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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.

Abstract A total of 129 symptomatic patients with multiple myeloma (MM) who underwent high‐dose chemotherapy with autologous stem cell transplantation (HDT/ASCT) were analyzed. The 4‐year overall survival (OS) of patients with maintenance (n = 82) was 80%, whereas that of patients without maintenance (n = 47) was 72% (p = 0.426). The 4‐year progression‐free survival (PFS) of patients with maintenance was 38%, whereas that of patients without maintenance was 27% (p = 0.088). Multivariate analysis revealed that an International Staging System score ≥2 was associated with worse PFS (hazard ratio 1.62, p = 0.043). Among the 129 patients, two were excluded owing to early relapse, 50 patients achieved complete response (CR), and 77 patients failed to achieve CR. Patients who achieved CR showed better 4‐year PFS than those who failed to achieve CR (41% vs. 30%, p = 0.027); however, 4‐year OS was not different (76% vs. 82%, p = 0.971). In patients who achieved CR, 4‐year OS with/without maintenance was 74%/81% (p = 0.357), 4‐year PFS with/without maintenance was 42%/40% (p = 0.954). In patients who failed to achieve CR, the 4‐year OS with/without maintenance was 97%/91% (p = 0.107), and 4‐year PFS with/without maintenance was 36%/16% (p

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.

Japan is currently suffering the fourth wave of the COVID-19 pandemic, with the dominant type being SARS-CoV-2 alpha variant. Patients with COVID-19 variant types show more aggressive symptoms. In the present study, three patients developed a red face during treatment. Two of them suddenly worsened shortly after. We assumed that the red face reflected a cytokine storm and conjectured that it may be a specific sign of variant type COVID-19, because we have never seen it in patients with non-variant type. Moreover, we believe that red face may be predictive of a sudden deterioration.

Several clinical manifestations of COVID-19 have been reported in the literature since then. In addition to upper respiratory symptoms, dysgeusia and anosmia are relatively common neurological manifestations with COVID-19. We had five cases of hiccups in succession; therefore, we assume that hiccups might be a specific symptom of COVID-19. We retrospectively analyzed 46 patients with COVID-19 diagnosed from February 2021 to May 2021. Among the 46 patients, 5 developed hiccups (11%). All patients were male. The median age of was 56 years. None of the patients were smokers. Further, all patients exhibited pneumonia without dysgeusia or anosmia. The median onset of hiccups was 5 days after diagnosis, with a median duration of 2 days. All patients recovered from hiccups and COVID-19. Hiccups might be a specific neurological symptom in male patients with COVID-19.

We report six cases of autoimmune acquired coagulation factor VIII deficiency, which is a rare bleeding disorder. It is an autoimmune disease, however, there are various causes. We experienced cases with malignancy, co-exist with another autoimmune disease, pregnancy, and unknown epidemiology with repeated bleeding episode. All patients were controlled the acute bleeding phase and they have been under treatment with immunosuppression.

We retrospectively analyzed twenty-six patients with primary plasma cell leukemia (pPCL) registered from May 2005 until April 2015 by the Kansai Myeloma Forum. Twenty patients received novel agents (bortezomib or lenalidomide), and their median survival of was 34 months. The median survival of patients who underwent autologous stem cell transplantation (SCT) was 40 months, those undergoing allogeneic SCT 55 months, and those undergoing both types of SCT (auto–allo) 61 months; whereas for those who did not undergo SCT it was 28 months (p = 0.845). The only statistically significant risk factor identified by multivariate analysis was hypercalcemia. Keywords: Primary plasma cell leukemia, Novel agent, Hypercalcemia, Stem cell transplantation

A 49-year-old woman diagnosed with chronic myeloid leukemia in the chronic phase was started on dasatinib treatment, after which she complained of myodesopsia. Nineteen months after diagnosis, the patient again complained of myodesopsia and developed bilateral optic neuritis. Cerebrospinal fluid analysis revealed an increase in blasts, although peripheral blood and bone marrow examination confirmed that the patient remained in a molecular response to tyrosine kinase inhibitor (TKI) therapy. The patient was diagnosed with an isolated central nervous system blast crisis, a rare occurrence with second-generation TKI therapy, and the initial presentation of myodesopsia represented a symptom of this condition. Keywords: Chronic myeloid leukemia, Tyrosine kinase inhibitor, Central nervous system, Blast crisis, Myodesopsia

