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Translational Andrology and Urology Sep 2023Upper urinary tract urothelial carcinomas (UTUCs) are often identified and first treated endoscopically. After proper risk stratification, adjuvant treatment may be... (Review)
Review
Upper urinary tract urothelial carcinomas (UTUCs) are often identified and first treated endoscopically. After proper risk stratification, adjuvant treatment may be recommended. Consequently, as adjuvant therapy becomes more common place in the oncological armamentarium, we seek to better characterize its existing and future therapeutic landscape. In this article, we present an overview of the most up-to-date information about intracavitary instillations as an adjuvant therapy in the context of UTUC. We reviewed the current literature on the epidemiology, disease characteristics, treatment, and outcomes of UTUC with a particularly focus on intraluminal adjuvant therapy for UTUC. This review provides a comprehensive overview of the most recent available data regarding adjuvant therapies used for UTUC. Intraluminal therapy plays an increasingly important role in the management of UTUC. Mitomycin C is the most common adjuvant treatment for UTUC with bacillus Calmette-Guerin (BCG) being utilized to a lesser extent. UGN-101 is a novel topical gel-based therapy that has shown promising results and thus recently garnered Food and Drug Administration (FDA) approval for UTUC. Other treatments such as BCG-IFN, gemcitabine, docetaxel, and drug-eluting stents (DES) may play a future role in UTUC treatment given further research. It is important to caveat that current studies on topical adjuvant treatments demonstrate varying degrees of effectiveness. This is largely due to limited research on UTUC, consisting of small sample sizes, and mostly retrospective experiences. Accordingly, further clinical trials are needed to evaluate the true benefit of these treatments.
PubMed: 37814698
DOI: 10.21037/tau-23-35 -
Cancers Nov 2023Non-small-cell lung cancer (NSCLC) is a prevalent and often fatal malignancy. Advancements in targeted therapies have improved outcomes for NSCLC patients in the last... (Review)
Review
Non-small-cell lung cancer (NSCLC) is a prevalent and often fatal malignancy. Advancements in targeted therapies have improved outcomes for NSCLC patients in the last decade. Kirsten rat sarcoma virus (KRAS) is a commonly mutated oncogene in NSCLC, contributing to tumorigenesis and proliferation. Though classically difficult to target, recently developed KRAS G12C inhibitors (sotorasib and adagrasib) have now overcome this therapeutic hurdle. We discuss the evidence for these medications, their pitfalls and adverse effects, as well as future directions in this space. Though these medications demonstrate substantial response rates in a heavily pre-treated advanced NSCLC cohort, as phase-3 evidence does not yet demonstrate an overall survival benefit versus standard-of-care chemotherapy, docetaxel. Additionally, these medications appear to have a negative interaction in combination with immunotherapies, with substantially greater hepatotoxicity rates observed. Despite this, it is undeniable that these medications represent an important advancement in targeted and personalised oncological treatment. Current and future trials assessing these medications in combination and through sequencing strategies will likely yield further clinically meaningful outcomes to guide treatment in this patient cohort.
PubMed: 38067288
DOI: 10.3390/cancers15235582 -
Asian Journal of Andrology Apr 2024This study compared different doublet and triplet therapies for efficacy and safety in metastatic hormone-sensitive prostate cancer (mHSPC). PubMed, EMBASE, and the...
This study compared different doublet and triplet therapies for efficacy and safety in metastatic hormone-sensitive prostate cancer (mHSPC). PubMed, EMBASE, and the Cochrane Library were comprehensively searched for eligible randomized controlled trials (RCTs) published from inception to October 2023. Interventions included abiraterone, apalutamide, enzalutamide, docetaxel, darolutamide, and androgen deprivation therapy (ADT), either as doublet or triplet therapies. The outcomes examined were overall survival (OS), progression-free survival (PFS), castration-resistant prostate cancer (CRPC)-free survival, time to symptomatic skeletal event (SSE), and toxicity. The surface under the cumulative ranking curve (SUCRA) was determined to identify the preferred treatments. Ten RCTs were included. The combination of darolutamide, docetaxel, and ADT had the highest SUCRA of 84.3 for OS, followed by combined abiraterone, docetaxel, and ADT (SUCRA = 71.6). The highest SUCRAs for PFS were observed for triplet therapies (abiraterone, docetaxel, and ADT [SUCRA = 74.9], followed by enzalutamide, docetaxel, and ADT [SUCRA = 74.3]) and other androgen receptor axis-targeted therapy-based doublet therapies (SUCRAs: 26.5-59.3). Darolutamide, docetaxel, and ADT had the highest SUCRAs, i.e., 80.8 and 84.0 regarding CRPC-free survival and time to SSE, respectively. Regarding Grade >3 adverse events (AEs), the SUCRAs of triplet therapies (SUCRAs: 14.8-31.5) were similar to that of docetaxel and ADT (SUCRA = 39.5). Three studies had a low risk of bias in all categories; the remaining studies had at least an unclear risk of bias in at least one category. Triplet therapy demonstrated potentially enhanced effectiveness than doublet therapy in mHSPC, with acceptable safety concerns. Darolutamide might be the optimal option for triplet therapy in combination with docetaxel and ADT.
