Real-world clinical characteristics of post-essential thrombocythemia and post-polycythemia vera myelofibrosis.

There are few prospective studies on patients with post-essential thrombocythemia myelofibrosis (PET-MF) and post-polycythemia vera myelofibrosis (PPV-MF). Therefore, we conducted a nationwide longitudinal prospective survey to clarify the clinical characteristics of these diseases. A total of 197 PET-MF and 117 PPV-MF patients diagnosed between 2012 and 2021 were analyzed. The median age at diagnosis was 70.0 years for both diseases. The time from diagnosis of ET or PV to that of MF was 9.6 and 10.4 years, respectively, with no significant difference. Patients with PPV-MF had higher hemoglobin levels and white blood cell counts than those with PET-MF, whereas those with PET-MF had higher platelet counts than those with PPV-MF. Although splenomegaly was more frequent in patients with PPV-MF at diagnosis, there was no difference in the frequency of constitutional symptoms. Ruxolitinib was the most common treatment administered to 74.6% and 83.8% of patients with PET-MF and PPV-MF, respectively. Patients with PET-MF and PPV-MF had similar prognoses, with 3-year overall survival (OS) of 0.742 in PET-MF and 0.768 in PPV-MF patients. In both diseases, leukemic transformation was the leading cause of death, followed by infection. The 3-year OS for patients with PET/PPV-MF and primary MF diagnosed during the same period was 0.754 and 0.626, respectively, with no significant difference. This survey provides real-world clinical features and prognostic data on secondary myelofibrosis in the ruxolitinib era.

MAIT Cells in the Bone Marrow of Patients with Aplastic Anemia.

Mucosal-associated invariant T cells (MAIT cells) are a subset of T cells with innate, effector-like properties that play an essential role in the immune response to microbial infections. In humans, MAIT cells are detectable in the blood, liver, and lungs, but little is known about the frequency of these cells in the bone marrow. Also, the pathogenic role, if any, of MAIT cells in the development of aplastic anemia, a disease with an exquisite origin in the bone marrow, is currently unknown. We investigated the frequency and clinical relevance of bone marrow MAIT cells in a cohort of 14 patients (60.6 ± 23 and 57% women) with aplastic anemia. MAIT cells in the bone marrow samples obtained at diagnosis were evaluated by flow cytometry, and their association with various blood cell parameters and the patients' clinical features was analyzed. MAIT cells were detectable in the bone marrow of all patients, with considerable variations among them. Bone marrow MAIT cells expressing the activator receptor natural killer group 2D - NKG2D (NKG2D+ MAIT cells) were significantly more abundant in the specimens of the aplastic anemia patients than in patients with bone marrow failure distinct from aplastic anemia. In addition, the NKG2D+ MAIT cells positively correlated with whole blood cell counts (WBC), platelet counts, and neutrophil counts, as well as with various inflammatory markers, including neutrophil-to-lymphocyte rate (NLR), platelet-to-lymphocyte rate (PLR), and systemic inflammatory index (SII). In functional studies, bone marrow CD34+ hematopoietic cells exposed to phytohemagglutinin or bacterial-derived lipopolysaccharide and acetyl-6-formylpterin upregulated MR1 (major histocompatibility complex, class I-related, known to interact with MAIT cells) and MICA/B (MHC class I chain-related gene A, a ligand of NKG2D) proteins on their cell surface, suggesting that under stress conditions, CD34+ hematopoietic cells are more likely to interact with NKG2D+ MAIT cells. In addition, NKG2D+ MAIT cells upregulated perforin and granzyme B in response to their interaction with recombinant MICA protein in vitro. This study reports for the first time the frequency of MAIT cells in the bone marrow of patients with aplastic anemia and assesses the potential implications of these cells in the pathogenesis or progression of aplastic anemia.

Effect of preoperative physical activity on postoperative outcomes in esophageal cancer.

