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Aims The CONtrolling NUTritional status (CONUT) score represents the nutritional status of patients with heart failure (HF). Although high CONUT scores on admission are associated with increased risks of cardiovascular (CV) events in patients with HF, the impact of CONUT changes during hospitalization on their long‐term prognosis is unclear. This study aimed to investigate the impact of CONUT score changes on the clinical outcomes of patients with HF after discharge. Methods and results This observational study included 1705 patients hospitalized with HF who were discharged alive. The patients were categorized depending on their CONUT scores at admission and discharge into persistently high, high at admission and normal at discharge, normal at admission and high at discharge, and persistently normal CONUT groups. The primary endpoint was a composite of CV death and readmission for HF after discharge. The primary endpoint occurred in 652 patients (38%) during the median 525 day follow‐up period. Patients with persistently high CONUT scores had the highest composite endpoint rate (log‐rank trend test: P

Minimal residual disease (MRD) is a surrogate marker for survival in multiple myeloma (MM), while the lymphocyte-to-monocyte ratio (LMR) is a prognostic factor associated with the patients' immunological status. We retrospectively evaluated the clinical impact of MRD negativity and LMR. MRD was analyzed by multicolor flowcytometry (threshold, 1 × 10-5). Fifty-eight patients (median age 70 years) who achieved complete response were included in this study. Twenty-two patients received autologous stem cell transplantation, 14 received daratumumab-based chemotherapy, and 22 received another treatment. Forty-one (70.7%) patients achieved MRD negativity. Over the median follow-up time of 15.1 months, PFS in MRD-negative patients was significantly longer than in MRD-positive patients (P = 0.020). In addition, a high LMR at MRD assessment was associated with MRD negativity (P = 0.019) and long PFS (P = 0.009). Finally, neither MRD negativity nor high LMR at MRD assessment was associated with significantly shorter PFS compared with MRD positivity or low LMR (P = 0.002). In conclusion, high LMR was associated with MRD negativity and can be used as a predictor of long PFS. Change of treatment strategy might be essential for patients with MRD positivity and high LMR at MRD assessment due to their short PFS.

Introduction: Elotuzumab and lenalidomide plus dexamethasone (ERd) is a standard salvage chemotherapy for multiple myeloma, and elotuzumab is commonly administered every 2 weeks after cycle 3 (conventional ERd). Alternatively, elotuzumab may often be used every 4 weeks (monthly ERd) in real-world practice. The purpose of this multicenter observational study was to investigate the efficacy and tolerability of monthly ERd. Methods: We investigated the efficacy and tolerability between conventional and monthly ERd regimens for the myeloma patients in six institutes retrospectively. Results: Seventy-five patients were included in this study. The median patient age was 68 years. The median number of prior chemotherapies was two (1–5). The number of patients with prior lenalidomide exposure was 57 (76.0%). The numbers of progressive disease (PD) and non-PD before ERd were 23 (30.7%) and 52 (69.3%), respectively. The frequency of PD before ERd was significantly lower in the monthly ERd group than in the conventional ERd group. In 26.9 months of median follow-up period, the 2-year progression-free survival (PFS) rate in the monthly ERd group was significantly longer than that in the conventional ERd group (95.0% and 62.0%, hazard ratio 0.082, p = 0.002). However, no significant difference in PFS between these two ERd groups was found using multivariate analysis. The complete response rates were similar between the monthly and conventional ERd groups (55.0% and 32.7%, p = 0.109). There was no significant difference in the incidence of adverse events between the monthly and conventional ERd groups (35.0% and 54.5%, p = 0.192). There was no significant difference in the kinetics of the mean absolute lymphocyte count, CD4, CD8, CD16, CD56, and CD57 positive lymphocyte counts, and CD4 to CD8 ratio between the monthly and conventional ERd groups. Discussion: The efficacy and tolerability of monthly ERd were similar to those of conventional ERd. Thus, monthly ERd might be a reasonable option, considering the quality of life of patients and convenience.

