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BioRxiv : the Preprint Server For... Mar 2024Hereditary Hemorrhagic Telangiectasia (HHT) is a rare congenital disease in which fragile vascular malformations focally develop in multiple organs. These can be small...
UNLABELLED
Hereditary Hemorrhagic Telangiectasia (HHT) is a rare congenital disease in which fragile vascular malformations focally develop in multiple organs. These can be small (telangiectasias) or large (arteriovenous malformations, AVMs) and may rupture leading to frequent, uncontrolled bleeding. There are few treatment options and no cure for HHT. Most HHT patients are heterozygous for loss-of-function mutations for Endoglin (ENG) or Alk1 (ACVRL1), however, why loss of these genes manifests as vascular malformations remains poorly understood. To complement ongoing work in animal models, we have developed a microphysiological system model of HHT. Based on our existing vessel-on-a-chip (VMO) platform, our fully human cell-based HHT-VMO recapitulates HHT patient vascular lesions. Using inducible (Alk1)-knockdown, we control timing and extent of endogenous Alk1 expression in primary human endothelial cells (EC) in the HHT-VMO. HHT-VMO vascular lesions develop over several days, and are dependent upon timing of Alk1 knockdown. Interestingly, in chimera experiments AVM-like lesions can be comprised of both Alk1-intact and Alk1-deficient EC, suggesting possible cell non-autonomous effects. Single cell RNA sequencing data are consistent with microvessel pruning/regression as contributing to AVM formation, while loss of PDGFB expression implicates mural cell recruitment. Finally, lesion formation is blocked by the VEGFR inhibitor pazopanib, mirroring the positive effects of this drug in patients. In summary, we have developed a novel HHT-on-a-chip model that faithfully reproduces HHT patient lesions and that is sensitive to a treatment effective in patients. The VMO-HHT can be used to better understand HHT disease biology and identify potential new HHT drugs.
SIGNIFICANCE
This manuscript describes development of an organ-on-a-chip model of Hereditary Hemorrhagic Telangiectasia (HHT), a rare genetic disease involving development of vascular malformations. Our VMO-HHT model produces vascular malformations similar to those seen in human HHT patients, including small (telangiectasias) and large (arteriovenous malformations) lesions. We show that VMO-HHT lesions are sensitive to a drug, pazopanib, that appears to be effective in HHT human patients. We further use the VMO-HHT platform to demonstrate that there is a critical window during vessel formation in which the HHT gene, Alk1, is required to prevent vascular malformation. Lastly, we show that lesions in the VMO-HHT model are comprised of both Alk1-deficient and Alk1-intact endothelial cells.
PubMed: 38559155
DOI: 10.1101/2024.03.11.584490 -
Circulation Journal : Official Journal... Jan 2024Heart failure (HF) is one of the potential adverse events of pazopanib treatment for soft tissue sarcoma (STS), but detailed reports of such HF cases are scarce. This...
BACKGROUND
Heart failure (HF) is one of the potential adverse events of pazopanib treatment for soft tissue sarcoma (STS), but detailed reports of such HF cases are scarce. This study determined the incidence and risk factors of HF following pazopanib treatment for STS at our Institute and the clinical outcomes.Methods and Results:This study retrospectively analyzed the cases of STS patients treated with pazopanib (n=151) between 2012 and 2020. HF occurred in 6 patients (3.9%) at the median onset of 137 (range 14-468) days after the treatment initiation. When their HF was diagnosed, pazopanib was interrupted in all 6 patients. No patients experienced HF-related death, and HF development was not a significant factor for poor overall survival. The cumulative doses of anthracyclines (>225 mg/m) before pazopanib initiation (83% vs. 37%, P=0.031), pazopanib initiation at age ≥60 years (83% vs. 35%, P=0.026), and the baseline B-type natriuretic peptide (BNP) concentration (≥50 pg/mL) before pazopanib (67% vs. 11%, P=0.002) initiation were predictive factors for post-pazopanib treatment HF.
CONCLUSIONS
The study findings highlight the effect of past anthracycline exposure and baseline BNP for pazopanib-associated HF. Although the study patients' clinical outcomes were generally favorable, periodic monitoring of cardiac function using ultrasonic echocardiography or serum markers is essential to detect events early and begin therapeutic intervention appropriately under a cardiologist's instructions.
