[Association of Geriatric Nutritional Risk Index with Adverse Events and Time to Treatment Failure in Malignant Lymphoma Patients Treated with(R-)EPOCH].

To date, there are no reports that examine the relationship between geriatric nutritional risk index(GNRI)at the start of chemotherapy for malignant lymphoma and adverse effects. In this study, we investigated the relationship between GNRI at the start of chemotherapy and the incidence of side effects and time to treatment failure(TTF)in(R-)EPOCH-treated patients with relapsed or refractory malignant lymphoma. A significant difference in the incidence of Grade 3 or higher thrombocytopenia was observed between high and low GNRI groups(p=0.043). The GNRI may be an indicator of hematologic toxicity in malignant lymphoma patients treated with(R-)EPOCH. There was a statistically significant difference in TTF between the high and low GNRI groups(p=0.025), suggesting that nutritional status at the start of(R-)EPOCH may affect treatment continuation.

The efficacy and safety of reduced-dose sulfamethoxazole-trimethoprim for chemoprophylaxis of Pneumocystis pneumonia in patients with rheumatic diseases.

OBJECTIVES: Pneumocystis pneumonia (PCP) is a life-threatening opportunistic infection. Sulfamethoxazole-trimethoprim (SMX/TMP) is the first-line drug for PCP prophylaxis. However, adverse events (AEs) force clinicians to alter or reduce the drug dosage. METHODS: We retrospectively reviewed all patients with rheumatic diseases who received SMX/TMP for prophylaxis and glucocorticoid therapy between April 2004 and March 2018. The rates of AEs, SMX/TMP discontinuation, and incidence of PCP were analyzed. Patients were divided into the conventional group and the dose-reduction group. RESULTS: One hundred forty-five patients and 75 patients were included in the conventional group and the dose-reduction group, respectively. Compared to the dose-reduction group, the conventional group had a significantly high frequency of AEs (10.7% vs. 24.1%; p = .017); however, the rate of discontinuing SMX/TMP was not significantly different (8.0% vs. 14.5%; p = .165). Thirteen conventional group patients required a reduced SMX/TMP dose because of AEs; no patient developed PCP. The conventional SMX/TMP dose and renal dysfunction were associated with AEs in multivariate analysis. CONCLUSION: Patients who received a reduced SMX/TMP dose did not have PCP and had a lower frequency of AEs. A reduction in SMX/TMP for PCP prophylaxis is effective and safe in patients with rheumatic disease.

γ-Tocotrienol reduces human airway smooth muscle cell proliferation and migration.

AIMS: Vitamin E is an antioxidant that occurs in 8 different forms (α, ß, γ, and δ tocopherol and tocotrienol). Clinical trials of tocopherol supplementation to assess the impact of antioxidant activity in asthma have yielded equivocal results. Tocotrienol exhibits greater antioxidant activity than tocopherol in several biological phenomena in vivo and in vitro. We tested the effect of tocotrienol on human airway smooth muscle (ASM) cell growth and migration, both of which mediate airway remodeling in asthma. MAIN METHODS: We measured platelet-derived growth factor-BB (PDGF-BB)-induced ASM cell proliferation and migration by colorimetric and Transwell migration assays in the presence and absence of γ-tocotrienol (an isoform of tocotrienol). KEY FINDINGS: PDGF-BB-induced ASM cell proliferation and migration were inhibited by γ-tocotrienol. This effect was associated with inhibition of RhoA activation, but it had no effect on p42/p44 mitogen-activated protein kinase (MAPK) or Akt1 activation. We confirmed that pharmacological inhibition of Rho kinase activity was sufficient to inhibit PDGF-BB-induced ASM cell proliferation and migration. SIGNIFICANCE: γ-Tocotrienol could impart therapeutic benefits for airway remodeling in asthma by inhibiting human ASM cell proliferation and migration.

