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European Journal of Clinical... Feb 2016The possible role of BRAF(V) (600E) mutation in the diagnosis and prognosis of papillary thyroid carcinoma (PTC) remains controversial. A systematic review to... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The possible role of BRAF(V) (600E) mutation in the diagnosis and prognosis of papillary thyroid carcinoma (PTC) remains controversial. A systematic review to investigate the diagnostic and prognostic role of BRAF(V) (600E) mutation in patients with PTC is urgently needed.
METHODS
A systematic review of relevant literatures was performed in PubMed, EMBASE and CENTRAL. The incremental accuracy (IA) of fine needle aspiration biopsy plus BRAF(V) (600E) mutation analysis over fine needle aspiration biopsy alone, and the statistical data about the association of BRAF(V) (600E) mutation and the prognosis of PTC (risk ratios (RR) for dichotomous data, standard mean differences for continuous data and hazard ratios (HRs) for disease-free survival (DFS) were pooled. Subgroup analysis was performed to explain the heterogeneities.
RESULTS
A total of 67 studies were included. The pooled IA was 2% (95% confidence interval (CI): 0·5-4%). The pooled RR for gender, multifocality, lymph node metastasis, extrathyroidal invasion and pathological stage was 1·11 (95% CI: 0·98-1·25), 1·17 (95% CI: 1·09-1·24), 1·36 (95% CI: 1·20-1·53), 1·60 (95% CI: 1·41-1·82), and 1·49 (95% CI: 1·33-1·68), respectively. The pooled standard mean differences for age and tumour size were 0·14 (95% CI: 0·04-0·23) and 0·21 (95% CI: 0·1-0·32), respectively. The pooled HR for DFS was 1·96 (95% CI: 1·62-2·37). Subgroup analysis showed that these statistical results were affected by the geographical background of patients, study design and detection methods.
CONCLUSIONS
BRAF(V) (600E) mutation analysis can not only be used in the diagnosis of PTC, but can also predict its prognosis.
Topics: Biopsy, Fine-Needle; Carcinoma; Carcinoma, Papillary; Disease-Free Survival; Humans; Mutation; Prognosis; Proportional Hazards Models; Proto-Oncogene Proteins B-raf; Thyroid Cancer, Papillary; Thyroid Neoplasms
PubMed: 26648183
DOI: 10.1111/eci.12577 -
European Urology Dec 2017The European Association of Urology Renal Cell Carcinoma Guideline Panel recently conducted a systematic review of treatment options for patients with advanced... (Review)
Review
CONTEXT
The European Association of Urology Renal Cell Carcinoma Guideline Panel recently conducted a systematic review of treatment options for patients with advanced non-clear-cell renal cell carcinomas (RCCs), which showed a substantial lack of evidence for management recommendations.
OBJECTIVE
To improve the outcomes of patients with rare kidney cancers (RKCs), we performed a subsequent unstructured review to determine current treatment strategies and druggable pathways, involving key stakeholders with a global perspective to generate recommendations.
EVIDENCE ACQUISITION
Based on the systematic review, literature was queried in Pubmed, Medline, and abstracts from proceedings of European Society for Medical Oncology and American Society of Clinical Oncology, in addition to consulting key opinion leaders and stakeholders. A conventional narrative review strategy was adopted to summarize the data.
EVIDENCE SYNTHESIS
The systematic review showed an absence of evidence for treating RKCs, with data only supporting sunitinib or MET inhibitors for some specific subtypes. However, a growing body of evidence implicates druggable pathways in specific RKC subtypes. To test hypotheses, the small patient numbers in each subtype require coordinated multicenter efforts. Many RKC patients are currently excluded from studies or are not analyzed using subtype-specific parameters, despite their unmet medical need.
CONCLUSIONS
We recognize the need for additional multicenter studies and subtype-specific analyses; however, we present management recommendations based on the data available. Web-based tools facilitating subtype-specific global registries and shared translational research resources will help generate sufficient data to formulate evidence-based recommendations for guidelines.
