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BACKGROUND/AIM: Hyperthermia represents an adjuvant local anticancer strategy which relies on the increase of temperature beyond the physiological level. In this study, we investigated the anticancer potential of Fe3O4 and Fe3O4core Aushell nanoparticles as hyperthermic agents in terms of cytotoxicity and studied the expression of cellular markers of proliferation (changes in mRNA levels via real-time polymerase chain reaction). MATERIALS AND METHODS: The human breast cancer cell line SK-BR-1 was incubated with either Fe3O4 or Fe3O4core Aushell nanoparticles stabilized with tryptophan, prior to hyperthermia treatment. The normal HEK293 cell line was used as a control. Toxicity was determined using the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay to estimate possible toxic effects of the tested nanoparticles. After RNA extraction and cDNA synthesis, mRNA expression of three indicators of proliferation, namely marker of proliferation Ki-67, DNA topoisomerase II alpha (TOP2A) and TPX2 microtubule nucleation factor (TPX2), was investigated. RESULTS: At each concentration tested, Fe3O4core Aushell nanoparticles showed greater toxicity compared to Fe3O4, while SK-BR-3 cells were more susceptible to their cytotoxic effects compared to the HEK293 cell line. The expression of Ki-67, TOP2A and TPX2 was reduced in SK-BR-3 cells by both Fe3O4 or Fe3O4core Aushell nanoparticles compared to untreated cells, while the only observed change in HEK293 cells was the up-regulation of TOP2A. CONCLUSION: Both Fe3O4core Aushell and Fe3O4 NPs exhibit increased cytotoxicity to the cancer cell line tested (SK-BR-3) compared to HEK293 cells. The down-regulation in SK-BR-3 cells of the three proliferative markers studied, Ki-67, TOP2A and TPX2, after incubation with NPs suggests that cells that survived thermal destruction were not actively proliferating.
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Neoplasias da Mama , Proteínas de Ciclo Celular , Proliferação de Células , DNA Topoisomerases Tipo II , Hipertermia Induzida , Antígeno Ki-67 , Proteínas Associadas aos Microtúbulos , Proteínas de Ligação a Poli-ADP-Ribose , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , DNA Topoisomerases Tipo II/metabolismo , DNA Topoisomerases Tipo II/genética , Proliferação de Células/efeitos dos fármacos , Hipertermia Induzida/métodos , Antígeno Ki-67/metabolismo , Antígeno Ki-67/genética , Linhagem Celular Tumoral , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Feminino , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/genética , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , Células HEK293 , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genéticaRESUMO
To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10-8) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10-5). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study.
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Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Ovarianas , Polimorfismo de Nucleotídeo Único , Humanos , Feminino , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Carcinoma Epitelial do Ovário/genética , Transcriptoma , Fatores de Risco , Genômica/métodos , Estudos de Casos e Controles , MultiômicaRESUMO
BACKGROUND: Dose-dense sequential (dds) chemotherapy has changed the clinical outcome of patients with early breast cancer (BC). To investigate the impact of dose intensity (DI) in the adjuvant setting of BC, this observational trial (HE 10/10) was conducted assessing the long-term survival outcome, safety and toxicity of a currently widely used chemotherapeutic regimen. In addition, the prognostic significance of tumor infiltrating lymphocytes (TILs) and infiltrating CD8+ lymphocytes were also evaluated in the same cohort. PATIENTS AND METHODS: Totally, 1054 patients were prospectively enrolled in the current study with 1024 patients being eligible, while adequate tissue was available for 596 of them. TILs, CD8+ lymphocytes in intratumoral areas in contact with malignant cells (iCD8), CD8+ lymphocytes in tumor stroma (sCD8) as well as the total number of CD8+ lymphocytes within the tumor area (total CD8) were