods: This study included 100 patients with intermediate coronary artery stenosis at 4 Japanese hospitals. For these lesions, FFR and dPR were measured using a guidewire with a sensor and a monitor to measure intravascular pressure. The correlation and diagnostic agreement between FFR and dPR were assessed. When both FFR and dPR were negative or positive, the results were considered to be concordant. When one was positive and the other was negative, the result was regarded as discordant (positive discordance, FFR > 0.80 and dPR ≤ 0.89; negative discordance, FFR ≤ 0.80 and dPR > 0.89)., Results: Overall, the FFR and dPR were well-correlated (R = 0.841). FFR and dPR were concordant in 89% of cases (concordant normal, 43%; concordant abnormal, 46%) and discordant in 11% (positive discordance, 7%; negative discordance, 4%). No significant difference was observed in the rate of concordant results between patients with and without diabetes mellitus. The diagnostic concordance rate was significantly different among the 3 coronary arteries (right coronary artery, 93.3%; left anterior descending artery, 93.2%; and left circumflex artery, 58.3%; P = .001). Additionally, the rate of concordant results tended to be higher when using intravenous administration of adenosine than when using intracoronary bolus injection of nicorandil (adenosine, 95.1%; nicorandil, 84.7%; P = .103)., Conclusion: We found that dPR was highly correlated with FFR, and diagnostic discordance was observed in 11% of the lesions. Several factors, including lesion location and medication for hyperemia, may cause the diagnostic discordance between dPR and FFR., Competing Interests: The authors have no conflicts of interest to disclose. Dr. Hideki Ishii received lecture fees from Astellas Pharma, AstraZeneca, Bayer Pharmaceutical Co.Ltd., Boehringer Ingelheim Japan, Bristol Myers Squibb, Daiichi-Sankyo, Mochida Pharma, Pfizer Japan Inc., and Tanabe Mitsubishi. Dr. Toyoaki Murohara received an unrestricted research grant for Department of Cardiology, Nagoya University Graduate School of Medicine from Astellas Pharma Inc., Daiichi-Sankyo Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Kowa Co., Ltd., MSD K. K., Mitsubishi Tanabe Pharma Co., Nippon Boehringer Ingelheim Co., Ltd., Novartis Pharma K. K., Otsuka Pharma Ltd., Pfizer Japan Inc., Sanofi-aventis K. K., Takeda Pharmaceutical Co., Ltd., and Teijin Pharma Ltd..Dr. Masahiko Ando received research grant from Kyowa Kirin Co. Ltd. None of the remaining authors none have declared any conflict of interest., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Spinal muscular atrophy (SMA) is an autosomal recessive genetic neuromuscular disorder with progressive muscle weakness and atrophy, mainly caused by lower motor neuron degeneration resulting from decreased levels of the survival motor neuron protein. Recently, 3 disease-modifying therapies for SMA (nusinersen, onasemnogene abeparvovec, and risdiplam) were approved in Japan that are expected to improve the prognosis of patients with SMA. Long-term clinical follow-up of adult patients treated with disease-modifying therapies and the natural history of SMA are essential to assess the real-world effectiveness of available treatments. Until recently, nusinersen was the only treatment option for patients with SMA in Japan; however, because Japanese approval of nusinersen was based on global clinical trials in infants and children aged 0-15 years with SMA, the effectiveness of nusinersen in adult patients has not been fully assessed in Japan. In addition, longitudinal clinical data of adult patients have not been systematically collected in Japan., Objective: This longitudinal observational study of adult patients with SMA who have been diagnosed with 5q-SMA in Japan aims to gain a better understanding of the natural history of SMA, as well as the long-term effectiveness of disease-modifying therapies. Here, we describe the protocol for the study., Methods: The Japan Registry for Adult Subjects of Spinal Muscular Atrophy (jREACT-SMA) study is a longitudinal (prospective and retrospective) observational study with a 60-month prospective follow-up being conducted at 19 investigational sites using the newly established jREACT-SMA registry. Patients aged ≥18 years with genetically confirmed 5q-SMA were planned to be enrolled in the registry from December 2020 to May 2022. The planned enrollment was 100 patients. The protocol was approved on September 28, 2020 (approval 2020-0289) by the ethical review committee of Nagoya University. Registration, demographics, genetic diagnosis, motor functions, patient-reported outcomes/quality-of-life outcomes, and other clinical data have been or will be collected., Results: As of May 2022, 113 patients had been enrolled, and the completion of patient registration has been extended from May 2022 to December 2022. Data at registration and during the follow-up period were and will be prospectively collected at least once a year until November 2025 (maximum 60 months). Data analyses will be conducted when all data have been collected. Results are expected to be available in 2026 and the study is expected to be completed by March 2027., Conclusions: This jREACT-SMA study will provide longitudinal prospective follow-up data in adult patients with SMA in Japan, including data on the natural history of the disease and data on the long-term effectiveness of disease-modifying therapies., Trial Registration: University Hospital Medical Information Network Center Clinical Trials Registry UMIN000042015; https://rctportal.niph.go.jp/en/detail?trial&#95;id=UMIN000042015., International Registered Report Identifier (irrid): DERR1-10.2196/38878., (©Kentaro Sahashi, Atsushi Hashizume, Yachiyo Kuwatsuka, Madoka Chinen, Ai Saotome-Nakamura, Masahiko Ando, Masahisa Katsuno. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 15.12.2022.)