Background: Although eltrombopag has recently been approved for treating AA, the effects of its clinical use remain unknown. Methods: We retrospectively analyzed 11 patients with AA, who had been treated with eltrombopag from August 2017 to May 2018. Results: Overall response rate was 55%. There was tri-lineage recovery in four patients and platelet recovery in two. The reactive time was within 8 weeks after treatment initiation. Stage at the initial assessment, the neutrophil-to-lymphocyte ratio and platelet counts were significantly different between the responders and non-responders. Conclusion: Eltrombopag is a promising agent for treating patients with any degree of AA. Keywords: Eltrombopag, Aplastic anemia, Neutrophil-to-lymphocyte ratio, Real-world setting

The survival of multiple myeloma patients has improved significantly over the last several decades. However, the median overall survival of these patients remains less than 5 years. In this report, we discuss 4 cases of multiple myeloma patients that showed long survival. Interestingly, these patients had severe organ damage at diagnosis, used only conventional agents, and did not always show deep response. Although current guidelines recommend novel agents to achieve deep response, the current cases suggest that some multiple myeloma patients may not need intensive treatment. Here, we discuss 4 cases of symptomatic but indolent transplant-ineligible myeloma.

Interstitial lung disease (ILD) is a serious and potentially fatal adverse event in lung cancer therapy. Nanoparticle albumin-bound paclitaxel (nab-PTX) is a novel, solvent-free formulation of paclitaxel (PTX). Although the incidence of nab-PTX-induced ILD is not clear, it is generally considered that this formulation presents a similar risk of developing ILD as PTX. Here, we report 3 patients who developed severe ILD following treatment with nab-PTX. We draw attention to the risk of developing drug-induced ILD following nab-PTX treatment, and highlight that this novel formulation might therefore not be as safe as PTX with respect to the development of ILD.

Pure red cell aplasia (PRCA) is a rare disorder characterized by marked erythroid hypoplasia with maturation arrest in the bone marrow. Secondary acquired PRCA may be associated with hematologic disorders. A few case reports have described PRCA associated with multiple myeloma (MM). However, the clinical course and mechanism of PRCA associated with MM remain unknown. We herein report two cases of PRCA associated with MM in patients undergoing treatment with lenalidomide. Keywords: Pure red cell aplasia, Multiple myeloma, Lenalidomide

We report the case of a man who developed myelodysplastic syndrome (MDS) and refractory cytopenia of unilineage dysplasia, 5 months after aortic valve replacement surgery. He also developed fever of unknown origin. After bone marrow- and other laboratory examinations, he was diagnosed with tuberculosis.

A 63-year-old man was diagnosed with a rare variant of acute promyelocytic leukemia (APL) with t(4;17)(q12; q21) that showed atypical morphological features and two different clinical symptoms. He was started on standard induction chemotherapy for acute myeloid leukemia, which decreased myeloblast numbers; however, APL-like blasts remained. He then received a salvage therapy that added all-trans retinoic acid (ATRA). After ATRA commenced, APL-like blasts disappeared and cytogenetic analysis became normal. However, myeloblasts subsequently increased, and he became resistant. In summary, this patient exhibited two different clinical courses of acute myeloid leukemia and APL.

Background: Neutrophil-to-lymphocyte ratio (NLR) has been recognized as a poor prognostic indicator in various solid tumors. Methods: We retrospectively analyzed 530 patients with de novo DLBCL who were diagnosed from April 2002 to November 2017. Results: The median age of patients was 69 (range, 20–95) years, and 59% were male. The optimal cutoff for NLR was 5.2. NLR (5.2) was not associated with overall and progression free survival. Conclusion: Our study failed to reveal the predictive value of NLR and demonstrated that the NCCN-IPI might be the most powerful predictor in DLBCL. Keywords: Neutrophil-to-lymphocyte ratio, Diffuse large B cell lymphoma, NCCN-IPI