[Purpose] This study aimed to examine the characteristics of preoperative physical activity and its impact on the postoperative period in patients who underwent surgery for esophageal cancer. [Participants and Methods] The participants were 30 patients who were diagnosed with esophageal cancer, underwent surgery, and fulfilled their conditions. Preoperative physical activity was measured using the step count, and metabolic equivalents as the amount of physical activity. We examined the relationships between preoperative step count and METs, patient demographics, treatment-related factors, preoperative physical function, and activities of daily living. Moreover, we examined the relationships of preoperative step count and METs with postoperative mobilization, physical activity, physical function, and activities of daily living. [Results] Preoperative step count was related to age, Glasgow prognostic score, and preoperative functional independence and associated with step count on postoperative days 7-13, METs on postoperative days 7-9, 6-min walking distance, and functional independence measures at discharge. [Conclusion] Improving the nutritional status and increasing preoperative physical activity by walking for esophageal cancer may help improve physical activity after postoperative day 7, exercise tolerance, and activities of daily after discharge.

Autoimmune Thyroiditis Shifting from Hashimoto's Thyroiditis to Graves' Disease.

In 15-20% of cases, Graves' disease (GD) shifts to Hashimoto's thyroiditis (HT), while the shift from HT to GD is rare. We present a case of a patient in whom HT shifted to GD, along with a literature review. A 50-year-old woman with myxedema was diagnosed with Hashimoto's disease due to hypothyroidism and the presence of antibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TgAb); she also had thyroid stimulating antibodies (TSAb) without any signs of GD. Although thyroid hormone replacement therapy improved her thyroid function, 2 months later, hyperthyroidism appeared and did not improve after discontinuation of the replacement therapy. The patient was diagnosed with GD, which improved with antithyroid agent administration. To date, only 50 cases regarding conversion from HT to GD have been reported. The median age is 44 years (range, 23-82 years), and the median time of conversion is 7 years (range, 0.1-27 years). The male-to-female ratio of HT conversion to GD is 1:9, closer to that of regular GD (1:10) than that of general HT (1:18). All patients received thyroid hormone replacement therapy for hypothyroidism due to HT. Continuous evaluation of TSAb levels is recommended in HT, particularly in cases of TSAb-positive and those under replacement, since it may help predict conversion to GD. Evaluating the clinical characteristics of patients with HT preceding GD is crucial to ensure appropriate treatment and reduce the risk of adverse events.

Relationship between muscle activity characteristics and physical therapy parameters during posterior gait assistance with knee-ankle-foot orthosis in severe acute stroke hemiplegic patients.

[Purpose] This study aimed to verify muscle activity patterns during posterior gait assistance with a knee-ankle-foot orthosis (KAFO) in patients with severe acute stroke hemiplegia and clarify its relationships with physical therapy parameters. [Participants and Methods] We measured activity in the rectus femoris, biceps femoris, tibialis anterior, and gastrocnemius muscles in 30 patients with acute stroke during KAFO posterior gait assistance and examined their muscle activity patterns using the Japan Coma Scale (JCS), Brunnstrom Recovery Stage (BRS), Berg Balance Scale (BBS), Functional Movement Screen (FMS), and Functional Independence Measure (FIM). We divided lower extremity muscle activity into first and second half of the stance phase, compared muscle activity during the first half of the stance phase and the second half of the stance phase. In addition, the relationship between muscle activity during gaiting and each parameter was analyzed. [Results] All four muscles showed significantly higher values in the first half of the stance phase than in the second half of the stance phase. Rectus femoris first half of the stance phase muscle activity showed a moderate correlation with the BRS, BBS, and FMS scores. [Conclusion] The amount of gastrocnemius muscle activity when KAFO assists walking from behind increases in the latter half of stance in healthy individuals. However, in patients with stroke, the activity was lower and deviated from the gastrocnemius muscle activity during walking in healthy individuals.

Rehabilitation intervention safety in patients with malignant lymphoma with low blood cell counts.