assessed by immunohistochemistry. RESULTS: Within a median follow-up of 125.18 months, a total of 200 disease-free survival (DFS) events (19.5%) were reported. Importantly, the 10-year DFS and OS rates were 78.4% (95% CI 75.0-81.5) and 81.7% (95% CI 79.0-84.1), respectively. Interestingly, higher CD8+ T cells as well as TILs in the tumor microenvironment were associated with an improved long-term survival outcome. CONCLUSIONS: In conclusion, this study confirms the significance of dds adjuvant chemotherapeutic regimen in terms of long-term survival outcome, safety and toxicity as well as the prognostic significance of TILs and infiltrating CD8+ lymphocytes in BC patients with early-stage disease.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Epirubicina , Docetaxel/uso terapêutico , Linfócitos T CD8-Positivos/patologia , Linfócitos do Interstício Tumoral/patologia , Ciclofosfamida , Prognóstico , Intervalo Livre de Doença , Microambiente TumoralRESUMO
Ovarian cancer (OC) is one of the deadliest cancers worldwide; late diagnosis and drug resistance are two major factors often responsible for high morbidity and treatment failure. Epithelial-to-mesenchymal transition (EMT) is a dynamic process that has been closely linked with cancer. Long non-coding RNAs (lncRNAs) have been also associated with several cancer-related mechanisms, including EMT. We conducted a literature search in the PubMed database in order to sum up and discuss the role of lncRNAs in regulating OC-related EMT and their underlying mechanisms. Seventy (70) original research articles were identified, as of 23 April 2023. Our review concluded that the dysregulation of lncRNAs is highly associated with EMT-mediated OC progression. A comprehensive understanding of lncRNAs' mechanisms in OC will help in identifying novel and sensitive biomarkers and therapeutic targets for this malignancy.
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Neoplasias Ovarianas , RNA Longo não Codificante , Humanos , Feminino , RNA Longo não Codificante/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/diagnóstico , Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão GênicaRESUMO
BACKGROUND/AIM: Nivolumab is an FDA-approved immune checkpoint inhibitor (ICI) for patients with advanced, pre-treated non-small cell lung cancer (NSCLC). However, treatment profiles and patient outcomes often differ in routine clinical practice while the financial impact of approved therapies is largely unknown. In this study, we investigated the efficacy, tolerability, and economic impact of nivolumab in real-world settings (RWS) in Greece. PATIENTS AND METHODS: Patients diagnosed with advanced pre-treated NSCLC, receiving nivolumab were recruited from October 2015 until November 2019 across 18 different clinical centers in Greece. Endpoints included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and safety. Cost analysis was conducted using a third-party public-payer perspective (National Organization for Healthcare Services Provision; EOPYY). RESULTS: A total of 346 patients, median age 66.5 years, were included. With 43.4 months median follow-up, median PFS was 7.8 months and median OS 15.8 months. The 1-year OS rate was 56.5%, 2-year OS 38.8%, and 3-year OS 27.3%. The ORR was 29.5% and DCR 58.7%, with a median response duration of 26.8 months. Patients with objective response were more likely to experience long-term survival (HR=0.14, p<0.001). Only 8.4% of patients experienced grade 3-4 adverse events. The presence of immune-related adverse events was associated with improved OS (HR=0.77, p=0.043). Nivolumab-associated economic burden accounted for 2,214.10 per cycle for each patient, mainly attributed to drug-acquisition costs. CONCLUSION: This is the first report of real-world efficacy, safety, and economic burden of nivolumab in pre-treated patients with NSCLC in Greece. Indirectly compared to clinical trials, nivolumab was associated with improved efficacy in RWS, further supporting its use in clinical practice and providing insights on clinical prognosticators. The main cost component affecting the nivolumab economic burden was drug-acquisition costs, while toxicity-associated cost was negligible.
