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Numerous cellular and molecular processes during embryonic development prompt the fundamental question of how their tempos are coordinated and whether a common global modulator exists. While the segmentation clock tempo scales with the kinetics of gene expression and degradation processes of the core clock gene Hes7 across mammals, the coordination of these processes remains unclear. This study examines whether metabolic activities serve as a global modulator for the segmentation clock, finding them to be selective instead. Several metabolic inhibitions extend the clock period but affect key processes differently: glycolysis inhibition slows Hes7 protein degradation and production delay without altering intron delay, while electron transport chain inhibition extends intron delay without influencing the other processes. Combinations of distinct metabolic inhibitions exhibit synergistic effects. We propose that the scaled kinetics of segmentation clock processes across species may result from combined selective modulators shaped by evolutionary constraints, rather than a single global modulator., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: Isatuximab, an anti-CD38 antibody, has been widely used in treatments for patients with relapsed/refractory multiple myeloma (MM). Despite its high efficacy, not all patients achieve a lasting therapeutic response with isatuximab., Objective: We tried to identify biomarkers to predict the effectiveness of isatuximab by focusing on the host's immune status before treatment., Methods: We retrospectively analyzed the cases of 134 relapsed/refractory MM patients in the Kansai Myeloma Forum database who had received only a first isatuximab treatment., Results: Among the 134 patients, an isatuximab, pomalidomide and dexamethasone (Isa-PD) regimen, isatuximab, carfilzomib and dexamethasone (Isa-KD) regimen and isatuximab and/or dexamethasone (Isa-D) regimen were used in 112, 15 and 7 patients, respectively. The median age at treatment, number of prior treatment regimens, and progression-free survival (PFS) were 71, 6, and 6.54 months, respectively. Multivariate analysis showed that the PFS under the Isa-PD regimen was longer in patients with higher lymphocyte/monocyte ratio (LMR ≥ 4), fewer prior treatment regimens (< 6), and no use of prior daratumumab treatment. The OS under the Isa-PD regimen was longer in patients with higher white blood cell counts (WBC counts ≥ 3000/μL) and higher LMR. The PFS under the Isa-D regimen was longer in patients with fewer prior treatment regimens in univariate analysis, but no parameters were correlated with PFS/OS under the Isa-KD regimen., Conclusion: We found that the patients with higher LMR (≥ 4) could obtain longer PFS and OS under the Isa-PD regimen. Other cohort studies of isatuximab treatment might be necessary to substantiate our results., (© 2024. The Author(s).)

We conducted a multicenter, prospective observational study of acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML) in Japan. From August 2011 to January 2016, we enrolled 6568 patients. Herein, we report the results for MDS (n = 2747) and CMML (n = 182). The percentage of patients aged 65 years or older was 79.5% for MDS and 79.7% for CMML. The estimated overall survival (OS) rate and cumulative incidence of AML evolution at 5 years were 32.3% (95% confidence interval: 30.2-34.5%) and 25.7% (23.9-27.6%) for MDS, and 15.0% (8.9-22.7%) and 39.4% (31.1-47.6%) for CMML. Both diseases were more common in men. The most common treatment for MDS was azacitidine, which was used in 45.4% of higher-risk and 12.7% of lower-risk MDS patients. The 5-year OS rate after treatment with azacitidine was 12.1% (9.5-15.1%) for of higher-risk MDS patients and 33.9% (25.6-42.4%) for lower-risk patients. The second most common treatment was erythropoiesis-stimulating agents, given to just 20% of lower-risk patients. This is the first paper presenting large-scale, Japanese data on survival and clinical characteristics in patients with MDS and CMML., (© 2023. Japanese Society of Hematology.)

This report covers acute myeloid leukemia (AML) results from a multicenter, prospective observational study of AML, myelodysplastic syndromes, and chronic myelomonocytic leukemia in Japan. From August 2011 to January 2016, 3728 AML patients were registered. Among them, 42% were younger than 65, and the male-to-female ratio was 1.57:1. With a median follow-up time of 1807 days (95% confidence interval [CI]: 1732-1844 days), the estimated 5-year overall survival (OS) rate in AML patients (n = 3707) was 31.1% (95% CI: 29.5-32.8%). Trial-enrolled patients had a 1.7-fold higher OS rate than non-enrolled patients (5-year OS, 58.9% [95% CI: 54.5-63.1%] vs 35.5% [33.3-37.8%], p < 0.0001). Women had a higher OS rate than men (5-year OS, 34% [95% CI; 31.4-36.7%] vs 27.7% [25.7-29.7%], p < 0.0001). The OS rate was lower in patients aged 40 and older than those under 40, and even lower in those over 65 (5-year OS for ages < 40, 40-64, 65-74, ≥ 75: 74.5% [95% CI; 69.3-79.0%] vs 47.5% [44.4-50.6%] vs 19.3% [16.8-22.0%] vs 7.3% [5.5-9.4%], respectively). This is the first paper to present large-scale data on survival and clinical characteristics in Japanese AML patients., (© 2023. Japanese Society of Hematology.)

