-
International Journal of Molecular... Dec 2022Mucositis is a common and most debilitating complication associated with the cytotoxicity of chemotherapy. The condition affects the entire alimentary canal from the... (Review)
Review
Mucositis is a common and most debilitating complication associated with the cytotoxicity of chemotherapy. The condition affects the entire alimentary canal from the mouth to the anus and has a significant clinical and economic impact. Although oral and intestinal mucositis can occur concurrently in the same individual, these conditions are often studied independently using organ-specific models that do not mimic human disease. Hence, the purpose of this scoping review was to provide a comprehensive yet systematic overview of the animal models that are utilised in the study of chemotherapy-induced mucositis. A search of PubMed/MEDLINE and Scopus databases was conducted to identify all relevant studies. Multiple phases of filtering were conducted, including deduplication, title/abstract screening, full-text screening, and data extraction. Studies were reported according to the updated Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. An inter-rater reliability test was conducted using Cohen's Kappa score. After title, abstract, and full-text screening, 251 articles met the inclusion criteria. Seven articles investigated both chemotherapy-induced intestinal and oral mucositis, 198 articles investigated chemotherapy-induced intestinal mucositis, and 46 studies investigated chemotherapy-induced oral mucositis. Among a total of 205 articles on chemotherapy-induced intestinal mucositis, 103 utilised 5-fluorouracil, 34 irinotecan, 16 platinum-based drugs, 33 methotrexate, and 32 other chemotherapeutic agents. Thirteen articles reported the use of a combination of 5-fluorouracil, irinotecan, platinum-based drugs, or methotrexate to induce intestinal mucositis. Among a total of 53 articles on chemotherapy-induced oral mucositis, 50 utilised 5-fluorouracil, 2 irinotecan, 2 methotrexate, 1 topotecan and 1 with other chemotherapeutic drugs. Three articles used a combination of these drugs to induce oral mucositis. Various animal models such as mice, rats, hamsters, piglets, rabbits, and zebrafish were used. The chemotherapeutic agents were introduced at various dosages via three routes of administration. Animals were mainly mice and rats. Unlike intestinal mucositis, most oral mucositis models combined mechanical or chemical irritation with chemotherapy. In conclusion, this extensive assessment of the literature revealed that there was a large variation among studies that reproduce oral and intestinal mucositis in animals. To assist with the design of a suitable preclinical model of chemotherapy-induced alimentary tract mucositis, animal types, routes of administration, dosages, and types of drugs were reported in this study. Further research is required to define an optimal protocol that improves the translatability of findings to humans.
Topics: Animals; Rats; Mice; Humans; Rabbits; Swine; Zebrafish; Reproducibility of Results; Mucositis; Irinotecan; Fluorouracil; Antineoplastic Agents; Stomatitis; Methotrexate
PubMed: 36499758
DOI: 10.3390/ijms232315434 -
Cancers Dec 2022Cervical cancer (CC) constitutes the fourth most common tumor among the female population. Therapeutic approaches to advanced CC are limited, with dismal results in... (Review)
Review
BACKGROUND
Cervical cancer (CC) constitutes the fourth most common tumor among the female population. Therapeutic approaches to advanced CC are limited, with dismal results in terms of survival, mainly after progression to platinum-based regimens. Immune checkpoint inhibitors (ICIs) are remodeling the therapeutic scenario of many solid tumors. The role of ICIs in CC should be addressed. Therefore, we systematically reviewed the latest clinical trials employing ICIs in advanced CC to assess which ICIs have been employed and how ICIs might meet the need for new therapeutic options in terms of efficacy and safety.
METHODS
The review was conducted following the PRISMA guidelines. The following efficacy outcomes were specifically collected: overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS); for safety: type, number, and grade of adverse events (AEs).
RESULTS
A total of 17 studies were analyzed. Anti-PD1 (pembrolizumab, nivolumab, cemiplimab, balstilimab, and tislelizumab), anti-PD-L1 (atezolizumab), and anti-CTLA-4 (ipilimumab, zalifrelimab) agents were employed both as single agents or combinations. Overall ORR ranged from 0% to 65.9%. ORR ranged from 5.9% to 69.6% in PD-L1-positive patients and from 0% to 50% in PD-L1-negative patients. DCR was 30.6-94.1%. mPFS ranged from 2 to 10.4 months. mOS ranged from 8 months to not reached. PD-L1 status did not impact survival. A total of 33.9% to 100% of patients experienced AEs.