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Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Idoso , Nivolumabe/uso terapêutico , Grécia/epidemiologia , Análise Custo-Benefício , Antineoplásicos Imunológicos/efeitos adversos , Estudos RetrospectivosRESUMO
INTRODUCTION/BACKGROUND: Adjuvant capecitabine monotherapy is an option for colon and upper rectum adenocarcinoma patients, providing they have stage II disease with an intermediate risk of recurrence, or stage III but they are above 70's or they have comorbidities. We wanted to examine whether the number of chemotherapy cycles and the relative dose intensity (RDI) of capecitabine monotherapy in the adjuvant setting are affecting disease recurrence. PATIENTS AND METHODS: We included patients with completely resected stage II and III colon and upper rectum cancer who received adjuvant capecitabine monotherapy, from 2003 until May 2020. Patients with early relapse, i.e. during chemotherapy or within 6 months after the completion of adjuvant chemotherapy, and those with rectal cancer who received radiotherapy were excluded. Patients were divided into 3 groups based on the number of chemotherapy cycles received and the RDI. Group A included patients with ≤4 cycles of chemotherapy, group B patients with >4 cycles of chemotherapy and RDI ≤80%, and group C patients with >4 cycles of chemotherapy and RDI >80%. Study's endpoint, was recurrence free survival (RFS). RESULTS: Two hundred twenty six patients with stage II and III disease (164 and 62 respectively) were included. Sixteen, 166 and 44 were included in groups A, B and C respectively. After a median follow-up of 41 months, 21 patients (9,3%) had relapsed. Patients belonging to group C were found to have a trend for lower relapse rate compared to patients belonging to group A or group B. CONCLUSION: Number of adjuvant capecitabine cycles and RDI might play a role in RFS in patients with stage II and III colon and upper rectum adenocarcinoma.
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Adenocarcinoma , Neoplasias Retais , Humanos , Capecitabina , Fluoruracila , Incidência , Reto/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Retais/patologia , Quimioterapia Adjuvante/efeitos adversos , Colo/patologia , Recidiva , Adenocarcinoma/patologia , Estadiamento de NeoplasiasRESUMO
The incidence of thyroid metastases among patients suffering from primary colorectal cancer is rare, and only a few cases have been described in the literature. As these metastases are usually asymptomatic, they most frequently present as incidentalomas on follow-up imaging. Hereby, we present and discuss an interesting case of metastatic sigmoid adenocarcinoma of the thyroid gland, diagnosed and treated at our institution.
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Hyperthermia has the potential to damage cancerous tissue by increasing the body temperature. However, targeting cancer cells whilst protecting the surrounding tissues is often challenging, especially when implemented in clinical practice. In this direction, there are data showing that the combination of nanotechnology and hyperthermia offers more successful penetration of nanoparticles in the tumor environment, thus allowing targeted hyperthermia in the region of interest. At the same time, unlike radiotherapy, the use of non-ionizing radiation makes hyperthermia an attractive therapeutic option. This review summarizes the existing literature regarding the use of hyperthermia and nanoparticles in cancer, with a focus on nanoparticle-induced cytotoxicity mechanisms.
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Hipertermia Induzida , Nanopartículas , Neoplasias , Humanos , Hipertermia , Neoplasias/terapiaRESUMO
Tumor-infiltrating lymphocytes (TILs) contribute to breast cancer (BC) prognosis. We investigated the prognostic impact of CD8+ TILs in patients with early breast cancer treated with adjuvant chemotherapy in a large observational clinical trial. Along with a 10 year follow-up, considering the efficacy and safety, we report the results of the translational part of our study. We examined the patients' tumors for total (t), stromal (s), and intratumoral (i) CD8 lymphocyte density (counts/mm2) on tissue-microarray cores. The impact of CD8+ TILs counts on DFS and OS, and its correlation with breast cancer subtypes and standard clinicopathological parameters, were investigated, along with efficacy and safety data. Among the 928 eligible patients, 627 had available CD8+ data. Of which, 24.9% had a high expression of sCD8, iCD8, and total CD8, which were correlated with higher Ki67, TILs density, ER/PgR negativity, and higher histological grade. The 5year DFS and OS rates were 86.1% and 91.4%, respectively. Patients with high iCD8 and tCD8 had longer DFS and OS compared to those with low counts/mm2 (DFS: HR = 0.58, p = 0.011 and HR = 0.65, p = 0.034 and OS: HR = 0.63, p = 0.043 and HR = 0.58, p = 0.020, respectively). Upon adjustment for clinicopathological parameters, iCD8 and tCD8 retained their favorable prognostic significance for DFS and OS, whereas high sCD8 was only prognostic for DFS. Menopausal status, tumor size, and nodal status retained their prognostic significance in all examined multivariate models. CD8+ TILs, and especially their intratumoral subset, represent a potential favorable prognostic factor in early BC.