PubMed: 38624195
DOI: 10.4103/aja20242 -
Frontiers in Immunology 2023CXCL12 is a vital factor in physiological and pathological processes, by inducing migration of multiple cells. We aimed to comprehensively detect the role of CXCL12 in...
BACKGROUND
CXCL12 is a vital factor in physiological and pathological processes, by inducing migration of multiple cells. We aimed to comprehensively detect the role of CXCL12 in breast cancer, and explore novel CXCL12-related biomarkers through integrative multi-omics analyses to build a powerful prognostic model for breast cancer patients.
METHODS
Immunohistochemistry analysis of the tissue microarray was performed to evaluate the correlation between CXCL12 expression levels and breast cancer patient outcomes. Combined single-nucleus and spatial transcriptomics data was used to uncover the expression distribution of CXCL12 in breast cancer microenvironment. CXCL12-related genes were identified by WGCNA analysis. Univariate Cox and LASSO regression analyses were then conducted to screen prognostic genes from above CXCL12-related genes, followed by the construction of the CXCL12-related prognostic signature, identification of risk groups, and external validation of the prognostic signature. Analyses of biological function, mutation landscape, immune checkpoint genes and immune cells, were performed to further reveal the differences between high/low-risk groups. Paired single-cell RNA-seq and bulk RNA-seq were analyzed to further disclose the association between the risk score and the complex tumor immune microenvironment. To screen potential therapeutic agents for breast cancer patients, analyses of gene-drug correlation and sensitivity to immunotherapy were conducted.
RESULTS
High expression of CXCL12 was linked with a prolonged survival in breast cancer. A total of 402 genes were identified by WGCNA analysis and 11 genes, covering and , were screened as the candidate prognostic genes. Next, the prognostic signature was built and validated using these genes to predict the outcomes of breast cancers. The high-risk group patients exhibited significantly inferior prognoses. The combination of the risk score and tumor mutational burden (TMB) had remarkably improved performance in predicting patient outcomes. Besides, high-risk group patients showed higher infiltration of M2-like macrophages. Finally, several potential anticancer drugs were identified. The high-risk group patients were more sensitive to immunotherapy but resistant to docetaxel.
CONCLUSIONS
CXCL12 has important immunological implication and prognostic significance in breast cancer. The CXCL12-related prognostic model could well predict the prognosis and treatment response of breast cancers.
Topics: Humans; Female; Breast Neoplasms; Prognosis; Proprotein Convertase 9; Multiomics; Tumor Microenvironment; Neuropeptides; GPI-Linked Proteins; Chemokine CXCL12
PubMed: 37564657
DOI: 10.3389/fimmu.2023.1188351 -
Journal For Immunotherapy of Cancer Nov 2023It is possible to induce immunomodulation in HER2-positive breast cancer (BC) by modifying the route of administration of trastuzumab. (Randomized Controlled Trial)
Randomized Controlled Trial
Randomized, open-label, phase II, biomarker study of immune-mediated mechanism of action of neoadjuvant subcutaneous trastuzumab in patients with locally advanced, inflammatory, or early HER2-positive breast cancer-Immun-HER trial (GOIRC-01-2016).
BACKGROUND
It is possible to induce immunomodulation in HER2-positive breast cancer (BC) by modifying the route of administration of trastuzumab.
METHODS
In this multicenter randomized phase II trial, all enrolled patients (pts) with T2-T4d HER2-positive BC received 3 cycles of neoadjuvant treatment (NAT) with fluorouracil, epirubicin and cyclophosphamide every 3 weeks (q21), followed by docetaxel/pertuzumab plus intravenous trastuzumab (arm A) or, docetaxel/pertuzumab plus subcutaneous (SC) trastuzumab (arm B) q21x4 cycles. After surgical operation, each pt was treated with trastuzumab q21x14 cycles using the same SC or intravenous formulation of NAT. Primary endpoint was the proportion of subjects with high stromal tumor-infiltrating lymphocytes (sTILs) in postneoadjuvant residual disease (RD).
