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Expert Opinion on Investigational Drugs Jun 2008Enzastaurin is a novel antineoplastic and antiangiogenic agent that acts through inhibition of protein kinase C (PKC). (Review)
Review
BACKGROUND
Enzastaurin is a novel antineoplastic and antiangiogenic agent that acts through inhibition of protein kinase C (PKC).
OBJECTIVE
This review summarizes the scientific rationale and current clinical evidence for the use of enzastaurin in oncology.
METHODS
We performed a systematic review of the literature using the keywords protein kinase C-beta and enzastaurin in order to characterize the therapeutic target PKC-beta. We then reviewed the in-vitro, Phase I, and Phase II data for enzastaurin with a focus on hematologic malignancies.
RESULTS/CONCLUSIONS
After preliminary Phase I trials established a favorable toxicity profile, enzastaurin has been studied in completed and ongoing Phase II and III studies in solid and hematologic malignancies, including B-cell lymphomas where the rationale for its use is most promising.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Clinical Trials as Topic; Enzyme Activation; Humans; Indoles; Neoplasm Invasiveness; Neoplasm Proteins; Neoplasms; Neovascularization, Pathologic; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Protein Kinase C; Protein Kinase C beta; Protein Kinase Inhibitors; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; Salvage Therapy; Signal Transduction; Vascular Endothelial Growth Factor A
PubMed: 18491994
DOI: 10.1517/13543784.17.6.939 -
BMC Cancer Apr 2016Brain metastases (BM) from colorectal cancer (CRC) are a rare event. However, the implications for affected patients are severe, and the incidence has been reported to... (Review)
Review
BACKGROUND
Brain metastases (BM) from colorectal cancer (CRC) are a rare event. However, the implications for affected patients are severe, and the incidence has been reported to be increasing. For clinicians, knowledge about the characteristics associated with BM is important and could lead to earlier diagnosis and improved survival.
METHOD
In this paper, we describe the incidence as well as characteristics associated with BM based on a systematic review of the current literature, following the PRISMA guidelines.
RESULTS
We show that the incidence of BM in CRC patients ranges from 0.6 to 3.2%. BM are a late stage phenomenon, and young age, rectal primary and lung metastases are associated with increased risk of developing BM. Molecular markers such as KRAS, BRAF, NRAS mutation as well as an increase in CEA and CA19.9 levels are suggested predictors of brain involvement. However, only KRAS mutations are reasonably well investigated and associated with an increased risk of BM.
CONCLUSION
The incidence of BM from CRC is 0.6 to 3.2% and did not seem to increase over time. Development of BM is associated with young age, lung metastases, rectal primary and KRAS mutation. Increased awareness of brain involvement in patients with these characteristics is necessary.
Topics: Age Factors; Brain Neoplasms; Colorectal Neoplasms; Female; GTP Phosphohydrolases; Genetic Association Studies; Humans; Lung Neoplasms; Male; Membrane Proteins; Mutation; Prognosis; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins p21(ras); Risk Factors
PubMed: 27037031
DOI: 10.1186/s12885-016-2290-5 -
Asian Pacific Journal of Cancer... Mar 2023Cholangiocarcinoma (CCA) is the second most frequent hepatobiliary cancer after hepatocellular carcinoma with a poor prognosis and limited treatment options. This study...
BACKGROUND
Cholangiocarcinoma (CCA) is the second most frequent hepatobiliary cancer after hepatocellular carcinoma with a poor prognosis and limited treatment options. This study aimed to review existing knowledge on the genetic basis of CCA, molecular targets/signaling pathways involved in the pathogenesis, disease progression and prognosis, including potential targets for targeted therapies of CCA.
METHODS
The systematic review was performed in compliance with PRISMA guidelines. A systematic search in PubMed and Science Direct databases was performed using the following keywords: "cholangiocarcinoma", AND "molecular target" AND/OR "signaling pathway", AND/OR "targeted therapy", AND/OR "cancer chemotherapy." The eligibility criteria included: i) full-text articles published in English, ii) articles with in vitro and/or in vivo and/or clinical studies of molecular targets/signaling pathwanys related to CCA pathogenesis/disease progression/prognosis and/or targeted therapy. Seventy-three studies that fulfilled the eligibility criteria were finally included in the final data synthesis.