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Gastric cancer (GC) is the fifth most commonly diagnosed malignancy and the fourth leading cause of cancer death worldwide. Skin metastases from internal organs are rare; skin metastasis from GC occurs even more rarely than skin metastases originating from other organs, and is associated with systematic disease and poor prognosis. The present study described an interesting and rare case of an extensive skin rash in a 42-year-old man diagnosed with GC, which was mainly affecting his left hemithorax, abdomen and back. The rash masqueraded as erysipelas and was initially treated as such; however, it did not respond to antibiotics, corticosteroids and antihistamines. Due to its persistence and location, the rash was biopsied and GC metastasis was confirmed. Third-line chemotherapy was administered and the rash decreased in size; however, the patient suffered from disease deterioration with lung metastases and respiratory failure. The patient eventually died 4 months after the diagnosis of skin metastasis. In conclusion, cutaneous metastasis should be considered as a late and difficult to treat metastasis of GC, which requires high surveillance from medical oncologists, and a multidisciplinary approach for prompt and accurate diagnosis.
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BACKGROUND: Dose-dense sequential chemotherapy with anthracyclines and taxanes achieved an 18% reduction of recurrence risk in early breast cancer (BC). The optimal chemotherapy schedule and interval between cycles remain under investigation. METHODS: Overall, 990 patients were randomised to receive either three cycles of epirubicin (E, 110 mg/m2) every 2 weeks followed by 3 cycles of paclitaxel (T, 200 mg/m2) every 2 weeks followed by three cycles of intensified CMF (Control Arm A, E-T-CMF) that was previously used in BC or three cycles of epirubicin followed by three cycles of CMF followed by nine consecutive weekly cycles of docetaxel (wD) 35 mg/m2 (Arm B, E-CMF-wD) or nine consecutive weekly cycles of paclitaxel (wT) 80 mg/m2 (Arm C, E-CMF-wT). Trastuzumab was administered for HER2-positive disease. RESULTS: At a median follow-up of 13.3 years, 330 disease-free survival (DFS) events (33.3%) were reported. DFS and overall survival (OS) did not differ between patients in the combined B and C arms versus arm A either in the entire cohort (HR = 0.90, P = 0.38 and HR = 0.85, P = 0.20) or among trastuzumab-treated patients (HR = 0.69, P = 0.13 and HR = 0.67, P = 0.13). Thirty-four patients (3.4%) developed secondary neoplasms. CONCLUSIONS: Overall, no significant differences in survival were found amongst the studied regimens after a long-term observational period. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000151033.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Austrália , Quimioterapia Adjuvante , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Epirubicina/efeitos adversos , Feminino , Fluoruracila/efeitos adversos , Humanos , Paclitaxel/efeitos adversos , Trastuzumab/efeitos adversosRESUMO
Multiple primary cancer (MPC) is defined as more than one primary tumour diagnosed at the same patient, either simultaneously or sequentially. Its incidence is low and varies in reporting among medical centers. Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL) while gastric cancer (GC) is the fifth most frequently diagnosed malignancy. The aim of this article is to present a rare case of a female patient who was diagnosed with two synchronous malignancies, an adenocarcinoma of the stomach (SRCC) and an aggressive extranodal NH lymphoma (DLBCL) within 2 months. Given the fact that there is an expanding availability of more sensitive diagnostic and screening methods, we aim to increase surveillance amongst medical doctors and provide valuable information for further systematic analysis and identification of such rare cases of concurrent malignancies.