Background: Although anti-PD-1 antibody monotherapy (PD-1) is commonly used to treat advanced acral melanoma (AM), its efficacy is limited. Further, data on the efficacy of PD-1 plus anti-CTLA-4 antibody (PD-1+CTLA-4) for the treatment of AM are limited. Therefore, we compared the efficacy of PD-1+CTLA-4 and PD-1 in the treatment of Japanese patients with advanced AM., Methods: This retrospective study evaluated patients with advanced AM who were treated with PD-1 or PD-1+CTLA-4 as first-line immunotherapy in 24 Japanese institutions between 2014 and 2020. Treatment efficacy focussing on the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was compared between the two groups., Results: In total, 254 patients (palm and sole melanoma [PSM], n = 180; nail apparatus melanoma [NAM], n = 74) were included. Among the patients with PSM, the ORR (19% vs. 31%; P = 0.44), PFS (5.9 vs. 3.2 months; P = 0.74), and OS (23.1 vs. not reached; P = 0.55) did not differ significantly between the PD-1 and PD-1+CTLA-4 groups. Among the patients with NAM, the ORR (61% vs. 10%; P < 0.001) was significantly higher and PFS was longer (6.4 vs. 3.8 months; P = 0.10) in the PD-1+CTLA-4 group than in the PD-1 group. Cox multivariate analysis demonstrated that PD-1+CTLA-4 is an independent predictor of a favourable PFS in patients with NAM (P = 0.002)., Conclusions: The efficacy of PD-1+CTLA-4 is not superior to that of PD-1 for the treatment of advanced PSM. However, PD-1+CTLA-4 may be more efficacious than PD-1 for the treatment of advanced NAM., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yasuhiro Nakamura has served as a consultant and/or received honoraria from Merck Sharp & Dohme (MSD), Novartis, Bristol-Myers Squibb (BMS), Maruho, Ono Pharma, Taisho Toyama, and Taiho Pharma. Kenjiro Namikawa has served as a consultant and/or received honoraria from BMS, MSD, Novartis, and Ono Pharma. Yukiko Kiniwa has received honoraria from Novartis and Ono Pharma. Hiroshi Kato has received honoraria from Novartis and Ono Pharma. Osamu Yamasaki has received research funding and/or honoraria from Ono Pharma. Shusuke Yoshikawa has received honoraria from Novartis and Ono Pharma. Takeo Maekawa has received honoraria from BMS, MSD, Novartis, and Ono Pharma. Shigeto Matsushita has received honoraria from BMS, MSD, Novartis, and Ono Pharma. Tatsuya Takenouchi has received honoraria from BMS, MSD, Novartis, and Ono Pharma. Takashi Inozume has received honoraria from BMS, MSD, and Ono Pharma. Satoshi Fukushima has received research funding from Ono Pharma. Shintaro Saito has received honoraria from Ono Pharma. Atsushi Otsuka has served as a consultant and/or received honoraria from BMS, MSD, Novartis, and Ono Pharma, and has received research funding from Eisai. Noriki Fujimoto has received honoraria from Novartis and Ono Pharma. Taiki Isei has served as a consultant and/or received honoraria from Ono Pharma, Pfizer, BMS, and Novartis. Yoshiyasu Umeda has received honoraria from Ono Pharma and Novartis. Naoya Yamazaki has received research funding from Bristol-Myers Squibb, MSD, Novartis, Ono Pharma, and Takara Bio, and has served as a consultant and/or received honoraria from BMS, MSD, Novartis, and Ono Pharma. The other authors have no conflicts of interest to disclose., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The BLd regimen, which is a triplet regimen of bortezomib (Bor), lenalidomide (Len), and dexamethasone (Dex), is effective against newly diagnosed multiple myeloma (NDMM). However, non-hematological toxicities, such as peripheral neuropathy (PN), often hamper long-term continuation of the regimen, particularly in older adult patients. In this study, we examined the efficacy and safety of the modified BLd regimen with reduced-intensity Bor and standard-dose Len. The chemotherapy regimen consisted of 1.3 mg/m 2 Bor administered subcutaneously on days 1 and 8, 25 mg Len administered on days 1-14, and 20 mg Dex on days 1-2 and 8-9 of a 3 week cycle for 8 cycles, followed by a 4 week cycle of Dex (40 mg weekly). Among the 30 patients enrolled, 60.0% (95% CI 40.6-77.3) had a very good partial response or better, and the best overall response rate was 96.7% (95% CI 82.8-99.9). Eight patients (26.7%) achieved a complete response. Grade 3 or higher PN was not observed and hematological toxicity was the most common adverse event. The modified BLd regimen showed favorable efficacy with a manageable safety profile, which suggests it could be a treatment option for transplant-ineligible NDMM., (© 2022. Japanese Society of Hematology.)

Aim: Recently, we demonstrated the efficacy of etelcalcetide in the control of secondary hyperparathyroidism (SHPT). This post hoc analysis aimed to evaluate changes in fibroblast growth factor-23 (FGF23) and calciprotein particles (CPPs) after treatment with calcimimetics., Methods: The DUET trial was a 12-week multicenter, open-label, parallel-group, randomized (1:1:1) study with patients treated with etelcalcetide plus active vitamin D (E + D group; n = 41), etelcalcetide plus oral calcium (E + Ca group; n = 41), or control (C group; n = 42) under maintenance haemodialysis. Serum levels of FGF23 and CPPs were measured at baseline, and 6 and 12 weeks after the start., Results: In the linear mixed model, serum levels of FGF23 in etelcalcetide users were significantly lower than those in non-users at week 6 (p < .001) and week 12 (p < .001). When compared the difference between the E + Ca group and the E + D group, serum levels of FGF23 in the E + Ca group were significantly lower than those in the E + D group at week 12 (p = .017). There were no significant differences in the serum levels of CPPs between etelcalcetide users and non-users at week 6 and week 12, while CPPs in the E + Ca group were significantly lower than those in the E + D group (p < .001) at week 12., Conclusion: Etelcalcetide may be useful through suppression of FGF23 levels among haemodialysis patients with SHPT. When correcting hypocalcaemia, loading oral calcium preparations could be more advantageous than active vitamin D for the suppression of both FGF23 and CPPs., (© 2022 Asian Pacific Society of Nephrology.)