Tripod immobilization of triphenylphosphane on a silica-gel surface to enable selective mono-ligation to palladium: application to Suzuki-Miyaura cross-coupling reactions with chloroarenes.

A silica-supported triphenylphosphane (Silica-3p-TPP) with a Ph3P-type core, immobilized on a silica surface, was synthesized and characterized by nitrogen-absorption measurements and solid-state NMR spectroscopy. The tripodal immobilization constrains the mobility of the phosphane molecule and causes the lone pair on the phosphorus atom to face in the direction perpendicular to the support, resulting in the selective formation of a 1:1 metal-phosphane species that is free from unfavorable steric repulsions caused by the silica surface. Heterogeneous Pd catalysts created in this manner enabled room-temperature Suzuki-Miyaura cross-coupling reactions with unactivated chloroarenes, despite the moderate electronic and steric nature of the Ph3P-based ligands. These catalysts also showed potential in reactions with more challenging substrates under mild conditions. Tripodally immobilized and well-dispersed phosphanes on the silica surface were crucial for high catalytic activity.

Prognostic Value of Pretreatment Fetal Hemoglobin Levels in Patients with Myelodysplastic Syndromes and Acute Myeloid Leukemia Treated with Azacitidine: A Single-center Retrospective Study.

Objective Azacitidine (AZA) has been the standard of care for elderly patients with high-risk myelodysplastic syndromes (MDS). However, reliable clinical predictors of outcome have yet to be identified. The prognostic value of fetal hemoglobin (HbF) levels has been reported for decitabine therapy. We evaluated pretreatment HbF levels in AZA monotherapy as a prognostic marker in MDS/acute myeloid leukemia (AML). Methods This study included chemotherapy-naïve patients who had received seven-day treatment schedules of AZA and whose HbF levels were measured at the onset of treatment between March 2011 and July 2020. Patients were grouped into HbF-normal (<1.0%) or HbF-elevated (≥1.0%) groups. Responses were classified according to the International Working Group 2006 criteria. Patients Twenty-nine patients were included and classified as having either MDS (n=21), chronic myelomonocytic leukemia (n=5), myelodysplastic/myeloproliferative neoplasm unclassifiable (n=1), or AML with <30% marrow blasts (n=2) based on the World Health Organization 2016 diagnostic criteria. According to the revised International Prognostic Scoring System classification, 20/29 patients were at intermediate, high, or very high risk. Pretreatment HbF levels were elevated in 13/29 patients. Results The median follow-up duration was 13.0 (range 1.5-93.5) months. The HbF-elevated group was associated with a significantly higher hematologic improvement rate (76.9% vs. 25%, p=0.009) and better overall survival (median, 21.0 vs. 13.0 months, p=0.048) than the HbF-normal group. Conclusion These results suggest that elevated pretreatment HbF levels can predict better outcomes in patients with MDS/AML treated with AZA.

Exploring the association between asthma and chronic comorbidities: impact on clinical outcomes.

Asthma remains a significant global health challenge. While both the incidence and mortality rates have shown a decline, older individuals with asthma exhibit not just more severe symptoms but also demonstrate an elevated mortality rate. This phenomenon could be attributed to the presence of chronic comorbidities that exert an influence on clinical outcomes among adult patients with asthma. This review aims to present various aspects of asthma comprehensively, including the prevalence, incidence, mortality rates, and causes of death in adult patients with asthma. Additionally, this review delves into the impact of chronic comorbidities that contribute to the morbidity and mortality of patients with asthma on a global scale, encompassing conditions such as chronic kidney disease, diabetes mellitus, lung cancer, obesity, and cardiovascular disease, concerning asthma. Furthermore, the manuscript reviews the distinctions between asthma and asthma chronic obstructive pulmonary disease overlap and adds perspective on asthma as an occupational lung disease. Thus, this review aims to enhance clinicians' awareness of the significance of chronic comorbidities in the management of patients with asthma. It seeks to provide insights that contribute to a more comprehensive approach to managing patients with asthma who also have comorbid conditions.

