Is Phase Angle Useful in Screening for Sarcopenia in Patients with Hematologic Malignancies?

The purposes of this study were to investigate the relationship between sarcopenia and phase angle (PhA), and to examine whether PhA cutoff values can be used to identify sarcopenia in patients with hematologic malignancies. The study population comprised 108 patients with hematologic malignancies who were admitted for chemotherapy, and were undergoing rehabilitation for exercise therapy. The diagnostic criteria for sarcopenia were determined according to the Asian Working Group for Sarcopenia 2019. Muscle strength, endurance, and body composition (including PhA), were assessed. Logistic regression and receiver operating characteristic (ROC) curve analyses were performed to investigate associations between sarcopenia and PhA, and to determine cutoff values. Sarcopenia was found in 17.6% of the participants. PhA was significantly associated with sarcopenia (p < 0.01). The areas under the curve were 0.84 for the males and 0.87 for the females, and the cutoff values were 4.75° for the males (sensitivity 69%, specificity 83%) and 3.95° for the females (sensitivity 78%, specificity 85%). Our results suggest that PhA, which can be measured noninvasively, objectively, and rapidly, can be used as a screening tool for sarcopenia in patients with hematologic malignancies.

Impact of Sarcopenia on Outcome of Exercise Therapy in Older Non-Hodgkin Lymphoma Patients.

PURPOSE: The aim of this study was to investigate the effects of exercise therapy on physical function and quality of life (QOL) in older patients with non-Hodgkin lymphoma undergoing inpatient chemotherapy, including differences between patients with and without sarcopenia. METHODS: Thirty-one inpatients aged 70 years or older participated in this study. Grip and knee extensor strength, 6-minute walking test, body composition, nutritional status, fatigue and health-related QOL at admission and discharge were compared. In addition, the patients were classified into sarcopenic and non-sarcopenic groups, and a comparison between admission and discharge and 2-way ANOVA were performed. RESULTS: Overall, grip strength and skeletal muscle mass were significantly lower at discharge than at admission (P < .05); however, QOL significantly improved (P < .05). In the non-sarcopenia group, grip strength, right knee extension muscle strength, and skeletal muscle mass were all significantly lower at discharge than at admission (P < .05); however, this was not the case in the sarcopenia group. In terms of QOL, improvements were observed in different items in the non-sarcopenia and sarcopenia groups. There was a significant interaction between admission to discharge time period and sarcopenia regarding left grip strength, right knee extensor strength, and QOL. CONCLUSION: Exercise therapy is effective in improving QOL in older non-Hodgkin lymphoma patients undergoing inpatient chemotherapy. However, the effect of exercise therapy and optimal exercise load may differ between non-sarcopenia and sarcopenia patients. Therefore, it is necessary to consider exercise therapy in the future, taking into account the presence or absence of sarcopenia.

Exacerbation of autoimmune hemolytic anemia associated with pure red cell aplasia after COVID-19: A case report.

Autoimmune hemolytic anemia (AIHA) and pure red cell aplasia (PRCA) are rare complications of coronavirus disease 2019 (COVID-19). Herein, we report the case of a 28-year-old Japanese man who showed severe AIHA exacerbation associated with PRCA after COVID-19. AIHA was diagnosed and maintained for 5 years. Approximately 4 weeks after COVID-19, the patient developed severe anemia (hemoglobin level, 3.4 g/dL). Laboratory test results confirmed hemolytic exacerbation of IgG-mediated warm-type AIHA. Despite the hemolysis phase, the bone marrow revealed extreme hypoplasia of erythroblasts with a decreased reticulocyte count, similar to that observed in patients with PRCA. During oral prednisolone treatment, the patient recovered from anemia and showed increased reticulocyte count and reduced hypoplasia of marrow erythroblasts. Exacerbation of AIHA and PRCA was triggered by COVID-19 because other causes were ruled out. Although this case report highlights that COVID-19 could lead to hematological complications such as AIHA and PRCA, the exact mechanisms remain unclear.

Physical function, nutritional status, and quality of life before and after chemotherapy in patients with malignant lymphoma.