Topics: Humans; Middle Aged; Retrospective Studies; Sarcoma; Pyrimidines; Antibiotics, Antineoplastic; Heart Failure; Indazoles; Sulfonamides
PubMed: 35314578
DOI: 10.1253/circj.CJ-21-0808 -
Cancer Chemotherapy and Pharmacology Apr 2024Pazopanib is known to cause liver toxicity. A relationship between pazopanib exposure and alanine transaminase elevations has been described in clinical trials. This... (Observational Study)
Observational Study
PURPOSE
Pazopanib is known to cause liver toxicity. A relationship between pazopanib exposure and alanine transaminase elevations has been described in clinical trials. This study investigated the relation between pazopanib exposure and liver toxicity in real-world patients and evaluated the management of pazopanib-induced liver toxicity in routine care.
METHODS
A retrospective observational cohort study was performed in patients treated with pazopanib in whom pazopanib exposure was measured. The percentage of patients with and without liver toxicity during treatment with pazopanib was calculated as well as the average pazopanib exposure in both groups. Furthermore, the management of patients with liver toxicity was evaluated.
RESULTS
Liver toxicity was observed in 25 out of the 133 patients included (19%). Pazopanib exposure was comparable in patients with or without liver toxicity (27.7 mg/L versus 28.1 mg/L). Seven patients permanently discontinued pazopanib after the occurrence of liver toxicity. Of the remaining 18 patients, continuation or restart of pazopanib after liver toxicity was successful in 16 patients and half of these patients were able to safely continue pazopanib at the same dose as prior to liver toxicity for the remaining duration of treatment.
CONCLUSION
Our study did not demonstrate a clear relationship between pazopanib exposure and the occurrence of pazopanib-induced liver toxicity. Half of the patients were able to safely continue or restart pazopanib treatment after liver toxicity and received the same dose as prior to drug withdrawal. Successful interventions to address pazopanib-induced toxicity in the clinic led to an algorithm for the management of pazopanib-induced liver toxicity.
Topics: Humans; Carcinoma, Renal Cell; Retrospective Studies; Sarcoma; Kidney Neoplasms; Indazoles; Drug-Related Side Effects and Adverse Reactions; Liver; Pyrimidines; Sulfonamides
PubMed: 38104304
DOI: 10.1007/s00280-023-04615-7 -
Translational Psychiatry Mar 2024Melatonin improves chronic stress-induced hippocampal damage and depression-like behaviors, but the mechanism needs further study. This study was to explore the...
Melatonin alleviates chronic stress-induced hippocampal microglia pyroptosis and subsequent depression-like behaviors by inhibiting Cathepsin B/NLRP3 signaling pathway in rats.
Melatonin improves chronic stress-induced hippocampal damage and depression-like behaviors, but the mechanism needs further study. This study was to explore the mechanism of melatonin inhibiting microglia pyroptosis. In virtro experiments, melatonin improved corticosterone-induced the ultrastructure and microstructure damage of HAPI cells by inhibiting pyroptosis, thereby increasing cell survival rate. Protein-protein interaction network and molecular autodocking predicted that Cathespin B might be the target of melatonin inhibition of NLRP3-mediated pyroptosis. Melatonin inhibited corticosterone-induced Cathespin B expression. Both Cathepsin B inhibitor CA-074Me and NLRP3 knockout inhibited the HAPI cells pyroptosis. Similarly, melatonin inhibited Cathepsin B agonist Pazopanib-induced activation of Cathepsin B/NLRP3 signaling pathway and HAPI cells pyroptosis. In vivo studies, melatonin inhibited chronic restraint stress (CRS)-induced activation of Cathepsin B/NLRP3 signaling pathway and alleviated hippocampal microglia pyroptosis in rats. Inhibition of microglia pyroptosis improved CRS-induced depression-like behaviors of rats. In addition, inhibition of Cathepsin B and NLRP3 alleviated hippocampal pyroptosis. Melatonin inhibited Pazopanib-induced activation of Cathepsin B/NLRP3 signaling pathway and hippocampal pyroptosis. These results demonstrated that melatonin could alleviate CRS-induced hippocampal microglia pyroptosis by inhibiting Cathepsin B/NLRP3 signaling pathway, thereby improving depression-like behaviors in rats. This study reveals the molecular mechanism of melatonin in the prevention and treatment of chronic stress-related encephalopathy.