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BRAF/MEK inhibitors are considered standard of care in the treatment of advanced BRAF-mutated malignant melanoma, and have been, in rare cases, associated with granulomatous reactions, mostly limited to skin lesions. The present study reported the case of a patient with metastatic melanoma developing a sarcoid-like reaction manifesting as asymptomatic mediastinal and right hilar lymphadenopathy while on antineoplastic therapy with dabrafenib and trametinib. To the best of our knowledge, this is the first reported case of isolated lymphadenopathy as a manifestation of drug-induced sarcoid-like reaction under dabrafenib and trametinib. Overall, only 17 other cases of granulomatosis have been reported in the literature. Although uncommon, such reactions should be considered in the differential diagnosis of lymph node enlargement, and distinguishing them from tumor progress is important and can be challenging in clinical practice.
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Thromboprophylaxis, as a preventive measure for cancer-associated thrombosis (CAT), may be beneficial for patients with active cancer and high-risk for thrombosis. The present post hoc analysis include a total of 407 patients enrolled in the Greek Management of Thrombosis study, who received thromboprophylaxis with tinzaparin. The objectives of the present analysis were: i) To obtain sufficient evidence for the administration of prophylaxis in patients with active cancer, irrespective of Khorana risk assessment model score; ii) to identify the selection criteria for both dose and duration of tinzaparin; and iii) to evaluate the efficacy and safety of tinzaparin administered for CAT prophylaxis. The main tumor types for the patients included in the present study were as follows: Lung (25.1%), pancreatic (14.3%), breast (9.1%), stomach (8.4%), colorectal (7.9%) and ovarian (7.6%). Furthermore, metastatic disease was observed in 69.5% of the patients. High thrombotic burden agents (HTBAs) were administered to 66.3% of the patients, and 17.4% received erythropoietin. A total of 43.7% of the patients exhibited a Khorana score <2. The results of the present study demonstrated that both the presence of metastatic disease and the use of HTBAs seemed to influence oncologists' decisions for the use of thromboprophylaxis in patients with active cancer, regardless of Khorana score. Tinzaparin, in dose expressed in the standard notation for heparins, i.e., anti-Xa factor international units (Anti-Xa IU), was administered at an intermediate dose (InterD; 8,000-12,000 Anti-Xa IU; once daily) to 52.4% of patients, while the remaining patients received a prophylactic dose (ProD; ≤4,500 Anti-Xa IU; once daily). The average duration of thromoprophylaxis was 5 months. Furthermore, a total of 14 (3.4%) thrombotic events and 6 (1.5%) minor bleeding events were recorded. A total of four thrombotic events were observed following an InterD treatment of tinzaparin, while 10 thrombotic events were observed following ProD treatment. The present study also demonstrated that an InterD of tinzaparin was administered more frequently to patients with a body mass index >30 kg/m2, a history of smoking and a history of metastatic disease, along with administration of erythropoietin. InterD tinzaparin treatment was found to be potentially more efficacious and without safety concerns. The present study is a registered clinical trial (ClinicalTrials.gov code, NCT03292107; registration date, September 25, 2017).
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INTRODUCTION: During the evolution of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, several drug candidates have been proposed for repositioning towards a quest for more effective treatments. METHODOLOGY: We reviewed recent literature (Pubmed, Google, Clinicaltrials.gov), as of the middle of May 2021, for evidence regarding the potential benefit from poly(ADP-ribose)-polymerase inhibitors and vascular endothelial growth factor blockade in severe SARS-CoV-2 infection. RESULTS: poly(ADP-ribose)-polymerase inhibitors have been suggested as potential agents against coronavirus disease 2019 (COVID-19) by a variety of mechanisms. vascular endothelial growth factor-associated vascular permeability is implicated with increased vascular leakage and pulmonary oedema. Thus, anti-angiogenesis factors, such as bevacizumab are being investigated in critically ill COVID-19 patients. CONCLUSIONS: The synergistic potential of these two classes of inhibitors in severe COVID-19 management could be beneficial. Further research should be carried out in order to support this hypothesis.