Impact of obesity on airway remodeling in asthma: pathophysiological insights and clinical implications.

The prevalence of obesity among asthma patients has surged in recent years, posing a significant risk factor for uncontrolled asthma. Beyond its impact on asthma severity and patients' quality of life, obesity is associated with reduced lung function, increased asthma exacerbations, hospitalizations, heightened airway hyperresponsiveness, and elevated asthma-related mortality. Obesity may lead to metabolic dysfunction and immune dysregulation, fostering chronic inflammation characterized by increased pro-inflammatory mediators and adipocytokines, elevated reactive oxygen species, and reduced antioxidant activity. This chronic inflammation holds the potential to induce airway remodeling in individuals with asthma and obesity. Airway remodeling encompasses structural and pathological changes, involving alterations in the airway's epithelial and subepithelial layers, hyperplasia and hypertrophy of airway smooth muscle, and changes in airway vascularity. In individuals with asthma and obesity, airway remodeling may underlie heightened airway hyperresponsiveness and increased asthma severity, ultimately contributing to the development of persistent airflow limitation, declining lung function, and a potential increase in asthma-related mortality. Despite efforts to address the impact of obesity on asthma outcomes, the intricate mechanisms linking obesity to asthma pathophysiology, particularly concerning airway remodeling, remain incompletely understood. This comprehensive review discusses current research investigating the influence of obesity on airway remodeling, to enhance our understanding of obesity's role in the context of asthma airway remodeling.

ß-Tocotrienol Decreases PDGF-BB-Induced Proliferation and Migration of Human Airway Smooth Muscle Cells by Inhibiting RhoA and Reducing ROS Production.

BACKGROUND: Tocotrienols exhibit antioxidant and anti-inflammatory activities. RhoA, a small GTPase protein, plays a crucial role in regulating contractility in airway smooth muscle (ASM). Previous studies have demonstrated that γ-tocotrienols reduce ASM proliferation and migration by inhibiting the activation of RhoA. In this present study, we investigate the effect of another vitamin E isoform, ß-tocotrienols, on human ASM cell proliferation and migration stimulated by platelet-derived growth factor-BB (PDGF-BB). METHODS: Human ASM cells were pre-treated with ß-tocotrienol prior to being stimulated with PDGF-BB to induce ASM cell proliferation and migration. The proliferation and migration of PDGF-BB-induced human ASM cells were assessed using colorimetric and transwell migration assays. The intracellular ROS assay kit was employed to quantify reactive oxygen species (ROS) in human ASM cells. Additionally, we explored the effect of ß-tocotrienols on the signaling pathways involved in PDGF-BB-induced ASM proliferation and migration. RESULTS: ß-tocotrienol inhibited PDGF-BB-induced ASM cell proliferation and migration by reducing RhoA activation and ROS production. However, in this present study, ß-tocotrienol did not affect the signaling pathways associated with cyclin D1, phosphorylated Akt1, and ERK1/2. CONCLUSIONS: In conclusion, the inhibition of RhoA activation and ROS production by ß-tocotrienol, resulting in the reduction in human ASM proliferation and migration, suggests its potential as a treatment for asthma airway remodeling.

Efficacy, Safety, and Continuation of Biological Therapy in Older Patients with Asthma in a Real-World Setting: A Retrospective Observational Study.