Despite the development of anti-myeloma therapeutics, such as proteasome inhibitors, immunomodulatory drugs, anti-CD38 monoclonal antibodies, and autologous stem cell transplantation (ASCT), multiple myeloma remains incurable. A trial treatment combining four drugs—daratumumab, carfilzomib, lenalidomide, and dexamethasone—followed by ASCT frequently results in minimal residual disease (MRD) negativity and prevents progressive disease in patients with standard- and high-risk cytogenetics; however, it is insufficient to overcome the poor outcomes in patients with ultra-high-risk chromosomal aberration (UHRCA). In fact, MRD status in autografts can predict clinical outcomes after ASCT. Therefore, the current treatment strategy might be insufficient to overcome the negative impact of UHRCA in patients with MRD positivity after the four-drug induction therapy. High-risk myeloma cells lead to poor clinical outcomes not only by aggressive myeloma behavior but also via the generation of a poor bone marrow microenvironment. Meanwhile, the immune microenvironment effectively suppresses myeloma cells with a low frequency of high-risk cytogenetic abnormalities in early-stage myeloma compared to late-stage myeloma. Therefore, early intervention might be key to improving clinical outcomes in myeloma patients. The purpose of this review is to improve clinical outcomes in patients with UHRCA by considering MRD assessment results and improvement of the microenvironment.

At the J-PARC muon facility (MUSE), new beamlines started operation recently. H-line is a high-intensity pulsed muon beamline for fundamental physics experiments. The first beam of the H-line was delivered to its first branch (H1 area) in January 2022, where a precise measurement of the muonium hyperfine structure and a search for μ-e conversion will be conducted. Further extension of the second branch of the H-line for a muon g-2/EDM experiment and a transmission muon microscope project is also ongoing. In addition, the second branch of the surface muon beamline (S2 area of the S-line) was opened for a muonium 1S-2S spectroscopy experiment in FY2021. In this paper, the recent upgrade and present status of the J-PARC muon facility and its prospects are presented.

New drugs for multiple myeloma (MM) have dramatically improved patients’ overall survival (OS). Autologous stem cell transplantation (ASCT) remains the mainstay for transplant‐eligible MM patients. To investigate whether the post‐ASCT prognosis of MM patients has been improved by new drugs, we undertook a retrospective observational analysis using the Transplant Registry Unified Management Program database in Japan. We analyzed 7323 patients (4135 men and 3188 women; median age, 59 years; range 16‐77 years) who underwent upfront ASCT between January 2007 and December 2018. We categorized them by when they underwent ASCT according to the drugs’ introduction in Japan: group 1 (2007‐2010), group 2 (2011‐2016), and group 3 (2017‐2018). We compared the groups’ post‐ASCT OS. The 2‐year OS rates (95% confidence interval [CI]) of groups 1, 2, and 3 were 85.8% (84.1%‐87.4%), 89.1% (88.0%‐90.1%), and 92.3% (90.0%‐94.2%) (P, The overall survival of patients with multiple myeloma (MM) after autologous stem cell transplantation has improved over time along with the introduction of new drugs for the treatment of MM.

Simple Summary Improving the immunological environment and eradicating minimal residual disease (MRD) are the two main treatment goals for long-term survival in patients with multiple myeloma (MM). An improved immunological environment may be useful for maintaining MRD negativity. Whether the ongoing treatment should be continued or changed if the MRD status remains positive is controversial. In this case, genetic, immunophenotypic, and clinical analysis of residual myeloma cells may be necessary to select the effective treatment for the residual myeloma cells. The purpose of this review is to discuss the MM treatment strategy to “cure MM” based on currently available therapies and expected immunotherapies via improvement of the immunological environment and maintenance of MRD negativity. Abstract Improving the immunological environment and eradicating minimal residual disease (MRD) are the two main treatment goals for long-term survival in patients with multiple myeloma (MM). Immunomodulatory drugs (IMiDs), monoclonal antibody drugs (MoAbs), and autologous grafts for autologous stem cell transplantation (ASCT) can improve the immunological microenvironment. ASCT, MoAbs, and proteasome inhibitors (PIs) may be important for the achievement of MRD negativity. An improved immunological environment may be useful for maintaining MRD negativity, although the specific treatment for persistent MRD negativity is unknown. However, whether the ongoing treatment should be continued or changed if the MRD status remains positive is controversial. In this case, genetic, immunophenotypic, and clinical analysis of residual myeloma cells may be necessary to select the effective treatment for the residual myeloma cells. The purpose of this review is to discuss the MM treatment strategy to “cure MM” based on currently available therapies, including IMiDs, PIs, MoAbs, and ASCT, and expected immunotherapies, such as chimeric antigen receptor T cell (CAR-T) therapy, via improvement of the immunological environment and maintenance of MRD negativity.