To evaluate the specific prognostic value of CAs, we conducted an analysis of 923 symptomatic multiple myeloma patients. Among this cohort, 480 patients had complete data set of high-risk CAs by interphase fluorescent in situ hybridization at diagnosis. In the high-risk group analysis, the median OS of patients without CAs ( n  = 338, 72 %) was 6.5 years, patients with del(17p) ( n  = 42, 9 %) was 4.4 years, patients with t(4;14) or t(14;16) ( n  = 72, 15 %) was 4.4 years, and patients with double-positive CAs(del(17p) and t(4;14) or t(14;16)) ( n  = 18, 4 %) was 2.1 years ( p  = 0.032). Patients with double-positive CAs had a significantly worse prognosis., Competing Interests: All authors received research funding from ONO PHARMACEUTICAL CO., LTD., Bristol-Myers Squibb Company. JKU is appointed as an officer or advisor at Kansai Medical Net. JKU received lecture honoraria from Bristol-Myers Squibb Company, Janssen Pharmaceutical K. K., Sanofi K.K., ONO PHARMACEUTICAL CO., LTD., AbbVie GK., Takeda Pharmaceutical Company Limited, and Novartis Pharma KK. AT received lecture honoraria from Bristol-Myers Squibb Company, Novartis Pharma KK, Kyowa Kirin Co., Ltd., Astellas Pharma Inc., Nippon Shinyaku Co., Ltd., JANSSEN PHARMACEUTICAL K.K., Otsuka Pharmaceutical Co., Ltd. MH received lecture honoraria from Novartis Pharma K.K., Takeda Pharmaceutical Company, Limited, Bristol-Myers Squibb., Otsuka Pharmaceutical Co., Ltd. IM received lecture honoraria from Novartis Pharma KK, Bristol-Myers Squibb Company, Pfizer Japan Inc., DAIICHI SANKYO COMPANY, LIMITED., Otsuka Pharmaceutical Co., Ltd., Astellas Pharma Inc., Janssen Pharmaceutical K.K, AbbVie GK., Takeda Pharmaceutical Company Limited, ONO PHARMACEUTICAL Co., Ltd., SymBio Pharmaceuticals Limited. HS received lecture honoraria from Takeda Pharmaceutical Company, Limited., ONO PHARMACEUTICAL CO., LTD., Novartis Pharma K.K., Bristol-Myers Squibb K.K., JANSSEN PHARMACEUTICAL K.K., CHUGAI PHARMACEUTICAL CO., LTD., Sanofi K.K., AstraZeneca K.K. TI received lecture honoraria from Bristol-Myers Squibb, Mundipharma K.K., Novartis Pharma K.K., Pfizer Japan Inc., Takeda Pharmaceutical Company, Limited., AbbVie GK., CHUGAI PHARMACEUTICAL CO., LTD., Sanofi K.K., Nippon Shinyaku Co., Ltd., CSL Behring K.K., Otsuka Pharmaceutical Co., Ltd., NIHON PHARMACEUTICAL CO., LTD., JANSSEN PHARMACEUTICAL K.K.. SF received lecture honoraria from Takeda Pharmaceutical Company, Ltd., Sanofi K.K., JANSSEN PHARMACEUTICAL K.K., ONO PHARMACEUTICAL CO., LTD., Bristol-Myers Squibb K.K. TT received lecture honoraria from Sanofi K.K.. JKU received writing fees from JANSSEN PHARMACEUTICAL K.K., Bristol-Myers Squibb K.K. JKU received grants for research from Bristol-Myers Squibb Company, ONO PHARMACEUTICAL CO., LTD., Sysmex Corporation, Takeda Pharmaceutical Company, Limited, Otsuka Pharmaceutical Co., Ltd., Incyte Corporation, JANSSEN PHARMACEUTICAL K.K., Pfizer Japan Inc., CHUGAI PHARMACEUTICAL Co., Ltd., Kyowa Kirin Co., Ltd., IQVIA Services Japan K.K. AT received grants for research from ONO PHARMACEUTICAL Co., Ltd., COGNANO, Inc., DKS Co., Ltd.. IM received grants for research from Chugai Pharmaceutical Co., Ltd., Novartis Pharma K.K., Astellas Pharma Inc., AbbVie GK., Pfizer Japan Inc., Takeda Pharmaceutical Company Limited., Alexion, Otsuka Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K. NH received grants for research from Otsuka Pharmaceutical Co., Ltd. HS received grants for research from JANSSEN PHARMACEUTICAL K.K., ONO PHARMACEUTICAL CO., LTD., Bristol-Myers Squibb K.K., Novartis Pharma K.K., AstraZeneca K.K., AbbVie GK., Eisai Co., Ltd., HUYABIO International, CHUGAI PHARMACEUTICAL CO., LTD., PharmaEssentia Japan KK. TI received grants for research from Bristol-Myers Squibb. JKU recieved scolarship grant from Kyowa Kirin Co., Ltd., CHUGAI PHARMACEUTICAL CO., LTD., DAIICHI SANKYO COMPANY, LIMITED, ONO PHARMACEUTICAL CO., LTD., Sanofi K.K., Eisai Co., Ltd., Dainippon Sumitomo Pharma Co., Ltd., Takeda Pharmaceutical Company, Limited., Nippon Shinyaku Co., Ltd. AT received scholarship grants from Takeda Pharmaceutical Company, Limited, Nippon Shinyaku Co., Ltd., Kyowa Kirin Co., Ltd., CHUGAI PHARMACEUTICAL CO., LTD., Sanofi K.K., Otsuka Pharmaceutical Co., Ltd., Astellas Pharma Inc., Eisai Co., Ltd., OHARA Pharmaceutical Co., Ltd., Popuri, Kinshikouraininjin, AbbVie, SHIONOGI & CO., LTD., Asahi Kasei Pharma Corporation., the Japanese Society of Hematology. MH recieved scholarship grants from CHUGAI PHARMACEUTICAL CO., LTD., Kyowa Kirin Co., Otsuka Pharmaceutical Co., Ltd., TAIHO PHARMACEUTICAL CO., LTD., Takeda Pharmaceutical Company, Limited., ONO PHARMACEUTICAL CO., LTD. IM received scholarship grants from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited., Shionogi & Co., Ltd., ASAHI KASEI PHARMA CORPORATION, Eisai Co., Ltd., TAIHO PHARMACEUTICAL CO., LTD., NIPPON SHINYAKU CO.,LTD., Otsuka Pharmaceutical Co., Ltd, AbbVie GK., ONO PHARMACEUTICAL CO., LTD., Sanofi K.K., Mitsubishi Tanabe Pharma Corporation. IM received scholarship grants from Chugai Pharmaceutical Co., Ltd., Kyowa Kirin Co., Ltd, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited., Shionogi & Co., Ltd., ASAHI KASEI PHARMA CORPORATION, Eisai Co., Ltd., TAIHO PHARMACEUTICAL CO., LTD., NIPPON SHINYAKU CO.,LTD., Otsuka Pharmaceutical Co., Ltd, AbbVie GK., ONO PHARMACEUTICAL CO., LTD., Sanofi K.K., Mitsubishi Tanabe Pharma Corporation. HS received scholarship grants from Astellas Pharma Inc., TEIJIN PHARMA LIMITED, SHIONOGI & CO., LTD., Eisai Co., Ltd., TAIHO PHARMACEUTICAL CO., LTD., Nippon Shinyaku Co., Ltd. CS received lecture honoraria from Sanofi K.K., JANSSEN PHARMACEUTICAL K.K., Bristol-Myers Squibb K.K., (© 2023 The Author(s).)

To investigate the real-world clinical outcomes and management of novel drug-containing therapies for newly diagnosed multiple myeloma (MM) patients, we retrospectively analyzed data on the first-line treatment for newly diagnosed transplant-ineligible MM patients from Kansai Myeloma Forum, a registry network in Japan. A total of 598 patients treated with novel drugs between March 2007 and February 2018 were analyzed. Regimens used were VD (n = 305), Rd (n = 103), VMP (n = 97), VCD (n = 71), and VRd (n = 22). Younger patients tended to receive VRd or VCD, whereas the regimen with the highest median patient age was Rd. More than three-quarters of patients in the Rd group received a reduced dose of lenalidomide. The Rd and VRd groups had a relatively high incidence of infection and skin complications, and the VMP group had the highest incidence of peripheral neuropathy. Overall response rate did not differ significantly between regimens. Multivariate analysis in all patients revealed several poor prognostic factors, such as poor performance status. Novel drug-containing regimens for newly diagnosed MM showed a durable response with manageable AEs in the real-world setting., (© 2023. Japanese Society of Hematology.)