RESULTS
A total of 833 relevant articles published up to April 2022 were identified and 73 sttudies that fulfilled the eligibility criteria were finally included in the analysis. The molecular biomarkers and drugs targeting signalling pathways were reported. Recent research has been focused on targeting the apoptotic and cell proliferation pathways, and in addition, the angiogenesis and metastasis pathway. More effort focused on testing the efficacy of combination therapies against the cancer cell and specifically CCA. The PI3K (Phosphoinositide 3-kinases)/ERK/Akt (AKT serine/threonine kinase 1)/mTOR (mammalian target of rapamycin) signaling pathway and HER2 (Human epidermal growth factor receptor 2) and EGFR (Epidermal Growth Factor Receptor) pathways are the most potential targets for CCA therapy.
CONCLUSION
The information obtained could be exploited for further development of diagnostic tools for early diagnosis of CCA, as well as effective CCA-targeted therapies.
Topics: Humans; Proto-Oncogene Proteins c-akt; Signal Transduction; Cholangiocarcinoma; Cell Proliferation; Phosphatidylinositol 3-Kinases; Bile Ducts, Intrahepatic; Bile Duct Neoplasms; Disease Progression; Cell Line, Tumor
PubMed: 36974526
DOI: 10.31557/APJCP.2023.24.3.741 -
Lung Cancer (Amsterdam, Netherlands) Jul 2021Increased thromboembolism (TE) has been reported in ALK+ and ROS1+ non-small cell lung cancer (NSCLC). (Meta-Analysis)
Meta-Analysis
INTRODUCTION
Increased thromboembolism (TE) has been reported in ALK+ and ROS1+ non-small cell lung cancer (NSCLC).
MATERIALS AND METHODS
Odds ratios (OR) and hazard ratios (HR) of TE were calculated from meta-analysis and time-to-event analysis respectively for either ALK+ or ROS1+ NSCLC patients.
RESULTS
We identified eight studies (766 ALK+, 143 ROS1+, 2314 non-ALK+ and non-ROS1+ NSCLC patients) for the meta-analysis. For ALK+ NSCLC, the pooled OR was 2.00 (95% CI: 1.60-2.50) for total TE (TTE) by random-effects model, 2.10 (95% CI: 1.70-2.60) for venous thromboembolism (VTE), and 1.24 (95% CI: 0.80-1.91) for arterial thromboembolism (ATE). For ROS1+ NSCLC, the pooled OR was 3.08 (95% CI: 1.95-4.86) for TTE, and 3.15 (95% CI: 1.83-5.43) for VTE. Six studies (739 ALK+, 137 ROS1+, 561 EGFR+, 714 "wildtype" NSCLC patients) were included in the time-to-event analysis. The TTE incidence rate was 17.4 (95% CI: 15.3-19.5) per 100 pateint-years for ALK+ NSCLC, and 32.1 (95% CI: 24.6-39.6) per 100 patient-years for ROS1+ NSCLC with a 50 % cumulative incidence rate at year 3 of diagnosis. HR for TTE was 2.35 (95% CI: 1.90-2.92, p < 0.001) and 3.23 (95% CI: 2.40-4.34, p < 0.001) for ALK+ and ROS1+ NSCLC, respectively. Comparing ROS1+ NSCLC to ALK+ NSCLC, HR for TTE was 1.37 (95% CI: 1.05-1.79, p = 0.020).
CONCLUSIONS
ALK+ and ROS1+ NSCLC patients had an increased risk of TE. ROS1+ NSCLC had further increased risk of TE over ALK+ NSCLC.