Dasatinib is currently approved for clinical use as a first-line treatment agent for newly diagnosed chronic myeloid leukemia (CML). However, only a few clinical trials have been performed to evaluate dasatinibinduced PE following first-line therapy. We investigated the incidence and clinical features of dasatinib-induced PE following first-line therapy in Japanese CML patients of real world clinical practice settings. Among 22 patients, the median age of PEpositive patients was higher than that of PEnegative patients. Major molecular response was achieved in 75% of PE-positive patients and 50% of PE-negative patients. Most patients developed PE more than 1 year after treatment. Appearance of PE is associated with better clinical response during dasatinib treatment, however it is developed at any time. Elderly and high-risk patients tend to develop PE. The clinical features of dasatinib-induced PE following first-line therapy might be late onset and might not immediately follow the increasing of large granular lymphocyte.

Lenalidomide is an immunomodulating derivative of thalidomide, which shows anti-tumor activity against myeloma cells with immunomodulation including augmentation of T-cell and natural killer cell function. Continuous treatment with this agent shows better survival benefit in patients with multiple myeloma and combined lenalidomide with dexamethasone (LEN-DEX) is a standard treatment regimen. However, fatigue is a frequent symptom resulting from lenalidomide administration. This side-effect therefore reduces quality of life for elderly patients and, furthermore, is a reason for treatment discontinuation. Unfortunately, appropriate preventive countermeasures against lenalidomide-related fatigue have not been established. Ninjin'yoeito is a traditional Chinese medicine made from the extracts of 12 herbal plants, which positively affects immunity and inflammation. It is used to treat fatigue, decreased appetite, anemia, and general malaise associated with malignant tumors and chemotherapy. We have previously reported that ninjin'yoeito significantly improved patients' subjective fatigue symptoms treated with melphalan-prednisone for multiple myeloma. In the present study, we assessed the benefits of ninjin'yoeito as a supplementary treatment for patients with myeloma, and its effect on lenalidomide treatment regime compliance. We retrospectively analyzed 36 cases of newly diagnosed or relapsed/refractory multiple myeloma. The study included patients receiving LEN-DEX with onset of general fatigue after lenalidomide administration (13 and 23 patients with or without ninjin'yoeito, respectively). Frequency of subjective fatigue was significantly decreased in patients administered ninjin'yoeito, compared to those treated with LEN-DEX alone (92.3 and 47.8 % of patients with and without ninjin'yoeito, respectively; p = 0.008). In addition, combined use of ninjin'yoeito and LEN-DEX showed a trend toward reduced rates of treatment discontinuation (7.7 % and 34.8 % of patients with and without ninjin'yoeito, respectively; p = 0.076). Our results suggest that ninjin'yoeito is an effective method for treating subjective fatigue caused by lenalidomide and may have the potential to extend lenalidomide treatment duration.

Post-transplant lymphoproliferative disorder (PTLD) is a well-recognized complication of organ transplantation. Progress has recently been made in the pathological classification of PTLD. However, the clinical course has not been clarified because of the rarity of this disease. We experienced a case of PTLD with a fulminant clinical course. The patient had been under longterm immunosuppressive treatment for aplastic anemia. He received related allogeneic hematopoietic stem cell transplantation. Soon after transplantation, he developed PTLD. According to the guidelines, we reduced immunosuppression. However, the disease course was so fulminant that there was no time for the patient to respond, and he died of multi-organ failure. There may be various clinical types of PTLD, which may include some fulminant cases. In such a case, it is not sufficient to reduce immunosuppression. The patient should be carefully observed and an appropriate individual treatment should be chosen.

