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Cell Transplantation 2024Chronic graft-versus-host disease (cGVHD) is a potentially life-threatening complication after allogeneic hematopoietic stem cell transplantation. Standard steroid...
Chronic graft-versus-host disease (cGVHD) is a potentially life-threatening complication after allogeneic hematopoietic stem cell transplantation. Standard steroid first-line treatment could not satisfy therapeutic needs due to limited efficacy. As a highly selective Janus kinase (JAK) 1 inhibitor, SHR0302 exhibits a reduced inhibition effect on JAK2 and might have less effect on hematopoiesis. This phase I clinical trial investigated the tolerability and safety of SHR0302 in combination with prednisone, and its early efficacy evidence as a potential first-line treatment to moderate/severe cGVHD. The standard 3 + 3 dose escalation was implemented to find the optimal dose of SHR0302. And prednisone was concurrently administrated with a dose of 1 mg/kg/d and then gradually tapered after 2 weeks. Eighteen patients were enrolled into the study. Grade ≥ 3 treatment-related adverse events were observed in 38.9% of patients. Only one patient developed DLT (grade ≥ 3 hypercholesterolemia) in the highest dose-level group who had pre-existing hypercholesterolemia. The maximum tolerated dose was not reached. No patient discontinued treatment due to AEs. Sixteen out of 18 patients were evaluable for responses, the ORR at week 4 and week 24 were 94.4 and 87.5%, respectively. Overall, the treatment of SHR0302 combined with prednisone was safe and well-tolerated, preliminary clinical results presented a high response for previously untreated cGVHD and a significant reduction in prednisone use in this study. A phase II trial will be conducted to further investigate its therapeutic effects clinically.
Topics: Humans; Graft vs Host Disease; Prednisone; Male; Female; Adult; Middle Aged; Janus Kinase 1; Chronic Disease; Young Adult; Hematopoietic Stem Cell Transplantation; Aged; Drug Therapy, Combination; Bronchiolitis Obliterans Syndrome
PubMed: 38798038
DOI: 10.1177/09636897241254678 -
Medicina (Kaunas, Lithuania) Apr 2024Ocular adnexa region (OAR) primary lymphomas are uncommon, accounting for 1-2% of non-Hodgkin lymphomas and 8% of extranodal lymphomas. Extranodal marginal zone lymphoma...
Ocular adnexa region (OAR) primary lymphomas are uncommon, accounting for 1-2% of non-Hodgkin lymphomas and 8% of extranodal lymphomas. Extranodal marginal zone lymphoma (EMZL) originates from several epithelial tissues, including the stomach, salivary gland, lung, small intestine, thyroid gland, and ocular adnexa region. Here, we report a 66-year-old female patient who was diagnosed with EMZL of OAR. In consideration of the possible side effect of radiotherapy, such as conjunctivitis, visual acuity impairment, and even retinal complications, she received six cycles of triweekly targeted chemotherapy with rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) without radiotherapy. Then, she remained in complete remission up to the present day.
Topics: Humans; Female; Aged; Lymphoma, B-Cell, Marginal Zone; Orbital Neoplasms; Rituximab; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38792889
DOI: 10.3390/medicina60050706 -
Biomedicines Apr 2024Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder identified by hematological abnormalities including anemia, leukopenia, and thrombocytopenia....
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder identified by hematological abnormalities including anemia, leukopenia, and thrombocytopenia. Complement system disturbance is implicated in the pathogenesis of SLE. In this work, we aim to study how a full assessment of the complement system, which includes the evaluation of its three pathways, relates to blood cell counts in a population of patients with SLE. New-generation functional assays of the classical, alternative, and lectin pathways of the complement system were conducted in 284 patients with SLE. Additionally, serum levels of inactive molecules (C1q, C2, C3, C4, factor D) and activated molecules (C3a), as well as regulators (C1-inhibitor and factor H), were evaluated. Complete blood cell counts were analyzed. Multivariable linear regression analysis was performed to study the relationship of hematological profiles with this full characterization of the complement system. After multivariable adjustments that included age, sex, SLICC-DI (damage), and SLEDAI (activity) scores, as well as the use of aspirin, prednisone, methotrexate, azathioprine, and mycophenolate mofetil, several relationships were observed between the C pathways and the individual products and blood cells profile. Lower values of C1q and C2 were associated with lower hemoglobin levels. Lower leukocyte counts showed significantly lower values of C4, C1 inhibitor, C3, factor D, and alternative pathway functional levels. Neutrophil counts showed significant negative relationships only with the alternative pathway and C1-inh. In the case of lymphocytes, associations were found, especially with functional tests of the classical and alternative pathways, as well as with C2, C4, C3, and C3a. On the contrary, for platelets, significance was only observed, after multivariable adjustment, with lower C2 concentrations. In conclusion, the serum complement system and hematological profile in SLE are independently linked, after adjustment for disease activity and damage. These relationships are basically negative and are predominantly found in lymphocytes.