[Purpose] We established criteria for patients with malignant lymphoma with low blood counts, who did not meet the criteria to discontinue rehabilitation or the blood transfusion criteria even though they were borderline for discontinuing rehabilitation. We investigated physical symptoms, activities of daily living, and adverse events in patients who were permitted to undergo rehabilitation intervention using the new criteria. [Participants and Methods] Forty-two patients met the criteria to discontinue rehabilitation based on blood data, and the new-criteria group included 153 patients who received permission for rehabilitation from a hematologist despite not meeting the criteria to discontinue rehabilitation. The survey items were Barthel index at the time of admission and discharge and the length of hospital stay. A two-group comparison was performed, and the occurrence of adverse events associated with exercise intervention were investigated. [Results] The length of hospital stay was shortened in the new-criteria group, and the rehabilitation intervention rate improved. [Conclusion] For patients with malignant lymphoma with low blood cell counts, continuing rehabilitation intervention with physician permission may prevent a decline in activities of daily living as well as maintain and improve motor function.

Factors associated with improvement in impaired consciousness during the acute phase of cerebral infarction: a prospective observational study.

[Purpose] In this study, we investigated factors that contribute to improvement in impaired consciousness following cerebral infarction. [Participants and Methods] This prospective observational study included 186 patients with cerebral infarction. We investigated 21 variables including the rehabilitation status to determine factors that contribute to improvement in impaired consciousness. [Results] Improvement in impaired consciousness was correlated with age, delirium, the Japan Coma Scale score at initiation of rehabilitation, worsening, cerebral edema, and standing practice. [Conclusion] We conclude that the aforementioned factors may serve as predictors of possible improvement and that standing practice may contribute to improvement in impaired consciousness.

Donor lymphocyte infusion after haploidentical hematopoietic stem cell transplantation for acute myeloid leukemia.

Although haploidentical donor lymphocyte infusion (DLI) is a valid treatment option for relapsed acute myeloid leukemia (AML), the incidence and risk factors for graft-versus-host disease (GVHD) and the efficacy of haploidentical DLI have not been fully evaluated. We retrospectively analyzed the outcomes after haploidentical DLI for 84 patients with AML using a nationwide database and additional questionnaires. The median number of DLI cycles and infused CD3+ cell dose was 1 and 1.0 × 106/kg, respectively. The infused CD3+ cell count of 5.0 × 105/kg or higher was associated with acute GVHD (grade II-IV, 32.1% vs. 10.5%, p = 0.03; grade III-IV, 21.4% vs. 5.3%, p = 0.10). Patients who developed grade III-IV acute GVHD more frequently succumbed to treatment-related mortality (46.7% vs. 15.8% at 1 year, p = 0.002), although the relapse-related mortality was significantly low (40.0% vs. 72.2% at 1 year, p = 0.025). The overall response to DLI was significantly higher in the preemptive DLI group (47.4%) than in the therapeutic group (13.9%, p = 0.002). In the multivariate analysis, preemptive DLI was the predictive factor for overall response (odds ratio, 5.58; p = 0.003). Our results indicated the substantial risk of acute GVHD after haploidentical DLI with CD3+ cell count of 5.0×105/kg or higher and the favorable outcomes after preemptive DLI.

Molecular Immunology in Hematological Disorders.

This Special Issue aims to highlight the molecular mechanisms involved in the development and progression of hematologic malignancies such as leukemia, lymphoma, and myeloma [...].

Anti-Diabetes, Anti-Gout, and Anti-Leukemia Properties of Essential Oils from Natural Spices Clausena indica, Zanthoxylum rhetsa, and Michelia tonkinensis.

