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Steroids Jun 2024Occupancy of prostate cancer (PCa) cell androgen receptors (AR) signals proliferation, therefore testosterone biosynthesis inhibitors and AR antagonists are important...
In silico studies on the molecular interactions of steroid hormones and steroid hormone mimicking drugs in the androgen receptor binding cleft - Implications for prostate cancer treatment.
Occupancy of prostate cancer (PCa) cell androgen receptors (AR) signals proliferation, therefore testosterone biosynthesis inhibitors and AR antagonists are important PCa treatments. Conversely, androgen mimics (e.g., prednisone) used in management of PCa might cause proliferation. The balance between PCa proliferation and inhibition predicts treatment success. We used in silico molecular modelling to explore interactions between ARs, androgens (testosterone, dihydrotestosterone (DHT)) and drugs used to treat (bicalutamide) and manage (dexamethasone, prednisone, hydrocortisone) PCa. We found that hydrogen (H-) bonds between testosterone, DHT and Arg752, Asn705 and Thr877 followed by ligand binding cleft hydrophobic interactions signal proliferation, whereas bicalutamide antagonism is via Phe764 interactions. Hydrocortisone, dexamethasone and prednisone H-bond Asn705 and Thr877, but not Arg752 in the absence of a water molecule. Studies with a bicalutamide agonist AR mutation showed different amino acid interactions, indicating testosterone and DHT would not promote proliferation as effectively as via the native receptor. However, hydrocortisone and bicalutamide form Arg752 and Asn705 H-bonds indicating agonism. Our results suggest that as PCa progresses the resulting mutations will change the proliferative response to androgens and their drug mimics, which have implications for the treatment of prostate cancer.
PubMed: 38889811
DOI: 10.1016/j.steroids.2024.109456 -
The Oncologist Jun 2024Immune checkpoint inhibitors (ICIs) have revolutionized cancer care with incredible reductions in mortality. One of the most devastating complications of treatment is...
BACKGROUND
Immune checkpoint inhibitors (ICIs) have revolutionized cancer care with incredible reductions in mortality. One of the most devastating complications of treatment is ICI-related pneumonitis (ICI-p). Despite this, little is known regarding risk factors for severe pneumonitis and treatment effectiveness of various therapeutic options for steroid-refractory disease. To address this, we conducted a retrospective study on patients with cancer who developed ICI-p.
METHODS
We examined consecutive patients who received ICIs and developed ICI-p. Risk factors of interest for severe disease and steroid-refractory ICI-p, including pre-treatment pulmonary function tests (PFTs) and chest imaging, were compared between patients with severe (grades 3-5) and mild (grades 1-2) pneumonitis. The clinical and treatment courses for patients with steroid-refractory ICI-p were recorded.
RESULTS
A total of 132 patients developed ICI-p, with 60 patients having mild and 72 with severe disease. We found that lower forced vital capacity percent predicted (66.24 vs 85.05, P = .05), lower total lung capacity percent predicted (85.23 vs 99.71, P = .13), and specific radiographic patterns on pre-treatment chest imaging were predictors of severe disease. Initial corticosteroid dose of less than 1 milligram per kilogram prednisone equivalent (P = .14) was correlated with partially steroid-responsive or steroid-refractory ICI-p. Ten patients had steroid refractory ICI-p, and those who received IVIG alone as the immune suppressant beyond corticosteroids had improved survival (P = 05).
CONCLUSIONS
We are the first to identify pre-treatment PFTs and chest imaging abnormalities as risk factors for severe ICI-p. We also found that lower corticosteroid doses were associated with partially steroid-responsive and steroid-refractory ICI-p. Larger, prospective studies are needed to validate our results.
PubMed: 38886156
DOI: 10.1093/oncolo/oyae147 -
The New England Journal of Medicine Jun 2024
Topics: Humans; Male; Bone Marrow; Histiocytosis, Non-Langerhans-Cell; Adult; Prednisone; Hydroxychloroquine; Methotrexate; Skin; Biopsy; Antirheumatic Agents
PubMed: 38884326
DOI: 10.1056/NEJMicm2313532 -
Clinical Case Reports Jun 2024Vincristine therapy can be effective in refractory Immune thrombocytopenia (ITP) following COVID-19 vaccination. Our case report highlights the need for further research...
KEY CLINICAL MESSAGE
Vincristine therapy can be effective in refractory Immune thrombocytopenia (ITP) following COVID-19 vaccination. Our case report highlights the need for further research to establish standard management guidelines for COVID-19-vaccine-associated ITP.