PubMed: 38790929
DOI: 10.3390/biomedicines12050967 -
Current Issues in Molecular Biology May 2024The proto-oncogene MYC is frequently dysregulated in patients with diffuse large B-cell lymphoma (DLBCL) and plays a critical role in disease progression. To improve the...
The proto-oncogene MYC is frequently dysregulated in patients with diffuse large B-cell lymphoma (DLBCL) and plays a critical role in disease progression. To improve the clinical outcomes of patients with DLBCL, the development of strategies to target MYC is crucial. The use of medicinal plants for developing anticancer drugs has garnered considerable attention owing to their diverse mechanisms of action. In this study, 100 plant extracts of flora from the Republic of Korea were screened to search for novel agents with anti-DLBCL effects. Among them, (Nakai) K. Bremer and Humphries extract (APKH) efficiently suppressed the survival of DLBCL cells, while showing minimal toxicity toward normal murine bone marrow cells. APKH suppressed the expression of anti-apoptotic BCL2 family members, causing an imbalance between the pro-apoptotic and anti-apoptotic BCL2 members. This disrupted mitochondrial membrane potential, cytochrome c release, and pro-caspase-3 activation and eventually led to DLBCL cell death. Importantly, MYC expression was markedly downregulated by APKH and ectopic expression of MYC in DLBCL cells abolished the pro-apoptotic effects of APKH. These results demonstrate that APKH exerts anti-DLBCL effects by inhibiting MYC expression. Moreover, when combined with doxorubicin, an essential component of the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone), APKH synergistically enhanced the therapeutic effect of doxorubicin. This indicates that APKH may overcome drug resistance, which is common in patients with refractory/relapsed DLBCL. To identify compounds with anti-DLBCL activities in APKH, the chemical profile analysis of APKH was performed using UPLC-QTOF/MS analysis and assessed for its anticancer activity. Based on the UPLC-QTOF/MS chemical profiling, it is conceivable that APKH may serve as a novel agent targeting MYC and sensitizing drug-resistant DLBCL cells to CHOP chemotherapy. Further studies to elucidate how the compounds in APKH exert tumor-suppressive role in DLBCL are warranted.
PubMed: 38785546
DOI: 10.3390/cimb46050278 -
Cureus Apr 2024The current pharmaceutical management of myasthenia gravis (MG) is widely accepted to be pyridostigmine and prednisone, both known to cause adverse effects and incur...
The current pharmaceutical management of myasthenia gravis (MG) is widely accepted to be pyridostigmine and prednisone, both known to cause adverse effects and incur significant costs. This treatment may be particularly burdensome for patients primarily complaining of localized ocular MG, and little is known about the management of MG ptosis with topical medications. Oxymetazoline hydrochloride 0.1% ophthalmic solution has recently been approved by the FDA for the treatment of ptosis, but there have been limited studies in MG ptosis and no report to date of symptomatic improvement with the intranasal formulation. This case report discusses a 71-year-old female whose newly diagnosed MG ptosis resolved after three days of intranasal oxymetazoline hydrochloride 0.05%, followed by three days of intranasal flunisolide. Our patient's rapid resolution of symptoms, along with the favorable side effect profile and over-the-counter availability, highlights the promising indication for the use of intranasal oxymetazoline and flunisolide as potential alternatives or adjuncts in MG management. Further research in larger cohorts is necessary to confirm the efficacy of these nasal sprays in treating MG ptosis.
PubMed: 38784340
DOI: 10.7759/cureus.58812 -
Cureus Apr 2024Eculizumab is a biologic medication used for the treatment of complement-related disorders including anti-acetylcholine receptor antibody-positive generalized myasthenia...
Eculizumab is a biologic medication used for the treatment of complement-related disorders including anti-acetylcholine receptor antibody-positive generalized myasthenia gravis. It targets C5 complement, preventing its cleavage into active terminal components. Thus, vaccination against encapsulated organisms is advised before starting this treatment. C5 also has a critical role against infection. Here, we present a case of a 34-year-old man with a history of myasthenia gravis who was treated with prednisone and azathioprine in addition to eculizumab that was added to his regimen about a year ago, and who came to the hospital with headache, and was found to have Cryptococcus meningitis with disseminated cryptococcosis. The patient was negative for human immunodeficiency virus. He was treated with antifungal medications, and his condition improved. Although rarely reported, it is important to have a low threshold for diagnosis of cryptococcosis in patients on eculizumab given its complement inhibition mechanism of action.
