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Frontiers in Medicine 2024Lymphangioleiomyomatosis (LAM) is a rare lung disease predominantly affecting women, and it is characterized by the proliferation of smooth muscle cells and cystic lung...
Lymphangioleiomyomatosis (LAM) is a rare lung disease predominantly affecting women, and it is characterized by the proliferation of smooth muscle cells and cystic lung destruction. LAM diagnosis is challenging due to varied clinical presentations and resemblance to common conditions such as asthma. We present two female cases where LAM was initially misdiagnosed. Case 1 describes a woman treated for asthma-chronic obstruction pulmonary disease overlap syndrome, while also undergoing treatment with vascular endothelial growth factor (VEGF) inhibitor pazopanib for a retroperitoneal leiomyoma, the latter responding well to treatment. Due to progressive dyspnea, pazopanib-induced pneumonitis was suspected. High-resolution computed tomography (HRCT) showed changes compatible with LAM. A revision of biopsies showed that the leiomyoma was in fact a lymphangioleiomyoma, and VEGF-D was increased. Both supported the LAM diagnosis. Treatment with mTORC1 inhibitor sirolimus was initiated. Case 2 describes a woman, who in resemblance with the woman from case 2 was also suspected of asthma and did not respond clinically to treatment. After several years, HRCT was performed and suspicion of LAM was raised. Transbronchial biopsy and later, an increased VEGF-D supported the LAM diagnosis. As in case 1, treatment with sirolimus was initiated. These cases underscore the importance of reevaluating diagnoses when treatments fail to yield expected results. Improved awareness and early detection of LAM can enhance patient outcomes and life quality. Early LAM diagnosis is vital as mTORC1 inhibitors such as sirolimus can prevent further decline in lung function. Notably, the response of case 2 to pazopanib treatment supports suggestions of its potential as a second-line therapy for perivascular epithelioid cell tumors (PEComas), including LAM.
PubMed: 38410750
DOI: 10.3389/fmed.2024.1328471 -
Clinical Journal of Gastroenterology Jun 2024A 69-year-old woman presented to our department with the chief complaint of diarrhea. She had undergone left nephrectomy for renal cancer 14 years earlier. Three years...
A 69-year-old woman presented to our department with the chief complaint of diarrhea. She had undergone left nephrectomy for renal cancer 14 years earlier. Three years earlier, metastasis was detected in the left retroperitoneal cavity, and pazopanib administration was initiated. In the 29th month after the start of chemotherapy, the patient developed diarrhea, and on the 31st month, computed tomography showed thickening of the intestinal wall. Colonoscopy revealed white villi, intramucosal hemorrhage in the terminal ileum, and rough inflammatory mucosa with inflammatory polyps extending from the transverse to the sigmoid colon. Suspecting pazopanib-induced enteritis, we discontinued the medication, and the diarrhea resolved within 3 days. On the 21st day after discontinuation, colonoscopy revealed that the inflammatory polyps had shrunk, and the inflammatory findings had improved. Biopsy of the white villi of the ileum revealed histiocytes. The patient resumed treatment with pazopanib at 400 mg/day and developed soft stool on the 7th day after resumption. Compared with other tyrosine-kinase inhibitor-induced enteritis cases, this case showed less bleeding and more extensive inflammatory findings. There are similarities as well as differences from cases of previously reported pazopanib-induced enteritis. The mechanisms and characteristics of this disease require further investigation.
Topics: Humans; Female; Pyrimidines; Aged; Carcinoma, Renal Cell; Sulfonamides; Indazoles; Kidney Neoplasms; Enteritis; Diarrhea; Angiogenesis Inhibitors; Colonoscopy
PubMed: 38407743
DOI: 10.1007/s12328-024-01919-w -
European Heart Journal. Case Reports Feb 2024Primary intimal sarcomas of the heart are extremely rare and have a dismal prognosis. Their management represents a complex clinical challenge since complete surgical...
BACKGROUND
Primary intimal sarcomas of the heart are extremely rare and have a dismal prognosis. Their management represents a complex clinical challenge since complete surgical resection is the only reliable possibility of cure but is only possible in 50% of patients. In non-resectable disease, anthracycline-based therapy is the most effective treatment, but pazopanib may be used in patients unfit to receive anthracyclines.
CASE SUMMARY
A 38-year-old man presented with acute right heart failure symptoms due to a primary intimal sarcoma of the heart. A definite diagnosis was made after cardiac surgery. Multi-modality cardiac imaging showed early recurrence of disease with mitral valve and pulmonary veins' invasion, and the patient was deemed inoperable. Due to chronic kidney disease and previous heart failure symptoms, he was started on first-line pazopanib palliative treatment. After 11 months of chemotherapy, there was good clinical tolerance and no evidence of disease progression, which occurred after 13 months.