ABSTRACT
Adult immune thrombocytopenia (ITP) can occur as a rare complication following several viral infections or a rare adverse event or complication of vaccination. In this paper, we report a case of a 39-year-old male patient with severe refractory ITP that began 4-weeks after receiving his third (booster) dose of the COVID-19 vaccine (BNT162b2, Pfizer-BioNTech). He was given oral dexamethasone 40 mg daily for 4 days followed by prednisone at 1 mg/kg (85 mg daily) for 10 days. In the following weeks, we attempted several other lines of therapy to treat his ITP, including anti-RhD immunoglobulin, which, unfortunately, caused moderate hemolysis requiring packed red blood cell transfusion, intravenous immunoglobulin (given at a subtherapeutic dose of 0.4 g/kg for only 1 day since it was not available), rituximab, and eltrombopag. The patient, unfortunately, showed no response to any of these treatments. This was an indicator to initiate salvage therapy with vincristine 2 mg weekly for 3 weeks. The patient's platelet count started to increase remarkably during the third week of vincristine and normalized after 4 weeks. We review the findings, clinical characteristics, and management approaches that were reported in the literature regarding COVID-19-vaccine-induced ITP. More in-depth research is needed to delineate standard guidelines for the management of such cases. This report underscores the importance of resorting to vincristine and eltrombopag as great options for severe and refractory ITP related to the COVID-19 vaccine.
PubMed: 38883219
DOI: 10.1002/ccr3.9070 -
Cureus May 2024A 75-year-old woman, with hypertension and atrial fibrillation but no prior renal history, presented to the hospital for chest discomfort and dyspnea. She was found to...
A 75-year-old woman, with hypertension and atrial fibrillation but no prior renal history, presented to the hospital for chest discomfort and dyspnea. She was found to be in acute renal failure, with a serum creatinine of 5.1, increased from a baseline of 0.9, and urine analysis revealing proteinuria and hematuria with dysmorphic red blood cells. Subsequent work up was significant for positive perinuclear antineutrophil cytoplasmic antibody (p-ANCA) and myeloperoxidase antibodies. She underwent a renal biopsy, which revealed necrotizing crescents in 12 of 14 glomeruli, and she was diagnosed with rapidly progressive glomerulonephritis due to microscopic polyangiitis. Despite aggressive treatment with plasmapheresis, high-dose prednisone, and rituximab infusions, renal function worsened, and she required initiation of hemodialysis. She was ultimately discharged after a three-week admission, with plans to continue rituximab infusions and three times weekly hemodialysis in the outpatient setting. Due to her poor response to traditional therapies, initiation of a new targeted immunomodulator known as avacopan, a complement 5a receptor antagonist, was considered. Such targeted immunomodulators are also of particular interest as possible ways to reduce the risk of severe infection associated with current broad immunosuppressive modalities. In addition, when used in place of steroids, they reduce the morbidity associated with cumulative glucocorticoid toxicity. For patients with ANCA-associated vasculitis refractory to standard therapies, targeted immunomodulators such as avacopan should be considered as alternative or adjunct therapy.
PubMed: 38883118
DOI: 10.7759/cureus.60366 -
SAGE Open Medical Case Reports 2024Atopic dermatitis is a chronic inflammatory skin disease that may progress to erythroderma in severe cases. Biologic agents such as dupilumab have recently become the...
Atopic dermatitis is a chronic inflammatory skin disease that may progress to erythroderma in severe cases. Biologic agents such as dupilumab have recently become the mainstay of systemic treatment for moderate-to-severe cases, yet many patients remain refractory to therapy. Here, we present a case of erythrodermic atopic dermatitis, resistant to prednisone and dupilumab, with remarkably rapid achievement of remission following treatment with upadacitinib, an oral selective Janus kinase 1 inhibitor.
PubMed: 38881978
DOI: 10.1177/2050313X241260497 -
Translational Cancer Research May 2024Programmed cell death-1 (PD-1) inhibitors and anti-angiogenic drugs have become a hotspot in research of anti-tumor programs; however, they can also cause some rare...
BACKGROUND
Programmed cell death-1 (PD-1) inhibitors and anti-angiogenic drugs have become a hotspot in research of anti-tumor programs; however, they can also cause some rare drug-related adverse reactions. Immune checkpoint inhibitors (ICIs) cause adverse reactions in the body, collectively known as immune-related adverse events (irAEs). Ocular side effects can occur in both targeted and immunotherapy patients, including dry eye, blurred vision, uveitis, conjunctivitis, retinopathy, or thyroid eye disease. To our knowledge, this is the first case report describing corneal ulcers secondary to dry eye in a patient treated with the combination of PD-1 inhibitor sintilimab and multi-targeted receptor tyrosine kinase inhibitor (TKI) anlotinib.
CASE DESCRIPTION
A 65-year-old woman with non-small cell lung cancer (NSCLC) and bone metastases, without pre-existing ocular conditions, experienced mild dry eye symptoms 1 month following treatment with sintilimab (200 mg q3w) in combination with anlotinib (12 mg q3w). Unrelieved dry eye symptoms occurred after the third cycle of chemotherapy, and she was diagnosed with dry eye syndrome. Subsequently, she received corneal protective lens, sodium hyaluronate eye drops, and prednisone treatment. Her corneal epithelial damage did not improve significantly, and within the following 2 months, her vision decreased in both eyes and progressed to bilateral corneal ulcers. Oral administration of sintilimab and anlotinib was interrupted, and treatments such as corticosteroids, anti-inflammatory drugs, and corneal repair were administered; however, both eyes presented with corneal subepithelial defect and corneal scarring. Due to a shortage of donors, no corneal transplantation surgery could be performed.