The Asia-Pacific Blood and Marrow Transplantation Group (APBMT) has been conducting annual surveys on the activity of hematopoietic stem cell transplants since 2007. The APBMT Data Center collected the following data in 2017. A total of 21,504 transplants were registered from 733 transplant centers of 20 countries/regions in the Asia-Pacific (AP) region. Five countries/regions comprised 89.4% of all transplants - China (6,979), Japan (5,794), South Korea (2,626), India (2,034), and Australia (1,789). The number of centers in these five countries/regions also comprised 88.9% of all centers: Japan (373), China (123), India (66), Australia (45), and South Korea (44). The overall ratio between autologous and allogeneic transplants was 37.0% and 63.0%, respectively, but the ratios varied significantly among countries/regions. Autologous transplants have surpassed allogeneic transplants in Thailand, Australia, Vietnam, New Zealand, Singapore, and Iran. In contrast, the proportion of allogeneic transplants comprised over 70% of all transplants in Pakistan, China, and Hong Kong. These ratios were compared by the Data Center among countries/regions that performed more than 50 transplants. The proportion of related and unrelated transplants also differed among countries/regions. The number of unrelated transplants was more than related ones in Japan (2,551 vs. 1,202) and Australia (329 vs. 291), whereas more than 80% of all transplants were related transplants in Malaysia (90.9%), India (89.5%), Iran (87.2%), Vietnam (85.7%), China (80.9%), and Thailand (80.6%). All transplant activities were related transplants in Pakistan, the Philippines, Myanmar, and Nepal, and no allogeneic transplants were performed in Bangladesh and Mongolia. Regarding the indications for transplants, acute myeloid leukemia (AML) was the most common disease for allogeneic transplant (4,759, 35.1% of allogeneic transplants), while plasma cell disorder (PCD) was the most common disease for autologous transplant (3,701, 27.3% of all autologous transplants). Furthermore, the number of transplants for hemoglobinopathy has steeply increased in this region compared with the rest of disease indications (677, 3.1% of all transplants). APBMT covers a broad area globally, including countries/regions with diverse disease distribution, development of HSCT programs, population, and economic power. Consistent and continuous activity surveys considering those elements in each country/region revealed the HSCT field's diverse characteristics and background factors in this region., Competing Interests: The authors declare no conflict of interest. Disclosure forms provided by the authors are available on the website. MI, AS, and SO are members of the Editor of Blood Cell Therapy. They were not involved in the editorial evaluation or the decision to accept this article for publication., (Copyright Ⓒ2022 Asia-Pacific Blood and Marrow Transplantation Group (APBMT).)

Objectives: To determine if the male responders with post-prostatectomy incontinence in the ADRESU study, which is a clinical trial of regenerative therapy by periurethral injection of adipose-derived regenerative cells, are influenced by any background characteristics., Methods: Briefly, autologous adipose-derived regenerative cells isolated from abdominal adipose tissue and a mixture of adipose-derived regenerative cells with fat tissue were transurethrally injected into the rhabdosphincter and submucosal space of the urethra, respectively. Sixteen out of 43 patients (37.2%) responded to treatment (responders) and exhibited improvement in the urine leakage volume, defined as >50% reduction from baseline determined by the 24-hour pad test at 52 weeks of treatment (or last visit within 52 weeks). Background data such as age, body weight, method of prostatectomy, baseline frequency of leaks, number of leaks, number of pad changes, International Consultation on Incontinence Questionnaire-Short Form, King's Health Questionnaire, urodynamic urethral function including functional profile length and maximum urethral closure pressure, and abdominal leak point pressure were collected and compared between responders and nonresponders., Results: None of the background factors influenced improvement in the responders as compared with the nonresponders. However, a significant between-group difference in the rates of decrease in urine leakage volume was noted in patients of younger age (<70 years), compared with those of older age (≥70 years) from 2 to 26 weeks of treatment., Conclusion: A greater decrease in urine leakage volume was noted in the younger patient group than in the older patient group., (© 2022 John Wiley & Sons Australia, Ltd.)

Introduction: Immunoglobulin A (IgA) nephropathy is a disease that presents with urinary symptoms such as glomerular hematuria and urinary protein positivity, with predominant deposition of IgA in the mesangial region of the glomerulus. Corticosteroids are mainly used for treatment; however, infection is a serious adverse event, and evidence regarding therapeutic efficacy is insufficient, thus new treatments are strongly desired. Mesenchymal stem cells (MSCs) contribute to the amelioration of inflammation and recovery of organ function in inflammatory environments by converting the character of leukocytes from inflammatory to anti-inflammatory and inducing the proliferation and differentiation of organ component cells, respectively. These properties of MSCs have led to their clinical application in various inflammatory diseases, but this study is the first clinical trial of MSCs for refractory glomerulonephritis in the world. This study is registered and assigned the number, jRCT2043200002 and NCT04342325., Methods: This will be a phase 1, open-label, multiple-center, dose-escalation study of adult patients with refractory IgA nephropathy resistant to or difficult to treat with existing therapies. ADR-001 will be administered intravenously to from three to six patients at a dose of 1 × 10 8 cells once in the first cohort and to six patients twice at 2-week intervals in the second cohort, and observation will continue until 52 weeks. The primary endpoint will be the evaluation of adverse events up to 6 weeks after the start of ADR-001 administration. Secondary endpoints will be the respective percentages of patients with adverse events, clinical remission, partial remission, remission of urine protein, remission of hematuria, time to remission, changes in urine protein, hematuria, and estimated glomerular filtration rate., Results: Following the administration of ADR-001 to patients with IgA nephropathy, the respective percentages of patients with adverse events, asymptomatic pulmonary emboli, clinical remission, partial remission, urine protein remission, hematuria remission, their time to remission, changes in urine protein, hematuria, and glomerular filtration rate will be determined., Conclusion: This study will evaluate the safety and tolerability of ADR-001 and confirm its therapeutic efficacy in adult patients with refractory IgA nephropathy., Competing Interests: The authors declare a potential conflict of interest and state it below: We received research funding and the investigational product ADR-001 from ROHTO Pharmaceutical Co., Ltd., (Copyright © 2022 Tanaka, Furuhashi, Fujieda, Maeda, Saito, Mimura, Saka, Naruse, Ishimoto, Kosugi, Kinoshita, Kuwatsuka, Shimizu, Nakai and Maruyama.)