PubMed: 38784297
DOI: 10.7759/cureus.58852 -
BMC Neurology May 2024Ectopic cervical thymoma (ECT) is an extremely rare tumor, especially in association with myasthenia gravis (MG).
BACKGROUND
Ectopic cervical thymoma (ECT) is an extremely rare tumor, especially in association with myasthenia gravis (MG).
CASE PRESENTATION
We report a case of myasthenia gravis with an ectopic thymoma in the neck, whose myasthenic symptoms significantly improved after complete removal of the mass. A 55-year-old woman with generalized myasthenia gravis (MG) experienced worsening neuromuscular weakness after abruptly discontinuing pyridostigmine. Testing revealed acetylcholine receptor-antibody (AChR-Ab) positivity and a cervical mass initially thought to be thyroid or parathyroid was identified as a thymoma, type A. Post-surgery and radiation therapy, her myasthenic symptoms improved significantly with less prednisone and pyridostigmine requirements over time and no need for additional immunotherapies.
CONCLUSIONS
Diagnosing ECTs is challenging due to rarity, atypical locations, and inconclusive fine needle aspiration cytology (FNAC) results, often misinterpreted as thyroid or parathyroid lesions. As proper management of patients with MG, including thymectomy, offers favorable clinical outcomes such as significant improvement in myasthenic complaints and reduced immunosuppressive medication requirements, clinicians should be vigilant of the ectopic locations of thymomas to ensure timely diagnosis and intervention.
Topics: Humans; Female; Myasthenia Gravis; Middle Aged; Thymoma; Thymus Neoplasms; Choristoma
PubMed: 38783232
DOI: 10.1186/s12883-024-03656-6 -
Pulmonary Therapy May 2024The presence of antibiotic allergy labels can have harmful impacts on clinical outcomes, particularly among immunosuppressed patients, in whom there have been...
INTRODUCTION
The presence of antibiotic allergy labels can have harmful impacts on clinical outcomes, particularly among immunosuppressed patients, in whom there have been associations with increased complications, readmission rates, and mortality. We explore the effects of a sulfonamide allergy label (SAL) on clinical outcomes in adult patients with Pneumocystis jirovecii pneumonia (PJP).
METHODS
In this retrospective matched cohort study, we utilized TriNetX, a multicenter national database, to match 535 adult patients with PJP and SAL to an equal number of controls. We identified cases indexed between 01/01/2010 and 01/01/2023 utilizing ICD-10 codes for PJP and allergy status to sulfonamides and through detection of P. jirovecii antigen with immunofluorescence or PCR. Propensity score matching was performed in a 1:1 fashion for demographics and comorbidities, and our analysis included clinical outcomes that occurred within 30 days after the occurrence of the index event.
RESULTS
While hospitalization risk tended to be lower among patients with SAL as compared to controls (RR: 0.90; 95% CI 0.81-1.01), there were no major differences in the risk of respiratory failure (RR: 0.94; 95% CI 0.84-1.05), prednisone use (RR: 1; 95% CI 0.91-1.10), intensive level of care requirement (RR: 0.85; 95% CI 0.69-1.06), intubation (RR: 0.85; 95% CI 0.61-1.19), or mortality (RR: 0.98; 95% CI 0.68-1.42). The presence of SAL did however impact antibiotic prescription patterns, with an underutilization of trimethoprim (RR: 0.50; 95% CI 0.43-0.59) and sulfamethoxazole (RR, 0.47; 95% CI 0.40-0.56) and overuse of alternative agents by patients with SAL as compared to controls. Yet, there was no difference in the occurrence of adverse outcomes such as hepatotoxicity (RR: 1.09; 95% CI 0.49-2.45) or acute kidney injury (RR: 0.94; 95% CI 0.78-1.14) between patients with SAL and controls.
CONCLUSIONS
The presence of SAL alters antibiotic prescription patterns among adults with Pneumocystis infection but has no clinically significant impact on outcomes.
PubMed: 38782820
DOI: 10.1007/s41030-024-00260-4 -
Cureus Apr 2024Hypersensitivity pneumonitis (HP) is a pulmonary disease characterized by inflammation and fibrosis of the lung parenchyma following chronic exposure to immunogenic...