PATIENT SUMMARY
Patients confronted with rare kidney cancers are often treated the same way as clear-cell renal cell carcinoma patients, despite little evidence from randomized trials. Molecular characterization of tumors to stratify patients may improve outcomes. Availability of potential agents and trials remain a problem. Collaboration among medical centers is important to pool scarce data.
Topics: Antineoplastic Agents, Immunological; Carcinoma, Renal Cell; Genomics; Humans; Kidney Neoplasms; Molecular Targeted Therapy; Nephrectomy; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Rare Diseases; Signal Transduction
PubMed: 28720391
DOI: 10.1016/j.eururo.2017.06.040 -
Critical Reviews in Oncology/hematology Nov 2021Despite a well-known prognostic role in colorectal cancer, the genomic profiling of tumour budding remains to be elucidated. We aim to review the association of common... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Despite a well-known prognostic role in colorectal cancer, the genomic profiling of tumour budding remains to be elucidated. We aim to review the association of common mutations with tumour budding.
METHODS
A systematic review of studies relating to tumour budding and genetic mutation in CRC was performed. The relationship between mutational status and tumour budding was evaluated using meta-analysis.
RESULTS
A total of 6153 patients from 17 articles were included. According to the meta-analysis, high-grade tumour budding was significantly associated with KRAS mutation (OR = 1.52, 95 %CI: 1.13-2.02, P = 0.005) and MSS/pMMR (OR = 2.06, 95 %CI: 1.42-2.97, P = 0.0001).
CONCLUSION
The significant association between high-grade tumour budding and mutated KRAS or MSS/pMMR may suggest a role of these mutations in the development of the tumour budding phenotype and be useful for stratifying patient outcome in CRC.
Topics: Colorectal Neoplasms; Humans; Mutation; Phenotype; Prognosis; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras)
PubMed: 34619332
DOI: 10.1016/j.critrevonc.2021.103490 -
European Heart Journal Dec 2013We conducted a systematic review and meta-analysis of studies reporting circulating IL-6 in AAA, and new investigations of the association between a common... (Meta-Analysis)
Meta-Analysis Review
METHODS
We conducted a systematic review and meta-analysis of studies reporting circulating IL-6 in AAA, and new investigations of the association between a common non-synonymous functional variant (Asp358Ala) in the IL-6R gene (IL6R) and AAA, followed the analysis of the variant both in vitro and in vivo. Inflammation may play a role in the development of abdominal aortic aneurysms (AAA). Interleukin-6 (IL-6) signalling through its receptor (IL-6R) is one pathway that could be exploited pharmacologically. We investigated this using a Mendelian randomization approach.
RESULTS
Up to October 2011, we identified seven studies (869 cases, 851 controls). Meta-analysis demonstrated that AAA cases had higher levels of IL-6 than controls [standardized mean difference (SMD) = 0.46 SD, 95% CI = 0.25-0.66, I(2) = 70%, P = 1.1 × 10-5 random effects]. Meta-analysis of five studies (4524 cases/15 710 controls) demonstrated that rs7529229 (which tags the non-synonymous variant Asp358Ala, rs2228145) was associated with a lower risk of AAA, per Ala358 allele odds ratio 0.84, 95% CI: 0.80-0.89, I(2) = 0%, P = 2.7 × 10-11). In vitro analyses in lymphoblastoid cell lines demonstrated a reduction in the expression of downstream targets (STAT3, MYC and ICAM1) in response to IL-6 stimulation in Ala358 carriers.
CONCLUSIONS
A Mendelian randomization approach provides robust evidence that signalling via the IL-6R is likely to be a causal pathway in AAA. Drugs that inhibit IL-6R may play a role in AAA management.