DISCUSSION
This case highlights the value of a multi-modality imaging approach for cardiac masses. Most importantly, it reports the successful treatment of a young patient with a primary intimal sarcoma of the heart who was started on palliative pazopanib, with a significantly higher progression-free survival than is reported in the literature. This finding may support pazopanib as a good alternative as first-line treatment when there is contraindication for anthracycline-based chemotherapy.
PubMed: 38374987
DOI: 10.1093/ehjcr/ytae071 -
Science Advances Feb 2024Osteoarthritis (OA) is characterized by cartilage damage, inflammation, and pain. Vascular endothelial growth factor receptors (VEGFRs) have been associated with OA...
Osteoarthritis (OA) is characterized by cartilage damage, inflammation, and pain. Vascular endothelial growth factor receptors (VEGFRs) have been associated with OA severity, suggesting that inhibitors targeting these receptors alleviate pain (via VEGFR1) or cartilage degeneration (via VEGFR2). We have developed a nanoparticle-based formulation of pazopanib (Votrient), an FDA-approved anticancer drug that targets both VEGFR1 and VEGFR2 (Nano-PAZII). We demonstrate that a single intraarticular injection of Nano-PAZII can effectively reduce joint pain for a prolonged time without substantial side effects in two different preclinical OA rodent models involving either surgical (upon partial medial meniscectomy) or nonsurgical induction (with monoiodoacetate). The injection of Nano-PAZII blocks VEGFR1 and relieves OA pain by suppressing sensory neuronal ingrowth into the knee synovium and neuronal plasticity in the dorsal root ganglia and spinal cord. Simultaneously, the inhibition of VEGFR2 reduces cartilage degeneration. These findings provide a mechanism-based disease-modifying drug strategy that addresses both pain symptoms and cartilage loss in OA.
Topics: Animals; Vascular Endothelial Growth Factor A; Osteoarthritis; Pain; Knee Joint; Arthralgia; Disease Models, Animal
PubMed: 38354243
DOI: 10.1126/sciadv.adi5501 -
Pharmacological Research Mar 2024The vascular endothelial growth factors (VEGFs) and their cognate receptors (VEGFRs), besides their well-known involvement in physiological... (Review)
Review
The vascular endothelial growth factors (VEGFs) and their cognate receptors (VEGFRs), besides their well-known involvement in physiological angiogenesis/lymphangiogenesis and in diseases associated to pathological vessel formation, play multifaceted functions in the central nervous system (CNS). In addition to shaping brain development, by controlling cerebral vasculogenesis and regulating neurogenesis as well as astrocyte differentiation, the VEGFs/VEGFRs axis exerts essential functions in the adult brain both in physiological and pathological contexts. In this article, after describing the physiological VEGFs/VEGFRs functions in the CNS, we focus on the VEGFs/VEGFRs involvement in neurodegenerative diseases by reviewing the current literature on the rather complex VEGFs/VEGFRs contribution to the pathogenic mechanisms of Alzheimer's (AD) and Parkinson's (PD) diseases. Thereafter, based on the outcome of VEGFs/VEGFRs targeting in animal models of AD and PD, we discuss the factual relevance of pharmacological VEGFs/VEGFRs modulation as a novel and potential disease-modifying approach for these neurodegenerative pathologies. Specific VEGFRs targeting, aimed at selective VEGFR-1 inhibition, while preserving VEGFR-2 signal transduction, appears as a promising strategy to hit the molecular mechanisms underlying AD pathology. Moreover, therapeutic VEGFs-based approaches can be proposed for PD treatment, with the aim of fine-tuning their brain levels to amplify neurotrophic/neuroprotective effects while limiting an excessive impact on vascular permeability.
Topics: Animals; Parkinson Disease; Alzheimer Disease; Vascular Endothelial Growth Factor Receptor-1; Central Nervous System; Brain
PubMed: 38336311
DOI: 10.1016/j.phrs.2024.107101 -
Thoracic Cancer Mar 2024Pericardial synovial sarcomas (PSS) have a low incidence rate and are highly invasive with a dismal prognosis. Standard treatment includes surgery, radiotherapy and...