This study investigates the efficacy of and gender differences in exercise therapy in patients with malignant lymphoma undergoing chemotherapy. Twenty-six patients (13 men, 13 women) received physical therapy (based on the Borg Scale 13) during hospitalization. Physical function was measured using grip and knee extension strength, 6-minute walking distance, and body composition; nutritional status assessed via Mini Nutritional Assessment (MNA®); and serum albumin levels analyzed. Fatigue was evaluated using the Brief Fatigue Inventory, and health-related quality of life was assessed with the Medical Outcome Study 36-Item Short-Form Health Survey (SF-36v2). The analysis of all patients indicated that the right grip strength, skeletal muscle mass, skeletal muscle index, and leg muscle mass significantly decreased, whereas the serum albumin level, MNA® score, and scores of many items of the SF-36v2 significantly increased after chemotherapy. In a gender-specific analysis, only men showed significant declines in the skeletal muscle mass and skeletal muscle index, and improvement in the MNA® score after chemotherapy. In the SF-36v2, there were significant improvements in general health and physical component summary scores among men, and general health and mental component summary scores among women. Exercise therapy at a Borg Scale intensity of 13 may not prevent muscle mass decline in patients with malignant lymphoma, especially male patients. In addition, this study revealed that there is a gender difference in the effect of exercise therapy on quality of life. Thus, gender should be considered in exercise therapy for patients with malignant lymphoma.

Development of multiple myeloma after 15 years of treatment for polycythemia vera and successful treatment using bortezomib: A case report.

Multiple myeloma (MM) and polycythemia vera (PV) rarely coexist; the clinical manifestations and treatment of this coexistence have not been described. An 81-year-old woman developed MM 15 years after undergoing PV treatment and was successfully treated using bortezomib. Herein, we share our experience of treating MM under such unusual conditions.

The suppressive effects of Mer inhibition on inflammatory responses in the pathogenesis of LPS-induced ALI/ARDS.

The pathogenesis of sepsis-induced acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) has not yet been fully elucidated. Growth arrest-specific 6 (Gas6) has marked effects on hemostasis and reduces inflammation through its interaction with receptor tyrosine kinases of the TAM family: Tyro3, Axl, and Mer. Here, we found that plasma concentrations of Gas6 and soluble Mer were greater in patients with severe sepsis or septic ALI/ARDS compared with those in normal healthy donors. To determine whether the Gas6-Mer axis was critical in the pathogenesis of ALI/ARDS, we investigated the effects of intravenous administration of the selective Mer inhibitor UNC2250 on lipopolysaccharide (LPS)-induced ALI in mouse models subjected to inhalation of LPS. UNC2250 markedly inhibited the infiltration into the lungs of neutrophils and monocytes with increased amounts of Gas6 and Mer proteins, severe lung damage, and increased amounts of reactive oxygen species (ROS) in LPS-induced ALI in mice. In human pulmonary aortic endothelial cells, LPS induced decreases in the amounts of endothelial nitric oxide synthase, thrombomodulin, and vascular endothelial-cadherin, which was blocked by treatment with UNC2250. UNC2250 also inhibited the LPS-dependent increases in cell proliferation and enhanced apoptosis in HL-60 cells, a human neutrophil-like cell line, and RAW264.7 cells, a mouse monocyte/macrophage cell line. These data provide insights into the potential multiple beneficial effects of the Mer inhibitor UNC2250 as a therapeutic reagent to treat inflammatory responses in ALI/ARDS.

Physical therapy for multiple myeloma patients with severely hindered daily living activities due to bone lesions: a report of two cases.

[Purpose] Physical therapy for patients with multiple myeloma requires appropriate exercise intensity and risk management due to osteolytic lesions. However, the optimal strategy for setting exercise intensity remains unclear. We report cases in which physical therapy was performed using the Borg scale and the Common Terminology Criteria for Adverse Events v4.0 as indicators of improvement in the performance of activities of daily living without causing adverse events. [Participants and Methods] Two patients with multiple myeloma, whose performance status was 4, underwent resistance training of the upper and lower limbs and activities of daily living practice in stages according to their functional status. Each exercise was performed for 20 to 40 minutes twice a day for 6 days a week. The exercise intensity was set to 13 on the Borg scale as a guide, and the allowable bone pain was up to Grade 1 according to Common Terminology Criteria for Adverse Events v4.0. [Results] No adverse events occurred in either patient, and the performance status improved to 1 or 2. Subsequently, autologous peripheral hematopoietic stem cell transplantation was performed. [Conclusion] Physical therapy with exercise intensity set to 13 on the Borg scale and Grade 1 per Common Terminology Criteria for Adverse Events v4.0 may safely improve the performance of activities of daily living of patients with multiple myeloma.

