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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 -
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 -
Cureus Feb 2024Low-grade endometrial stromal sarcoma (LGESS) typically has a favorable prognosis. Hormone therapy is considered the first choice of treatment for recurrent LGESS. In...
Low-grade endometrial stromal sarcoma (LGESS) typically has a favorable prognosis. Hormone therapy is considered the first choice of treatment for recurrent LGESS. In this report, we describe a case of recurrent LGESS where hormone therapy was ineffective, chemotherapy showed a partial response (PR), and pazopanib resulted in stable disease (SD). A 50-year-old patient with LGESS underwent a simple total hysterectomy and bilateral adnexectomy (pT1aN0M0, stage IA). Five years later, pelvic tumors and ascites were observed. Exploratory laparoscopy revealed bloody ascites, an 8 cm pelvic tumor, and extensive peritoneal dissemination. Nuclear atypia of the tumor cells was mild, pleomorphism and mitotic figures could not be confirmed, and necrosis was not observed. Immunostaining was positive for CD10 and estrogen receptor, negative for the BCL6 corepressor (BCOR), and showed a low Ki-67 index. Fluorescence in situ hybridization (FISH) examination of the tissue showed rearrangement of the JAZF zinc finger 1 (JAZF1) gene. Multigene panel testing revealed a homozygous deletion of cyclin-dependent kinase inhibitor 2A (CDKN2A). Accordingly, the patient was diagnosed with recurrent LGESS and was treated with an aromatase inhibitor, followed by medroxyprogesterone acetate; both were ineffective. The patient had a PR to chemotherapy (doxorubicin/ifosfamide) and SD to pazopanib. The patient died 1.5 years after recurrence. In conclusion, we present a case of LGESS with a poor prognosis where hormone therapy was ineffective, and chemotherapy and pazopanib were both partially effective. The poor prognosis may have been associated with the CDKN2A homozygous deletion.
PubMed: 38481894
DOI: 10.7759/cureus.54066 -
Cancer Medicine Jun 2024We previously reported that metastases are generally characterized by a core program of gene expression that activates tissue remodeling/vascularization, alters ion...
BACKGROUND
We previously reported that metastases are generally characterized by a core program of gene expression that activates tissue remodeling/vascularization, alters ion homeostasis, induces the oxidative metabolism, and silences extracellular matrix interactions. This core program distinguishes metastases from their originating primary tumors as well as from their destination host tissues. Therefore, the gene products involved are potential targets for anti-metastasis drug treatment.
METHODS
Because the silencing of extracellular matrix interactions predisposes to anoiks in the absence of active survival mechanisms, we tested inhibitors against the other three components.
RESULTS
Individually, the low-specificity VEGFR blocker pazopanib (in vivo combined with marimastat), the antioxidant dimethyl sulfoxide (or the substitute atovaquone, which is approved for internal administration), and the ionic modulators bumetanide and tetrathiomolybdate inhibited soft agar colony formation by breast and pancreatic cancer cell lines. The individual candidate agents have a record of use in humans (with limited efficacy when administered individually) and are available for repurposing. In combination, the effects of these drugs were additive or synergistic. In two mouse models of cancer (utilizing 4T1 cells or B16-F10 cells), the combination treatment with these medications, applied immediately (to prevent metastasis formation) or after a delay (to suppress established metastases), dramatically reduced the occurrence of disseminated foci.
CONCLUSIONS
The combination of tissue remodeling inhibitors, suppressors of the oxidative metabolism, and ion homeostasis modulators has very strong promise for the treatment of metastases by multiple cancers.
Topics: Animals; Humans; Mice; Sulfonamides; Cell Line, Tumor; Pyrimidines; Female; Indazoles; Neoplasm Metastasis; Molybdenum; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Pancreatic Neoplasms; Xenograft Model Antitumor Assays
PubMed: 38826119
DOI: 10.1002/cam4.7291 -
International Journal of Molecular... Jun 2024The tumor microenvironment (TME) is crucial in tumor development, metastasis, and response to immunotherapy. DNA methylation can regulate the TME without altering the...
Identification and Validation of Tumor Microenvironment-Associated Signature in Clear-Cell Renal Cell Carcinoma through Integration of DNA Methylation and Gene Expression.