RESULTS
Sixty-three pts (31 (arm A) and 32 (arm B)) were enrolled. Pathological complete response was obtained by 20/31 pts (64.5%; 95% CI 45.4% to 80.1%) in arm A and 19/32 pts (59.4%; 95% CI 40.1% to 76.3%) in arm B. High sTILs were observed in 27% and 46% of postneoadjuvant residual tumors in arms A and B, respectively. CD8+ T cells increased significantly in RDs of both arms (p=0.014 and 0.002 for arm A and B, respectively), whereas a significant decline in the level of CD4+ FoxP3+ regulatory T cells was observed only in arm B (p=0.016). A significant upregulation of PD-1 on sTILs was found in RD of pts enrolled in arm B (p=0.012), while programmed death-ligand 1 (PD-L1) was significantly overexpressed in residual tumors of arm A (p=0.02). A strong negative correlation was reported in arm B between expression of PD-L1 on pretreatment sTILs and CD3 expression on sTILs in RD (τ: -0.73). Grade≥3 AE incidence rates were similar between the two arms.
CONCLUSIONS
SC trastuzumab induced relevant sTILs enrichment, with favorable variations of immune parameters in HER2-positive BC pts with RD after NAT. Novel immunotherapy strategies should be tested to achieve SC-specific, antitumor immune response.
TRIAL REGISTRATION NUMBER
NCT03144947, and EudraCT number: 2016-000435-41.
Topics: Humans; Female; Trastuzumab; Breast Neoplasms; B7-H1 Antigen; Docetaxel; Neoadjuvant Therapy; Neoplasm, Residual; Receptor, ErbB-2; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38016718
DOI: 10.1136/jitc-2023-007667 -
Radiation Oncology (London, England) Sep 2023Definitive radiotherapy plus concurrent chemotherapy has been a standard treatment for esophagus patients who are unfit to undergo surgery. However, there are a variety... (Randomized Controlled Trial)
Randomized Controlled Trial
Definitive concurrent chemoradiotherapy with docetaxel plus cisplatin versus 5-fluorouracil plus cisplatin in patients with esophageal squamous cell carcinoma: long-term follow-up results of a phase II randomized controlled trial.
BACKGROUND
Definitive radiotherapy plus concurrent chemotherapy has been a standard treatment for esophagus patients who are unfit to undergo surgery. However, there are a variety of concurrent chemotherapy regimens with varying efficacy. In this phase II prospective study, we compared the efficacy and toxicity of DP (docetaxel and cisplatin) and PF (cisplatin and 5-fluorouracil) regimens with concurrent chemoradiotherapy (CCRT) in patients with esophageal squamous cell carcinoma (ESCC) and analyzed the 5-year overall survival (OS) and progression free survival (PFS). We also summarized the salvage treatments and late toxicities.
METHODS
We enrolled 86 patients with clinical stage II-IVA from the Sun Yat-sen University Cancer Center. The patients were divided into two groups: PF group (41) and DP group (45). Statistics were analyzed using SPSS version 19.0.
RESULTS
The 5-year OS rates were 62.9% ± 7.6% in PF group, and 52.7% ± 7.5% in DP group (P = 0.131), respectively. The 5-year PFS rates were 43.9% ± 7.8% for PF group, and 40.0% ± 7.3% for DP group (P = 0.398), respectively. Sixteen patients in the DP group and thirteen in the PF group received salvage treatment. For those patients with local residual or local recurrent disease, the median survival time after salvage treatment was 13.5 months and the 1, 2, and 3-year survival rates were 79.0%, 50.3%, and 43.1%, respectively. For all patients, thirteen (15.1%) had Grade 2 late cardiac toxicities. One patient had Grade 2 pleural effusion and required diuretic. Most patients with pneumonia are mild, and only one patient in PF group had Grade 2 pneumonia. One patient in the DP group developed tracheoesophageal fistula.
CONCLUSIONS
The 5-year follow-up confirmed that definitive CCRT with the DP regimen did not improve the treatment response, OS, or PFS in patients with ESCC compared to the PF regimen. The PF regimen remains the standard regimen for definitive CCRT for patients with locally advanced ESCC. Long-term follow-up also suggested that appropriate and active salvage treatment has a survival benefit for some patients, and late cardiopulmonary toxicities should be noticed during follow-up.
TRIAL REGISTRATION
The trial was registered at https://clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT02969473, October 2010).