Background: Major randomized clinical trials have shown that biological therapy can reduce the exacerbation rate and oral corticosteroid (OCS) dosage in patients with severe eosinophilic asthma. However, data on the continuation, efficacy, and safety of biological therapy in older patients with asthma are limited. Therefore, the aim of this study was to evaluate the differences in the continuation rate, efficacy, and safety of biological therapy between older (≥ 65 years) and younger (< 65 years) patients with asthma. Methods: In this single-center retrospective observational study, we collected clinical data of patients with asthma who were administered biological drugs such as omalizumab, mepolizumab, benralizumab, and dupilumab between April 2009 and August 2022. We comparatively analyzed the continuation, efficacy, and safety of biological therapy between older (age ≥ 65 years) and younger patient (age < 65 years) groups. The reasons for discontinuation or switching of biological drugs were also evaluated. Results: Sixty-two (31 older and 31 younger) patients were treated with 91 biologics during the observational period. The mean age of older patients was 74.3 ± 5.1 years and that of younger patients was 48.0 ± 14.0 years. The continuation rate of biological therapy was not significantly different between the groups. Social background was the most common reason for discontinuation of biological therapy in both groups, and insufficient effect was the most common reason for switching to biological drugs. Asthma exacerbations decreased in both groups within the first 12 months of biologic therapy. The dosage of OCS tended to decrease in the older group and significantly decrease in the younger group. Conclusion: Biologic therapy for older patients with asthma can be continued, with efficacy and safety similar to those in younger patients with asthma.

Pembrolizumab-induced asthma exacerbation with hypereosinophilia and elevated interleukin-5 in endometrial cancer: A case report.

Pembrolizumab is an anti-programmed cell death-1 (PD-1) antibody used to treat various cancer types. Treatments with such immune checkpoint inhibitors cause immune-related adverse events. However, airway inflammation caused by immune-related adverse events has rarely been reported. A 54-year-old woman with endometrial cancer experienced asthma exacerbation, and increased blood eosinophil counts 3 months after pembrolizumab administration. Although asthma exacerbation improved, the resumption of pembrolizumab caused the recurrence of dry cough and hypereosinophilia. The discontinuation of pembrolizumab improved her symptoms. Serum interleukin-5 levels increased during pembrolizumab treatment but decreased upon discontinuation. The blockade of PD-1 and its ligand may exacerbate asthma through eosinophilic inflammation.

Extrathoracic subclavian venipuncture by using only the J-type guidewire for permanent pacemaker electrode placement.

Extrathoracic subclavian/axillar venipuncture is an accepted method for implanting pacemaker leads. Although several procedures have been reported, no standard method has been established yet. We evaluated the usefulness of a method in which only J-type guidewires are used. Between August 2011 and November 2012, 33 patients (20 men and 13 women; age, 77.5 ± 10.3 years) underwent permanent pacemaker lead insertion by extrathoracic subclavian venipuncture at our hospital. Thirty-two of the patients underwent primary implantation, whereas 1 patient required an additional lead because of lead fracture. The guidewires were inserted from the cubital vein to the subclavian vein. After the pacemaker pockets were created, we set the X-ray projection in the ipsilateral anterior oblique view. The distal edge of the guidewire was positioned on the ventral side of the first rib on fluoroscopy. The needle tip was positioned within the Ushaped distal tip of the J-type guidewire. The needle was held parallel to the X-ray angle and advanced towards the first rib until the tip entered the subclavian vein. The guidewire was inserted through the cubital vein in 31 patients, and through the femoral vein in 2 patients. Using this method, we successfully performed subclavian venipunctures in all 33 patients (total, 60 punctures) without any complications. Extrathoracic subclavian venipuncture using only a J-type guidewire is an easy, safe, and economical method for pacemaker lead implantation.

Threefold cross-linked polystyrene-triphenylphosphane hybrids: mono-P-ligating behavior and catalytic applications for aryl chloride cross-coupling and C(sp(3))-H borylation.

Covalently bound polystyrene-phosphane hybrids were prepared by a method based on radical emulsion polymerization of styrenes in the presence of a tris(p-vinylphenyl)phosphane cross-linker. These hybrids favor mono-P-ligation to transition-metal complexes and are useful for challenging catalysis, such as Pd-catalyzed CC/CN couplings with unactivated chloroarenes and Ir- or Rh-catalyzed C(sp(3) )H borylations.

The Clinical Characteristics of Allergic Bronchopulmonary Mycosis Differ Among Pathogenic Fungi.