Differential speeds in biochemical reactions have been proposed to be responsible for the differences in developmental tempo between mice and humans. However, the underlying mechanism controlling the species-specific kinetics remains to be determined. Using in vitro differentiation of pluripotent stem cells, we recapitulated the segmentation clocks of diverse mammalian species varying in body weight and taxa: marmoset, rabbit, cattle, and rhinoceros. Together with mouse and human, the segmentation clock periods of the six species did not scale with the animal body weight, but with the embryogenesis length. The biochemical kinetics of the core clock gene HES7 displayed clear scaling with the species-specific segmentation clock period. However, the cellular metabolic rates did not show an evident correlation. Instead, genes involving biochemical reactions showed an expression pattern that scales with the segmentation clock period. Altogether, our stem cell zoo uncovered general scaling laws governing species-specific developmental tempo., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Novel therapeutic drugs have dramatically improved the overall survival of patients with multiple myeloma. We sought to identify the characteristics of patients likely to exhibit a durable response to one such drug, elotuzumab, by analyzing a real-world database in Japan. We analyzed 179 patients who underwent 201 elotuzumab treatments. The median time to next treatment (TTNT) with the 95% confidence interval was 6.29 months (5.18-9.20) in this cohort. Univariate analysis showed that patients with any of the following had longer TTNT: no high risk cytogenic abnormalities, more white blood cells, more lymphocytes, non-deviated κ/λ ratio, lower β 2 microglobulin levels (B2MG), fewer prior drug regimens, no prior daratumumab use and better response after elotuzumab treatment. A multivariate analysis showed that TTNT was longer in patients with more lymphocytes (≥ 1400/μL), non-deviated κ/λ ratio (0.1-10), lower B2MG (< 5.5 mg/L) and no prior daratumumab use. We proposed a simple scoring system to predict the durability of the elotuzumab treatment effect by classifying the patients into three categories based on their lymphocyte counts (0 points for ≥ 1400/μL and 1 point for < 1400/μL) and κ/λ ratio (0 points for 0.1-10 and 1 point for < 0.1 or ≥ 10) or B2MG (0 points for < 5.5 mg/L and 1 point for ≥ 5.5 mg/L). The patients with a score of 0 showed significantly longer TTNT (p < 0.001) and better survival (p < 0.001) compared to those with a score of 1 or 2. Prospective cohort studies of elotuzumab treatment may be needed to validate the usefulness of our new scoring system., (© 2023. The Author(s).)

We report a mother and an adult son with Darier's disease. The mother, 76 years old and Japanese, had positivity for anti-desmoglein (Dsg)1 antibodies. She had erythema with hyperkeratosis and seborrheic and interstitial blistering. A high level of anti-Dsg1 antibodies was detected in the serum. Histopathological examination showed acantholysis and direct immunofluorescence testing revealed intercellular IgG and C3 deposition of the epidermis. Although she was diagnosed as having pemphigus foliaceus, the skin lesions slightly improved with immunosuppressive therapy. Her son, 47 years old, had similar skin lesions on the seborrheic and interstitial parts, but the anti-Dsg1 antibodies were negative in his serum. Histopathological examination showed acantholysis and dyskeratotic cells. Although Hailey-Hailey disease was first suspected, no mutation in the ATP2C1 was detected in either patient. Trio-exome analysis including the father showed a heterozygous c.2027C>A transition on exon 14 of ATP2A2, causing a replacement at amino acid 676 (p.Ala676Asp) in the mother and son only. The two patients were then diagnosed as having Darier's disease. Exome analysis further showed that a novel heterozygous missense mutation of DSG1 was identified only in the affected mother. Anti-Dsg1 antibody-positive Darier's disease is reported here for the first time. Very rare coexistence of Darier's disease and anti-Dsg1 antibody-positivity might be associated with this novel heterozygous DSG1 mutation. Experimental evidence is required to validate this hypothesis., (© 2022 Japanese Dermatological Association.)