Topics: Animals; Rats; Cathepsin B; Melatonin; Corticosterone; Depression; Microglia; NLR Family, Pyrin Domain-Containing 3 Protein; Pyroptosis; Signal Transduction; Hippocampus; Indazoles; Pyrimidines; Sulfonamides
PubMed: 38538614
DOI: 10.1038/s41398-024-02887-y -
Chinese Clinical Oncology Aug 2023Tumor lysis syndrome (TLS) is recognized as an oncologic disorder with a variable incidence. TLS can cause the rapid destruction of tumor cells in response to oncologic...
BACKGROUND
Tumor lysis syndrome (TLS) is recognized as an oncologic disorder with a variable incidence. TLS can cause the rapid destruction of tumor cells in response to oncologic therapy and is characterized by multiple electrolyte disturbances as well as its secondary complications, including death. This disease is common among patients with hematologic neoplasms, but very rare among those with solid tumors, as is the case with sarcomas. Such patients have a poor prognosis and increased risk of mortality. In the patient's particular case, this occurred after initiating third-line systemic therapy with gemcitabine associated with pazopanib, an event not previously described in the literature.
CASE DESCRIPTION
We report the case of a patient with a history of high-grade sarcoma of the left lower limb T4N1M0 stage IIIB undergoing surgical management and exhibiting tumor progression with the need for third-line systemic therapy with pazopanib and gemcitabine. The patient presented with pain at the amputation site, inflammatory changes, and a tumor mass of large components on admission. They later developed electrolyte imbalance and acute renal injury compatible with TLS after systemic therapy was initiated. Pharmacological therapy, including rasburicase, was initiated based on the clinical and laboratory findings. Due to the progression of renal involvement, it was necessary to initiate haemodialysis, and during her hospital stay, the patient presented febrile syndrome associated with pancytopenia. The patient showed a favourable clinical response to the proposed antibiotic therapy and recovery of renal function, for which reason therapy was restarted with pazopanib and gemcitabine, the latter with a 20% reduction for the following cycles. Outpatient follow-up continued, completing eight cycles of treatment with good tolerance and partial clinical response; the patient died of respiratory complications eight months after discharge.
CONCLUSIONS
There is limited evidence for TLS in patients with high-grade sarcoma in the literature related to the oncologic therapy used; this indicates that early risk evaluation along with prompt initiation of effective therapies is required to prevent the appearance of this type of complications in the short and long term.
Topics: Female; Humans; Gemcitabine; Tumor Lysis Syndrome; Sarcoma; Electrolytes
PubMed: 37599513
DOI: 10.21037/cco-22-111 -
American Journal of Translational... 2023Gastric cancer (GC) has a high incidence and poor prognosis. Senescence genes are suggested to participate in immune cell infiltration, thus affecting the immunotherapy...
AIM
Gastric cancer (GC) has a high incidence and poor prognosis. Senescence genes are suggested to participate in immune cell infiltration, thus affecting the immunotherapy of GC. In this research, we established a senescence-related GC model to explore and verify the role of senescence genes in the prognosis, treatment, and tumor microenvironment (TME) of GC.
METHODS
The TCGA GC (TCGA-STAD) dataset was used to screen key senescence genes from differentially expressed genes (DEGs). A prognostic risk model was trained utilizing the TCGA-STAD dataset and validated using an external GEO dataset. The CIBERSORT algorithm was run to explore the relationship between senescence genes and TME. The chemotherapy drug sensitivities in GC patients were calculated utilizing R package pRRophetic.
RESULTS
A total of 37 senescence-related DEGs were obtained. Five key senescence-related genes were further screened to establish a senescence-related risk model based on Cox regression. The survival status of GC patients in the high-risk group was found to be worse than that in the low-risk group. According to the results of gene set enrichment analysis, the senescence-related risk was mainly associated with cytokine activity, immune mechanism, and related pathways. By analyzing the sensitivity of common chemotherapy drugs in GC patients, it was revealed that the sensitivities of high-risk patients to Dasatinib, Lapatinib, and Pazopanib were lower than those of low-risk patients. The CIBERSORT algorithm was executed to analyze the TME in the high-risk group, revealing elevated levels of CD8 T cells, Macrophages M2, and resting Mast cells. In addition, decreased levels of resting memory CD4 T cells , resting NK cells, activated Dendritic cells, and activated Mast cells were also observed.