Essential oils (EOs) of Clausena indica fruits, Zanthoxylum rhetsa fruits, and Michelia tonkinensis seeds were analyzed for their phytochemical profiles and biological activities, including anti-diabetes, anti-gout, and anti-leukemia properties. Sixty-six volatile compounds were identified by gas chromatography-mass spectrometry (GC-MS), in which, myristicin (68.3%), limonene (44.2%), and linalool (49.3%) were the most prominent components of EOs extracted from C. indica, Z. rhetsa, and M. tonkinensis, respectively. In addition, only EOs from C. indica inhibited the activities of all tested enzymes comprising α-amylase (IC50 = 7.73 mg/mL), α-glucosidase (IC50 = 0.84 mg/mL), and xanthine oxidase (IC50 = 0.88 mg/mL), which are related to type 2 diabetes and gout. Remarkably, all EOs from C. indica, Z. rhetsa (IC50 = 0.73 mg/mL), and M. tonkinensis (IC50 = 1.46 mg/mL) showed a stronger anti-α-glucosidase ability than acarbose (IC50 = 2.69 mg/mL), a known anti-diabetic agent. Moreover, the growth of leukemia cell Meg-01 was significantly suppressed by all EOs, of which, the IC50 values were recorded as 0.32, 0.64, and 0.31 mg/mL for EOs from C. indica, Z. rhetsa, and M. tonkinensis, respectively. As it stands, this is the first report about the inhibitory effects of EOs from C. indica and Z. rhetsa fruits, and M. tonkinensis seeds on the human leukemia cell line Meg-01 and key enzymes linked to diabetes and gout. In conclusion, the present study suggests that EOs from these natural spices may be promising candidates for pharmaceutical industries to develop nature-based drugs to treat diabetes mellitus or gout, as well as malignant hematological diseases such as leukemia.

Effects of In Vitro Digestion on Anti-α-Amylase and Cytotoxic Potentials of Sargassum spp.

This is the first study to examine the effects of in vitro digestion on biological activities of Sargassum spp., a broadly known brown seaweed for therapeutic potential. Three fractions (F1-F3) were obtained from hexane extract by column chromatography. Under in vitro simulated digestion, the anti-α-amylase capacity of F1 in oral and intestinal phases increases, while it significantly decreases in the gastric phase. The α-amylase inhibition of F2 promotes throughout all digestive stages while the activity of F3 significantly reduces. The cytotoxic activity of F1 against U266 cell-line accelerates over the oral, gastric, and intestinal stages. The fractions F2 and F3 exhibited the declined cytotoxic potentialities in oral and gastric phases, but they were strengthened under intestinal condition. Palmitic acid and fucosterol may play an active role in antidiabetic and cytotoxic activity against multiple myeloma U266 cell line of Sargassum spp. However, the involvement of other phytochemicals in the seaweed should be further investigated.

Cytotoxicity of Callerya speciosa Fractions against Myeloma and Lymphoma Cell Lines.

Callerya speciosa is widely distributed in tropical and subtropical countries and is traditionally used for preventing numerous disorders. In this study, a bioguided fractionation of ethyl acetate extract (SE) from C. speciosa root was carried out to target antioxidant and cytotoxic activities. Of the four fractions (SE1-SE4) obtained by column chromatography, SE4 had the strongest anti-radical ability in the DPPH and ABTS assays (IC50 = 0.05 and 0.17 mg/mL, respectively), with results close to butylated hydroxytoluene (BHT), a common antioxidant agent. The cytotoxic activities against the selected cells were analyzed in this study by MTT assay. Accordingly, SE2, SE3, and SE4 significantly inhibited the viability of multiple myeloma cell lines, comprising U266 (IC50 = 0.38, 0.09, and 0.11 mg/mL, respectively) and KMS11 (IC50 = 0.09, 0.17, and 0.15 mg/mL, respectively), mantle cell lymphoma Mino (IC50 = 0.08, 0.16, and 0.15 mg/mL, respectively), and the noncancerous cell line LCL (IC50 = 0.40, 0.32, and 0.21 mg/mL, respectively). At a concentration of 125 µg/mL, SE2, SE3, and SE4 induced the cell apoptosis of U266 (32.2%, 53.2%, and 55.6%, respectively), KMS11 (36.9%, 40.8%, and 47.9%, respectively), Mino (36.6%, 39.8%, and 22.0%, respectively), and LCL (12.4%, 17.5%, and 23.5%, respectively) via annexin V assay. The dominant compounds detected in fractions by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS), were identified as isoflavones. This is the first report describing C. speciosa as a promising natural source of antileukemia and antimyeloma agents, which may be useful for the development of blood cancer treatments.

Changes in cerebral blood flow before, during, and after forward and backward walking in stroke patients trained using virtual reality walking videos with deliberately induced inaccuracies in walking speed estimations.