Background: Daratumumab is one of the most widely used treatments for relapsed/refractory multiple myeloma (MM) patients. However, not all patients achieve a lasting therapeutic response with daratumumab., Objectives: We hypothesized that a durable response to daratumumab could be predicted by the balance between the MM tumor burden and host immune status., Design: We conducted a retrospective study using the real-world data in the Kansai Myeloma Forum (KMF) database., Methods: We retrospectively analyzed 324 relapsed/refractory MM patients who were treated with daratumumab in the KMF database., Results: In this study, 196 patients were treated with daratumumab, lenalidomide, and dexamethasone (DLd) regimen and 128 patients were treated with daratumumab, bortezomib, and dexamethasone (DBd) regimen. The median age at treatment, number of prior treatment regimens and time-to-next-treatment (TTNT) were 68, 4 and 8.02 months, respectively. A multivariate analysis showed that the TTNT under the DLd regimen was longer with either higher monocyte counts (analysis 1), higher white blood cell (WBC) counts (analysis 2), lower β 2 microglobulin (B2MG < 5.5 mg/L) or fewer prior regimens (<4). No parameters were correlated with TTNT under the DBd regimen., Conclusion: We propose a simple scoring model to predict a durable effect of the DLd regimen by classifying patients into three categories based on either monocyte counts (0 points for ⩾200/μl; 1 point for <200/μl) or WBC counts (0 points for ⩾3500/μl; 1 point for <3500/μl) plus B2MG (0 points for <5.5 mg/L; 1 point for ⩾5.5 mg/L). Patients with a score of 0 showed significantly longer TTNT and significantly better survival compared to those with a score of 1 or 2 (both p  < 0.001). To confirm this concept, our results will need to be validated in other cohorts., Competing Interests: The authors declare no conflicts of interest except JK received honorarium from Bristol-Myers Squibb Co, Janssen Pharmaceutical K.K., Takeda Pharmaceutical Co., Ltd., Sanofi K.K. and Ono Pharma Inc., and is an advisory role in Janssen Pharmaceutical K.K, and Novartis Pharma K.K. TI received honorarium from Bristol-Myers Squibb Co, Takeda Pharmaceutical Co., Ltd. and Sanofi K.K.; and research funding from Bristol-Myers Squibb Co. KI received honorarium from Bristol-Myers Squibb Co, Janssen Pharmaceutical K.K., Takeda Pharmaceutical Co., Ltd., Ono Pharma Inc., Novartis Pharma K.K., Kyowa Kirin Co., Ltd., Celgene K.K., Nippon Shinyaku Co., Ltd., Chugai Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co. Ltd., Astellas Pharma Inc., Sumitomo Dainippon Pharma Co., Ltd. and Meiji Seika Pharma Co. Ltd. SF received honoraria from Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Janssen Pharmaceutical K.K., Sanofi K.K., Bristol-Myers Squibb Co., Ltd., and Celgene K.K. HT received personal fees from Bristol-Myers Squibb Co (Celgene K.K.), personal fees from Novartis Pharma K.K., grants from Kyowa Kirin Co., Ltd. HS reports honoraria from Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Novartis Pharma K.K., Celgene K.K., Janssen Pharmaceutical K.K., Chugai Pharmaceutical Co., Ltd., Sanofi K.K., AstraZeneca K.K., AbbVie G.K., SymBio Pharmaceuticals Ltd., Eisai Co., Ltd., and Kyowa Kirin Co., Ltd.; and research funding from Pharma Essentia Japan K.K., Janssen Pharmaceutical K.K., Ono Pharmaceutical Co., Ltd., Celgene K.K., Novartis Pharma K.K., Sanofi K.K., AstraZeneca K.K., AbbVie G.K., Eisai Co., Ltd., HUYA Bioscience International, LLC., and Chugai Pharmaceutical Co., Ltd.; and scholarship endowment from Astellas Pharma Inc., Teijin Pharma Ltd., Shionogi & Co., Ltd., Eisai Co., Ltd., Sanofi K.K., Taiho Pharmaceutical Co., Ltd., and Nippon Shinyaku Co., Ltd. CS received honoraria from Bristol-Myers Squibb Co., Celgene K.K., Janssen Pharmaceutical K.K., and Sanofi K.K. IM received personal fees from Bristol-Myers Squibb Co. (Celgene K.K.), personal fees from Novartis Pharma K.K., grants and personal fees from Otsuka Pharmaceutical Co., Ltd., personal fees from Pfizer Japan Inc., during the conduct of the study; grants from Ono Pharmaceutical Co., Ltd., personal fees from Janssen Pharmaceutical K.K, grants from Nippon Shinyaku Co., Ltd., grants from Kyowa Kirin Co., Ltd., grants from Sumitomo Dainippon Pharma Co., Ltd., grants from Shionogi & Co., Ltd., grants from Teijin Pharma Ltd., grants from Boehringer Ingelheim Co., Ltd., grants from Sanofi K.K., grants from Chugai Pharmaceutical Co., Ltd., grants from Eisai Co., Ltd., grants from MSD K.K, grants from Asahi Kasei Pharma Corporation, grants and personal fees from Astellas Pharma Inc., grants and personal fees from Takeda Pharmaceutical Co., Ltd., grants from Japan Blood Products Organization, grants from Nihon Pharmaceutical Co., Ltd., grants and personal fees from AbbVie GK, grants from Taiho Pharmaceutical Co., Ltd., grants from Mitsubishi Tanabe Pharma Corporation, grants from Nippon Kayaku Co., Ltd., grants from CSL Behring LLC, grants from Mundipharma K.K, grants from Ayumi Pharmaceutical Corporation, grants from Eli Lilly Japan K.K., grants from Actelion Pharmaceuticals Japan Ltd., personal fees from Amgen BioPharma K.K., outside the submitted work. AT-K serves as an advisor for Megakaryon and receives research fundings from Ono Pharmaceutical Co., Ltd., DSK, and Cognano. JK received research funding from Kyowa Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Eisai Co., Ltd., Bristol-Myers Squibb Co., Sysmex, Dainippon Sumitomo Pharma Co., Ltd., Nippon Shinyaku Co., Ltd., AbbVie GK, Teijin Pharma Ltd. and Otsuka Pharmaceutical Co. Ltd., has received honoraria from Janssen Pharmaceutical K.K, Kyowa Kirin Co., Ltd., Chugai Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Eisai Co., Ltd., SymBio Pharmaceutical Limited, Bristol-Myers Squibb Co., Astellas Pharma Inc., Pfizer Japan Inc., Nippon Shinyaku Co., Ltd., Daiichi Sankyo Co. Ltd., Dainippon Sumitomo Pharma Co., Ltd., AbbVie G.K. and Otsuka Pharmaceutical Co. Ltd., and is a consultant for Janssen Pharmaceutical K.K, and Bristol-Myers Squibb Co., (© The Author(s), 2022.)

The hypomethylating agent azacitidine (AZA) significantly extends overall survival (OS) in patients with higher risk myelodysplastic syndromes (MDS), when compared with other conventional care regimens, including supportive care and low-dose and intensive chemotherapy. However, the effects of 5- and 7-day treatment schedules of AZA (AZA-5 and AZA-7, respectively) on the OS of MDS patients had not been compared prospectively. We started a phase 3 trial comparing the effects of AZA-7 and AZA-5 on MDS patients with refractory anemia with excess blasts (RAEB) and RAEB in transformation (RAEB-T). However, this trial was prematurely terminated because of poor recruitment. Using all data, there was no significant difference in the OS of patients between AZA-7 (92 patients) and AZA-5 (95 patients), with the 2-year OS rates of AZA-7 and AZA-5 at 36.4% and 25.8%, respectively (P = 0.293). Adverse event profiles were similar between the two groups. Interestingly, data of the centrally diagnosed RAEB and RAEB-T cases showed that AZA-7 significantly prolonged the time to leukemia transformation compared with AZA-5 (P = 0.022), confirmed by multivariate analysis. Although this trial could not provide definite evidence, the results support the use of AZA-7 for RAEB and RAEB-T. (UMIN Clinical Trials Registry UMIN000009633)., (© 2022. Japanese Society of Hematology.)