Pericardial synovial sarcomas (PSS) have a low incidence rate and are highly invasive with a dismal prognosis. Standard treatment includes surgery, radiotherapy and chemotherapy but with limited response. Here, we report the case of a 15-year-old nonsmoking youngster diagnosed with PSS who developed disease relapsed from surgery after 1 month. Next-generation sequencing (NGS) using baseline tissue was performed, and BRCA2 c.968dupT was detected. Then pazopanib (a multitargeted inhibitor) plus nivolumab (an immune checkpoint inhibitor) was administered, with a partial response and progression-free survival of 14 months. BRCA2 c.968dupT has not previously been reported in PSS and its response to targeted combination immunotherapy are not well characterized. Here, we report the efficacy of pazopanib combined with nivolumab in a PSS patient harboring BRCA2 c.968dupT and also provide the clinical evidence of the utility of NGS in exploring actionable mutations for solid tumor. Combination therapy based on immunotherapy may be a potential treatment choice for PSS harboring BRCA2 mutation.
Topics: Humans; Adolescent; Sarcoma, Synovial; Nivolumab; Pyrimidines; Sulfonamides; Mediastinal Neoplasms; Thymus Neoplasms; Heart Neoplasms; Pleural Neoplasms; BRCA2 Protein; Indazoles
PubMed: 38323364
DOI: 10.1111/1759-7714.15237 -
Frontiers in Pharmacology 2023Small molecule compounds targeting multiple kinases involved in neoangiogenesis have shown survival benefits in patients with unresectable hepatocellular carcinoma...
Small molecule compounds targeting multiple kinases involved in neoangiogenesis have shown survival benefits in patients with unresectable hepatocellular carcinoma (HCC). Nonetheless, despite the beneficial effects of multikinase inhibitors (MKIs), a lack of boosting adjuvant limits their objective response rate. Lipid conjugates have been used to improve delivery efficacy or pharmaceutical benefits for decades. However, the feasibility of utilizing lipid-drug conjugates (LDCs) in HCC regimens remains untested. In this study, oral feeding of linoleate-fluorescein isothiocyanate conjugates showed that the compound was well distributed in a spontaneous HCC mouse model. Therefore, a rationale design was developed for chemically synthesizing a linoleate-pazopanib conjugate (LAPC). The LAPC showed a significantly improved cytotoxicity compared to the parental drug pazopanib. Pazopanib's angiogenic suppressing signals were not observed in LAPC-treated HCC cells, potentially suggesting an altered mechanism of action (MOA). In an efficacy trial comparing placebo, oral pazopanib, and LAPC treatments in the hepatitis B virus transgene-related spontaneous HCC mouse model (HBVtg-HCC), the LAPC treatment demonstrated superior tumor ablating capacity in comparison to both placebo and pazopanib treatments, without any discernible systemic toxicity. The LAPC exposure is associated with an apoptosis marker (Terminal deoxynucleotidyl transferase dUTP nick end labeling [TUNEL]) and an enhanced ferroptosis (glutathione peroxidase 4 [GPX4]) potential in HBVtg-HCC tumors. Therefore, the LAPC showed excellent HCC ablative efficacy with altered MOA. The molecular mechanisms of the LAPC and LDCs for HCC therapeutics are of great academic interest. Further comprehensive preclinical trials (e.g., chemical-manufacture-control, toxicity, distribution, and pharmacokinetics/pharmacodynamics) are expected.
PubMed: 38293667
DOI: 10.3389/fphar.2023.1281067 -
Oxford Medical Case Reports Jan 2024The treatment landscape of advanced kidney cancer has radically changed over the years. Targeting tumor angiogenesis from historical cytokines to multi-tyrosine kinase...
The treatment landscape of advanced kidney cancer has radically changed over the years. Targeting tumor angiogenesis from historical cytokines to multi-tyrosine kinase inhibitors and recently the advent of immunotherapy resulted in a radical improvement in survival but presented substantial challenges in terms of toxicity management. In countries where the access to immune checkpoints inhibitors is still very limited, tyrosine-kinase inhibitors remain the optimal choice. The toxicity profile of these agents can influence both the clinician and the patient's preference for one molecule over another. This report describes the case of a young man treated with Pazopanib in a first-line setting for stage IV renal carcinoma who developed trismus under treatment. The occurrence of this off-target toxicity has made the patient ineligible for anti-angiogenic drugs. Although side effects of tyrosine kinase inhibitors seem manageable and reversible, some less known and unusual effects may evolve into severe and irreversible complications.
PubMed: 38292153
DOI: 10.1093/omcr/omad146 -
Therapeutic Advances in Medical Oncology 2024Dimensional response is an unmet need in second lines of advanced soft tissue sarcomas (STS). Indeed, the three approved drugs, pazopanib, trabectedin, and eribulin,...