CONCLUSION
Senescence genes were related to the prognosis, response to chemotherapy drugs, and TME of GC. Our senescence-related risk model could forecast the survival of patients, their response to chemotherapy drugs, and the TME to a certain extent.
PubMed: 38187003
DOI: No ID Found -
Therapeutic Advances in Urology 2023Novel receptor tyrosine kinase inhibitors and immune checkpoint inhibitors have been introduced to the treatment of advanced renal cell carcinoma (aRCC) during the past...
BACKGROUND
Novel receptor tyrosine kinase inhibitors and immune checkpoint inhibitors have been introduced to the treatment of advanced renal cell carcinoma (aRCC) during the past decade. However, the adoption of novel treatments into clinical practice has been unknown in Finland.
OBJECTIVES
Our aim was to evaluate the use of systemic treatments and treatment outcomes of aRCC patients in Southwest Finland during 2010-2021.
DESIGN AND METHODS
Clinical characteristics, treatments for aRCC, healthcare resource utilization, and overall survival (OS) were retrospectively obtained from electronic medical records. Patients were stratified using the International Metastatic RCC Database Consortium (IMDC) risk classification.
RESULTS
In total, 1112 RCC patients were identified, 336 (30%) patients presented with aRCC, and 57% of them ( = 191) had received systemic treatment. Pre-2018, sunitinib (79%) was the most common first-line treatment, and pazopanib (17%), axitinib (17%), and cabozantinib (5%) were frequently used in the second-line. Post-2018, sunitinib (52%), cabozantinib (31%), and the combination of ipilimumab and nivolumab (10%) were most commonly used in the first-line, and cabozantinib (23%) in the second-line. Median OS for patients with favorable, intermediate, and poor risk were 61.9, 28.6, and 8.1 months, respectively. A total of 73%, 74%, and 35% of the patients with favorable, intermediate, and poor risk had received second-line systemic treatment. In poor-risk patients, the number of hospital inpatient days was twofold higher compared to intermediate and fourfold higher compared to favorable-risk patients.
CONCLUSION
New treatment options were readily adopted into routine clinical practice after becoming reimbursed in Finland. OS and the need for hospitalization depended significantly on the IMDC risk category. Upfront combination treatments are warranted for poor-risk patients as the proportion of patients receiving second-line treatment is low.
REGISTRATION
Clinical trial identifier: ClinicalTrials.gov NCT05363072.
PubMed: 37941979
DOI: 10.1177/17562872231206243 -
Biomedical Journal May 2024Given the heterogeneity and high mortality associated with metastatic soft tissue sarcoma, this study aims to evaluate the therapeutic efficacy of combining Lu-FAPI-46...
BACKGROUND
Given the heterogeneity and high mortality associated with metastatic soft tissue sarcoma, this study aims to evaluate the therapeutic efficacy of combining Lu-FAPI-46 with Pazopanib against this malignancy.
METHODS
Patient-derived xenograft (PDX)-bearing mice were randomly divided into three groups: the control group, the Lu-FAPI-46 monotherapy group, and the Lu-FAPI-46 combined with Pazopanib therapy group. Therapeutic efficacy was regularly monitored.
RESULTS
The microPET imaging showed a 0.84-fold decrease in the T/M ratio of 68Ga-FAPI-46 on day 7/8 post combination therapy, while the control group exhibited a 1.23-fold increase. Combination therapy significantly inhibited tumor proliferation, as evidenced by reduced Ki-67 and increased caspase 3 expressions. Notably, there was no significant body weight loss observed in any group.
CONCLUSION
This study successfully demonstrated the reduction in FAP expression and suppression of tumor volume in sarcoma PDX following the combination therapy of Lu-FAPI-46 with Pazopanib.
PubMed: 38729609
DOI: 10.1016/j.bj.2024.100744 -
Journal of Cancer Research and Clinical... Aug 2023The purpose of our study was to determine whether data on the clinical effectiveness of second-line therapy collected in a real-world setting provide additional valuable...