We previously reported that a novel haemoglobin-platelet index (HPI) based on anaemia and thrombocytopenia was useful to predict the prognosis of patients with diffuse large B-cell lymphoma not otherwise specified (DLBCL NOS). Here, we analyse the utility of HPI in a new validation cohort with DLBCL NOS (n  = 94). As a result, we confirm that HPI was effective for differentiating progression-free survival (PFS) and overall survival in this validation cohort. So, we further compare the utility of HPI with previously reported prognostic markers such as the National Comprehensive Center Network-International Prognostic Index (NCCN-IPI), Glasgow prognostic score (GPS), and platelet-albumin (PA) score, using a larger number of 160 patients consisting of the derivation cohort (n  = 66) and a validation cohort (n  = 94). As a result, the patients with a higher HPI score had significantly worse outcomes, and HPI predicted the prognosis of DLBCL NOS independently of NCCN-IPI. HPI was more sensitive than GPS and almost the same as PA score in predicting PFS. Moreover, the patients whose lymphoma cells were positive for interleukin-6 (IL-6) (75/111 cases) judged by immunohistochemical staining had significantly lower haemoglobin levels and platelet counts than IL-6-negative cases (36/111 cases), suggesting the involvement of IL-6 produced by lymphoma cells in anaemia and thrombocytopenia in DLBCL NOS patients., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Little is known about the real-world survival benefits and safety profiles of carfilzomib-lenalidomide-dexamethasone (KRd) and carfilzomib-dexamethasone (Kd)., Methods: We performed a retrospective analysis to evaluate their efficacy and safety in 157 patients registered in the Kansai Myeloma Forum database., Results: A total of 107 patients received KRd. Before KRd, 99% of patients had received bortezomib (54% were refractory disease), and 82% had received lenalidomide (57% were refractory disease). The overall response rate (ORR) was 68.2%. The median progression-free survival (PFS) and overall survival (OS) were 8.8 and 29.3 months, respectively. Multivariate analysis showed that reduction of the carfilzomib dose and non-IgG M protein were significantly associated with lower PFS and reduction of the carfilzomib dose and refractoriness to prior bortezomib-based regimens were significantly associated with lower OS. A total of 50 patients received Kd. Before Kd, 96% of patients had received bortezomib (54% were refractory disease). The ORR was 62.0%. The median PFS and OS were 7.1 and 20.9 months, respectively. Based on the multivariate analysis, reduction of the carfilzomib dose and International Staging System Stage III (ISS III) were significantly associated with lower PFS. Grade III or higher adverse events were observed in 48% of KRd cases and 54% of Kd cases. Cardiovascular events, cytopenia, and infections were frequent, and 4 KRd patients died due to heart failure, arrhythmia, cerebral hemorrhage, and pneumonia., Conclusion: Our analysis showed that an adequate dose of carfilzomib is important for achieving the best survival benefits in a real-world setting. Adverse effects after KRd and Kd therapy should also be considered., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: All authors received research funding from Ono Pharma. and Celgene (Current Bristol Myers Squibb). JKa, SF, TI, HT, HS, SY, KS, KO, MH, CS, and JKu received speaker’s bureau from Ono Pharma. JKa, SF, TI, HT, HS, SY, SK, KO, IM, MH, CS, AT-K, and JKu received speaker’s bureau from Celgene (Current Bristol Myers Squibb). SF, TI, TH, HS, SY, SK, KO, IM, MH, CS, and JKu received speaker’s bureau from Janssen. JKa, SF, TI, HT, HS, SY, SK, KO, IM, MH, CS, and JKu received speaker’s bureau from Takeda Pharma. JKa, SF, TI, HT, HS, SY, SK, MH, CS, and JKu received speaker’s bureau from Sanofi. JKa, TI, HT, HS, SY, SK, KO, IM, MH, AT-K, and JKu received speaker’s bureau from Novartis. SK and JKu received speaker’s bureau from Fujimoto Pharma. TI, HS, MH, and JKu received research funding from Celgene (Current Bristol Myers Squibb). HS received research funding from Janssen. IM and JKu received research funding from Takeda Pharma. HS, IM, and JKu received research funding from Sanofi. HS and MH received research funding from Novartis. JKu received research funding from Fujimoto Pharma. JKa received consulting fees from Janssen and Takeda Pharma. MH received scholarship donations from Takeda Pharma. and Ono Pharma. AT-K received scholarship donations from Takeda Pharma. and Sanofi., (© The Author(s), 2022.)

During embryonic development, epithelial cell blocks called somites are periodically formed according to the segmentation clock, becoming the foundation for the segmental pattern of the vertebral column. The process of somitogenesis has recently been recapitulated with murine and human pluripotent stem cells. However, an in vitro model for human somitogenesis coupled with the segmentation clock and epithelialization is still missing. Here, we report the generation of human somitoids, organoids that periodically form pairs of epithelial somite-like structures. Somitoids display clear oscillations of the segmentation clock that coincide with the segmentation of the presomitic mesoderm. The resulting somites show anterior-posterior and apical-basal polarities. Matrigel is essential for epithelialization but dispensable for the differentiation into somite cells. The size of somites is rather constant, irrespective of the initial cell number. The amount of WNT signaling instructs the proportion of mesodermal lineages in somitoids. Somitoids provide a novel platform to study human somitogenesis., (© 2022. The Author(s).)

We previously examined the utility of rituximab-bendamustine (RB) in patients with follicular lymphoma (FL) exhibiting less than optimal responses to 2 cycles of the R-CHOP chemotherapy regimen. The aim of this study was to identify molecular biomarkers that can predict prognosis in RB-treated patients in the context of the prospective cohort. We first analyzed the mutational status of 410 genes in diagnostic tumor specimens by target capture and Sanger sequencing. CREBBP, KMT2D, MEF2B, BCL2, EZH2, and CARD11 were recurrently mutated as reported before, however none was predictive for progression-free survival (PFS) in the RB-treated patients (n = 34). A gene expression analysis by nCounter including 800 genes associated with carcinogenesis and/or the immune response showed that expression levels of CD8 + T-cell markers and half of the genes regulating Th1 and Th2 responses were significantly lower in progression of disease within the 24-mo (POD24) group (n = 8) than in the no POD24 group (n = 31). Collectively, we selected 10 genes (TBX21, CXCR3, CCR4, CD8A, CD8B, GZMM, FLT3LG, CD3E, EOMES, GZMK), and generated an immune infiltration score (IIS) for predicting PFS using principal component analysis, which dichotomized the RB-treated patients into immune IIS high (n = 19) and IIS low (n = 20) groups. The 3-y PFS rate was significantly lower in the IIS low group than in the IIS high group (50.0% [95% CI: 27.1-69.2%] vs. 84.2% [95% CI: 58.7-94.6%], P = .0237). Furthermore, the IIS was correlates with absolute lymphocyte counts at diagnosis (r = 0.460, P = .00355). These results suggest that the T-cell-associated immune markers could be useful to predict prognosis in RB-treated FL patients. (UMIN:000 013 795, jRCT:051 180 181)., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The standard treatment for adults with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in Japan is imatinib-based chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, ∼40% of patients cannot undergo HSCT in their first complete remission (CR1) because of chemotherapy-related toxicities or relapse before HSCT or older age. In this study, we evaluated dasatinib-based 2-step induction with the primary end point of 3-year event-free survival (EFS). The first induction (IND1) was dasatinib plus prednisolone to achieve CR, and IND2 was dasatinib plus intensive chemotherapy to achieve minimal residual disease (MRD) negativity. For patients who achieved CR and had an appropriate donor, HSCT during a consolidation phase later than the first consolidation, which included high-dose methotrexate, was recommended. Patients with pretransplantation MRD positivity were assigned to receive prophylactic dasatinib after HSCT. All 78 eligible patients achieved CR or incomplete CR after IND1, and 52.6% achieved MRD negativity after IND2. Nonrelapse mortality (NRM) was not reported. T315I mutation was detected in all 4 hematological relapses before HSCT. Fifty-eight patients (74.4%) underwent HSCT in CR1, and 44 (75.9%) had negative pretransplantation MRD. At a median follow-up of 4.0 years, 3-year EFS and overall survival were 66.2% (95% confidence interval [CI], 54.4-75.5) and 80.5% (95% CI, 69.7-87.7), respectively. The cumulative incidence of relapse and NRM at 3 years from enrollment were 26.1% and 7.8%, respectively. Dasatinib-based 2-step induction was demonstrated to improve 3-year EFS in Ph+ ALL. This study was registered in the UMIN Clinical Trial Registry as #UMIN000012173., (© 2022 by The American Society of Hematology. 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.)