Topics: Aged; Aortic Aneurysm, Abdominal; Cell Line; Epidemiologic Methods; Female; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Male; Mendelian Randomization Analysis; Middle Aged; Proto-Oncogene Proteins c-myc; Receptors, Interleukin-6; STAT3 Transcription Factor; Signal Transduction
PubMed: 23111417
DOI: 10.1093/eurheartj/ehs354 -
International Journal of Molecular... Jun 2023Pituitary tumors (PT) are mostly benign, although occasionally they demonstrate aggressive behavior, invasion of surrounding tissues, rapid growth, resistance to... (Review)
Review
Pituitary tumors (PT) are mostly benign, although occasionally they demonstrate aggressive behavior, invasion of surrounding tissues, rapid growth, resistance to conventional treatments, and multiple recurrences. The pathogenesis of PT is still not fully understood, and the factors responsible for its invasiveness, aggressiveness, and potential for metastasis are unknown. RAF/MEK/ERK and mTOR signaling are significant pathways in the regulation of cell growth, proliferation, and survival, its importance in tumorigenesis has been highlighted. The aim of our review is to determine the role of the activation of PI3K/AKT/mTOR and RAF/MEK/ERK pathways in the pathogenesis of pituitary tumors. Additionally, we evaluate their potential in a new therapeutic approach to provide alternative therapies and improved outcomes for patients with aggressive pituitary tumors that do not respond to standard treatment. We perform a systematic literature search using the PubMed, Embase, and Scopus databases (search date was 2012-2023). Out of the 529 screened studies, 13 met the inclusion criteria, 7 related to the PI3K/AKT/mTOR pathway, and 7 to the RAF/MEK/ERK pathway (one study was used in both analyses). Understanding the specific factors involved in PT tumorigenesis provides opportunities for targeted therapies. We also review the possible new targeted therapies and the use of mTOR inhibitors and TKI in PT management. Although the RAF/MEK/ERK and PI3K/AKT/mTOR pathways play a pivotal role in the complex signaling network along with many interactions, further research is urgently needed to clarify the exact functions and the underlying mechanisms of these signaling pathways in the pathogenesis of pituitary adenomas and their role in its invasiveness and aggressive clinical outcome.
Topics: Humans; MAP Kinase Signaling System; Proto-Oncogene Proteins c-akt; Pituitary Neoplasms; Phosphatidylinositol 3-Kinases; TOR Serine-Threonine Kinases; Mitogen-Activated Protein Kinase Kinases; Carcinogenesis
PubMed: 37446128
DOI: 10.3390/ijms241310952 -
Acta Oncologica (Stockholm, Sweden) Jan 2020There is conflicting evidence regarding the association between mutations and clinicopathological features of colorectal cancer (CRC). We performed a comprehensive... (Meta-Analysis)
Meta-Analysis
There is conflicting evidence regarding the association between mutations and clinicopathological features of colorectal cancer (CRC). We performed a comprehensive meta-analysis investigating the association between mutations and clinicopathological features in CRC, including subgroup analysis of mutations in exons 9 and 20, to elucidate the role of mutations in CRC. A detailed literature search was performed within the PubMed, Web of Science, and Embase databases, examining the associations between mutations and demographic characteristics, clinicopathologic parameters, and molecular features in patients with CRC. The odds ratios with 95% confidence intervals were used to estimate the effect of mutations on outcome parameters. Forty-four studies enrolling 17621 patients were eligible for inclusion. mutations were associated with proximal tumor location, mucinous differentiation, mutations, and microsatellite instability (MSI). Subgroup analysis demonstrated that exon 9 mutations were positively associated with proximal tumor location and mutations, and negatively associated with mutations and MSI; exon 20 mutations were associated with proximal tumor location, mutations, mutations and MSI. Our findings suggest that overall or exon-specific mutations showed null associations with key clinicopathological parameters, including disease stage and tumor differentiation, indicating that mutations do not predict aggressive clinicopathological characteristics in CRC. As mutations were found to be closely associated with mutations, their relationship warrants further investigation. Since exon 9 and 20 mutations showed different tendencies with regard to mutation and MSI status, they may have distinct molecular impacts on CRC.