Topics: Carcinoma, Non-Small-Cell Lung; Gene Rearrangement; Humans; Lung Neoplasms; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases
PubMed: 34049720
DOI: 10.1016/j.lungcan.2021.05.019 -
International Journal of Radiation... Dec 2014Primary mucosal melanoma of the head and neck (MMHN) comprises approximately 1% of all malignant melanomas. It presents more commonly in an elderly population and has no... (Review)
Review
Primary mucosal melanoma of the head and neck (MMHN) comprises approximately 1% of all malignant melanomas. It presents more commonly in an elderly population and has no significant gender predominance. Given its rarity, most evidence of the causes, behavior, and treatment approaches for MMHN originates from isolated case reports and retrospective series. Between 1945 and 2011, at least 1951 cases of MMHN have been reported in the literature. Despite numerous technological developments in surgery and radiation therapy, as well as advances in systemic modalities, MMHN is an aggressive malignancy with a very poor prognosis. Complete surgical excision with clear margins remains the primary treatment modality. Adjuvant postoperative radiation therapy may improve locoregional control but does not appear to affect survival. Definitive particle radiation therapy promises to provide high rates of local control for nonoperable patients. Recent molecular evidence suggests that proto-oncogene KIT aberrations in a subset of mucosal melanomas may represent a potential diagnostic value and serve as a therapeutic target for tyrosine kinase inhibitors in an adjuvant setting for patients with advanced MMHN.
Topics: Age Factors; Aged; Female; Head and Neck Neoplasms; Humans; Lymphatic Irradiation; Male; Melanoma; Middle Aged; Mucous Membrane; Mutation; Prognosis; Proto-Oncogene Mas; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-kit; Radiotherapy Dosage; Radiotherapy, Adjuvant; Rare Diseases; Survival Rate
PubMed: 25539369
DOI: 10.1016/j.ijrobp.2014.03.042 -
Reviews in Endocrine & Metabolic... Feb 2024Differentiated thyroid cancer (DTC) is a rare disease in the paediatric population (≤ 18 years old. at diagnosis). Increasing incidence is reflected by increases in... (Review)
Review
Differentiated thyroid cancer (DTC) is a rare disease in the paediatric population (≤ 18 years old. at diagnosis). Increasing incidence is reflected by increases in incidence for papillary thyroid carcinoma (PTC) subtypes. Compared to those of adults, despite aggressive presentation, paediatric DTC has an excellent prognosis. As for adult DTC, European and American guidelines recommend individualised management, based on the differences in clinical presentation and genetic findings. Therefore, we conducted a systematic review to identify the epidemiological landscape of all genetic alterations so far investigated in paediatric populations at diagnosis affected by thyroid tumours and/or DTC that have improved and/or informed preventive and/or curative diagnostic and prognostic clinical conduct globally. Fusions involving the gene RET followed by NTRK, ALK and BRAF, were the most prevalent rearrangements found in paediatric PTC. BRAF V600E was found at lower prevalence in paediatric (especially ≤ 10 years old) than in adults PTC. We identified TERT and RAS mutations at very low prevalence in most countries. DICER1 SNVs, while found at higher prevalence in few countries, they were found in both benign and DTC. Although the precise role of DICER1 is not fully understood, it has been hypothesised that additional genetic alterations, similar to that observed for RAS gene, might be required for the malignant transformation of these nodules. Regarding aggressiveness, fusion oncogenes may have a higher growth impact compared with BRAF V600E. We reported the shortcomings of the systematized research and outlined three key recommendations for global authors to improve and inform precision health approaches, glocally.
Topics: Adult; Humans; Child; Adolescent; Proto-Oncogene Proteins B-raf; Carcinoma, Papillary; Thyroid Neoplasms; Mutation; Thyroid Cancer, Papillary; Ribonuclease III; DEAD-box RNA Helicases
PubMed: 37874477
DOI: 10.1007/s11154-023-09840-2 -
Breast (Edinburgh, Scotland) Oct 2023Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have an extremely important impact on the treatment of hormone-sensitive breast cancer (BC) and have radically changed... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have an extremely important impact on the treatment of hormone-sensitive breast cancer (BC) and have radically changed the first-line treatment for metastatic disease with increased rates of treatment response, overall survival (OS), and progression-free survival (PFS). We performed a pooled analysis of randomized trials to validate or refute the hypothesis that there is a significant survival benefit of adding anti-CDK4/6 inhibitors to standard endocrine therapy (ET) in older patients with advanced BC.
METHODS
We selected only English-language phase II/III randomized controlled trials that compared ET alone with ET with anti-CDK4/6 inhibitors in the treatment of advanced BC, with subgroups reporting the outcomes of elderly patients (usually at least 65 years). The primary endpoint was OS.