The genetic basis of leukemogenesis in adults with B-cell acute lymphoblastic leukemia (B-ALL) is largely unclear, and its clinical outcome remains unsatisfactory. This study aimed to advance the understanding of biological characteristics, improve disease stratification, and identify molecular targets of adult B-ALL. Adolescents and young adults (AYA) (15 to 39 years old, n = 193) and adults (40 to 64 years old, n = 161) with Philadelphia chromosome-negative (Ph-) B-ALL were included in this study. Integrated transcriptomic and genetic analyses were used to classify the cohort into defined subtypes. Of the 323 cases included in the RNA sequencing analysis, 278 (86.1%) were classified into 18 subtypes. The ZNF384 subtype (22.6%) was the most prevalent, with 2 novel subtypes (CDX2-high and IDH1/2-mut) identified among cases not assigned to the established subtypes. The CDX2-high subtype (3.4%) was characterized by high expression of CDX2 and recurrent gain of chromosome 1q. The IDH1/2-mut subtype (1.9%) was defined by IDH1 R132C or IDH2 R140Q mutations with specific transcriptional and high-methylation profiles. Both subtypes showed poor prognosis and were considered inferior prognostic factors independent of clinical parameters. Comparison with a previously reported pediatric B-ALL cohort (n = 1003) showed that the frequencies of these subtypes were significantly higher in AYA/adults than in children. We delineated the genetic and transcriptomic landscape of adult B-ALL and identified 2 novel subtypes that predict poor disease outcomes. Our findings highlight the age-dependent distribution of subtypes, which partially accounts for the prognostic differences between adult and pediatric B-ALL., (© 2022 by The American Society of Hematology.)

Pseudoxanthoma elasticum (PXE) is a progressive hereditary disease that affects tissues such as the skin, retina, blood vessels, and gastrointestinal tracts. Therefore, comprehensive medical care across clinical departments specialized in specific organs is needed to provide the best clinical practices to PXE patients. The Japanese version of clinical guidelines developed by the Japanese Dermatological Association was published in 2017, and aimed to promote equal accessibility of PXE-related medical care. Here, the English version of Japanese guideline is reported, and is intended to be worldwide reference for medical care of PXE., (© 2022 Japanese Dermatological Association.)

Previous Japanese studies have shown that bone marrow transplantation (BMT) is associated with better survival compared with peripheral blood stem cell transplantation (PBSCT) from a matched related donor (MRD). PBSCT recipients have shown higher incidences of severe graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) compared with BMT recipients. In recent years, the efficacy and safety of antithymocyte globulin (ATG) for PBSCT recipients has been evaluated worldwide. In the present study, we aimed to compare BMT and PBSCT recipients to identify current improvements and unmet needs among MRD PBSCT recipients. In addition, we evaluated the impact of ATG administration on the outcomes of PBSCT recipients. We retrospectively analyzed patients age ≥16 years with acute leukemia, myelodysplastic syndrome, or chronic myelogenous leukemia who underwent their first BMT or PBSCT from an MRD between 2009 and 2018 in Japan. A total of 3599 transplantations were performed (BMT, n = 1218; PBSCT without ATG [PBSCT-ATG(-)], n = 2288; PBSCT with ATG [PBSCT-ATG(+)], n = 93). The PBSCT-ATG(-) group had a higher NRM (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.08 to 1.57; P = .005) and lower overall survival (OS) (HR, 1.16; 95% CI, 1.04 to 1.30; P = .011) compared with the BMT group. Furthermore, the PBSCT-ATG(-) group had higher incidences of grade III-IV, stage 2-4 gut, high-risk, and steroid-refractory acute GVHD compared with the BMT group. Acute GVHD had a negative impact on NRM and OS. The PBSCT-ATG(-) group also was associated with an elevated risk of chronic GVHD (HR, 1.89; 95% CI, 1.24 to 2.57; P < .001) and extensive chronic GVHD (HR, 1.44; 95% CI, 1.23 to 1.68; P < .001). The incidences of acute GVHD, chronic GVHD, and NRM and chronic GVHD-free relapse-free survival rates were comparable between the PBSCT-ATG(+) and BMT groups. The OS of patients with acute GVHD was similar in the 3 donor groups. Patients treated with reduced-intensity conditioning in the PBSCT-ATG(+) group had a higher relapse rate and lower OS rate compared with those in the BMT group. In this Japanese cohort, standard calcineurin inhibitor-based GVHD prophylaxis was not sufficient for recipients of MRD PBSCT because of the high incidence of severe acute GVHD. Prophylactic ATG was found to be a promising strategy against GVHD., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Cancer-associated fibroblasts (CAFs) are an important component of the tumour microenvironment. Recent studies revealed CAFs are heterogeneous and CAF subset(s) that suppress cancer progression (cancer-restraining CAFs [rCAFs]) must exist in addition to well-characterised cancer-promoting CAFs (pCAFs). However, the identity and specific markers of rCAFs are not yet reported. We recently identified Meflin as a specific marker of rCAFs in pancreatic and colon cancers. Our studies revealed that rCAFs may represent proliferating resident fibroblasts. Interestingly, a lineage tracing experiment showed Meflin-positive rCAFs differentiate into α-smooth muscle actin-positive and Meflin-negative CAFs, which are generally hypothesised as pCAFs, during cancer progression. Using a pharmacological approach, we identified AM80, a synthetic unnatural retinoid, as a reagent that effectively converts Meflin-negative pCAFs to Meflin-positive rCAFs. We aimed to investigate the efficacy of a combination of AM80 and gemcitabine (GEM) and nab-paclitaxel (nab-PTX) in patients with advanced pancreatic cancer., Methods: The phase I part is a 3 + 3 design, open-label, and dose-finding study. The dose-limiting toxicity (DLT) of these combination therapies would be evaluated for 4 weeks. After the DLT evaluation period, if no disease progression is noted based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or if the patient has no intolerable toxicity, administration of AM80 with GEM and nab-PTX would be continued for up to 24 weeks. The phase II part is an open-label, single-arm study. The maximum tolerated dose (MTD) of AM80 with GEM and nab-PTX, determined in phase I, would be administered until intolerable toxicity or disease progression occurs, up to a maximum of 24 weeks, to confirm efficacy and safety. The primary endpoints are frequency of DLT and MTD of AM80 with GEM and nab-PTX in the phase I part and response rate based on the RECIST in the phase II part. Given the historical control data, we hope that the response rate will be over 23% in phase II., Discussion: Strategies to convert pCAFs into rCAFs have been developed in recent years. We hypothesised that AM80 would be a promising enhancer of chemosensitivity and drug distribution through CAF conversion in the stroma., Trial Registration: Clinicaltrial.gov: NCT05064618 , registered on 1 October 2021. jRCT: jRCT2041210056 , registered on 27 August 2021., (© 2022. The Author(s).)