Weight Loss Intervention before Cord Blood Transplantation in an Obese Patient with Acute Myeloid Leukemia: A Case Study.

BACKGROUND: A severely obese woman (39.8 kg/m2) with relapsed acute myeloid leukemia was admitted to our hospital to undergo salvage chemotherapy followed by cord blood transplantation (CBT). CASE: During the salvage chemotherapy period, a 70-day weight loss program addressing diet and exercise was administered. After the 70-day intervention, the patient's body weight and body fat mass had decreased (8.6% and 15.0%, respectively) without any adverse events. The number of available cord blood units with total nucleated cells per body weight greater than 2 × 107/kg was zero at admission and two after weight loss; therefore, CBT could be performed. DISCUSSION: Considering this case, we suggest that a weight loss program combining exercise and nutrition therapy may help patients scheduled for hematopoietic stem cell transplantation by focusing on risk management.

A critical role of the Gas6-Mer axis in endothelial dysfunction contributing to TA-TMA associated with GVHD.

Endothelial dysfunction in the early phases of hematopoietic stem cell transplantation (HSCT) contributes to a common pathology between transplant-associated thrombotic microangiopathy (TA-TMA) and graft-versus-host disease (GVHD), which are serious complications of HSCT. Growth arrest-specific (Gas) 6 structurally belongs to the family of plasma vitamin K-dependent proteins working as a cofactor for activated protein C, and has growth factor-like properties through its interaction with receptor tyrosine kinases of the TAM family: Tyro3, Axl, and Mer. Serum Gas6 levels were significantly increased in HSCT patients with grade II to IV acute GVHD (aGVHD), and Gas6 and Mer expression levels were upregulated in aGVHD lesions of the large intestine and skin. The increased serum Gas6 levels were also correlated with elevated lactate dehydrogenase, d-dimer, and plasmin inhibitor complex values in HSCT patients with aGVHD. In human umbilical vein endothelial cells (ECs), exogenous Gas6 or the exposure of sera isolated from patients with grade III aGVHD to ECs induced the downregulation of thrombomodulin and the upregulation of PAI-1, as well as the upregulation of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1, which were inhibited by UNC2250, a selective Mer tyrosine kinase inhibitor. In mouse HSCT models, we observed hepatic GVHD with hepatocellular apoptosis, necrosis, and fibrosis, as well as TA-TMA, which is characterized pathologically by thrombosis formation in the microvasculature of the liver and kidney. Of note, intravenous administration of UNC2250 markedly suppressed GVHD and TA-TMA in these mouse HSCT models. Our findings suggest that the Gas6-Mer axis is a promising target for TA-TMA after GVHD.

Steroid-resistant autoimmune myelofibrosis in a patient with autoimmune hepatitis and Evans syndrome complicated with increased expression of TGF-ß in the bone marrow: a case report.

We here report a 47-year-old female with autoimmune myelofibrosis (AIMF) associated with liver damage caused by autoimmune hepatitis and Evans syndrome. Bone marrow biopsy revealed hypocellular marrow with grade 2 reticulin fibrosis and increased levels of B lymphocytes (CD20+), T lymphocytes (CD3+, CD8+), and plasma cells (CD138+). Immunohistochemical analysis revealed increased expression of transforming growth factor-ß (TGF-ß) in infiltrating lymphocytes and macrophages in the bone marrow. She was initially treated with oral prednisolone (PSL) for 2 months, which had a limited effect. However, after treatment with rituximab, the patient's pancytopenia showed improvement, allowing us to rapidly reduce the PSL dosage. The present case suggests the possibility that increased expression of TGF-ß in infiltrating lymphocytes and macrophages of bone marrow may contribute to the pathogenesis of AIMF. Prednisolone combined with rituximab may thus be an effective option for steroid-refractory cases.