RESULTS
The review process led to the inclusion of 12 articles and two meeting abstracts, including a total of 10 trials. The addition of CDK4/6 inhibitors to ET (letrozole or fulvestrant) significantly reduced mortality risk by 20% in younger patients (fixed-effect model; HR 0.80; 95% CI 0.72-0.9; p < 0.01) and 21% in older BC patients (HR 0.79; 95% CI 0.69-0.91; p < 0.01). No OS data were available for patients ≥70 years.
CONCLUSION
This large, pooled analysis is the first to demonstrate that CDK4/6 inhibitors confer OS and PFS benefits in elderly patients (those aged ≥65 years) with advanced ER + BC and to indicate that it should be discussed with and offered to all patients after geriatric assessment and according to the toxicity profile.
Topics: Aged; Humans; Female; Breast Neoplasms; Cyclin-Dependent Kinase 4; Receptor, ErbB-2; Cyclin-Dependent Kinase 6; Fulvestrant; Protein Kinase Inhibitors; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37198053
DOI: 10.1016/j.breast.2023.05.002 -
Journal of Diabetes and Its... 2014The aim of this study was to perform a systematic meta-analysis of biomarkers investigated with diabetic retinopathy (DR) in the vitreous, and to explore the molecular... (Meta-Analysis)
Meta-Analysis Review
The aim of this study was to perform a systematic meta-analysis of biomarkers investigated with diabetic retinopathy (DR) in the vitreous, and to explore the molecular pathway interactions of these markers found to be consistently associated with DR. Relevant databases [PubMed and ISI web of science] were searched for all published articles investigating molecular biomarkers of the vitreous associated with DR. Based on set exclusion/inclusion criteria available data from studies with human vitreous samples were extracted and used for our meta-analysis. The interactions of significant biomarkers in DR were investigated via STRING and KEGG pathway analysis. Our meta-analysis of DR identifies eleven biomarkers as potential therapeutic candidates alternate to current anti-VEGF therapy. Four of these are deemed viable therapeutic targets for PDR; ET receptors (ET A and ET B), anti-PDGF-BB, blocking TGF-β using cell therapy and PEDF. The identification of supplementary or synergistic therapeutic candidates to anti VEGF in the treatment of DR may aid in the development of future treatment trials.
Topics: Becaplermin; Biomarkers; Diabetic Retinopathy; Humans; Proto-Oncogene Proteins c-sis; Receptor, Endothelin A; Receptor, Endothelin B; Transforming Growth Factor beta; Vitreous Body
PubMed: 24630762
DOI: 10.1016/j.jdiacomp.2013.09.010 -
Clinical & Translational Oncology :... Feb 2024The purpose of this meta-analysis is to evaluate the efficacy and safety of TAS-102 in treating metastatic colorectal cancer (mCRC) using the most recent data available. (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
The purpose of this meta-analysis is to evaluate the efficacy and safety of TAS-102 in treating metastatic colorectal cancer (mCRC) using the most recent data available.
METHODS
The literature on the efficacy and safety of TAS-102 versus placebo and/or best supportive care (BSC) in mCRC was obtained through a systematic search of PubMed, Embase, and Web of Science databases through January 2023. Identify the included literature and extract pertinent data, such as the overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), disease control rate (DCR), incidence of adverse events (AEs) and serious adverse events (SAEs).
RESULTS
There were eight eligible articles that included 2903 patients (1964 TAS-102 versus 939 Placebo and/or BSC). In this meta-analysis, TAS-102 treatment resulted in longer OS, PFS, TTF, and higher DCR in patients with mCRC versus placebo and/or BSC. TAS-102 improved OS and PFS in subgroup analyses of mCRC patients with KRAS wild-type and KRAS mutant-type. In addition, TAS-102 did not increase the incidence of serious adverse events.
CONCLUSION
TAS-102 can enhance the prognosis of mCRC patients whose standard therapy has failed, regardless of KRAS mutation status, and its safety is acceptable.
Topics: Humans; Trifluridine; Uracil; Colorectal Neoplasms; Proto-Oncogene Proteins p21(ras); Colonic Neoplasms; Rectal Neoplasms; Drug Combinations; Antineoplastic Combined Chemotherapy Protocols; Pyrrolidines; Thymine
PubMed: 37414979
DOI: 10.1007/s12094-023-03268-5 -
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