Background: Allergic bronchopulmonary mycosis (ABPM) occurs with fungi, other than Aspergillus fumigatus. However, the clinical characteristics of ABPM caused by non-Aspergillus species are unspecified. Methods: We retrospectively reviewed all patients with ABPM who visited to our hospital between April 2005 and December 2020. The causative fungi and clinical characteristics were analyzed. Patients were divided into the Aspergillus group and the non-Aspergillus group. Results: Fourteen patients and five patients were included in the Aspergillus group and the non-Aspergillus group, respectively. Compared to the Aspergillus group, the non-Aspergillus group had a significantly low serum immunoglobulin E level and low forced vital capacity. In addition, the non-Aspergillus group had a lower rate of the requirement for oral corticosteroid treatment and a low frequency of recurrence. Conclusion: Patients with non-Aspergillus ABPM had lower type 2 inflammation than did patients with allergic bronchopulmonary aspergillosis.

[A case of pulmonary sarcoidosis complicated with bronchial asthma that proved eosinophilic invasion].

A 33-year-old man complaining of cough admitted our hospital for examination of bilateral hilar and mediastinal lymphadenopathy. He diagnosed pulmonary sarcoidosis, because of elevation of serum angiotensin converting enzyme (ACE), epitheloid granuloma with noncaseating necrosis from transbronchial lung biopsy (TBLB) specimen, increasing of lymphocyte and elevation of the CD4/CD8 ratio in bronchoalveolar lavage fluid (BALF). Furthermore, eosinophil ratio in BALF was 3%, hyperplasia of goblet cell, eosinophilic invasion to bronchial epithelium, and thickened basal membrane were found in same biopsy specimen. He had mild reversible airway obstruction. He was diagnosed pulmonary sarcoidosis complicated with bronchial asthma. Sarcoidosis is characteristic of the T helper type 1 (Th1) mediated immune response, and bronchial asthma is characteristic of the Th2. This case histopathologically revealed that both Th1 mediated immune response and Th2 could be coexisted.

Neutrophils and Asthma.

Although eosinophilic inflammation is characteristic of asthma pathogenesis, neutrophilic inflammation is also marked, and eosinophils and neutrophils can coexist in some cases. Based on the proportion of sputum cell differentiation, asthma is classified into eosinophilic asthma, neutrophilic asthma, neutrophilic and eosinophilic asthma, and paucigranulocytic asthma. Classification by bronchoalveolar lavage is also performed. Eosinophilic asthma accounts for most severe asthma cases, but neutrophilic asthma or a mixture of the two types can also present a severe phenotype. Biomarkers for the diagnosis of neutrophilic asthma include sputum neutrophils, blood neutrophils, chitinase-3-like protein, and hydrogen sulfide in sputum and serum. Thymic stromal lymphoprotein (TSLP)/T-helper 17 pathways, bacterial colonization/microbiome, neutrophil extracellular traps, and activation of nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 pathways are involved in the pathophysiology of neutrophilic asthma and coexistence of obesity, gastroesophageal reflux disease, and habitual cigarette smoking have been associated with its pathogenesis. Thus, targeting neutrophilic asthma is important. Smoking cessation, neutrophil-targeting treatments, and biologics have been tested as treatments for severe asthma, but most clinical studies have not focused on neutrophilic asthma. Phosphodiesterase inhibitors, anti-TSLP antibodies, azithromycin, and anti-cholinergic agents are promising drugs for neutrophilic asthma. However, clinical research targeting neutrophilic inflammation is required to elucidate the optimal treatment.

Successful hematopoietic stem cell transplantation for two patients with relapse of intrachromosomal amplification of chromosome 21-positive B-cell precursor acute lymphoblastic leukemia.