The combination of bortezomib, lenalidomide, and dexamethasone (VRD) is used as induction treatment in multiple myeloma; however, the optimum schedule for this regimen remains controversial. In this retrospective study, we compared the efficacy and tolerability of twice-weekly VRD (twVRD) and modified VRD-lite in transplant-eligible myeloma patients. Fifty-five patients (median age 61 years) were included; 22 received twVRD (bortezomib [1.3 mg/m2 on days 1, 4, 8, and 11] and lenalidomide [25 mg/body on days 1–14] over 21-day cycles) and 33 received modified VRD-lite (bortezomib [1.3 mg/m2 on days 1, 8, 15, and 22) and lenalidomide [15 mg/body on days 2–7, 9–14, 16–21] over 28-day cycles). Overall response, very good partial response, and complete response rates after VRD were 96.4%, 45.5%, and 20.0%, respectively (median follow-up period, 17.7 months). The 1-year progression-free survival (PFS) and overall survival rates were 95.8% and 98.2%, respectively. The response rate and PFS were similar between the groups, regardless of cytogenetic risk and age. The incidence of peripheral neuropathy ≥ grade 2 and thrombocytopenia ≥ grade 3 was higher in the twVRD group (27.2% vs. 0.0%, P = 0.003 and 27.2% vs. 0.0%, P = 0.003). In conclusion, modified VRD-lite had similar efficacy with, but better tolerability than, twVRD in transplant-eligible patients.

Maintenance ± consolidation or continuous therapy is considered a standard of care for both transplant–eligible and –ineligible patients with multiple myeloma (MM). However, long-term benefits of such therapy have not yet been clarified in the context of clinical practice. To clarify the efficacy of maintenance/continuous approach, we retrospectively analyzed the cohort data of newly diagnosed MM patients by propensity-score matching based on age, gender, revised International Staging System (R-ISS) stage, and implementation of transplantation to reduce the bias due to confounding variables. Among 720 patients, 161 were identified for each of the maintenance and no maintenance groups. Maintenance/continuous therapy employed immunomodulatory drugs (n = 83), proteasome inhibitors (n = 48), combination of both (n = 29), or dexamethasone alone (n = 1). Progression-free survival (PFS) was significantly prolonged in the maintenance group compared with the no maintenance group (median 37.7 and 21.9 months, p = 0.0002, respectively). Prolongation of PFS was observed in both transplanted and non-transplanted patients (p = 0.017 and p = 0.0008, respectively), with standard risk (p

A 68-year-old male presented with appetite loss and abdominal distention. The whole-body computed tomography scan revealed an ileocecal mass with a large amount of ascites, which was consistent with malignant lymphoma. Due to the worsening of his general condition following admission, he was intubated and admitted to the intensive care unit (ICU). In the ICU, we performed a core-needle biopsy (CNB) on the left peritoneal mass, the findings of which showed a pathological diffuse infiltration of CD20+ middle-sized lymphoid cells. After chemotherapy was initiated, the patient showed complete response, suggesting that CNB can be performed immediately and safely even on a critically ill patient.