Topics: Class I Phosphatidylinositol 3-Kinases; Colorectal Neoplasms; Humans; Microsatellite Instability; Mutation; Neoplasm Grading; Prognosis; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Signal Transduction
PubMed: 31545109
DOI: 10.1080/0284186X.2019.1664764 -
Indian Journal of Dental Research :... 2022Ameloblastoma is a benign, locally aggressive neoplasm that needs extensive surgical resection. The goal of this article is to obtain an in-depth review of benign... (Review)
Review
Ameloblastoma is a benign, locally aggressive neoplasm that needs extensive surgical resection. The goal of this article is to obtain an in-depth review of benign ameloblastomas to determine the available level of evidence and the possible benefit of targeted therapeutics for the treatment of ameloblastoma and BRAF V600E mutation in ameloblastoma. An electronic literature search was conducted according to PRISMA guidelines in PubMed/MEDLINE, EBSCO, and Web of Science for eligible studies published between 1975 and 2021. The systematic review is registered with INPLASY (INPLASY202260018). The review included 2 case series and 17 case reports. The histopathological type, anatomic location, expression of BRAF mutation, additional mutations, and molecular-targeted therapies of the 19 reviewed articles were summarized and tabulated. Interestingly, the majority of the primary site of ameloblastoma was located in the mandible (80.9%) compared to the maxilla (17%). The tumour size was reported in nine of the included studies. Most of the included studies in the review exhibited ameloblastoma with BRAF V600E mutations and responded to molecular-targeted therapies. Molecular therapies employing BRAF and/or MEK inhibitors in ameloblastoma with BRAF V600E mutations proved to be an appropriate treatment based on the limited available evidence. It is essential further to deepen our understanding at the clinical and molecular level to enhance the precision of management of ameloblastoma.
Topics: Humans; Ameloblastoma; Molecular Targeted Therapy; Mutation; Proto-Oncogene Proteins B-raf
PubMed: 36656197
DOI: 10.4103/ijdr.ijdr_456_22 -
Gynecologic Oncology Apr 2023The RAS/RAF/MEK/ERK (MAPK) pathway plays a role in ovarian carcinogenesis. Low-grade serous ovarian carcinoma (LGSOC) frequently harbors activating MAPK mutations. MAPK... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The RAS/RAF/MEK/ERK (MAPK) pathway plays a role in ovarian carcinogenesis. Low-grade serous ovarian carcinoma (LGSOC) frequently harbors activating MAPK mutations. MAPK inhibitors have been used in small subsets of ovarian carcinoma (OC) patients to control tumor growth. Therefore, we performed a meta-analysis to evaluate the effectiveness of MAPK inhibitors in OC patients. We aimed to determine the clinical benefit rate (CBR), the subgroup of MAPK inhibitors with the best CBR and overall response rate (ORR), and the most common adverse events.
METHODS
We conducted a search in PubMed, Embase via Ovid, the Cochrane library and clinicaltrials.gov on studies evaluating the efficacy of single MAPK pathway inhibition with MAPK pathway inhibitors in OC patients. Our primary outcome included the CBR, defined by the proportion of patients with stable disease (SD), complete (CR) and partial response (PR). Secondary outcomes included the ORR (including PR and CR) and grade 3 and 4 adverse events. Meta-analysis was performed using a random-effects model.
RESULTS
We included nine studies with a total of 319 OC patients, for which we determined a pooled CBR of 63% (95%-CI 39-84%, I = 92%). Combined treatment with Raf- and MEK inhibitors in in BRAF mutated LGSOC (n = 6) had the greatest efficacy with a CBR of 100% and ORR of 83%. MEK inhibitors had the best efficacy as a single agent. Subgroup analysis by tumor histology demonstrated a significantly higher CBR and ORR in patients with LGSOC, with a pooled CBR and ORR of 87% (95%-CI 81-92%, I = 0%) and 27% (95%-CI 10-48%, I = 77%) respectively. Adverse events of grade 3 or higher were reported frequently: 123 in 167 patients.
CONCLUSIONS
MEK inhibitors are the most promising single agents in (LGS)OC. However, dual MAPK pathway inhibition should be considered in patients with a BRAF mutation, or non-mutated OC with depleted treatment options due indications of higher efficacy and tolerable toxicity profiles.