CONCLUSION
Immunotherapy represents an appealing strategy for patients with advanced CC, as 2 out of 3 patients seem to respond to ICIs. PD-L1 status might be an indicator of response without impacting survival.
PubMed: 36497437
DOI: 10.3390/cancers14235955 -
Frontiers in Pharmacology 2022The Platinum-based combination has been proven to have an outstanding effect on patients with platinum-sensitive recurrent ovarian cancer (PSROC), but the best...
The Platinum-based combination has been proven to have an outstanding effect on patients with platinum-sensitive recurrent ovarian cancer (PSROC), but the best scientific combination has not been established yet. The present study is aimed to seek the best treatment plan for PSROC. We did a systematic review and Bayesian network meta-analysis, during which lite before March 2022 were retrieved on PubMed, Embase, Web of Science, and Cochrane Central Registry of Controlled databases. We included randomized controlled clinical trials comparing chemotherapy combinations with other treatments for patients with PSROC. The important outcomes concerned were progression-free survival (PFS) (the primary outcome), overall survival (OS), objective response rate (ORR), adverse events (AEs), and AEs-related discontinuation. All outcomes were ranked according to the surface under the cumulative ranking curve. 26 trials involving 10441 patients were retrieved in this study. For the initial treatment of PSROC, carboplatin plus pegylated liposomal doxorubicin (PLD) plus bevacizumab had the best PFS [hazard ratio (HR) 0.59, 95% credible interval (CI) 0.51-0.68]; Carboplatin plus paclitaxel plus bevacizumab resulted in the best OS (HR 1.22, 95% CI 1.09-1.35) and ORR [odds ratio (OR) 1.22, 95% CI 1.09-1.35]. For the maintenance therapy in PSROC, poly (ADP-ribose) polymerase inhibitors (PARPi) following platinum-based chemotherapy provided the best PFS (HR 0.64, 95% CI 0.61-0.68), the highest frequency of adverse events of grade three or higher (OR 0.18, 95% CI 0.07-0.44) but the treatment discontinuation was generally low. Subgroup analysis suggested that trabectedin plus PLD was comparable to single platinum in prolonging PFS in the platinum-free interval (6-12 months). Both platinum-based chemotherapy plus PARPi and platinum-based chemotherapy plus bevacizumab had higher survival benefits than other treatments in PSROC. Trabectedin plus PLD might be a potential alternative treatment strategy for the partially platinum-sensitive subpopulation with intolerance to platinum. : [https://www.crd.york.ac.uk/prospero/display_record.php?], identifier [CRD42022326573].
PubMed: 36438821
DOI: 10.3389/fphar.2022.1010626 -
Oncogene Jan 2023Over the last 40 years osteosarcoma (OS) survival has stagnated with patients commonly resistant to neoadjuvant MAP chemotherapy involving high dose methotrexate,...
Over the last 40 years osteosarcoma (OS) survival has stagnated with patients commonly resistant to neoadjuvant MAP chemotherapy involving high dose methotrexate, adriamycin (doxorubicin) and platinum (cisplatin). Due to the rarity of OS, the generation of relevant cell models as tools for drug discovery is paramount to tackling this issue. Four literature databases were systematically searched using pre-determined search terms to identify MAP resistant OS cell lines and patients. Drug exposure strategies used to develop cell models of resistance and the impact of these on the differential expression of resistance associated genes, proteins and non-coding RNAs are reported. A comparison to clinical studies in relation to chemotherapy response, relapse and metastasis was then made. The search retrieved 1891 papers of which 52 were relevant. Commonly, cell lines were derived from Caucasian patients with epithelial or fibroblastic subtypes. The strategy for model development varied with most opting for continuous over pulsed chemotherapy exposure. A diverse resistance level was observed between models (2.2-338 fold) with 63% of models exceeding clinically reported resistance levels which may affect the expression of chemoresistance factors. In vitro p-glycoprotein overexpression is a key resistance mechanism; however, from the available literature to date this does not translate to innate resistance in patients. The selection of models with a lower fold resistance may better reflect the clinical situation. A comparison of standardised strategies in models and variants should be performed to determine their impact on resistance markers. Clinical studies are required to determine the impact of resistance markers identified in vitro in poor responders to MAP treatment, specifically with respect to innate and acquired resistance. A shift from seeking disputed and undruggable mechanisms to clinically relevant resistance mechanisms may identify key resistance markers that can be targeted for patient benefit after a 40-year wait.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Cisplatin; Clinical Relevance; Doxorubicin; Neoplasm Recurrence, Local; Osteosarcoma; Drug Resistance, Neoplasm
PubMed: 36434179
DOI: 10.1038/s41388-022-02529-x -
Frontiers in Oncology 2022The ecteinascidins trabectedin and lurbinectedin are very interesting antineoplastic agents, with a favorable toxicity profile and peculiar mechanisms of action. These...