Simple Summary Multiple myeloma is an uncurable hematological malignancy, although the prognosis of myeloma patients is getting better using proteasome inhibitors (PIs), immune modulatory drugs (IMiDs), monoclonal antibodies (MoAbs), and cytotoxic agents. Drug resistance makes myeloma difficult to treat and it can be subdivided into two broad categories: de novo and acquired. De novo drug resistance is associated with the bone marrow microenvironment including bone marrow stromal cells, the vascular niche and endosteal niche. Acquired drug resistance is related to clonal evolution and non-genetic diversity. The initial treatment plays the most important role considering de novo and acquired drug resistance and should contain PIs, IMIDs, MoAbs, and autologous stem cell transplantation because these treatments improve the bone marrow microenvironment and might prevent clonal evolution via sustained deep response including minimal residual disease negativity. Abstract Multiple myeloma is an uncurable hematological malignancy because of obtained drug resistance. Microenvironment and clonal evolution induce myeloma cells to develop de novo and acquired drug resistance, respectively. Cell adhesion-mediated drug resistance, which is induced by the interaction between myeloma and bone marrow stromal cells, and soluble factor-mediated drug resistance, which is induced by cytokines and growth factors, are two types of de novo drug resistance. The microenvironment, including conditions such as hypoxia, vascular and endosteal niches, contributes toward de novo drug resistance. Clonal evolution was associated with acquired drug resistance and classified as branching, linear, and neutral evolutions. The branching evolution is dependent on the microenvironment and escape of immunological surveillance while the linear and neutral evolution is independent of the microenvironment and associated with aggressive recurrence and poor prognosis. Proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibody agents (MoAbs), and autologous stem cell transplantation (ASCT) have improved prognosis of myeloma via improvement of the microenvironment. The initial treatment plays the most important role considering de novo and acquired drug resistance and should contain PIs, IMIDs, MoAb and ASCT. This review summarizes the role of anti-myeloma agents for microenvironment and clonal evolution and treatment strategies to overcome drug resistance.

This is the rare case report that bilateral vagus nerve paralysis was emerged as the initial symptom of acute myelogenous leukemia (AML). An 83-year-old man admitted to our hospital because of dysphagia. His dysphagia progressed two months prior to admission. Although physical examination revealed no abnormality, videoendoscopy and videofluorography examination clearly revealed bilateral vagus nerve palsy. Brain MRI showed hypointense signals at the bilateral clivus on T1 weighted images, suggesting tumor infiltration to bilateral petroclivus. He was diagnosed as AML by blood samples and bone marrow biopsy. After initiation of the treatment including radiation therapy, dysphagia shows mild improvement. Although bilateral cranial nerve palsy due to malignant tumor involving at the clivus is very uncommon, we should pay attention to the symptom.