Hypersensitivity pneumonitis (HP) is a pulmonary disease characterized by inflammation and fibrosis of the lung parenchyma following chronic exposure to immunogenic antigens. The pathophysiology of HP involves type 3 and type 4 hypersensitivity reactions leading to acute and chronic manifestations, respectively. Clinically, it manifests as exertional dyspnea and wheezing. Pulmonary function tests display a pattern of restrictive lung disease, and high-resolution CT scans display a pattern of ground glass opacities, centrilobular nodules, and mosaic attenuation. Antigen avoidance remains the only method for primary prevention. Alternative therapy may be needed due to either the inability to avoid antigens or the lack of antigen identification. Prednisone 0.5 mg/kg per day is the first-line treatment for acute non-fibrotic forms of HP. In chronic or fibrotic HP, the immunomodulator mycophenolate mofetil (MMF) was shown to be an effective treatment in improving the diffusing capacity of the lungs for carbon monoxide and forced vital capacity, but not overall survival. The following study aims to bring to attention the need for additional prospective multicenter clinical trials to clarify the role of MMF as an immunomodulator in fibrosing HP.
PubMed: 38779275
DOI: 10.7759/cureus.58723 -
Clinical Epigenetics May 2024Large B-cell lymphoma (LBCL) is the most common lymphoma and is known to be a biologically heterogeneous disease regarding genetic, phenotypic, and clinical features....
BACKGROUND
Large B-cell lymphoma (LBCL) is the most common lymphoma and is known to be a biologically heterogeneous disease regarding genetic, phenotypic, and clinical features. Although the prognosis is good, one-third has a primary refractory or relapsing disease which underscores the importance of developing predictive biological markers capable of identifying high- and low-risk patients. DNA methylation (DNAm) and telomere maintenance alterations are hallmarks of cancer and aging. Both these alterations may contribute to the heterogeneity of the disease, and potentially influence the prognosis of LBCL.
RESULTS
We studied the DNAm profiles (Infinium MethylationEPIC BeadChip) and relative telomere lengths (RTL) with qPCR of 93 LBCL cases: Diffuse large B-cell lymphoma not otherwise specified (DLBCL, n = 66), High-grade B-cell lymphoma (n = 7), Primary CNS lymphoma (n = 8), and transformation of indolent B-cell lymphoma (n = 12). There was a substantial methylation heterogeneity in DLBCL and other LBCL entities compared to normal cells and other B-cell neoplasms. LBCL cases had a particularly aberrant semimethylated pattern (0.15 ≤ β ≤ 0.8) with large intertumor variation and overall low hypermethylation (β > 0.8). DNAm patterns could not be used to distinguish between germinal center B-cell-like (GC) and non-GC DLBCL cases. In cases treated with R-CHOP-like regimens, a high percentage of global hypomethylation (β < 0.15) was in multivariable analysis associated with worse disease-specific survival (DSS) (HR 6.920, 95% CI 1.499-31.943) and progression-free survival (PFS) (HR 4.923, 95% CI 1.286-18.849) in DLBCL and with worse DSS (HR 5.147, 95% CI 1.239-21.388) in LBCL. These cases with a high percentage of global hypomethylation also had a higher degree of CpG island methylation, including islands in promoter-associated regions, than the cases with less hypomethylation. Additionally, telomere length was heterogenous in LBCL, with a subset of the DLBCL-GC cases accounting for the longest RTL. Short RTL was independently associated with worse DSS (HR 6.011, 95% CI 1.319-27.397) and PFS (HR 4.689, 95% CI 1.102-19.963) in LBCL treated with R-CHOP-like regimens.
CONCLUSION
We hypothesize that subclones with high global hypomethylation and hypermethylated CpG islands could have advantages in tumor progression, e.g. by inactivating tumor suppressor genes or promoting treatment resistance. Our findings suggest that cases with high global hypomethylation and thus poor prognosis could be candidates for alternative treatment regimens including hypomethylating drugs.
Topics: Humans; Lymphoma, Large B-Cell, Diffuse; DNA Methylation; Female; Male; Prognosis; Middle Aged; Aged; Adult; Rituximab; Aged, 80 and over; Cyclophosphamide; Doxorubicin; Vincristine; Prednisone; Telomere; Antineoplastic Combined Chemotherapy Protocols; Telomere Shortening; Epigenesis, Genetic; CpG Islands
PubMed: 38773655
DOI: 10.1186/s13148-024-01680-4