Autocrine and Paracrine Interactions between Multiple Myeloma Cells and Bone Marrow Stromal Cells by Growth Arrest-specific Gene 6 Cross-talk with Interleukin-6.

The pathogenesis of multiple myeloma (MM) has not yet been fully elucidated. Our microarray analysis and immunohistochemistry revealed significant up-regulation of growth arrest-specific gene 6 (Gas6), a vitamin K-dependent protein with a structural homology with protein S, in bone marrow (BM) cells of MM patients. ELISA showed that the serum levels of soluble Gas6 were significantly increased in the MM patients when compared with healthy controls. Gas6 was overexpressed in the human CD138-positive MM cell line RPMI-8226. Exogenous Gas6 suppressed apoptosis induced by serum deprivation and enhanced cell proliferation of the MM cells. The conditional medium from the human BM stromal cell line HS-5 induced cell proliferation and anti-apoptosis of the MM cells with extracellular signal-regulated kinase, Akt, and nuclear factor-κB phosphorylation, which were reversed by the neutralizing antibody to Gas6 or IL-6. The TAM family receptor Mer, which has been identified as a Gas6 receptor, was overexpressed in BM cells of MM patients. The knockdown of Mer by siRNA inhibited cell proliferation, anti-apoptosis, and up-regulation of intercellular cell adhesion molecule-1 (ICAM-1) in MM cells stimulated by an HS-5 cell-conditioned medium. Furthermore, the Gas6-neutralizing antibody reduced the up-regulation of IL-6 and ICAM-1 induced by a HS-5 cell-conditioned medium in MM cells. The present study provides new evidence that autocrine and paracrine stimulation of Gas6 in concert with IL-6 contributes to the pathogenesis of MM, suggesting that Gas6-Mer-related signaling pathways may be a promising novel target for treating MM.

CD4+ T cells in aged or thymectomized recipients of allogeneic stem cell transplantations.

BACKGROUND: CD4+CD25highFOXP3+ regulatory T (Treg) cells, which include thymus-derived and peripherally induced cells, play a central role in immune regulation, and are therefore crucial to prevent graft-versus-host disease (GVHD). The increasing use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for elderly patients with thymus regression, and our case of allo-HSCT shortly after total thymectomy, raised questions about the activity of thymus-derived Treg cells and peripherally induced Treg cells, which are otherwise indistinguishable. RESULTS: We found that despite pre-transplant thymectomy or older age, both naïve and effector Treg cells, as well as naïve and effector conventional T cells, proliferated in allo-HSCT recipients. Higher proportions of total Treg cells 1 month post allo-HSCT, and naïve Treg cells 1 year post allo-HSCT, appeared in patients achieving complete chimera without developing significant chronic GVHD, including our thymectomized patient, compared with patients who developed chronic GVHD. CONCLUSIONS: Treg cells that modulate human allogeneic immunity may arise peripherally as well as in the thymus of allo-HSCT recipients.

Persistent complete remission of acute leukemic-phase CCR4-positive gamma-delta peripheral T-cell lymphoma by autologous stem cell transplantation with mogamulizumab.

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), frequently shows a poor outcome. Especially, expressions of CC chemokine receptor 4 (CCR4) and γδ T-cell receptor (TCR) are associated with worse prognosis in PTCL-NOS. We here report successful treatment with autologous peripheral blood stem cell transplantation (auto-PBSCT) combined with anti-CCR4 antibody mogamulizumab for a very rare case of CCR4+γδTCR+ PTCL-NOS that coexisted with Hodgkin's lymphoma. PTCL-NOS in this patient progressed to leukemic phase, whereas Hodgkin's lymphoma disappeared with standard chemotherapies within 4 years of the initial diagnosis. Leukemic-phase PTCL-NOS was refractory to several chemotherapies. However, auto-PBSCT following high-dose chemotherapy combined with pre- and post-transplant mogamulizumab, which is a humanized monoclonal antibody to CCR4, provided persistent complete remission of PTCL-NOS, despite residual γδTCR+ in the transplanted stem cell product, suggesting a purging effect of mogamulizumab. At 15 months after transplantation, we also found markedly fewer effector regulatory T cells, which may have contributed to prolonged remission. This case suggests that autologous stem cell transplantation combined with mogamulizumab may have a potential to cure T-cell neoplasms that express CCR4 including leukemic-phase PTCL-NOS.