Background: Novel agents capable of inducing deeper responses dramatically improve the prognosis of patients with multiple myeloma (MM). Innovative technologies such as multiparameter flow cytometry (MFC) and next-generation sequencing (NGS) are utilized to assess minimal residual disease (MRD) for further stratification of patients who achieve a complete response (CR). EuroFlow-next-generation flow (EuroFlow-NGF) is one of the gold standard MFC methods. Recently, both NGF and NGS have been used in many clinical trials to assess MRD levels associated with progression-free survival (PFS) and overall survival (OS). The present study prospectively assessed MRD levels by both NGF and NGS to elucidate the prognostic impact of both methods and clarify their characteristics in MM patients in an autologous stem cell transplantation (ASCT) setting. Methods: We prospectively assessed the response in Japanese patients with newly diagnosed MM who underwent ASCT and lenalidomide-based maintenance therapy at multiple Japanese medical centers between September 2016 and July 2021. The diagnosis of MM and patients' responses to therapy were assessed using the IMWG criteria. Only patients with CR or stringent CR on days 100-365 post-ASCT were included, and bone marrow (BM) samples were obtained to assess MRD. Four milliliters of BM was divided equally. Cells derived from 2 mL BM were analyzed by the NGF method (Flores-Montero et al., Leukemia 2017) at Kanazawa University, and DNA extracted from the remaining 2 mL BM cells was processed by Adaptive Biotechnologies' standardized NGS-MRD assay (Seattle, WA) (Ching et al., BMC Cancer 2020) to assess MRD levels. MRD levels in BM were also monitored at 1-year (± 20 days) and 2-year (± 20 days) post-ASCT. The prognostic value of MRD levels in BM was assessed, and their correlation between NGF and NGS was compared at a cut-off value of 1×10 -5. Sustained MRD negativity was defined as the maintenance of MRD negativity in the BM for more than 6 months. BM cells were analyzed for high-risk cytogenetics (del(17p), t(4;14), and t(14;16)) by FISH. Results: A total of 60 patients (male = 29, female = 31) underwent bortezomib-based induction therapy, ASCT conditioned with high-dose melphalan, and lenalidomide-based maintenance. The median age was 62 years at the ASCT (range 36-71; ISS 1 [n = 13], 2 [n = 24], and 3 [n = 23]). Thirty-three percent of patients showed high-risk chromosomal abnormalities (del17p (n=11), t(4;14) (n=10), t(14;16) (n=2)), 3 patients had double hit diseases, and five patients had extramedullary diseases. With a median follow-up of 3 years, the 3-year progression-free survival (PFS) and 3-year overall survival (OS) rates were 69.2% and 94.2%, respectively. In total, 148 samples were analyzed using NGF and 138 were analyzed using NGS. The rates of MRD negativity at least once using NGF and NGS were 80% and 61%, respectively. The patients who achieved at least one MRD negativity exhibited significantly better 3-year PFS (82.9% by NGF; 84.8% by NGS) than those who did not (P < 0.0001, 0% by NGF; P = 0.005, 49.1% by NGS). Patients who sustained MRD negativity for more than 6 months also showed significantly better 3-year PFS (96.7% by NGF; 92.3% by NGS) compared with those without sustained MRD negativity (Figure; P < 0.0001, 37.1% by NGF; P < 0.01, 50.9% by NGS). The MRD levels between the NGF and NGS methods were significantly correlated with each other (r = 0.9295, P < 0.0001). Among the 17 patients who developed PD after ASCT, seven cases showed discrepancies in the MRD results and two cases in which one case was MRD-positive and the other was MRD-negative by both methods progressed with extramedullary diseases. Five of the seven cases were MRD-positive by NGS and MRD-negative by NGF. Conclusions: In this prospective comparison study of MRD assessment in BM cells using EuroFlow-NGF and NGS approaches, MRD levels highly correlated with each other, and MRD negativity and sustained MRD negativity were significantly associated with prolonged PFS. Multiple MRD assessments by NGF or NGS are essential for predicting durable remission and prolonged clinical outcomes. Figure 1 Figure 1. Disclosures Takamatsu: Bristol-Myers Squibb: Honoraria, Research Funding; Adaptive Biotechnologies, Eisai: Honoraria; SRL: Consultancy; Janssen: Consultancy, Honoraria, Research Funding. Yoshihara: Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Novartis: Honoraria. Matsumoto: Sanofi: Honoraria; Janssen: Honoraria; Ono: Honoraria; Bristol-Myers Squibb: Honoraria. Yamashita: Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; celgene: Honoraria; Takeda: Honoraria. Fuchida: Takeda Pharmaceutical Co., Ltd.: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb Co., Ltd.: Honoraria; Celgene Co., Ltd.: Honoraria. Hiragori: BML: Current Employment. Suzuki: Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; ONO: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Abie: Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Nakao: Symbio: Consultancy; Kyowa Kirin: Honoraria; Novartis Pharma: Honoraria; Alexion Pharma: Research Funding. Durie: Amgen: Other: fees from non-CME/CE services ; Amgen, Celgene/Bristol-Myers Squibb, Janssen, and Takeda: Consultancy.