The aim of this trial is to evaluate the utility of rituximab-bendamustine (R-B) for untreated advanced follicular lymphoma (FL) showing non-optimal response (nOR) to R-CHOP, and to identify clinical prognostic factors for FL patients receiving R-B. Patients who failed to achieve complete response/complete response unconfirmed (CR/CRu) [nOR-group] after 2 cycles of R-CHOP subsequently received 6 cycles of R-B. The primary endpoint was the 3-year progression-free survival (PFS) rate. Secondary endpoints included determination of prognostic factors. Fifty-six patients initially received R-CHOP, 43/56 patients (76.8%) were judged as nOR, and 33/43 patients (76.7%) completed 6 cycles of R-B. At a median follow-up of 50.6 months in the nOR-group, the 3-year PFS rate was 69.0%, and the 3-year overall survival (OS) rate was 92.7%. The most common toxicities associated with R-B were grade 3-4 lymphopenia (93.0%) and neutropenia (74.4%), both of which were manageable. A multivariate analysis including dose intensity, serum soluble interleukin-2 receptor, and FL international prognostic index-2 revealed low absolute lymphocyte count (<  869/μL) at diagnosis was an independent poor prognostic factor for both PFS and OS in the R-B-treated nOR-group. This result was further confirmed in validation cohorts including R-B-treated de novo (n = 40) and relapsed (n = 49) FL patients., (© 2021. Japanese Society of Hematology.)

Objectives: This study aimed to investigate real-world data of ixazomib plus lenalidomide and dexamethasone (IRd) therapy for patients with relapsed and refractory multiple myeloma (RRMM)., Methods: We retrospectively analyzed 122 patients treated with IRd at 16 centers from May 2017 to January 2019 by using the Kansai Myeloma Forum database., Result: At the start of IRd, the median age was 72 years, 66.7% of patients had IgG type, and the median number of prior therapies was 4, comprising bortezomib (85.4%) and lenalidomide (89.3%)-based regimens. Disease progression and adverse events accounted for treatment discontinuation in 46 and 32 patients, respectively. The median overall survival (OS) was not reached, and the median progression-free survival (PFS) was 11.9 months. Sensitivity to bortezomib did not affect the PFS, whereas lenalidomide-refractory patients had significantly lower PFS than lenalidomide-sensitive patients, who were comparable to TOURMALINE-MM1 study. The patients with IgG type had significantly better PFS and OS than those with non-IgG type., Conclusion: This study presents the largest real-world data of patients treated with IRd in Asia. However, in real clinical practice, the patient background is different from the TOURMALINE-MM1 study, and IRd showed poor efficacy, especially in the non-IgG type and lenalidomide-refractory patients with RRMM., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

We retrospectively analyzed 51 patients with solitary plasmacytoma diagnosed from October 2002 to September 2018 from a cohort of 3575 patients with plasma cell dyscrasias registered in the Kansai Myeloma Forum. Twenty-seven patients had solitary bone plasmacytoma (SBP) and 24 had extramedullary plasmacytoma (EMP), with prevalence of 0.8% and 0.7%, respectively. The most frequent M protein was IgG (40%) in SBP, whereas non-secretory proteins were most frequent (50%) in EMP. Five-year overall survival was 78.2% in SBP and 80.8% in EMP (P = 0.894). Among patients with SBP, 44% progressed to MM with a median time of 10.5 months (2.4-93.3 months), whereas 8% of EMP patients progressed to MM with a median time of 18.6 months (13.0-24.2 months). The most frequent treatment was radiotherapy (41%) or observation (41%) in SBP, and chemotherapy (54%) in EMP. No statistically significant difference was observed upon univariate analysis of prognostic factors including age, sex, performance status, and IgG M protein. Our results suggest that there are biological differences between SBP and EMP in real-world settings.

Although mechanisms of embryonic development are similar between mice and humans, the time scale is generally slower in humans. To investigate these interspecies differences in development, we recapitulate murine and human segmentation clocks that display 2- to 3-hour and 5- to 6-hour oscillation periods, respectively. Our interspecies genome-swapping analyses indicate that the period difference is not due to sequence differences in the HES7 locus, the core gene of the segmentation clock. Instead, we demonstrate that multiple biochemical reactions of HES7 , including the degradation and expression delays, are slower in human cells than they are in mouse cells. With the measured biochemical parameters, our mathematical model accounts for the two- to threefold period difference between the species. We propose that cell-autonomous differences in biochemical reaction speeds underlie temporal differences in development between species., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Hailey-Hailey disease (HHD) is genetic skin disorder characterized by repeated and exacerbated skin lesions in friction regions. ATP2C1 , encoding SPCA1, was demonstrated to be the responsible gene for HHD pathogenesis. However, for some cases, no ATP2C1 mutation could be determined by standard Sanger sequencing, thereby obscuring the cause and diagnosis of HHD. In this study, we investigated the possibility that HHD is caused by complex ATP2C1 defects using multiplex ligation-dependent probe amplification (MLPA) analysis for 10 of 50 cases in our institute without ATP2C1 mutations. In one female Japanese patient and her father, who also show HHD, MLPA followed by polymerase chain reaction (PCR) analyses revealed a novel duplication of exons 8-16 of ATP2C1 . The duplication was predicted to add 20,615 base pairs, 882 nt, and 294-amino-acid residues to the genome, mRNA and SPCA1 protein, respectively. By reverse transcriptase-PCR using patient skin RNA, we could confirm that a larger transcript was produced and we found that the abundance of the normal transcript was clearly reduced in the patient. Putative structures of wild-type and duplicated proteins revealed differences in arrangement of SPCA1 domains that may have functional consequences. Strikingly, the phosphorylation and the nucleotide-binding domains were interrupted by insertion of a partial actuator, transmembrane, and phosphorylation domains. The additional 294 amino acids appear to disrupt SPCA1 structure and function, causing HHD. Our study expands the spectrum of genetic defects in HHD and showed that disruption of SPCA1 structure and function by the microduplication caused HHD in the patient and her father., (Copyright © 2020 Teye, Koga, Hamada, Matsuda, Ichiki, Numata, Ishii and Nakama.)