The correlation between human T-cell leukemia virus type І (HTLV-І) infection and malignant neoplasms other than adult T-cell lymphoma (ATL) remains unknown. We analyzed the frequency of primary malignant neoplasm in HTLV-І-seropositive patients. From January 2006 to December 2016, 203 patients were diagnosed as HTLV-І-seropositive at Kansai Medical University Hospital. Among them, 32 developed a primary malignant neoplasm. Their median age was 64 years old, 63% of them were male, and 69% of them were HTLV-I carriers. This group had the following distribution of ATL subtypes: 31% smoldering type, 0% chronic type, 3% acute type, and 3% lymphoma type. Among them, 53% was hematology malignancy, and solid tumor was 47%. The most frequent type of hematological malignancy was T-cell lymphoma (23%), followed B-cell lymphoma (16%), and myelodysplastic syndromes (6%). The most frequent primary solid tumor locations were the lung (15%), followed by the colon (9%), prostate (6%), kidney (6%), cervix (2%), breast (2%), liver (2%), pancreas (2%), and oral cavity (2%). Our results suggest that HTLV-Іinfection is often associated with the development of other malignant neoplasms. Therefore, HTLV-І-positive patients should be made aware of their increased risk for the onset of a malignant neoplasm and undergo increased surveillance.

To evaluate the National Comprehensive Cancer Network (NCCN) International Prognostic Index (IPI), we analyzed 284 patients treated with the combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in our institution in Japan. Their 5-year overall survival (OS) by risk level was 80.7%, 74.8%, 55.4% and 67.5% (P=0.005); and their 5-year progression-free survival (PFS) was 76.8%, 78.6%, 63.7% and 58.3% (P=0.0722). The NCCN-IPI is a simple scale that uses conventional clinical factors, but did not reflect survival in our cohort. The NCCN-IPI may require further evaluation for different regions and ethnicities before adopting it for routine clinical use.

A 69-year-old man with chronic-phase chronic myeloid leukemia was initially treated with 100 mg dasatinib once a day. Despite a major molecular response within 9 months, he developed hemorrhagic colitis 32 months after starting dasatinib. Colonoscopy identified multiple hemorrhagic ulcers in the transverse colon. The pathological findings indicated cytomegalovirus infection. Dasatinib was stopped and he was started on ganciclovir. Three months later, colonoscopy confirmed the disappearance of the hemorrhagic ulcers. Dasatinib is a second-generation tyrosine kinase inhibitor used to treat chronic myeloid leukemia. As a multi-kinase inhibitor that acts on SRC-family kinases, its broader off-target kinase-inhibitory activity may account for the adverse events of dasatinib. Although gastrointestinal bleeding is common in patients taking dasatinib, the combination of cytomegalovirus infection and hemorrhagic colitis in the absence of systemic immunodeficiency is rare. Based on this case of dasatinibinduced hemorrhagic colitis with cytomegalovirus infection, we describe a possible mechanism and effective treatment.

The acronym CRAB summarizes the most typical clinical manifestations of multiple myeloma, these being hypercalcemia, renal failure, anemia, and bone disease. CRAB can be used to distinguish between active, symptomatic multiple myeloma and monoclonal gammopathy of undermined significance or smoldering myeloma. The distinction is relevant not only for classification and diagnosis but also for therapy. CRAB factors influence the prognosis of multiple myeloma. However, it is unclear whether the presence of CRAB factors has an influence on the prognosis of myeloma treated with novel agents. In the current study, patients with hypercalcemia and bone disease showed a significantly worse prognosis, whereas anemia and renal failure showed no difference in survival. Novel agents used for treatment of patients with renal failure suggested a favorable outcome compared with conventional therapy. Bone disease was the most common factor and may have the strongest prognostic value in symptomatic myeloma patients using novel agents.

Patients undergoing hemodialysis are particularly vulnerable to severe outcomes of SARS-CoV-2 infection, with mortality rates higher than that of the general population. Vaccination reduces the risk of adverse outcomes, with booster doses being particularly beneficial. However, limited data are available on the effectiveness of subsequent vaccinations or their effect on increasing antibody levels. This single-center study aimed to investigate changes in SARS-CoV-2 IgG antibody titers following the fourth vaccination among 28 patients undergoing hemodialysis. Blood tests were conducted at various intervals post-vaccination, with a focus on identifying factors associated with antibody levels. The IgG antibody levels rapidly increased by Day 7 post-vaccination, with a median time to peak of 11 days. Antibody titers tended to be higher in male patients than in female patients. This study sheds light on the immune response to the fourth vaccination in patients undergoing hemodialysis. As this study included a small sample size, with a short observation period, further research is warranted to comprehensively understand the effectiveness of vaccination and the benefits of additional doses of vaccine.