Purpose: Minimally invasive examinations are particularly important in pediatric patients. Although the significance of urinary N 1 ,N 12 -diacetylspermine (DiAcSpm) as a tumor marker (TM) has been reported in many types of adult cancers, its usefulness in pediatric cancers has not been reported. This may be due to urinary DiAcSpm level variations with age. This study aims to measure the normal levels of urinary DiAcSpm in healthy individuals and investigate its usefulness as a TM in childhood cancer., Methods: Urinary samples were collected from pediatric patients with and without cancer. The urinary DiAcSpm levels were measured, and the values were compared., Results: A total of 32 patients with cancer and 405 controls were enrolled in the study. Of the 32 patients, 13 had neuroblastoma, 9 had malignant lymphoma (ML), and 10 had leukemia. In the control group, the urinary DiAcSpm values markedly fluctuated among those with young age, especially infants; meanwhile, the values converged among those aged roughly 10 years and above. The sensitivity of DiAcSpm was significantly different among the three types of cancers: neuroblastoma (30.8%), ML (77.8%), and leukemia (40%)., Conclusion: The urinary DiAcSpm value is a useful TM for both screening and follow-up of ML., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Anti-programmed cell death protein 1 (PD-1) antibody monotherapy (PD1) has led to favorable responses in advanced non-acral cutaneous melanoma among Caucasian populations; however, recent studies suggest that this therapy has limited efficacy in mucosal melanoma (MCM). Thus, advanced MCM patients are candidates for PD1 plus anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) combination therapy (PD1 + CTLA4). Data on the efficacy of immunotherapy in MCM, however, are limited. We aimed to compare the efficacies of PD1 and PD1 + CTLA4 in Japanese advanced MCM patients., Patients and Methods: We retrospectively assessed advanced MCM patients treated with PD1 or PD1 + CTLA4 at 24 Japanese institutions. Patient baseline characteristics, clinical responses (RECIST), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis, and toxicity was assessed to estimate the efficacy and safety of PD1 and PD1 + CTLA4., Results: Altogether, 329 patients with advanced MCM were included in this study. PD1 and PD1 + CTLA4 were used in 263 and 66 patients, respectively. Baseline characteristics were similar between both treatment groups, except for age (median age 71 versus 65 years; P < 0.001). No significant differences were observed between the PD1 and PD1 + CTLA4 groups with respect to objective response rate (26% versus 29%; P = 0.26) or PFS and OS (median PFS 5.9 months versus 6.8 months; P = 0.55, median OS 20.4 months versus 20.1 months; P = 0.55). Cox multivariate survival analysis revealed that PD1 + CTLA4 did not prolong PFS and OS (PFS: hazard ratio 0.83, 95% confidence interval 0.58-1.19, P = 0.30; OS: HR 0.89, 95% confidence interval 0.57-1.38, P = 0.59). The rate of ≥grade 3 immune-related adverse events was higher in the PD1 + CTLA4 group than in the PD1 group (53% versus 17%; P < 0.001)., Conclusions: First-line PD1 + CTLA4 demonstrated comparable clinical efficacy to PD1 in Japanese MCM patients, but with a higher rate of immune-related adverse events., Competing Interests: Disclosure YN receives institutional research funding from Kaken, Ono Pharma, Pola Pharma, and Torii, and has served as a consultant and/or has received honoraria from Bristol Myers Squibb (BMS), Maruho, Merck Sharp & Dohme (MSD), Novartis, Ono Pharma, Taisho Toyama, and Taiho Pharma. KN has served as a consultant and/or has received honoraria from BMS, MSD, Novartis, and Ono Pharma. SY has received honoraria from Novartis and Ono Pharma. YK has received honoraria from Novartis and Ono Pharma. TM has received honoraria from BMS, MSD, Novartis, and Ono Pharma. OY has received research funding and/or honoraria from Ono Pharma. TI has served as a consultant and/or has received honoraria from Ono Pharma, Pfizer, BMS, and Novartis Pharma. SM has received honoraria from Ono Pharma. SF has received research funding from Ono Pharma. SS has received honoraria from Ono Pharma. TT has received honoraria from BMS, MSD, Novartis, and Ono Pharma. HK has received honoraria from Novartis and Ono Pharma. AO has served as a consultant and/or has received honoraria from BMS, MSD, Novartis, and Ono Pharma and received research funding from Eisai. TI has received honoraria from BMS, MSD, and Ono Pharma. YU has received honoraria from Ono and Novartis Pharma. YT has received honoraria from BMS, Maruho, MSD, Novartis, and Ono Pharma. NY receives institutional research funding from BMS, MSD, Novartis, Ono, Takara Bio, Amgen, and Merck Biopharma, and has served as consultant and/or has received honoraria from BMS, MSD, Novartis, and Ono Pharma. The other authors have declared no conflicts of interest., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