Pluripotent stem cells are increasingly used to model different aspects of embryogenesis and organ formation 1 . Despite recent advances in in vitro induction of major mesodermal lineages and cell types 2,3 , experimental model systems that can recapitulate more complex features of human mesoderm development and patterning are largely missing. Here we used induced pluripotent stem cells for the stepwise in vitro induction of presomitic mesoderm and its derivatives to model distinct aspects of human somitogenesis. We focused initially on modelling the human segmentation clock, a major biological concept believed to underlie the rhythmic and controlled emergence of somites, which give rise to the segmental pattern of the vertebrate axial skeleton. We observed oscillatory expression of core segmentation clock genes, including HES7 and DKK1, determined the period of the human segmentation clock to be around five hours, and demonstrated the presence of dynamic travelling-wave-like gene expression in in vitro-induced human presomitic mesoderm. Furthermore, we identified and compared oscillatory genes in human and mouse presomitic mesoderm derived from pluripotent stem cells, which revealed species-specific and shared molecular components and pathways associated with the putative mouse and human segmentation clocks. Using CRISPR-Cas9-based genome editing technology, we then targeted genes for which mutations in patients with segmentation defects of the vertebrae, such as spondylocostal dysostosis, have been reported (HES7, LFNG, DLL3 and MESP2). Subsequent analysis of patient-like and patient-derived induced pluripotent stem cells revealed gene-specific alterations in oscillation, synchronization or differentiation properties. Our findings provide insights into the human segmentation clock as well as diseases associated with human axial skeletogenesis.

The international prognostic index (IPI) is a broadly utilized clinical tool to aid in predicting the prognosis of patients with aggressive non-Hodgkin's lymphomas (NHL). However, since this score was developed before the development of rituximab, and the introduction of combined rituximab plus CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) (R-CHOP) therapy for NHL has dramatically improved clinical outcomes, the IPI may be inadequate to assess prognosis in the R-CHOP era. In the present study, we assessed the utility of hemoglobin (Hb) level and platelet count to predict prognosis in diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), the largest category of aggressive NHL. A total of 89 patients newly diagnosed with nodal DLBCL, NOS and treated with R-CHOP therapy were included. The blood count results at diagnosis were statistically analyzed. Available biopsy specimens were immunostained for interleukin (IL)-6. Hb levels lower than 120 g/L (p = 0.0133) and platelet counts lower than 135 × 10 9 /L (p = 0.0233) were associated with worse overall survival (OS). Based on those levels as cutoff values, a hemoglobin-platelet (HP) index was calculated by assigning 1 point for an Hb level or a platelet count lower than the cutoff. The patients were divided into three groups based on the HP index: high, with a score of 2 (n = 8); intermediate, with a score of 1 (n = 39); and low, with a score of 0 (n = 42). A higher HP index was associated with worse OS (p = 0.0055). Patients with IL-6-positive tumors had significantly lower Hb levels than those with IL-6-negative tumors (p = 0.0264), suggesting that abnormal production of IL-6 by lymphoma cells is associated with anemia. On the other hand, there was no association between the platelet counts and the IL-6 expression in the lymphoma cells. In a multivariate analysis, the HP index predicted OS rate independently of the IPI. Since the HP index is based on inexpensive and broadly available laboratory values, we believe that this index will have great utility in clinical practice, and the addition of this index to IPI could more precisely predict prognosis.

Although azacitidine is the first-line drug for higher-risk myelodysplastic syndrome (MDS) patients, its efficacy for lower-risk MDS remains unestablished. Therefore, we conducted a prospective study to examine the efficacy and safety of a 5-day regimen of azacitidine (AZA-5) for lower-risk MDS. The primary endpoint was hematological improvement (HI) after 4 courses of therapy. A total of 51 patients with lower-risk MDS based on the French-American-British (FAB) classification (44 patients with refractory anemia [RA] and 7 patients with refractory anemia with ringed sideroblasts [RARS]) were enrolled from 6 centers in Japan. The median age was 75 years (range: 51-88). These patients received AZA-5 (75 mg/m 2 ; once daily for 5 sequential days). The median number of AZA-5 courses was 8 (range: 1-57), and 45 patients (88.2%) received more than 4 courses. HI and transfusion independency were seen in 24 patients (47.1%) and 11 patients (39.2%), respectively. A total of 11 patients (21.6%) achieved complete remission or marrow remission. WT1 mRNA levels were not significantly correlated with therapy response. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 26 (51.0%) and 11 (21.5%) patients, respectively. Nonhematological grade 3 or 4 adverse events were observed in 9 patients (17.6%). Together, these results indicate that AZA-5 is feasible and effective for lower-risk MDS patients as well as for higher-risk MDS patients., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

A 65-year-old man was admitted to our hospital with left-sided chest and back pain and dyspnea. Computed tomography demonstrated a marked circumferential left pleural thickening. A thoracoscopic pleural biopsy led to a diagnosis of high-grade B-cell lymphoma, not otherwise specified (HGBL, NOS). Lymphoma cells were positive for tumor necrosis factor (TNF) and interleukin-6. This is the first case report of TNF- and IL-6-producing aggressive HGBL, NOS in the pleura, in which radiological findings mimicked pleural mesothelioma. The aggressive tumor progression in the present case may have been caused by abnormal cytokine production from lymphoma cells.

Determinants of the efficacy and safety of pomalidomide (POM) monotherapy or POM plus dexamethasone (DEX) (POM/DEX) for relapsed and refractory multiple myeloma (RRMM) were examined retrospectively in a real-world clinical practice setting in Japan. The subjects were 108 patients registered with the Kansai Myeloma Forum, who were treated with either POM or POM/DEX. Of these, 79 (73%), 73 (68%), and 58 (54%) were resistant to bortezomib (BTZ), lenalidomide (LEN), and both BTZ and LEN, respectively. The median overall survival (OS) was not reached. The median time to treatment failure (TTF) was 4.4 months. The best response was recorded in 96 patients, with a 31% overall response rate (ORR) and a 79% rate of achieving at least stable disease. Number of pre-POM regimens ≥ 5, non-IgG-type M-protein, and time from initial therapy to POM or POM/DEX therapy < 2 years were associated with shorter TTF and OS. Frequent (> 10%) severe adverse events included neutropenia (55.1%), thrombocytopenia (33.7%), anemia (30.6%), febrile neutropenia (12.2%), fatigue (11.2%), and anorexia (10.2%). In conclusion, POM and POM/DEX showed substantial efficacy against RRMM, but new combination therapies with POM are needed to improve efficacy further without causing hematologic toxicities.

Competing Interests: CONFLICTS OF INTEREST: The authors have nothing to disclose.