The tumor microenvironment (TME) is crucial in tumor development, metastasis, and response to immunotherapy. DNA methylation can regulate the TME without altering the DNA sequence. However, research on the methylation-driven TME in clear-cell renal cell carcinoma (ccRCC) is still lacking. In this study, integrated DNA methylation and RNA-seq data were used to explore methylation-driven genes (MDGs). Immune scores were calculated using the ESTIMATE, which was employed to identify TME-related genes. A new signature connected with methylation-regulated TME using univariate, multivariate Cox regression and LASSO regression analyses was developed. This signature consists of four TME-MDGs, including , , , and , which exhibit high methylation and low expression in tumors. Validation was performed using qRT-PCR which confirmed their downregulation in ccRCC clinical samples. Additionally, the signature demonstrated stable predictive performance in different subtypes of ccRCC. Risk scores are positively correlated with TMN stages, immune cell infiltration, tumor mutation burden, and adverse outcomes of immunotherapy. Interestingly, the expression of four TME-MDGs are highly correlated with the sensitivity of first-line drugs in ccRCC treatment, especially pazopanib. Molecular docking indicates a high affinity binding between the proteins and pazopanib. In summary, our study elucidates the comprehensive role of methylation-driven TME in ccRCC, aiding in identifying patients sensitive to immunotherapy and targeted therapy, and providing new therapeutic targets for ccRCC treatment.
Topics: Carcinoma, Renal Cell; Humans; Tumor Microenvironment; DNA Methylation; Kidney Neoplasms; Gene Expression Regulation, Neoplastic; Pyrimidines; Indazoles; Sulfonamides; Biomarkers, Tumor; Female; Molecular Docking Simulation; Gene Expression Profiling; Male
PubMed: 38928496
DOI: 10.3390/ijms25126792 -
World Journal of Clinical Cases Nov 2023Malignant schwannoma is a rare tumor in the peripheral nervous system, accounting for approximately 5% to 10% of systemic soft tissue sarcomas. Especially, malignant...
BACKGROUND
Malignant schwannoma is a rare tumor in the peripheral nervous system, accounting for approximately 5% to 10% of systemic soft tissue sarcomas. Especially, malignant schwannoma occurring in the broad ligament of the uterus with hemophilic syndrome and bone marrow fibrosis is extremely rare in clinical practice. Here, we report the first case of an patient diagnosed with malignant peripheral nerve sheath tumor (MPNST) of the broad ligament of the uterus with hemophilic syndrome and bone marrow fibrosis, and share our reference clinical diagnosis and treatment experience.
CASE SUMMARY
A patient was diagnosed with MPNST of the uterus harboring hemophilic syndrome and bone marrow fibrosis. She received combination, and repeated imaging revealed further encountered rare complications (hemophilia syndrome and bone marrow fibrosis) after two cycles of chemotherapy. Thereafter, combined treatment with pazopanib, gemcitabine, and dacarbazine was initiated. Unfortunately, the patient succumbed to death at hospital after two weeks.
CONCLUSION
This report firstly provided reference clinical practice for a patient with MPNST of the uterus harboring hemophilic syndrome and bone marrow fibrosis. Our case raises a reminder about the tolerance and safety of combination therapy, especially in young women.
PubMed: 38078124
DOI: 10.12998/wjcc.v11.i31.7673 -
Research Square Jun 2024Hereditary Hemorrhagic Telangiectasia (HHT) is a rare congenital disease in which fragile vascular malformations (VM) - including small telangiectasias and large...
Hereditary Hemorrhagic Telangiectasia (HHT) is a rare congenital disease in which fragile vascular malformations (VM) - including small telangiectasias and large arteriovenous malformations (AVMs) - focally develop in multiple organs. There are few treatment options and no cure for HHT. Most HHT patients are heterozygous for loss-of-function mutations affecting Endoglin (ENG) or Alk1 (ACVRL1); however, why loss of these genes manifests as VMs remains poorly understood. To complement ongoing work in animal models, we have developed a fully human, cell-based microphysiological model based on our Vascularized Micro-organ (VMO) platform (the HHT-VMO) that recapitulates HHT patient VMs. Using inducible -knockdown, we control timing and extent of endogenous Alk1 expression in primary human endothelial cells (EC). Resulting HHT-VMO VMs develop over several days. 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 implicates mural cell recruitment. Finally, lesion formation is blocked by the VEGFR inhibitor pazopanib, mirroring 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 can be used to better understand HHT disease biology and identify potential new HHT drugs. Word Count: 213 Biological Sciences, Cell Biology.
PubMed: 38947000
DOI: 10.21203/rs.3.rs-4578507/v1 -
Internal Medicine (Tokyo, Japan) Jun 2024Objective Many vascular endothelial growth factor (VEGF) pathway inhibitors are used in the treatment of patients with various advanced cancers; however, treatments...
Correlation between Efficacy and Cardiovascular Adverse Events in Patients with Advanced Solid Cancer Who Received VEGF Pathway Inhibitors: Hypertension within the First Eight Weeks is Associated with Favorable Outcomes of Patients Treated with VEGF Pathway Inhibitors.