CD4+ T cells in aged or thymectomized recipients of allogeneic stem cell transplantations

BACKGROUND: CD4+CD25highFOXP3+ regulatory T (Treg) cells, which include thymus-derived and peripherally induced cells, play a central role in immune regulation, and are therefore crucial to prevent graft-versus-host disease (GVHD). The increasing use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for elderly patients with thymus regression, and our case of allo-HSCT shortly after total thymectomy, raised questions about the activity of thymus-derived Treg cells and peripherally induced Treg cells, which are otherwise indistinguishable. RESULTS: We found that despite pre-transplant thymectomy or older age, both naïve and effector Treg cells, as well as naïve and effector conventional T cells, proliferated in allo-HSCT recipients. Higher proportions of total Treg cells 1 month post allo-HSCT, and naïve Treg cells 1 year post allo-HSCT, appeared in patients achieving complete chimera without developing significant chronic GVHD, including our thymectomized patient, compared with patients who developed chronic GVHD. CONCLUSIONS: Treg cells that modulate human allogeneic immunity may arise peripherally as well as in the thymus of allo-HSCT recipients.

Severe immune thrombocytopenia possibly elicited by the anti-influenza viral agent peramivir.

A 44-year-old man whose platelet count had been at the lower limit of the normal range for years visited the urgent care department of our hospital for treatment of a high fever and severe fatigue. The influenza A virus was detected, and the patient therefore received the intravenous antiviral agent, peramivir. One week later, he developed systemic petechial rashes. A peripheral blood examination showed a markedly decreased platelet count (3.0×10(9) cells/L), and the bone marrow findings were compatible with a diagnosis of immune thrombocytopenia (ITP). Furthermore, a drug-induced lymphocyte-stimulating test was positive for peramivir. The thrombocytopenia slowly responded to treatment with oral prednisolone. This case suggests that neuraminidase inhibitors, including peramivir, can elicit or worsen ITP.

Pleural solitary fibrous tumor complicated with autoimmune hemolytic anemia.

We herein report a 74-year-old woman who presented with autoimmune hemolytic anemia (AIHA) associated with pleural solitary fibrous tumor (SFT). Her AIHA was initially treated with 1 mg/kg daily of oral prednisolone (PSL) for 2 months, which had a limited effect. However, after surgical tumor resection, the patient showed remarkable improvement of AIHA with normalizations of serum lactate dehydrogenase and bilirubin levels, and we were able to rapidly reduce the PSL dosage. This is the first description of a case of AIHA caused by SFT.

A Japanese case of chronic lymphocytic leukemia with t (1;6).

Chronic lymphocytic leukemia (CLL) rarely exhibits an aggressive clinical course and its patients often have chromosomal deletions or additions. Furthermore, reciprocal translocations are barely observed in CLL. There have only been a few reports of CLL with t(1;6), and here we report the first Asian case of CLL with reciprocal translocation t(1;6). Since our case and previously reported CLL patients with t(1;6) consistently showed aggressive clinical course, t(1;6) may define a distinct type of CLL.

Hematopoietic stem cell transplantation in the Department of Hematology, Fukushima Medical University.

From 1996 to the end of 2009, a total of 114 cases of hematopoietic stem cell transplantation were performed in the Department of Hematology, Fukushima Medical University. We report here a general overview of our results. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) was performed in 37 cases of acute leukemia, 10 of myelodysplastic syndrome, 5 of aplastic anemia, and 5 others. The 5-year survival rate with allo-HSCT was 51.1%. Autologous hematopoietic stem cell transplantation (auto-HSCT) was performed in 34 cases of malignant lymphoma, 15 of multiple myeloma, and 8 others. The 5-year patient survival rate was 75.2% with malignant lymphoma and 46.7% with multiple myeloma. These results are comparable to those from a nationwide survey in Japan, confirming that our hospital has attained a creditable level as a transplantation center.