[Purpose] The aim of this study was to examine the effects of virtual reality (VR) training, with deliberately induced inaccuracies in walking speed estimations, on brain activity. [Participants and Methods] The study participants were 21 stroke patients, and the walking tasks involved forward and backward walking. While the VR walking speed was set at 3 km/h, estimation errors were induced by using an actual walking speed of 1 km/h during the walking tasks. Cerebral blood flow was measured using two functional near-infrared spectroscopy (fNIRS) channels located over the left and right prefrontal cortices, to determine changes in oxyhemoglobin levels from the resting state. Cerebral hemodynamics were compared during and after the VR training. [Results] The backward walking task induced a significant increase in cerebral blood flow in the right prefrontal cortex during and after the VR training. No significant changes were observed during the forward walking task. [Conclusion] In the backward walking condition, greater activation of the right prefrontal cortex was observed during and immediately after the VR training. Watching VR may have led to inaccurate walking-speed estimations, necessitating postural control (which may be attributed to the activation of the prefrontal cortex) during walking.

Donor UNC-93 Homolog B1 genetic polymorphism predicts survival outcomes after unrelated bone marrow transplantation.

UNC-93 homolog B1 (UNC93B1) is a key regulator of toll-like receptors (TLRs), pattern recognition receptors that sense invading pathogens and manage the innate immune response and deliver them from the endoplasmic reticulum to their respective endosomal signaling compartments. Several types of TLRs are known to contribute to the inflammatory process after allogeneic hematopoietic stem cell transplantation (SCT), so UNC93B1 might play integral roles there. We investigated the influence of the UNC93B1 single-nucleotide polymorphism (SNP) rs308328 (T>C) on transplant outcomes in a cohort of 237 patients undergoing unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. The donor UNC93B1 C/C genotype was associated with a better 3-year overall survival than the donor UNC93B1 C/T or T/T genotype. An analysis of the UNC93B1 rs308328 genotype may therefore be useful for selecting the donor, estimating the prognosis, and creating therapeutic strategies after allogeneic SCT.

Pretreatment Immature Platelet Fraction as a Surrogate of Reticulated Platelets Predicts the Response to Corticosteroids in Adults with Immune Thrombocytopenia.

OBJECTIVES: Reticulated platelets circulating in the blood reflect megakaryopoietic activity and platelet turnover and can be automatically and low-invasively measured as the immature platelet fraction (IPF) using a Sysmex XN hematocytometer. The present study retrospectively investigated whether or not the IPF can predict the treatment response to corticosteroids in adult patients with primary immune thrombocytopenia (ITP). METHODS: Forty-six patients who had been newly diagnosed with primary treatment-naïve ITP and started treatment with corticosteroids were analyzed. RESULTS: Among the 46 primary ITP patients, 33 (72%) responded to the treatment and 13 (28%) did not. The percentage of IPF (IPF%) among the nonresponders was significantly lower than that of the responders (6.6 vs. 16.0%; p < 0.001). In the receiver operating characteristics analysis, the optimum IPF% cut-off value for predicting the treatment response was 12%, with a specificity of 85% and a sensitivity of 76%. CONCLUSIONS: Our findings thus suggest that measuring the IPF% as a surrogate of reticulated platelets is useful to identify patients likely to respond to corticosteroids.

The Impact of NLRP3 Activation on Hematopoietic Stem Cell Transplantation.

NLR family pyrin domain-containing 3 (NLRP3) is an intracellular protein that after recognizing a broad spectrum of stressors, such as microbial motifs and endogenous danger signals, promotes the activation and release of the pro-inflammatory cytokines IL-1ß and IL-18, thus playing an essential role in the innate immune response. Several blood cell types, including macrophages, dendritic cells, and hematopoietic stem and progenitor cells (HSPCs), express NLRP3, where it has been implicated in various physiological and pathological processes. For example, NLRP3 participates in the development and expansion of HSPCs, and their release from bone marrow into the peripheral blood has been implicated in certain hematological disorders including various types of leukemia. In addition, accumulating evidence indicates that activation of NLRP3 plays a pivotal role in the development of transplant complications in patients receiving hematopoietic stem cell transplantation (HSCT) including graft versus host disease, severe infections, and transplant-related mortality. The majority of these complications are triggered by the severe tissue damage derived from the conditioning regimens utilized in HSCT which, in turn, activates NLRP3 and, ultimately, promotes the release of proinflammatory cytokines such as IL-1ß and IL-18. Here, we summarize the implications of NLRP3 in HSCT with an emphasis on the involvement of this inflammasome component in transplant complications.