Objective Many vascular endothelial growth factor (VEGF) pathway inhibitors are used in the treatment of patients with various advanced cancers; however, treatments induce cardiovascular adverse events (CVAEs), such as hypertension, heart failure, arrhythmia, arterial or venous embolism, and hemorrhage. Some studies have suggested a correlation between efficacy and CVAEs; however, further evidence is required. This study evaluated real-world data concerning the frequency and degree of CVAEs and possible associations between CVAEs and efficacy in such patients. Methods and Patients We analyzed CVAEs observed in 294 patients with advanced cancer who were treated with ramucirumab, regorafenib, pazopanib, sunitinib, or sorafenib. Results CVAEs of any grade and proteinuria within 8 weeks after the initiation of VEGF pathway inhibitors (early) or during the treatment period (total period) were observed in 72%-85% and 77%-92% of the patients, respectively. The progression-free survival (PFS) of patients with a CVAE of grade ≥1 in the early period was favorable compared with the PFS of those who had no CVAE (median, 4.9 vs. 3.5 months, P = 0.016, log-rank test). Furthermore, the PFS of patients with a CVAE grade ≥3 in the early period was favorable compared to that of those with CVAEs of grades 0-2. Taken together, a higher degree of CVAE was correlated with favorable patient outcomes. Conclusion This study revealed the frequency and degree of CVAEs in patients with solid cancers who received VEGF pathway inhibitors in a real-world setting and added evidence regarding the correlation between CVAEs and efficacy of VEGF pathway inhibitors.
PubMed: 38866528
DOI: 10.2169/internalmedicine.3373-23 -
Discover Oncology May 2024This research strived to construct a new signature utilizing disulfidptosis-related ferroptosis (SRF) genes to anticipate response to immunotherapy, prognosis, and drug...
BACKGROUND
This research strived to construct a new signature utilizing disulfidptosis-related ferroptosis (SRF) genes to anticipate response to immunotherapy, prognosis, and drug sensitivity in individuals with colorectal cancer (CRC).
METHODS
The data for RNA sequencing as well as corresponding clinical information of individuals with CRC, were extracted from The Cancer Genome Atlas (TCGA) dataset. SRF were constructed with the help of the random forest (RF), least absolute shrinkage and selection operator (LASSO), and stepwise regression algorithms. To validate the SRF model, we applied it to an external cohort, GSE38832. Prognosis, immunotherapy response, drug sensitivity, molecular functions of genes, and somatic mutations of genes were compared across the high- and low-risk groups (categories). Following this, all statistical analyses were conducted with the aid of the R (version 4.23) software and various packages of the Cytoscape (version 3.8.0) tool.
RESULTS
SRF was developed based on five genes (ATG7, USP7, MMD, PLIN4, and THDC2). Both univariate and multivariate Cox regression analyses established SRF as an independent, prognosis-related risk factor. Individuals from the high-risk category had a more unfavorable prognosis, elevated tumor mutational burden (TMB), and significant immunosuppressive status. Hence, they might have better outcomes post-immunotherapy and might benefit from the administration of pazopanib, lapatinib, and sunitinib.
CONCLUSION
In conclusion, SRF can act as a new biomarker for prognosis assessment. Moreover, it is also a good predictor of drug sensitivity and immunotherapy response in CRC but should undergo optimization before implementation in clinical settings.
PubMed: 38787520
DOI: 10.1007/s12672-024-01031-y -
The American Journal of Case Reports Oct 2023BACKGROUND Desmoid tumors are a fibroblastic proliferation of soft tissues, with an extreme inclination for local dissemination and recurrence. Surgical excision is the...
Unusual Presentation of an Uncommon Malignancy: A 74-Year-Old Woman with Aggressive Fibromatosis of the Large Intestine Presenting as a Liver Mass and the Therapeutic Management.
BACKGROUND Desmoid tumors are a fibroblastic proliferation of soft tissues, with an extreme inclination for local dissemination and recurrence. Surgical excision is the usual treatment choice, with data regarding pharmaceutical treatment being scarce. CASE REPORT A 74-year-old female patient was admitted to "Laikon" General Hospital of Athens, Greece presenting with acute kidney injury secondary to diarrhea. The ultrasound, CT, and abdominal MRI performed showed a 12×6×10 cm tumorous liver lesion. Biopsy of the lesion revealed loosely organized, mesenchymal tissue with spindle cells, and myxoid stroma. Immunochemistry was positive for SMA and b-catenin. Right hemicolectomy was performed with tumor-free surgical margins (R0 resection) and tamoxifen was initiated. Six months after the last MRI (3 months after the use of tamoxifen), a follow-up MRI was performed. The tumor had increased to 14.2×11×12.3 cm, and at the next follow-up it had grown to 20.3×19 cm maximal dimensions; no new metastases were found. The patient received sorafenib and pazopanib. Our patient had PFS with sorafenib for more than 2 years and remained in a good performance status (ECOG 1). For Pazopanid, the median PFS for this treatment option was 6.5 months. CONCLUSIONS The results were good and show a promising method for the treatment of this rare but severe malignancy.
Topics: Female; Humans; Aged; Fibromatosis, Aggressive; Sorafenib; Tamoxifen; Liver Neoplasms
PubMed: 37812585
DOI: 10.12659/AJCR.939862