BACKGROUND AND OBJECTIVES
Dimensional response is an unmet need in second lines of advanced soft tissue sarcomas (STS). Indeed, the three approved drugs, pazopanib, trabectedin, and eribulin, achieved an overall response rate (ORR) of less than 10%. This fact potentially hinders the options for fast symptomatic relief or surgical rescue. The combination of trabectedin plus low-dose radiation therapy (T-XRT) demonstrated a response rate of 60% in phase I/II trial, while real-life data achieved 32.5% ORR, probably due to a more relaxed timing between treatments. These results were obtained in progressing and advanced STS. In this study, the merged databases (trial plus real life) have been analyzed, with a special focus on leiomyosarcoma patients.
DESIGN AND METHODS
As responses were seen in a wide range of sarcoma histologies (11), this study planned to analyze whether leiomyosarcoma, the largest subtype with 26 cases (30.6%) in this series, exhibited a better clinical outcome with this therapeutic strategy. In addition, four advanced and progressing leiomyosarcoma patients, all with extraordinarily long progression-free survival of over 18 months, were collected.
RESULTS
A total of 847 cycles of trabectedin were administered to 85 patients, with the median number of cycles per patient being 7 (1-45+). A trend toward a longer progression-free survival (PFS) was observed in leiomyosarcoma patients with median PFS (mPFS) of 9.9 months [95% confidence interval (CI): 1.1-18.7] 5.6 months (95% CI: 3.2-7.9) for the remaining histologies, = 0.25. When leiomyosarcoma and liposarcoma were grouped, this difference reached statistical significance, probably due to the special sensitivity of myxoid liposarcoma. The mPFS for L-sarcomas was 12.7 months (95% CI: 7-18.5) 4.3 months (95% CI: 3.3-5.3) for the remaining histologies, = 0.001. Cases with long-lasting disease control are detected among leiomyosarcoma patients.
CONCLUSION
Even when extraordinarily long-lasting responses do exist among leiomyosarcoma patients treated with T-XR, we were unable to demonstrate a significant difference favoring leiomyosarcoma patients in clinical outcomes.
PubMed: 38288156
DOI: 10.1177/17588359231225044 -
Frontiers in Bioscience (Landmark... Jan 2024Emerging evidence suggests the biological implications of N6-methyladenosine (m6A) in carcinogenesis. Herein, we systematically analyzed the role of m6A modification in...
OBJECTIVE
Emerging evidence suggests the biological implications of N6-methyladenosine (m6A) in carcinogenesis. Herein, we systematically analyzed the role of m6A modification in renal cell carcinoma (RCC) progression.
METHODS
Based on 23 m6A regulators, unsupervised clustering analyses were conducted to determine m6A modification subtypes across 893 RCC specimens in the Cancer Genome Atlas (TCGA) cohort. By performing principal component analysis (PCA) analysis, m6A scoring system was developed for evaluating m6A modification patterns of individual RCC patients. The activity of signaling pathways was assessed by gene-set variation analysis (GSVA) algorithm. The single-sample gene set enrichment analysis (ssGSEA) algorithm was applied for quantifying the infiltration levels of immune cells and the activity of cancer immunity cycle. Drug responses were estimated by genomics of drug sensitivity in cancer (GDSC), the Cancer Therapeutics Response Portal (CTRP) and Preservice Research Institute for Science and Mathematics (PRISM) database.
RESULTS
Five m6A modification subtypes were characterized by different survival outcomes, oxidative stress, cancer stemness, infiltrations of immune cells, activity of cancer immunity cycle, programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) expression and microsatellite instability (MSI) levels. According to m6A score, RCC patients were categorized into high and low m6A score groups. Patients with high m6A score displayed a prominent survival advantage, and the prognostic value of m6A score was confirmed in two anti-PD-1/PD-L1 immunotherapy cohorts. m6A score was significantly linked to oxidative stress-related genes, and high m6A score indicated the higher sensitivity to axitinib, pazopanib and sorafenib and the lower sensitivity to sunitinib.
CONCLUSION
This study analyzed the extensive regulatory mechanisms of m6A modification on oxidative stress, the tumor microenvironment, and immunity. Quantifying m6A scores may enhance immunotherapeutic effects and assist in developing more effective agents.
Topics: Humans; Carcinoma, Renal Cell; B7-H1 Antigen; Tumor Microenvironment; Kidney Neoplasms; Methylation
PubMed: 38287827
DOI: 10.31083/j.fbl2901033