Trabectedin and lurbinectedin: Mechanisms of action, clinical impact, and future perspectives in uterine and soft tissue sarcoma, ovarian carcinoma, and endometrial carcinoma.
The ecteinascidins trabectedin and lurbinectedin are very interesting antineoplastic agents, with a favorable toxicity profile and peculiar mechanisms of action. These drugs form adducts in the minor groove of DNA, which produce single-strand breaks (SSBs) and double-strand breaks (DSBs) and trigger a series of events resulting in cell cycle arrest and apoptosis. Moreover, the ecteinascidins interact with the tumor microenvironment, reduce the number of tumor-associated macrophages, and inhibit the secretion of cytokines and chemokines. Trabectedin has been approved by the Federal Drug Administration (FDA) for patients with unresectable or metastatic liposarcoma or leiomyosarcoma who received a prior anthracycline-based regimen. Moreover, trabectedin in combination with pegylated liposomal doxorubicin (PLD) has been approved in the European Union for the treatment of platinum-sensitive recurrent ovarian cancer. Lurbinectedin has been approved by the FDA for patients with metastatic small cell lung cancer with disease progression on or after platinum-based chemotherapy. The review assesses and experimental studies on the antineoplastic effects of both ecteinascidins as well as the clinical trials on the activity of trabectedin in uterine sarcoma and ovarian carcinoma and of lurbinectedin in ovarian carcinoma and endometrial carcinoma.
PubMed: 36408147
DOI: 10.3389/fonc.2022.914342 -
Therapeutic Advances in Medical Oncology 2022To investigate whether Adjunctive PD-1 inhibitors have improved clinical outcomes compared to chemotherapy alone in platinum-pretreated and platinum-naive recurrent or...
OBJECTIVE
To investigate whether Adjunctive PD-1 inhibitors have improved clinical outcomes compared to chemotherapy alone in platinum-pretreated and platinum-naive recurrent or metastatic nasopharyngeal carcinoma (R/M NPCA).
METHODS
The study involved a literature search from PubMed, Cochrane CENTRAL, and Google Scholar for randomized clinical trials (RCTs) on the use of PD-1 inhibitors chemotherapy alone in patients with R/M NPCA. Bias was assessed using Cochrane collaboration's risk of bias tool. Overall Survival (OS) was examined as the primary endpoint. Secondary endpoints were Progression-Free Survival (PFS), Objective Response Rate, Disease Control Rate (DCR), Duration of Response, and Serious/Grade ⩾3 Adverse Events. Outcomes were measured with either Mean Difference, Risk ratio (RR), or Hazard ratios (HRs) at 95% confidence interval.
RESULTS
Four RCTs were included in the meta-analysis and systematic review. OS for the monotherapy subgroup was a HR of 0.87 [0.67, 1.13] ( = 0.30) while the combination subgroup had 0.64 [0.45, 0.90] ( = 0.01). The monotherapy subgroup exhibited significantly worse outcomes in PFS (HR 1.31 [1.01, 1.68]) ( = 0.04) and DCR (RR 1.52 [1.12, 2.05]) ( = 0.007) but no significant difference in other outcomes. For combination therapy, a statistically significant benefit can be seen in all outcomes except DCR (RR 0.62 [0.38, 1.01]) ( = 0.06) which was a non-significant benefit favoring PD-1 inhibitors.
CONCLUSION
Combination PD-1 inhibitor + chemotherapy followed by maintenance PD-1 inhibitor therapy is superior to chemotherapy alone in the first-line treatment of R/M NPCA, implying a potential benefit with the use of PD-1 inhibitors + chemotherapy with maintenance PD-1 inhibitors as first-line in R/M NPCA compared to standard chemotherapy alone.