In Japan, esophagectomy after two courses of 5-fluorouracil plus cisplatin is regarded a standard strategy for treating resectable stage II or III esophageal squamous cell carcinoma (ESCC). However, 5-fluorouracil plus cisplatin does not benefit cohorts with clinical stage III ESCC, suggesting the requirement for a more effective regimen. We are conducting a single-arm phase II study to assess the safety and efficacy of neoadjuvant docetaxel, oxaliplatin plus S-1 (DOS) for treating patients with clinical stage III ESCC. The primary endpoint is the pathological response rate, and the target number is 45 patients. Safety, response rate, R0 resection rate, and survival are secondary endpoints. This trial is registered in the Japan Registry of Clinical Trials as jRCTs041210023. We are conducting a prospective phase II trial to evaluate the safety and efficacy of three courses of neoadjuvant DOS treatment followed by radical esophagectomy for clinical stage III ESCC., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Masahiko Ando: Grant from 10.13039/501100004095Kyowa Kirin Co. Ltd., outside the submitted work. Yasuhiro Kodera: 10.13039/100010795Chugai Pharma (Inst), Daiichi Sankyo (Inst), 10.13039/100009954Taiho Pharmaceutical (Inst), 10.13039/100008373Takeda (Inst), Abbott (Inst), 10.13039/100004339Sanofi (Inst), 10.13039/501100012030Yakult (Inst), Eli 10.13039/100004312Lilly (Inst), 10.13039/100004319Pfizer (Inst), 10.13039/501100013170Ono Pharmaceutical (Inst), Kaken Pharmaceutical (Inst), 10.13039/501100013420Tsumura (Inst), 10.13039/501100002736Covidien (Inst), 10.13039/100014421EA Pharma (Inst), Otsuka (Inst), Nippon Kayaku (Inst), 10.13039/501100007132Otsuka Pharmaceutical Factory (Inst), 10.13039/100004331Johnson & Johnson K.K. (Inst), Sawai Pharmaceutical (Inst), 10.13039/501100005612Shionogi and MSD (Inst) (RF); 10.13039/100010795Chugai Pharma, Eli 10.13039/100004312Lilly, 10.13039/100004331Johnson & Johnson, 10.13039/501100012030Yakult Honsha, 10.13039/100009954Taiho Pharmaceutical, 10.13039/501100013170Ono Pharmaceutical, Medtronic, MSD, 10.13039/100010477Intuitive Surgical, Miyalisan Pharmaceutical, Nippon Kayaku, Daiichi Sankyo, Otsuka, Sawai Pharmaceutical, and 10.13039/501100013420Tsumura (H). (RF) Research funding; (H) Honoraria received. Yuichi Ando: Dr. Ando reports grants and personal fees from 10.13039/100010795Chugai Pharmaceutical Co., Ltd., grants and personal fees from 10.13039/501100004095Kyowa Kirin Co., Ltd., grants and personal fees from Nippon Kayaku Co., Ltd., grants and personal fees from 10.13039/501100012030Yakult Honsha Co., Ltd., personal fees from 10.13039/100014422Eli Lilly Japan K.K., grants from Mochida Pharmaceutical Co., Ltd., grants and personal fees from 10.13039/501100013170Ono Pharmaceutical Co., Ltd., grants and personal fees from 10.13039/100009954Taiho Pharmaceutical Co., Ltd., personal fees from 10.13039/100008792Novartis Pharma K.K., personal fees from 10.13039/100004326Bayer Holding Ltd., personal fees from 10.13039/100002491Bristol-Myers Squibb, personal fees from Sawai Pharmaceutical Co., Ltd, grants and personal fees from 10.13039/501100002336Daiichi Sankyo Company, Ltd., grants and personal fees from 10.13039/501100003769Eisai Co., Ltd., personal fees from 10.13039/501100013420Tsumura & Co., personal fees from Otsuka Holdings Co., Ltd., personal fees from 10.13039/100016545Roche Diagnostics K.K., personal fees from 10.13039/100004325AstraZeneca K.K., personal fees from MSD K.K, outside the submitted work. The other Authors indicated no financial relationships., (© 2021 The Authors. Published by Elsevier Inc.)