In children with relapsed acute lymphoblastic leukemia (ALL), it is essential to identify patients in need of treatment intensification. Minimal residual disease (MRD)-based treatment stratification resulted in excellent survival in children with late relapsed B-cell precursor (BCP)-ALL. Chemotherapy alone produced a favorable outcome in patients with negative MRD after induction. The genetic abnormality also plays an important role in determining the prognosis and stratification for treatment. Intrachromosomal amplification of chromosome 21 (iAMP21) is associated with a poor outcome and a high risk for relapse, and there is no standard treatment after relapse. Herein, we present two patients with relapsed iAMP21-positive ALL who were successfully treated by cord blood transplantation (CBT). Although both patients had late bone marrow relapse and favorable MRD response, CBT was performed due to iAMP21 positive. Patients 1 and 2 have been in remission post-CBT for 15 and 45 months, respectively. Patients with relapsed iAMP21-positive ALL may be considered for stem cell transplantation even in late relapses and favorable MRD response.

Specialized Pro-Resolving Mediators Do Not Inhibit the Synthesis of Inflammatory Mediators Induced by Tumor Necrosis Factor-α in Synovial Fibroblasts.

Background: Tumor necrosis factor (TNF)-α, a proinflammatory cytokine, is involved in the pathogenesis of rheumatoid arthritis (RA). The omega-3 unsaturated fatty acid-derived metabolites resolvin (Rv) D1, RvE1, and maresin-1 (MaR1) have been reported as anti-inflammatory lipid mediators and are known as specialized pro-resolving mediators (SPMs). In this study, we aimed to investigate the anti-inflammatory effects of SPMs on TNF-α-induced responses in synovial fibroblasts. Methods: We investigated the effects of SPMs on gene expression and/or production of cyclooxygenase-2 (COX-2), microsomal prostaglandin E synthase-1 (mPGES-1), interleukin (IL)-6, and matrix metalloproteinase (MMP)-3, which are involved in TNF-α-induced synovitis in RA or OA synovial fibroblasts, by quantitative real-time PCR. We also investigated the effects of SPMs on the mitogen-activated protein kinase (MAPK) signaling pathway by western blotting. Anti-inflammatory effects of SPMs were evaluated by applying SPMs to cultured synovial fibroblasts, followed by TNF-α stimulation. Results: The induction of COX-2, mPGES-1, IL-6, and MMP-3 by TNF-α in synovial fibroblasts was not suppressed by omega 3-derived SPMs regardless of their origin such as RA or OA. SPMs had no effect on lipid mediator receptor gene expression induce by TNF-α and did not inhibit the TNF-α-activated MAPK signaling pathway. The production of COX-2 and IL-6 protein was significantly decreased by p38 inhibitor. Conclusion: Despite reports on the anti-inflammatory effect of omega 3-derived SPMs, its anti-inflammatory effect on TNF-α-induced responses was not observed in synovial fibroblasts. The reason may be that SPMs have no suppressive effect on p38 activation, which plays an important role in the production of inflammatory cytokines in synovial fibroblasts.

Hairy Cell Leukemia-Japanese Variant: Report of a Patient and Literature Review.

Hairy cell leukemia-Japanese variant (HCL-jv) shares some features with, but differs in other features from, HCL variant. Recently, it has been pointed out that HCL-jv and splenic diffuse red pulp small B-cell lymphoma (SDRPL) possibly constitute the same disease. We report a patient with HCL-jv, in which the neoplastic cells in the resected spleen were positive for CD11c, CD103, tartrate-resistant acid phosphatase (by immunohistochemistry), and weakly positive for cyclin D3. They were negative for CD25, CD123, annexin A1, and BRAF V600E-derived protein. Meta-analysis of HCL-jv cases in the literature showed considerable variation in the expression of HCL-related molecules. Although the clinical features and pattern of splenic involvement of HCL-jv are similar to those of SDRPL, some cytomorphological and phenotypical differences can be pointed out. To confirm whether the weak expression of cyclin D3 in our case suggests a spectrum from HCL-jv to SDRPL or one of the characteristics of HCL-jv, further studies on a large number of cases are necessary.