PubMed: 36407786
DOI: 10.1177/17588359221137429 -
Journal of the Association For Research... Feb 2023Identifying risk factors for tinnitus could facilitate not only the recommendations for prevention measures, but also identifying potential pathways for new... (Meta-Analysis)
Meta-Analysis
AIMS/HYPOTHESIS
Identifying risk factors for tinnitus could facilitate not only the recommendations for prevention measures, but also identifying potential pathways for new interventions. This study reports the first comprehensive systematic review of analytical observational studies able to provide information about causality (i.e., case-control and cohort designs).
METHODS
A literature search of four electronic databases identified epidemiological studies published on tinnitus and different exposures. Independent raters screened all studies, extracted data, and evaluated study quality using the Newcastle-Ottawa Scale. Reported relative risks (RR), hazard ratios (HR), odds ratios (OR), and prevalence ratios (PR) with 95% confidence intervals (CI) were used to compute crude estimates of RR for tinnitus risk factors.
RESULTS
From 2389 records identified, a total of 374 articles were read as full text (24 reviews, 301 cross-sectional studies, 42 cohort studies, and 7 case-control studies). However, from 49 case-control and cohort studies, only 25 adequately reported risk ratios. Using the findings from these studies, positive causal associations were found for various hearing-related factors (i.e., unspecified hearing loss, sensorineural hearing loss, occupational noise exposure, ototoxic platinum therapy, and otitis media). Evidence was also found for a number of non-otological risk factors including temporo-mandibular joint disorder, depression, chronic obstructive pulmonary disease, and hyperlipidemia. Negative associations indicating preventative effects were found for diabetes and high alcohol consumption. No associations were found for low alcohol consumption, body mass index, head injury, heart failure, hypertension, leisure noise exposure, migraine, rheumatoid arthritis, sex, smoking, stroke, and whiplash. However, with the exception of unspecified hearing loss, these findings resulted from pooling no more than 4 studies, illustrating that the vast majority of the associations still remain inconclusive.
CONCLUSIONS
These systematic review and meta-analysis confirm a number of otological and non-otological risk factors for tinnitus. By highlighting major gaps in knowledge, our synthesis can help provide direction for future research that will shed light on the pathophysiology, improve management strategies, and inform more effective preventions.
Topics: Humans; Tinnitus; Cross-Sectional Studies; Hearing Loss; Risk Factors; Hearing Loss, Sensorineural; Observational Studies as Topic
PubMed: 36380120
DOI: 10.1007/s10162-022-00874-y -
European Journal of Medical Research Nov 2022Neoadjuvant chemotherapy (NAC) for locally advanced gastric and gastroesophageal junction adenocarcinoma (LAGC) has been recommended in several guidelines. However,... (Meta-Analysis)
Meta-Analysis
The optimal neoadjuvant chemotherapy regimen for locally advanced gastric and gastroesophageal junction adenocarcinoma: a systematic review and Bayesian network meta-analysis.
BACKGROUND
Neoadjuvant chemotherapy (NAC) for locally advanced gastric and gastroesophageal junction adenocarcinoma (LAGC) has been recommended in several guidelines. However, there is no global consensus about the optimum of NAC regimens. We aimed to determine the optimal NAC regimen for LAGC.
METHODS
A systematic review and Bayesian network meta-analysis was performed. The literature search was conducted from inception to June 2022. The odds ratio (OR) value and 95% confidence interval (95% CI) were used for assessment of R0 resection rate and pathological complete response rate (pCR) as primary outcomes. The hazard ratio (HR) value and 95% CI were interpreted for the assessment of overall survival (OS) and disease-free survival (DFS) as second outcomes. The risk ratio (RR) value and 95% CI were used for safety assessment.
RESULTS
Twelve randomized controlled trials were identified with 3846 eligible participants. The network plots for R0 resectability, OS, and DFS constituted closed loops. The regimens of TPF (taxane and platinum plus fluoropyrimidine), ECF (epirubicin and cisplatin plus fluorouracil), and PF (platinum plus fluoropyrimidine) showed a meaningful improvement of R0 resectability, as well as OS and/or DFS, compared with surgery (including surgery-alone and surgery plus postoperative adjuvant chemotherapy). Importantly, among these regimens, TPF regimen showed significant superiority in R0 resection rate (versus ECF regimen), OS (versus ECF regimen), DFS (versus PF and ECF regimens), and pCR (versus PF regimen).
CONCLUSIONS
The taxane-based triplet regimen of TPF is likely the optimal neoadjuvant chemotherapy regimen for LAGC patients.