Although the major autoantigens in classic pemphigus are desmogleins, sera from various types of pemphigus react with a number of other molecules, including desmocollins and plakin proteins. However, other novel pemphigus-related autoantigens remain to be identified. In this study, immunoblotting for serum from an atypical autoimmune bullous disease patient identified an unknown 175 kDa protein. Subsequent studies using two-dimensional gel electrophoresis, immunoblotting and mass-spectrometry identified the 175 kDa protein as early endosome antigen 1 (EEA1). This finding was confirmed by subsequent immunological studies, including indirect immunofluorescence of skin and cultured keratinocytes, two-dimensional gel electrophoresis and immunoblotting with anti-EEA1 polyclonal antibody, and preabsorption with EEA1 recombinant protein. Finally, we developed a novel BIOCHIP assay using full-length EEA1 recombinant protein to detect anti-EEA1 antibodies. However, none of 35 sera from various types of pemphigus showed anti-EEA1 antibodies in the BIOCHIP assay, with the exception of the serum from the index case. In addition, various findings in the index case did not suggest pathogenic role of anti-EEA1 autoantibodies. Therefore, although we successfully identified the 175 kDa protein reacted by a serum of an atypical pemphigus-like patient as EEA1, novel BIOCHIP study for other pemphigus sera indicated that EEA1 is not a common and pathogenic autoantigen in pemphigus., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cell-type diversity in multicellular organisms is created through a series of binary cell fate decisions. Lateral inhibition controlled by Delta-Notch signalling is the core mechanism for the choice of alternative cell types by homogeneous neighbouring cells. Here, we show that cells engineered with a Delta-Notch-dependent lateral inhibition circuit spontaneously bifurcate into Delta-positive and Notch-active cell populations. The synthetic lateral inhibition circuit comprises transcriptional repression of Delta and intracellular feedback of Lunatic fringe (Lfng). The Lfng-feedback subcircuit, even alone, causes the autonomous cell-type bifurcation. Furthermore, the ratio of two cell populations bifurcated by lateral inhibition is reproducible and robust against perturbation. The cell-type ratio is adjustable by the architecture of the lateral inhibition circuit as well as the degree of cell-cell attachment. Thus, the minimum lateral inhibition mechanism between adjacent cells not only serves as a binary cell-type switch of individual cells but also governs the cell-type ratio at the cell-population level.

We retrospectively investigated the prognostic factor of lenalidomide plus low-dose dexamethasone (Rd) in Japanese patients with refractory or relapsed multiple myeloma (RRMM) registered in the Kansai Myeloma Forum from January 2006 to December 2013. A total of 140 patients were analyzed. The median age was 66 years. The overall response rate was 68.6 %, including 33.1 % with a better than very good partial response. At 13.0 months median follow-up, the median overall survival (OS) and progression-free survival (PFS) were 34.2 and 17.0 months, respectively. In univariate analyses, patients with one or two prior therapies had significantly longer OS (41.2 vs. 21.5 months; P = 0.002) and PFS (29.0 vs. 13.0 months; P = 0.006) than patients treated with three or more prior therapies. Prior use of thalidomide was associated with significantly shorter PFS (19.0 vs. 16.0 months; P = 0.045). The prior use of bortezomib or high-dose therapy with stem cell transplantation, and the International Staging System had no impact on long-term outcome. Multivariate analysis showed that only the number of prior therapies was a significant predictor of both OS and PFS. Our findings suggest that greater benefit may occur when Rd therapy is used at the first or second relapse in RRMM.

Background: Peeling skin syndrome (PSS) is a rare autosomal recessive form of ichthyosis showing skin exfoliation. PSS is divided into acral and generalized PSS, and the latter is further classified into non-inflammatory type (PSS type A) and inflammatory type (PSS type B). PSS type B is now called peeling skin disease (PSD). Different loss-of-function mutations in the corneodesmosin (CDSN) gene have been reported to cause PSD., Objective: The aim of this study was to determine genetic basis of disease in a 14-year-old Japanese patient with PSD., Methods and Results: Immunohistochemical study showed lack of corneodesmosin (CDSN) in the skin, and standard PCR for genomic DNA failed to amplify CDSN product, suggesting CDSN defect. Multiplex ligation-dependent probe amplification and genomic quantitative real-time PCR analyses detected large homozygous deletion of 59,184bp extending from 40.6kb upstream to 13.2kb downstream of CDSN, which included 6 genes (TCF19, CCHCR1, PSORS1C2, PSORS1C1, CDSN and C6orf15). The continuous gene lost did not result in additional clinical features. Inverted repeats with 85% similarity flanking the deletion breakpoint were considered to mediate the deletion by non-homologous end joining or fork stalling and template switching/microhomology-mediated break-induced replication. Parents were clinically unaffected and were heterozygote carriers of the same deletion, which was absent in 284 ethnically matched control alleles. We also developed simple PCR method, which is useful for detection of this deletion., Conclusion: Although 5 other genes were also deleted, homozygous deletion of CDSN was considered to be responsible for this PSD., (Copyright © 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

A previous study of cases of myelodysplastic syndrome harboring der(5;19)(p10;q10) found that they displayed common characteristics including predominance in elderly men, dysplasia involving three hematopoietic lineages and CD7 expression in blasts. However, the whole-arm translocation der(5;19)(p10;q10) has not been fully analyzed because of its rarity. In this study we used flow cytometry to evaluate the immunophenotype of two patients' bone marrow mononuclear cells. Both patients had involved der(5;19)(p10;q10) in their karyotype analyzed by standard G-banding technique. Both patients had the CD7+ and CD41+ phenotype, and the CD41 positivity suggested that the myeloid neoplasms involving der(5;19)(p10;q10) were of megakaryoblastic origin. The der(5;19)(p10;q10) abnormality is associated with unique characteristics of the immunophenotype. We address the clinical, immunophenotypic and morphological aspects of hematological malignancy involving der(5;19)(p10;q10), along with a review of the literature., (© 2012 Wiley Publishing Asia Pty Ltd.)

Expression of CD56 has recently been introduced as one of the adverse prognostic factors in acute promyelocytic leukemia (APL). However, the clinical significance of CD56 antigen in APL has not been well elucidated. We assessed the clinical significance of CD56 antigen in 239 APL patients prospectively treated with all-trans retinoic acid and chemotherapy according to the Japan Adult Leukemia Study Group APL97 protocol. All patients were prospectively treated by the Japan Adult Leukemia Study Group APL97 protocol. The median follow-up period was 8.5 years. Positive CD56 expression was found in 23 APL patients (9.6%). Expression of CD56 was significantly associated with lower platelet count (P = 0.04), severe disseminated intravascular coagulation (P = 0.04), and coexpression of CD2 (P = 0.03), CD7 (P = 0.04), CD34 (P < 0.01) and/or human leukocyte antigen-DR (P < 0.01). Complete remission rate and overall survival were not different between the two groups. However, cumulative incidence of relapse and event-free survival (EFS) showed an inferior trend in CD56(+) APL (P = 0.08 and P = 0.08, respectively). Among patients with initial white blood cell counts of 3.0 × 10(9)/L or more, EFS and cumulative incidence of relapse in CD56(+) APL were significantly worse (30.8% vs 63.6%, P = 0.008, and 53.8% vs 28.9%, P = 0.03, respectively), and in multivariate analysis, CD56 expression was an unfavorable prognostic factor for EFS (P = 0.04). In conclusion, for APL with higher initial white blood cell counts, CD56 expression should be regarded as an unfavorable prognostic factor., (© 2013 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)