Lenalidomide is an immunomodulatory drug that is administered commonly in patients with relapsed or refractory multiple myeloma (RRMM). Eosinophils have immunological functions, for instance, in allergic diseases and asthma. The purpose of this study was to investigate the clinical significance of elevated eosinophil levels in patients with RRMM treated with lenalidomide. A total of 59 patients were included. Elevated eosinophil level was defined as an increase in the eosinophil count of ≥250/µL from the eosinophil count on day 1 during the first cycle. The percentage of patients with elevated eosinophil levels was 22.0%. The overall response ratio in the elevated eosinophil group and nonelevated eosinophil group was 84.6% and 63.0% (P = .189), respectively. The median time to next treatment (TTNT) in the elevated eosinophil group was significantly longer than that in the nonelevated group (40.3 months vs 8.4 months; P = .017). Additionally, TTNT in the elevated eosinophil group with partial response (PR) or better was significantly longer than that in the nonelevated eosinophil group with PR or better (40.3 months vs 11.9 months; P = .021). We concluded that elevated eosinophil levels were frequently observed and might predict a longer TTNT in patients with RRMM treated with lenalidomide., Elevated eosinophils predicted significantly long time to next treatment in relapsed or refractory multiple myeloma patients treated with lenalidomide. Elevated eosinophils might show an immunological effect of lenalidomide. We considered that NKG2D and IL‐2 were associated with elevated eosinophils according to the literature review.

Background This study aimed to examine the impact of baseline eicosapentaenoic acid ( EPA ) to arachidonic acid ( AA ) ratio on clinical outcomes of patients with acute coronary syndrome. Methods and Results In the HIJ‐PROPER (Heart Institute of Japan Proper Level of Lipid Lowering With Pitavastatin and Ezetimibe in Acute Coronary Syndrome) study, 1734 patients with acute coronary syndrome and dyslipidemia were randomly assigned to pitavastatin+ezetimibe therapy or pitavastatin monotherapy. We divided the patients into 2 groups based on EPA / AA ratio on admission (cutoff 0.34 μg/mL as median of baseline EPA / AA ratio) and examined their clinical outcomes. The primary end point comprised all‐cause death, nonfatal myocardial infarction, nonfatal stroke, unstable angina pectoris, or ischemia‐driven revascularization. Percentage reduction of low‐density lipoprotein cholesterol and triglyceride from baseline to follow‐up was similar regardless of baseline EPA / AA ratio. Despite the mean low‐density lipoprotein cholesterol level during follow‐up being similar between the low‐ and high‐ EPA / AA groups, the mean triglyceride levels during follow‐up were significantly higher in the low‐ than in the high‐ EPA / AA group. After 3 years of follow‐up, the cumulative incidence of the primary end point in patients with low EPA / AA was 27.2% in the pitavastatin+ezetimibe group compared with 36.6% in the pitavastatin‐monotherapy group (hazard ratio 0.69; 95% CI , 0.52‐0.93; P =0.015). However, there was no effect of pitavastatin+ezetimibe therapy on the primary end point in patients with high EPA / AA (hazard ratio 0.92; 95% CI , 0.70‐1.20; P =0.52). Conclusions Among acute coronary syndrome patients who have dyslipidemia and low EPA / AA ratio, adding ezetimibe to statin decreases the risk of cardiovascular events compared with statin monotherapy. Clinical Trial Registration URL : http://www.umin.ac.jp/ctr . Unique identifier: UMIN 000002742

A 66-year-old man with a swollen right inguinal lymph node (LN) had pain on the lower side of the back. Computed tomography revealed bone disease in the back and swollen right inguinal LNs. Laboratory studies showed anemia and serum immunoglobulin G-lambda (IgG-λ) type monoclonal protein. The bone marrow contained 39.6% plasma cells. He was diagnosed with IgG-λ type multiple myeloma (MM). However, the pathological findings of the right inguinal LN were mixed cellular classical Hodgkin lymphoma (HL). The administration of melphalan, prednisone, and bortezomib (MPB) was started for MM; however, swelling in the right inguinal LN increased. After three cycles of MPB, the administration of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) was started for HL. However, HL was refractory to ABVD. Pancytopenia subsequently progressed and rapid swelling occurred in his LNs. He died 7 months after diagnosis. Multiple myeloma was diagnosed, based on the typical symptoms, although the pathological findings of the LN indicated a diagnosis of HL. We analyzed the molecular relationship between MM and HL cells using a direct sequencing method. The sequencing results demonstrated that the variable-diversity-joining (VDJ) region of the IgH gene was identified with 94.4% of IGLV3-32*01 in the bone marrow sample at diagnosis. Furthermore, clonotypic IgH sequence was identified in CD30-positive cells from the LN. These results suggested that the clonal HL cells were derived from the same source as the clonal MM cells and demonstrated that MM and HL in this patient may have originated from the same B cell progenitor.