Topics: Humans; Docetaxel; Follow-Up Studies; Esophageal Squamous Cell Carcinoma; Cisplatin; Esophageal Neoplasms; Prospective Studies; Chemoradiotherapy; Fluorouracil
PubMed: 37700348
DOI: 10.1186/s13014-023-02339-9 -
Prostate International Sep 2023Multiple oral chemotherapeutic agents for metastatic hormone-sensitive prostate cancer (mHSPC) have been developed for conjugated use with conventional androgen...
BACKGROUND
Multiple oral chemotherapeutic agents for metastatic hormone-sensitive prostate cancer (mHSPC) have been developed for conjugated use with conventional androgen deprivation therapy (ADT). Several randomized controlled trials (RCTs) report significant benefits in mHSPC patients. Therefore, we compared overall survival (OS) and progression-free survival (PFS) benefits among considerable mHSPC oral chemotherapeutic agents.
MATERIALS AND METHODS
We investigated mHSPC treatment efficacy through a systematic RCT-trial literature review (PubMed, Embase, Web of Science, the Cochrane Library, and Scopus). Two reviewers independently screened, extracted data, and assessed bias risk in duplicate.
RESULTS
We identified 18 RCTs ( = 13,509). Concerning OS, ADT + abiraterone, ADT + abiraterone + docetaxel, ADT + apalutamide, ADT + bicalutamide, ADT + darolutamide + docetaxel, ADT + enzalutamide, ADT + orteronel, and ADT + rezvilutamide were more effective than the standard of care (SOC). Comparing PFS, most treatments were more effective than SOC, excluding ADT + bicalutamide, nilutamide, flutamide, ADT + bicalutamide + palbociclib, and ADT + nilutamide. ADT + docetaxel with androgen receptor targeted agent (ARTA) triplet therapy was not among the top three treatments determined through ranking analysis.
CONCLUSIONS
Novel oral chemotherapeutic agent combination therapies must replace current ADT monotherapy and ADT + docetaxel SOC. Even so, ADT + docetaxel with ARTA triplet therapy still is not the best mHSPC treatment and requires further study.
PubMed: 37745904
DOI: 10.1016/j.prnil.2023.06.003 -
Advances in Therapy Oct 2023Docetaxel is an established standard therapy after osimertinib and platinum-based doublet chemotherapy (Pt-doublet) for locally advanced or metastatic non-small cell...
INTRODUCTION
Docetaxel is an established standard therapy after osimertinib and platinum-based doublet chemotherapy (Pt-doublet) for locally advanced or metastatic non-small cell lung cancer (NSCLC) with an epidermal growth factor receptor gene (EGFR) mutation. To facilitate future therapeutic developments in these patients after treatment with osimertinib and Pt-doublet, we estimated the outcomes of currently used post-treatment therapies.
METHODS
Data of patients with NSCLC who received at least one medication after osimertinib and Pt-doublet between April 2008 and August 2021 were extracted from the Medical Data Vision claims database. The duration of treatment (DoT) (first treatment after osimertinib and Pt-doublet) and overall survival (OS) were estimated. The index date was the first day on which the medication was prescribed.
RESULTS
In total, 731 patients (mean age 64 years) were screened. The most frequent post-treatments were docetaxel-based chemotherapy (30.2%), immune checkpoint inhibitor (ICI) alone or in combination (17.2%), first-/second-generation EGFR-tyrosine kinase inhibitors (16.7%), osimertinib (16.3%), and Pt-doublet (5.2%). The median DoT and OS (95% confidence interval) of all post-treatments were 3.5 (3.27, 3.77) and 10.3 (9.3, 12.1) months, respectively, reflecting the median DoT (3.8 months) and OS (10.0 months) of docetaxel-based chemotherapy. Among all post-treatment regimens, ICIs resulted numerically the shortest [2.77 (2.33, 3.00) months] and osimertinib the longest [4.40 (3.47, 5.67) months] median DoT. The median OS was shortest in patients post-treated with ICIs [7.07 (5.40, 9.90) months] and longest in patients rechallenged with Pt-doublet (12.27 months), followed by patients post-treated with osimertinib (11.70 months). In a subset analysis of patients who received first-line osimertinib and second-line Pt-doublet as well as Pt-doublet immediately after osimertinib, those post-treated with ICIs had the shortest median DoT.
CONCLUSION
Given the limited real-world efficacy on EGFR-mutant NSCLC resistant to osimertinib and platinum-based chemotherapy, the development of more highly potent post-treatment therapies is warranted.