Synergistic Effects of Venetoclax and Daratumumab on Antibody-Dependent Cell-Mediated Natural Killer Cytotoxicity in Multiple Myeloma.

The prognosis of multiple myeloma (MM) has drastically improved owing to the development of new drugs, such as proteasome inhibitors and immunomodulatory drugs. Nevertheless, MM is an extremely challenging disease, and many patients are still refractory to the existing therapies, thus requiring new treatment alternatives. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 that shows efficacy in MM not only as a single agent but also in combination therapy, especially for MM patients with translocation t(11;14). However, many patients are refractory to this drug. Here, we treated the MM cell lines KMS12PE and KMS27 with a combination treatment of venetoclax targeting BCL-2 and daratumumab targeting CD38 to evaluate the synergistic cytotoxicity of these drugs in vitro. MM cell lines were co-cultured with natural killer (NK) cells at an effector:target ratio of 0.3:1 in the presence of serial concentrations of daratumumab and venetoclax, and the resulting apoptotic MM cells were detected by flow cytometry using annexin V. These results indicated that the antibody-dependent cell-mediated NK cytotoxicity was enhanced in KMS12PE and KMS27 cells harboring t(11;14) with a high BCL-2 expression, suggesting that the combination treatment of venetoclax and daratumumab should be especially effective in patients with these characteristics.

[Trace metals and anemia].

Various factors have led to anemia, including a deficiency or excess of trace metals. Copper deficiency, zinc deficiency and lead poisoning are of particular clinical importance. Among them, it should be noted that copper deficiency is increasing due to the use of zinc preparations and the generalization of gastric and intestinal nutrition.

Verification of spatial recognition ability of stroke patients required to resume automobile driving.

[Purpose] To help patients who had a stroke resume automobile driving, we evaluated their ability to recognize three-dimensional space like that experienced in actual driving situations, with a focus on sensing car width. [Participants and Methods] Seven patients who had a stroke and 29 healthy adults participated in the study. Three 50-cm-wide chairs and 2 panels, 3 m apart, were placed 9 m from the chair in which the participant sat. One panel was fixed and the other panel could be moved toward the fixed panel in a horizontal direction. The participants were asked to signal when they believed that the width of the chair was the same as the space between the panels. [Results] In the simulation of driving a real car, the mean error in judging distance was 13.2 ± 10.4 cm for the Healthy group and that of the Stroke group was two times greater than that of the Healthy group. [Conclusion] These findings show that spatial recognition cannot be evaluated using paper-based two-dimensional higher brain function tests. To help patients who had a stroke resume driving requires evaluation of three-dimensional spatial recognition ability under circumstances that simulate actual driving situations.

Immediate effect of video viewing with an illusion of walking at a faster speed using virtual reality on actual walking of stroke patients.

[Purpose] The objective of this study was to provide cerebral stroke patients with virtual reality videos of gait occurring at a faster speed than their actual measured gait speed and ascertain the effect on generating errors of gait. [Participants and Methods] The participants were 12 stroke patients. They were given a 2-minute virtual reality presentation of gait occurring at a speed faster than their actual measured comfortable walking speed. Immediately following the presentation, their 10-m walking speed was measured again to observe the immediate effect of the intervention, after which the time required to walk at maximum gait speed was measured. Stride length, cadence, and walking speed before and after the intervention were compared. In addition, heard an immersive feeling. [Results] At a comfortable walking speed, the cadence improved significantly post-intervention. Walking speed and stride length also tended to increase. At the maximum walking speed, there were no significant differences in any parameter. There was no problem with the immersive feeling. [Conclusion] After watching virtual reality videos of gait at a speed faster than the patients' actual gait speed, their walking speed tended to increase in comfortable walking. It was speculated that this technique could be applied to walking training, depending on the device.