The previous Chapter revealed that Singapore has provided the highest orders for the Japanese contractors in recent years. In order for the Japanese contractors to learn from the successful project operations of the Japanese contractors in Singapore, this Chapter reviews the characteristics of the Singapore construction industry including the history relating to foreign contractors. In addition, the direction of the future Singapore construction industry is studied to deepen an understanding of future foreign contractors’ involvement in the construction industry.

This Chapter describes the context of Japanese contractors in more details by reviewing the characteristics of the Japanese construction industry. In order to deepen an understanding of the role of Japanese contractors in Japan, the structure of the Japanese construction industry is reviewed. The position of the Japanese contractors in overseas markets including Singapore is then reviewed. Based on the above reviews including the structure of the Japanese construction industry and the position of Japanese contractors in overseas markets, the problems on communication with people from a different culture that Japanese contractors face in project management for international construction projects are revealed.

The clinical features and prognostic significance of myeloma cells containing granules remain unclear. The purpose of this retrospective study was to investigate the clinical significance of granule‐containing myeloma cells in patients with newly diagnosed multiple myeloma (NDMM). We retrospectively analyzed the records of 122 patients diagnosed with NDMM between January 2007 and December 2013. Granule‐containing myeloma cells were defined as myeloma cells that exhibited three or more granules in their cytoplasm by May‐Giemsa staining. The patients were classified into two groups, the granule‐containing myeloma (GM) and nongranule‐containing myeloma (non‐GM) groups, depending on the proportion of myeloma cells that contained granules (cut‐off value: 10%). There were 25 (20.5%) patients in the GM group. Patients in the GM group displayed significantly higher CD56 and CD49e expression than those in the non‐GM group (t‐test, P = 0.027 and 0.042). None of the patient characteristics differed significantly between the two groups. There was no significant difference in the chemotherapy profiles of the two groups, and the overall response rates of the two groups were similar. During the median follow‐up period of 33.9 months, the overall survival (OS) in the GM group was similar to that in the non‐GM group; 4‐year OS of the GM and non‐GM groups were 78.5% and 51.9%, respectively (P = 0.126). We concluded that cases of NDMM involving granule‐containing myeloma cells are not infrequent. Moreover, CD56 and CD49e expression was significantly higher in the presence of myeloma cell populations, and the presence of granules did not affect survival.

Supplemental Digital Content is available in the text., Bromodomain and extraterminal protein (BET) inhibitors suppress the expression of c-MYC. U266, a human myeloma cell line, expresses the MYCL gene, but not the c-MYC gene. Our aim was to analyse the antimyeloma activity of BET inhibitors on U266 cells. Two BET inhibitors, I-BET151 and JQ1, were tested. U266 cell proliferation decreased to 61.5 and 54.0% of the control after incubation with 500 nmol/l I-BET151 for 72 and 96 h and to 53.5 and 56.4% of control after incubation with 500 nmol/l JQ1 for 72 and 96 h by MTS tetrazolium, respectively. BET inhibitors induced cell cycle arrest at the G1 phase in U266 cells, but did not induce apoptosis by flow cytometry. According to Gene Set Enrichment Analysis, MYC-related genes were significantly downregulated in U266 cells treated with I-BET151 similar to KMS11 cells that expressed c-MYC. The MYCL1 was expressed in U266 cells, whereas c-MYC and MYCN were not by quantitative real-time reverse-transcription-PCR. Incubation with I-BET151 induced downregulation of MYCL1 in U266 cells. BET inhibitors decreased the cell proliferation in U266 cells with overexpression of MYCL less than those without overexpression of MYCL. BET inhibitors induce G1 arrest without apoptosis and interfere with the proliferation of U266 myeloma cells, which express MYCL, but not c-MYC. BET inhibitors might be active in cancers that express MYCL, but not c-MYC.