Topics: Humans; Female; Proto-Oncogene Proteins B-raf; MAP Kinase Signaling System; Signal Transduction; Ovarian Neoplasms; Protein Kinase Inhibitors; Carcinoma, Ovarian Epithelial; Mutation; Mitogen-Activated Protein Kinase Kinases
PubMed: 36841040
DOI: 10.1016/j.ygyno.2023.01.038 -
Cancer Metastasis Reviews Mar 2023Pseudomyxoma peritonei (PMP) is a rare, progressive, slowly growing neoplastic condition which is poorly understood, with a 5-year progression-free survival rate as low... (Review)
Review
Pseudomyxoma peritonei (PMP) is a rare, progressive, slowly growing neoplastic condition which is poorly understood, with a 5-year progression-free survival rate as low as 48%. PMP is most commonly caused by appendiceal mucinous neoplasms (AMN), and understanding their genetic biology and pathogenicity may allow for the development of better novel systemic treatments to target key deleterious mutations and the implicated pathways. The primary aim of this systematic review was to identify the genetic profile of histologically confirmed human PMP or AMN samples. The secondary aim was to identify whether genetic marks could be used to predict patient survival. Ovid EMBASE, Ovid MEDLINE, PubMed, and Web of Science were searched to identify studies investigating the genetic profile of histologically-confirmed human PMP or AMN samples. We review findings of 46 studies totalling 2181 tumour samples. The most frequently identified somatic gene mutations in patients with PMP included KRAS (38-100%), GNAS (17-100%), and TP53 (5-23%); however, there were conflicting results of their effect on survival. Three studies identified molecular subtypes based on gene expression profiles classifying patients into oncogene-enriched, immune-enriched, and mixed molecular subtypes with prognostic value. This review summarises the current literature surrounding genetic aberrations in PMP and AMNs and their potential utility for targeted therapy. Given the recent advances in clinical trials to directly target KRAS and GNAS mutations in other cancers, we propose a rationale to explore these mutations in future pre-clinical studies in PMP with a view for a future clinical trial.
Topics: Humans; Pseudomyxoma Peritonei; Peritoneal Neoplasms; Appendiceal Neoplasms; Genetic Profile; Proto-Oncogene Proteins p21(ras)
PubMed: 36723696
DOI: 10.1007/s10555-023-10088-0 -
Dermatologic Therapy Mar 2020The current systematic review aimed to evaluate and compare the efficacy and safety of dabrafenib-trametinib with those of other therapeutic alternatives in the... (Meta-Analysis)
Meta-Analysis Review
Efficacy and safety of dabrafenib-trametinib in the treatment of unresectable advanced/metastatic melanoma with BRAF-V600 mutation: A systematic review and network meta-analysis.
The current systematic review aimed to evaluate and compare the efficacy and safety of dabrafenib-trametinib with those of other therapeutic alternatives in the treatment of patients with unresectable advanced/metastatic melanoma with BRAF-V600 mutation. The search was carried out on four databases up to July 2018. Two separate network meta-analyses (NMA) were performed using the frequentist method (random effects): one with an exclusive population with BRAF-V600 mutation (NMA-pBRAFV600) and another with mixed population (with or without the mutation: NMA-pMixed). An evidence profile was included using the GRADE method for NMA. The validity of the final estimator in the NMA-pMixed was assessed via a sensitivity analysis. Nine clinical trials were included in the NMA-pBRAFV600. Dabrafenib-trametinib was found to have a favorable effect on overall survival (OS) and progression-free survival (PFS) compared with dabrafenib, vemurafenib, and dacarbazine and on partial response rate (PRR) and overall response rate compared with dacarbazine and vemurafenib. In the NMA-pMixed, dabrafenib-trametinib was found to have a positive effect on OS versus ipilimumab 3 mg/kg and on PFS and PRR versus ipilimumab, nivolumab, and pembrolizumab. However, dabrafenib-trametinib and vemurafenib-cobimetinib significantly differed in terms of efficacy. In addition, dabrafenib-trametinib has a favorable effect on Grades 3 and 4 adverse events.
Topics: Antineoplastic Combined Chemotherapy Protocols; Humans; Imidazoles; Melanoma; Mutation; Network Meta-Analysis; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Neoplasms
PubMed: 31664762
DOI: 10.1111/dth.13145