Topics: Humans; Middle Aged; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Genes, erbB-1; Docetaxel; Platinum; ErbB Receptors; Treatment Outcome; Protein Kinase Inhibitors; Mutation
PubMed: 37572265
DOI: 10.1007/s12325-023-02616-9 -
Drug Resistance Updates : Reviews and... Mar 2024This study aims to explore the function and mechanism of G Protein-coupled receptor class C group 5 member A (GPRC5A) in docetaxel-resistance and liver metastasis of...
AIMS
This study aims to explore the function and mechanism of G Protein-coupled receptor class C group 5 member A (GPRC5A) in docetaxel-resistance and liver metastasis of breast cancer.
METHODS
Single-cell RNA transcriptomic analysis and bioinformatic analysis are used to screen relevant genes in breast cancer metastatic hepatic specimens. MeRIP, dual-luciferase analysis and bioinformation were used to detect m6A modulation. Mass spectrometry (MS), co-inmunoprecipitation (co-IP) and immunofluorescence colocalization were executed to explore the mechanism of GPRC5A in breast cancer cells.
RESULT
GPRC5A was upregulated in triple-negative breast cancer (TNBC) and was associated with a poor prognosis. In vitro and in vivo experiments demonstrated that knockdown of GPRC5A alleviated metastasis and resistance to docetaxel in TNBC. Overexpression of GPRC5A had the opposite effects. The m6A methylation of GPRC5A mRNA was modulated by METTL3 and YTHDF1, which facilitates its translation. GPRC5A inhibited the ubiquitination-dependent degradation of LAMTOR1, resulting in the recruitment of mTORC1 to lysosomes and activating the mTORC1/p70s6k signaling pathway.
CONCLUSION
METTL3/YTHDF1 axis up-regulates GPRC5A expression by m6A methylation. GPRC5A activates mTORC1/p70s6k signaling pathway by recruiting mTORC1 to lysosomes, consequently promotes docetaxel-resistance and liver metastasis.
Topics: Humans; Docetaxel; Triple Negative Breast Neoplasms; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Methylation; Liver Neoplasms; Receptors, G-Protein-Coupled; TOR Serine-Threonine Kinases; Mechanistic Target of Rapamycin Complex 1; Methyltransferases
PubMed: 38335844
DOI: 10.1016/j.drup.2024.101063 -
Research (Washington, D.C.) 2023Prostate cancer (PCa) is a common malignant tumor with high morbidity and mortality worldwide. The prostate cancer stem cell (PCSC) model provides novel insights into...
AZGP1P2/UBA1/RBM15 Cascade Mediates the Fate Determinations of Prostate Cancer Stem Cells and Promotes Therapeutic Effect of Docetaxel in Castration-Resistant Prostate Cancer via TPM1 m6A Modification.
Prostate cancer (PCa) is a common malignant tumor with high morbidity and mortality worldwide. The prostate cancer stem cell (PCSC) model provides novel insights into the pathogenesis of PCa and its therapeutic response. However, the roles and molecular mechanisms of specific genes in mediating fate decisions of PCSCs and carcinogenesis of PCa remain to be elusive. In this study, we have explored the expression, function, and mechanism of AZGP1P2, a pseudogene of AZGP1, in regulating the stemness and apoptosis of PCSCs and treatment resistance of docetaxel in castration-resistant prostate cancer (CRPC). We revealed that AZGP1P2 was downregulated in CRPC cell lines and PCSCs, while it was positively associated with progression-free interval. Upregulation of the AZGP1P2 enhanced the sensitivity of docetaxel treatment in CRPCs via inhibiting their stemness. RNA pull-down associated with mass spectrometry analysis, co-immunoprecipitation assay, and RNA immunoprecipitation assay demonstrated that AZGP1P2 could bind to UBA1 and RBM15 as a "writer" of methyltransferase to form a compound. UBA1, an E1 ubiquitin-activating enzyme, contributed to RBM15 protein degradation via ubiquitination modification. Methylated RNA immunoprecipitation assay displayed that RBM15 controlled the mRNA decay of TPM1 in m6A methylation. Furthermore, a xenograft mouse model and patient-derived organoids showed that the therapeutic effect of docetaxel in CRPC was increased by AZGP1P2 in vivo. Collectively, these results imply that AZGP1P2 mediates the stemness and apoptosis of PCSCs and promotes docetaxel therapeutic effect by suppressing tumor growth and metastasis via UBA1/RBM15-mediated TPM1 mRNA decay in CRPC.
PubMed: 37854295
DOI: 10.34133/research.0252