Myeloma cast nephropathy is a major complication of multiple myeloma. Recent evidence has demonstrated that the earlier induction of bortezomib-based chemotherapy with plasma exchange (PE) provides better results for kidney function and patient survival. Due to its non-selectivity, PE with albumin replacement carries the risk of fibrinogen loss, leading to bleeding. We herein report a case of successful treatment of myeloma cast nephropathy using bortezomib-based chemotherapy and selective PE. A 61-year-old woman who had a 20-year history of type II diabetes mellitus was admitted to our hospital for the evaluation of hypercalcemia, severe kidney dysfunction, and anemia. Subsequent bone marrow evaluation and renal biopsy revealed that she had multiple myeloma (IgG-κ) and myeloma cast nephropathy. Ten days after admission, bortezomib-based chemotherapy with selective PE achieved rapid and thorough free light-chain (FLC) reduction; within a month, her kidney function had been recovered (creatinine level, 1.2 mg/dl). Her serum fibrinogen level was not reduced, and no bleeding complication occurred. Five months later, autologous hematopoietic stem-cell transplantation was performed successfully, and the patient’s kidney function was stable (creatinine level, 1.1 mg/dl) thereafter. This case report demonstrates the importance of early induction therapy with bortezomib-based chemotherapy and PE in a patient with myeloma cast nephropathy, which is especially applicable in patients aged

Cancer-related fatigue (CRF) is one of the adverse events in multiple myeloma (MM) patients treated with cytotoxic agents, proteasome inhibitors (PIs), and immunomodulatory drugs (IMiDs) such as bortezomib, lenalidomide, and thalidomide. The aims of our study were to prospectively analyze the clinical significance of CRF, and to evaluate the cumulative incidence of CRF and the survival rates of 16 MM patients who were treated with PIs and IMiDs. Reactivation of salivary human herpes virus (HHV)-6 and HHV-7 was analyzed using real-time quantitative polymerase chain reaction (qPCR). CRF was evaluated using a visual analog scale (VAS). Eleven newly diagnosed multiple myeloma (NDMM) and five relapsed or refractory MM patients were enrolled in this study. The cumulative incidence of CRF was 54.9%. The treatment types were not associated with the CRF incidence. The cumulative incidence of reactivation of HHV-6 and HHV-7 was 73.1% and 45.6%, respectively. However, the reactivation of HHV-6 and HHV-7 was not related to CRF. The overall survival (OS) and progression-free survival (PFS) in NDMM patients with CRF was significantly shorter than in those without CRF. In conclusion, CRF was one of the major symptoms in MM patients, and predicted shorter OS and PFS in NDMM patients.

In recent years, environmental problems are becoming serious and renewable energy systems, especially wind power generation, have attracted much attention and been introduced into power systems. However, wind power generator output is intermittent, resulting frequency fluctuations in the connected power system. A doubly fed induction generator (DFIG) based diesel generation system is proposed in this paper to suppress the frequency fluctuations of the small power system with the squirrel cage induction generator (SCIG) based wind turbines installed. Simulation analyses have been performed using PSCAD/EMTDC software. The simulation results show that DIFG based diesel generation system is very effective to suppress the frequency fluctuations of the power system compared to conventional synchronous generator (SG) based diesel generation system.

Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPDs) sometimes occur following Anti-thymocyte globulin (ATG) administration for allogenic stem cell transplantation but are rare in aplastic anemia (AA) patients. A 55-year-old woman with AA following ATG developed refractory fever and was diagnosed with EBV-LPD. She was successfully treated with weekly rituximab monotherapy; however, she developed EBV encephalitis. She was admitted to the intensive care unit and finally recovered from unconsciousness. EBV-LPD should be considered after ATG for AA when symptoms appear. Because EBV-LPD following ATG for AA can rapidly progress, weekly monitoring of EBV-DNA and early intervention may be necessary.