Background: Immune checkpoint inhibitors (ICIs) have a lower efficacy in mucosal melanoma (MUM) than in cutaneous melanoma. The use of combination treatments with radiotherapy (RT) to improve the efficacy in MUM, however, requires further investigation., Methods: We retrospectively evaluated 225 advanced MUM patients treated with anti-PD-1 monotherapy (PD1; 115) or anti-PD-1 + anti-CTLA-4 combination therapy (PD1+CTLA4; 42) with or without RT (56 and 12, respectively). Treatment efficacy was estimated by determining the objective response rate (ORR) and survival rate with the Kaplan-Meier analysis., Results: The baseline characteristics between the two groups in each ICI cohort were similar, except for Eastern Cooperative Oncology Group performance status in the PD1 cohort. No significant differences in ORR, progression-free survival (PFS), and overall survival (OS) were observed between the PD1 alone and PD1+RT groups in the PD1 cohort (ORR 26% versus 27%, P > 0.99; median PFS 6.2 versus 6.8 months, P = 0.63; median OS 19.2 versus 23.1 months, P = 0.70) or between the PD1+CTLA alone and PD1+CTLA4+RT groups in the PD1+CTLA4 cohort (ORR 28% vs 25%, P = 0.62; median PFS 5.8 versus 3.5 months, P = 0.21; median OS 31.7 versus 19.8 months, P = 0.79). Cox multivariate analysis indicated that RT in addition to PD1 or PD1+CTLA4 did not have a positive impact on the PFS or OS., Conclusions: A prolonged survival benefit with RT in combination with ICIs was not identified for advanced MUM patients, although RT may improve local control of the tumour and relieve local symptoms., Competing Interests: Conflict of interest statement Yoshiyasu Umeda has received honoraria from Ono and Novartis Pharma. Shusuke Yoshikawa has received honoraria from Novartis and Ono Pharma. Yukiko Kiniwa has received honoraria from Novartis and Ono Pharma. Takeo Maekawa has received honoraria from Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Novartis, and Ono Pharma. Osamu Yamasaki has received research funding or/and honoraria from Ono Pharma. Taiki Isei has served as a consultant or/and has received honoraria from Ono, Pfizer, BMS, and Novartis Pharma. Shigeto Matsushita has received honoraria from Ono Pharma. Motoo Nomura has no conflicts of interest to disclose. Yasuo Nakai has no conflicts of interest to disclose. Satoshi Fukushima has received research funding from Ono Pharma. Shintaro Saito has received honoraria from Ono Pharma. Tatsuya Takenouchi has no conflicts of interest to disclose. Ryo Tanaka has no conflicts of interest to disclose. Hiroshi Kato has received honoraria from Novartis and Ono Pharma. Atsushi Otsuka has served as a consultant or/and has received honoraria from BMS, MSD, Novartis, Ono and received research funding from Eisai. Taisuke Matsuya has no conflicts of interest to disclose. Natsuki Baba has no conflicts of interest to disclose. Kotaro Nagase has no conflicts of interest to disclose. Takashi Inozume has received honoraria from BMS, MSD, and Ono Pharma. Takehiro Onuma has no conflicts of interest to disclose. Yutaka Kuwatsuka has no conflicts of interest to disclose. Noriki Fujimoto has no conflicts of interest to disclose. Takahide Kaneko has no conflicts of interest to disclose. Masazumi Onishi has no conflicts of interest to disclose. Kenjiro Namikawa has served as a consultant or/and has received honoraria from BMS, Eisai, MSD, Novartis, Ono, Pharma International, Toray Industries, and Takara Bio Pharma. Naoya Yamazaki receives institutional research funding from Bristol-Myers Squibb, MSD, Novartis, Ono, and Takara Bio, and has served as consultant or/and has received honoraria from BMS, MSD, Novartis, and Ono Pharma. Yasuhiro Nakamura has served as a consultant or/and has received honoraria from MSD, Novartis, BMS, Maruho, Ono, Taisho Toyama, and Taiho Pharma., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Cholesterol is de novo synthesized in the upper epidermis and plays an important role in maintaining the normality of skin. Studying the impact of the inhibition of cholesterol de novo synthesis in the epidermis may help understand how skin homeostasis is regulated., Objective: In this study, we created a gene expression profile to investigate the effect of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors on epidermal homeostasis., Methods: A microarray analysis was performed using normal keratinocytes with or without HMG-CoA reductase inhibitor (pitavastatin) treatment. Real-time PCR confirmed the reproducibility of genes with altered expression in keratinocytes treated with HMG-CoA reductase inhibitors. Among these genes, we focused on reduced expression of claudin 7 histologically confirmed by immunohistochemical staining, in situ hybridization, and immunoelectron microscopy., Results: Claudin-7 was highly expressed in the stratum granulosum of psoriatic lesions but was not expressed in the normal epidermis. Immunoelectron microscopy revealed that claudin-7 was localized in the keratohyalin granules of psoriatic lesions., Conclusion: These results indicate that claudin-7 expression was regulated by HMG-CoA reductase in the epidermis and might play a pathogenic role in the keratohyalin granules found in the epidermal granular layer of psoriasis., Competing Interests: Declaration of Competing Interest HM is a patent holder of ID: 5678566. Other authors have no conflicts of interest to declare., (Copyright © 2021 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Background: Keloid lesions are characterized by mesenchymal cell proliferation and excessive extracellular matrix deposition. Previous microarray analyses have been performed to investigate the mechanism of keloid development. However, the molecular pathology that contributes to keloid development remains obscure., Aim: To explore the underlying essential molecules of keloids using microarrays., Methods: We performed microarray analyses of keloid and nonlesional skin tissues both in vivo and in vitro. Gene expression levels were compared between tissues and cells. Quantitative reverse transcription (qRT)-PCR and immunohistochemical staining were used to determine the expression levels of molecules of interest in keloid tissues., Results: Several common molecules were upregulated in both keloid tissues and keloid-lesional fibroblasts. PTPRD and NTM were upregulated both in vivo and in vitro. The genes MDFI and ITGA4 were located at the centre of the gene coexpression network analysis using keloid tissues. qRT-PCR revealed significant expression levels of PTPRD and MDFI in keloid tissues. Immunopathological staining revealed that MDFI-positive cells, which have fibroblast characteristics, were located in the keloid-associated lymphoid tissue (KALT) portion of the keloid tissue., Conclusion: Our gene expression profiles of keloids could distinguish the difference between lesional tissue and cultured lesional fibroblasts, and MDFI was found to be commonly expressed in both tissues and cells. Thus, MDFI-positive cells, which were located in the KALT, may play an important role in keloid pathogenesis and thus might be useful for in vitro keloid studies., (© 2021 British Association of Dermatologists.)