IntroductionVaccination has been implemented as a useful measure to combat the COVID-19 pandemic. However, there is a tendency for individuals to avoid vaccination due to the possibility of adverse events, making it important to investigate the relationship between COVID-19 vaccines and their adverse events. This study explored longitudinal adverse event patterns and factors that influence adverse events following the second to fourth doses of the COVID-19 vaccine through a latent class analysis.MethodsParticipants were recruited from the Fukushima Prefecture and included individuals who had completed four doses of the COVID-19 mRNA vaccine. This study utilized data from questionnaire surveys and blood collection conducted between September 2021 and November 2022. In the questionnaire, factors such as sex, age, medical history, medication, type of vaccine administered, and adverse events following vaccination were recorded. Additionally, in the blood data, serological tests [IgG(S)] and cellular immune responses (T-spot) were measured. Descriptive statistics, latent class analysis, multivariable logistic regression, and multiple regression analyses were performed to identify the longitudinal adverse event patterns and influencing factors. By analyzing adverse events over time, we identified two distinct groups: those less prone to experiencing adverse events (Group 1) and those more susceptible (Group 2) to latent class analysis.ResultsA total of 1,175 participants were included after excluding those without any adverse events. The median age of the participants in Group 1 was 70 years, and in Group 2 it was 51 years. The proportion of female participants was 298 in Group 1 and 353 in Group 2. Patients in Group 2 were significantly younger (p

As we learned during the COVID-19 pandemic, vaccines are one of the most important tools in infectious disease control. To date, an unprecedentedly large volume of high-quality data on COVID-19 vaccinations have been accumulated. For preparedness in future pandemics beyond COVID-19, these valuable datasets should be analyzed to best shape an effective vaccination strategy. We are collecting longitudinal data from a community-based cohort in Fukushima, Japan, that consists of 2,407 individuals who underwent serum sampling two or three times after a two-dose vaccination with either BNT162b2 or mRNA-1273. Using the individually reconstructed time courses of the vaccine-elicited antibody response based on mathematical modeling, we first identified basic demographic and health information that contributed to the main features of the antibody dynamics, i.e., the peak, the duration, and the area under the curve. We showed that these three features of antibody dynamics were partially explained by underlying medical conditions, adverse reactions to vaccinations, and medications, consistent with the findings of previous studies. We then applied to these factors a recently proposed computational method to optimally fit an "antibody score", which resulted in an integer-based score that can be used as a basis for identifying individuals with higher or lower antibody titers from basic demographic and health information. The score can be easily calculated by individuals themselves or by medical practitioners. Although the sensitivity of this score is currently not very high, in the future, as more data become available, it has the potential to identify vulnerable populations and encourage them to get booster vaccinations. Our mathematical model can be extended to any kind of vaccination and therefore can form a basis for policy decisions regarding the distribution of booster vaccines to strengthen immunity in future pandemics.

Abstract Messenger RNA (mRNA) therapy is the intracellular delivery of mRNA to produce desired therapeutic proteins. Developing strategies for local mRNA delivery is still required where direct intra‐articular injections are inappropriate for targeting a specific tissue. The mRNA delivery efficiency depends on protecting nucleic acids against nuclease‐mediated degradation and safe site‐specific intracellular delivery. Herein, novel mRNA‐releasing matrices based on RGD‐moiety‐rich gelatin methacryloyl (GelMA) microporous annealed particle (MAP) scaffolds are reported. GelMA concentration in aerogel‐based microgels (µgels) produced through a microfluidic process, MAP stiffnesses, and microporosity are crucial parameters for cell adhesion, spreading, and proliferation. After being loaded with mRNA complexes, MAP scaffolds composed of 10% GelMA µgels display excellent cell viability with increasing cell infiltration, adhesion, proliferation, and gene transfer. The intracellular delivery is achieved by the sustained release of mRNA complexes from MAP scaffolds and cell adhesion on mRNA‐releasing scaffolds. These findings highlight that hybrid systems can achieve efficient protein expression by delivering mRNA complexes, making them promising mRNA‐releasing biomaterials for tissue engineering.