Sequential treatment of metastatic renal cell carcinoma patients after first-line vascular endothelial growth factor targeted therapy in a real-world setting: epidemiologic, noninterventional, retrospective-prospective cohort multicentre study.
PURPOSE
The purpose of our study was to determine whether data on the clinical effectiveness of second-line therapy collected in a real-world setting provide additional valuable information on the optimal sequence of metastatic renal cell carcinoma (mRCC) treatment.
METHODS
Patients diagnosed with mRCC who were treated with at least one dose of first-line vascular endothelial growth factor (VEGF)-targeted therapy with either sunitinib or pazopanib and with at least one dose of second-line everolimus, axitinib, nivolumab, or cabozantinib were included. The efficacy of different treatment sequences was analyzed based on the time to the second objective disease progression (PFS2) and the time to the first objective disease progression (PFS).
RESULTS
Data from 172 subjects were available for analysis. PFS2 was 23.29 months. The 1-year PFS2 rate was 85.3%, and the 3-year PFS2 rate was 25.9%. The 1-year overall survival rate was 97.0%, and the 3-year overall survival rate was 78.6%. Patients with a lower IMDC prognostic risk group had a significantly (p < 0.001) longer PFS2. Patients with metastases in the liver had a shorter PFS2 than patients with metastases in the other sites (p = 0.024). Patients with metastases in the lungs and lymph nodes (p = 0.045) and patients with metastases in the liver and bones (p = 0.030) had lower PFS2 rates than patients with metastases in other sites.
CONCLUSIONS
Patients with a better IMDC prognosis have a longer PFS2. Metastases in the liver lead to a shorter PFS2 than metastases in other sites. One metastasis site means a longer PFS2 than 3 or more metastasis sites. Nephrectomy performed in an earlier stage of disease or metastatic setting means higher PFS and higher PFS2. No PFS2 difference was found between different treatment sequences of TKI-TKI or TKI-immune therapy.
Topics: Humans; Carcinoma, Renal Cell; Vascular Endothelial Growth Factor A; Antineoplastic Agents; Kidney Neoplasms; Retrospective Studies; Prospective Studies; Disease Progression
PubMed: 36847839
DOI: 10.1007/s00432-023-04645-x -
Drugs - Real World Outcomes Jun 2024The tyrosine kinase inhibitors cabozantinib and axitinib have been widely used in England to treat advanced renal cell carcinoma following prior vascular endothelial...
BACKGROUND AND OBJECTIVE
The tyrosine kinase inhibitors cabozantinib and axitinib have been widely used in England to treat advanced renal cell carcinoma following prior vascular endothelial growth factor-targeted therapy, but data on real-world usage remain limited. Our objective was to describe the real-world treatment patterns and outcomes of patients with advanced renal cell carcinoma who received second-line or later-line (≥ 2L) cabozantinib or axitinib after vascular endothelial growth factor-targeted therapy in clinical practice in England.
METHODS
This retrospective cohort study used clinical practice data (collected 2011-20) from the English Cancer Analysis System database. Patient characteristics, treatment sequence and duration, and overall survival (time from initiation of cabozantinib/axitinib treatment to death) were evaluated.
RESULTS
Data from 1485 eligible adults with advanced renal cell carcinoma were analyzed: 440 received ≥ 2L cabozantinib (2L for 88.6% of them); 1045 received ≥ 2L axitinib (2L for 89.5%). The most common first-line treatments were sunitinib (2L cabozantinib subcohort, 48%; 2L axitinib subcohort, 46%) and pazopanib (46% and 54%, respectively); nivolumab was the most common third-line treatment (18% and 19%, respectively). Median (interquartile range) 2L therapy duration was 5.52 (2.73-11.74) months for cabozantinib and 4.60 (1.45-12.36) months for axitinib. Following adjustment for potential confounders using inverse probability weighting, overall survival (median [interquartile range]) was longer for ≥ 2L cabozantinib (11.2 [5.7-28.0] months) than for ≥ 2L axitinib (10.4 [4.7-22.0] months; log-rank p = 0.0034).
CONCLUSIONS
The Cancer Analysis System database is a valuable research resource providing extensive real-world clinical data. Real-world overall survival was longer with ≥ 2L cabozantinib than with axitinib.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, NCT04637204; registered November 2020.
PubMed: 38265633
DOI: 10.1007/s40801-023-00415-w