Purpose: The anti-leukemic activity of allogeneic hematopoietic cell transplantation (HCT) depends on both the intensity of conditioning regimen and the strength of the graft-versus-leukemia (GVL) effect. However, it is unclear whether the sensitivity of the GVL effects differs between donor type and graft source., Experimental Design: We retrospectively evaluated the effect of acute and chronic graft-versus-host disease (GVHD) on transplant outcomes for adults with acute leukemia ( n = 6,548) between 2007 and 2017 using a Japanese database. In all analyses, we separately evaluated three distinct cohorts based on donor type [(8/8 allele-matched sibling donor, 8/8 allele-matched unrelated donor, and unrelated single-cord blood (UCB)]., Results: The multivariate analysis, in which the development of GVHD was treated as a time-dependent covariate, showed a reductive effect of grade I-II acute GVHD on treatment failure (defined as 1-leukemia-free survival; P < 0.001), overall mortality (OM; P < 0.001), relapse ( P < 0.001), and non-relapse mortality (NRM; P < 0.001) in patients receiving from UCB. A reductive effect of limited chronic GVHD on treatment failure ( P < 0.001), OM ( P < 0.001), and NRM ( P < 0.001) was also shown in patients receiving from UCB. However, these effects were not always shown in patients receiving from other donors. The beneficial effects of mild acute and chronic GVHD after UCB transplantation on treatment failure were noted relatively in subgroups of patients with acute myelogenous leukemia and a non-remission status., Conclusions: These data suggested that the development of mild GVHD could improve survival after UCB transplantation for acute leukemia., (©2021 American Association for Cancer Research.)

To investigate the association between methotrexate (MTX) dosage and engraftment, graft-versus-host disease (GVHD) incidence, and survival in umbilical cord blood transplantation (UCBT), we compared transplant outcomes after UCBT with various GVHD prophylaxis regimens, using registry data with additional data collection. Patients transplanted for acute myeloid leukemia with a calcineurin inhibitor (CNI) and either MTX or mycophenolate mofetil (MMF) combination were selected. In total, 888 single-unit UCBTs (MTX 15-10-10 , 415; MTX 10-7-7 , 294; MTX 5-5-5 , 71; MMF, 108) were included. In multivariate analyses with MTX 15-10-10 as the reference, the likelihood of neutrophil and platelet engraftment was significantly worse in the MTX 10-7-7 group, and similarly better in MMF group compared with MTX 15-10-10 . All variables including CyA vs Tac and 4-group GVHD prophylaxis became significant for the risk of grade II-IV acute GVHD in the final multivariate model. We observed significant additional effects of combined MTX dose in the Tac group, which were larger with lower MTX dose and MMF. No significant difference was observed in survival risk among GVHD prophylaxis groups. Despite the potential background differences in the combined CNI and conditioning regimen, we conclude that the recommended GVHD prophylaxis is a combination of CyA plus MTX 15-10-10 or Tac plus MMF.

Hand eczema is a major occupational disease, especially in medical workers, reducing their quality of life (QOL) and work productivity. Daily wearing of fabric gloves to prevent loss of moisture and lipids from the surface of the hands has been regarded as good in the management of hand eczema. However, limited evidence is available regarding the efficacy of moisturizing care with daily gloves on hand eczema. This pilot study was performed to evaluate the efficacy of moisturizing intervention with daily wearing of fabric gloves on skin barrier function, disease severity, and microbiome in health-care workers with hand eczema. Study 1: Nurses in the neonatal intensive care unit or growing care unit with and without hand eczema were recruited in the study. Subjects were instructed to apply moisturizer and wear two types of fabric gloves, common cotton gloves and moisturizing fabric gloves containing malate, for 4 weeks. Study 2: Physicians and health-care workers were recruited and instructed to wear a cotton glove on one hand at nighttime for 4 weeks. Disease severity, skin barrier function, QOL, and hand microbiome (Study 1) were evaluated. Study 1 found that daily wearing of both types of fabric gloves accompanied by use of topical moisturizers reduced the severity of hand eczema without changing the variation of microbiome. Study 2 found no apparent change between wearing and not wearing cotton gloves. In summary, topical moisturizer is of fundamental importance, and concomitant use of fabric gloves may merely enhance the efficacy of moisturizer in the management of hand eczema., (© 2021 Japanese Dermatological Association.)

Intravascular large B-cell lymphoma (IVLBCL) is a unique type of extranodal lymphoma characterized by selective growth of tumor cells in small vessels without lymphadenopathy. Greater understanding of the molecular pathogenesis of IVLBCL is hampered by the paucity of lymphoma cells in biopsy specimens, creating a limitation in obtaining sufficient tumor materials. To uncover the genetic landscape of IVLBCL, we performed whole-exome sequencing (WES) of 21 patients with IVLBCL using plasma-derived cell-free DNA (cfDNA) (n = 18), patient-derived xenograft tumors (n = 4), and tumor DNA from bone marrow (BM) mononuclear cells (n = 2). The concentration of cfDNA in IVLBCL was significantly higher than that in diffuse large B-cell lymphoma (DLBCL) (P < .0001) and healthy donors (P = .0053), allowing us to perform WES; most mutations detected in BM tumor DNA were successfully captured in cfDNA and xenograft. IVLBCL showed a high frequency of genetic lesions characteristic of activated B-cell-type DLBCL, with the former showing conspicuously higher frequencies (compared with nodal DLBCL) of mutations in MYD88 (57%), CD79B (67%), SETD1B (57%), and HLA-B (57%). We also found that 8 IVLBCL (38%) harbored rearrangements of programmed cell death 1 ligand 1 and 2 (PD-L1/PD-L2) involving the 3' untranslated region; such rearrangements are implicated in immune evasion via PD-L1/PD-L2 overexpression. Our data demonstrate the utility of cfDNA and imply important roles for immune evasion in IVLBCL pathogenesis and PD-1/PD-L1/PD-L2 blockade in therapeutics for IVLBCL., (© 2021 by The American Society of Hematology.)