CONCLUSIONS
The development of corneal epithelial disorders in patients receiving target therapy and immunotherapy may not be reversed by reducing its dose. Although the condition is controlled with the use of glucocorticoids, some eye side effects cannot be cured. The timely detection and intervention of adverse effects of anti-tumor drugs by oncologists and ophthalmologists is critical for rational prescription. Ophthalmologists should be aware of eye side effects in patients using immunotherapy to ensure appropriate treatment and minimize potential eye complications such as dry eye, conjunctivitis, etc.
PubMed: 38881937
DOI: 10.21037/tcr-23-1952 -
Journal of Zoo and Wildlife Medicine :... Jun 2024Lymphoproliferative neoplasia has been reported in both free-ranging sea otters and those in managed care, but little information is available on the management of this...
Lymphoproliferative neoplasia has been reported in both free-ranging sea otters and those in managed care, but little information is available on the management of this neoplastic disease in this species. This case series describes clinical lymphoma in four northern sea otters () in managed care. Two otters presented with Stage 5 lymphoma with evidence of hematologic spread resulting in leukemia. Two additional otters presented with Stage 3 disease. Immunophenotypes in these cases included disseminated large B-cell lymphoma and lymphoblastic lymphoma of potential T-cell origin. Cases were managed with multiagent chemotherapy protocols including prednisone, L-asparaginase, cyclophosphamide, vincristine, cytosine arabinoside, lomustine, and doxorubicin. Unique approaches included the use of a vascular access port in one case and development of an autologous vaccine in another. Survival time ranged from 81 to 409 days. Diagnosis, staging, and treatment with multiagent protocols is recommended for the management of lymphoma in sea otters.
Topics: Animals; Otters; Female; Male; Lymphoma; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38875209
DOI: 10.1638/2022-0096 -
Journal of Vascular Surgery Cases and... Aug 2024We present a rare case of eosinophilic granulomatosis with polyangiitis (EGPA), involving a 26-year-old woman with a history of asthma and nasal polyps. The patient...
We present a rare case of eosinophilic granulomatosis with polyangiitis (EGPA), involving a 26-year-old woman with a history of asthma and nasal polyps. The patient presented with acute aortoiliac thrombosis and mitral insufficiency, which was successfully treated with thrombolysis, aortic thromboendarterectomy, and valve replacement. Peripheral hypereosinophilia with eosinophilic infiltration of the heart led to the diagnosis of antineutrophilic cytoplasmic antibody-negative EGPA. Treatment with prednisone and mepolizumab was started, resulting in a positive outcome. This case showcases an unusual manifestation of EGPA with large size vessel involvement and requiring surgical and pharmacological treatment. It also highlights the importance of early detection for timely intervention and an improved prognosis.
PubMed: 38873328
DOI: 10.1016/j.jvscit.2024.101515 -
European Journal of Cancer (Oxford,... Jun 2024Frailty in newly-diagnosed multiple myeloma (NDMM) patients is associated with treatment-related toxicity, which negatively affects health-related quality of life...
BACKGROUND
Frailty in newly-diagnosed multiple myeloma (NDMM) patients is associated with treatment-related toxicity, which negatively affects health-related quality of life (HRQoL). Currently, data on changes in HRQoL of frail and intermediate-fit MM patients during active treatment and post-treatment follow-up are absent.
METHODS
The HOVON123 study (NTR4244) was a phase II trial in which NDMM patients ≥ 75 years were treated with nine dose-adjusted cycles of Melphalan-Prednisone-Bortezomib (MPV). Two HRQoL instruments (EORTC QLQ-C30 and -MY20) were obtained before start of treatment, after 3 and 9 months of treatment and 6 and 12 months after treatment for patients who did not yet start second-line treatment. HRQoL changes and/or differences in frail and intermediate-fit patients (IMWG frailty score) were reported only when both statistically significant (p < 0.005) and clinically relevant (>MID).
RESULTS
137 frail and 71 intermediate-fit patients were included in the analysis. Compliance was high and comparable in both groups. At baseline, frail patients reported lower global health status, lower physical functioning scores and more fatigue and pain compared to intermediate-fit patients. Both groups improved in global health status and future perspective; polyneuropathy complaints worsened over time. Frail patients improved over time in physical functioning, fatigue and pain. Improvement in global health status occurred earlier than in intermediate-fit patients.
CONCLUSION
HRQoL improved during anti-myeloma treatment in both intermediate-fit and frail MM patients. In frail patients, improvement occurred faster and, in more domains, which was retained during follow-up. This implies that physicians should not withhold safe and effective therapies from frail patients in fear of HRQoL deterioration.
PubMed: 38870747
DOI: 10.1016/j.ejca.2024.114153