Topics: Humans; Neoadjuvant Therapy; Network Meta-Analysis; Bayes Theorem; Platinum; Stomach Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Adenocarcinoma; Taxoids; Esophagogastric Junction; Chemotherapy, Adjuvant; Fluorouracil
PubMed: 36352476
DOI: 10.1186/s40001-022-00878-7 -
Therapeutic Advances in Medical Oncology 2022The role of bevacizumab combined with paclitaxel and carboplatin in the first-line treatment of advanced non-squamous non-small-cell lung cancer (NSCLC) has been...
Efficacy and safety of adding bevacizumab biosimilar or original drug to platinum-based chemotherapy as first-line treatment in patients with advanced NSCLC: a systematic review and meta-analysis.
INTRODUCTION
The role of bevacizumab combined with paclitaxel and carboplatin in the first-line treatment of advanced non-squamous non-small-cell lung cancer (NSCLC) has been supported by a large number of data. However, whether bevacizumab biosimilars have the same efficacy and safety as the original drug is still controversial. This meta-analysis was designed to evaluate whether bevacizumab biosimilars have the same clinical efficacy and safety as the original drug in patients with advanced non-squamous NSCLC.
METHODS
Electronic databases (PubMed, Embase, Cochrane, CNKI, Wanfang, and VIP) and the ClinicalTrail.gov website were extensively searched using relevant search criteria. We included phase III randomized controlled trials (RCTs) to compare the efficacy and safety of marketed biosimilars and Avastin in the first-line treatment of patients with advanced NSCLC. The risk of bias of the included studies was assessed using the RoB 2 assessment scale, and the RevMan 5.4 statistical software was used for meta-analysis.
RESULTS
A total of 6360 patients were included in 11 RCTs. There was no statistical difference between the experimental group and the control group in terms of effectiveness [objective response rate (at week 18), disease control rate (at week 18), median duration of response, median progression-free survival, median overall survival (OS), and OS after 12 months]. In terms of safety [treatment-emergent adverse events (grade ⩾3) and treatment-related adverse events (grade ⩾3)], there was also no significant difference between biosimilars and Avastin.
CONCLUSIONS
The efficacy and safety of bevacizumab biosimilars in the treatment of advanced non-squamous NSCLC are highly similar to those of the original drug combined with paclitaxel and carboplatin, respectively.
PubMed: 36312816
DOI: 10.1177/17588359221130501 -
Cell Death & Disease Oct 2022PARP inhibitors (PARPi) have revolutionized the therapeutic landscape of epithelial ovarian cancer (EOC) treatment with outstanding benefits in regard to...
PARP inhibitors (PARPi) have revolutionized the therapeutic landscape of epithelial ovarian cancer (EOC) treatment with outstanding benefits in regard to progression-free survival, especially in patients either carrying BRCA1/2 mutations or harboring defects in the homologous recombination repair system. Yet, it remains uncertain which PARPi to apply and how to predict responders when platinum sensitivity is unknown. To shed light on the predictive power of genes previously suggested to be associated with PARPi response, we systematically reviewed the literature and identified 79 publications investigating a total of 93 genes. The top candidate genes were further tested using a comprehensive CRISPR-Cas9 mutagenesis screening in combination with olaparib treatment. Therefore, we generated six constitutive Cas9 EOC cell lines and profiled 33 genes in a CRISPR-Cas9 cell competition assay using non-essential (AAVS1) and essential (RPA3 and PCNA) genes for cell fitness as negative and positive controls, respectively. We identified only ATM, MUS81, NBN, BRCA2, and RAD51B as predictive markers for olaparib response. As the major survival benefit of PARPi treatment was reported in platinum-sensitive tumors, we next assessed nine top candidate genes in combination with three PARPi and carboplatin. Interestingly, we observed similar dropout rates in a gene and compound independent manner, supporting the strong correlation of cancer cell response to compounds that rely on DNA repair for their effectiveness. In addition, we report on CDK12 as a common vulnerability for EOC cell survival and proliferation without altering the olaparib response, highlighting its potential as a therapeutic target in EOC.
Topics: Humans; Female; Poly(ADP-ribose) Polymerase Inhibitors; Carcinoma, Ovarian Epithelial; Carboplatin; CRISPR-Cas Systems; Early Detection of Cancer; Phthalazines; Ovarian Neoplasms; Genes, Overlapping
PubMed: 36307400
DOI: 10.1038/s41419-022-05347-x