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Tratamento Farmacológico da COVID-19 , COVID-19 , Inibidores de Poli(ADP-Ribose) Polimerases , Fator A de Crescimento do Endotélio Vascular , COVID-19/epidemiologia , Humanos , Pandemias , Gravidade do Paciente , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , SARS-CoV-2 , Fator A de Crescimento do Endotélio Vascular/farmacologiaRESUMO
BACKGROUND: Colorectal cancer (CRC) is one of the most common types of cancer diagnosed worldwide with high morbidity; drug resistance is often responsible for treatment failure in CRC. Non-coding RNAs (ncRNAs) play distinct regulatory roles in tumorigenesis, cancer progression and chemoresistance. METHODS: A literature search was conducted in PubMed database in order to sum up and discuss the role of exosomal ncRNAs (ex-ncRNAs) in CRC drug resistance/response and their possible mechanisms. RESULTS: Thirty-six (36) original research articles were identified; these included exosome or extracellular vesicle (EV)-containing microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and small-interfering (siRNAs). No studies were found for piwi-interacting RNAs. CONCLUSIONS: Exosomal transfer of ncRNAs has been documented as a new mechanism of CRC drug resistance. Despite being in its infancy, it has emerged as a promising field for research in order to (i) discover novel biomarkers for therapy monitoring and/or (ii) reverse drug desensitization.
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Neoplasias Colorretais , Resistencia a Medicamentos Antineoplásicos/genética , Exossomos , RNA Neoplásico , RNA não Traduzido , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Exossomos/genética , Exossomos/metabolismo , Humanos , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , RNA não Traduzido/genética , RNA não Traduzido/metabolismoRESUMO
Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to individual level genotype data and a Bayesian framework with continuous shrinkage, "select and shrink for summary statistics" (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries; 7,669 women of East Asian ancestries; 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28-1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries; 1.14 (95% CI: 1.08-1.19, AUC: 0.538) in women of East Asian ancestries; 1.38 (95% CI: 1.21-1.58, AUC: 0.593) in women of African ancestries; hazard ratios of 1.36 (95% CI: 1.29-1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35-1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
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Neoplasias da Mama , Neoplasias Ovarianas , Teorema de Bayes , Carcinoma Epitelial do Ovário/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Neoplasias Ovarianas/epidemiologia , Neoplasias Ovarianas/genética , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de RiscoRESUMO
Colorectal cancer represents a leading cause of cancer-related morbidity and mortality. Despite improvements, chemotherapy remains the backbone of colorectal cancer treatment. The aim of this study is to investigate the variation of circulating microRNA expression profiles and the response to irinotecan-based treatment in metastatic colorectal cancer and to identify relevant target genes and molecular functions. Serum samples from 95 metastatic colorectal cancer patients were analyzed. The microRNA expression was tested with a NucleoSpin miRNA kit (Machnery-Nagel, Germany), and a machine learning approach was subsequently applied for microRNA profiling. The top 10 upregulated microRNAs in the non-responders group were hsa-miR-181b-5p, hsa-miR-10b-5p, hsa-let-7f-5p, hsa-miR-181a-5p, hsa-miR-181d-5p, hsa-miR-301a-3p, hsa-miR-92a-3p, hsa-miR-155-5p, hsa-miR-30c-5p, and hsa-let-7i-5p. Similarly, the top 10 downregulated microRNAs were hsa-let-7d-5p, hsa-let-7c-5p, hsa-miR-215-5p, hsa-miR-143-3p, hsa-let-7a-5p, hsa-miR-10a-5p, hsa-miR-142-5p, hsa-miR-148a-3p, hsa-miR-122-5p, and hsa-miR-17-5p. The upregulation of microRNAs in the miR-181 family and the downregulation of those in the let-7 family appear to be mostly involved with non-responsiveness to irinotecan-based treatment.
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Neoplasias Colorretais , MicroRNAs , Humanos , Irinotecano/farmacologia , Irinotecano/uso terapêutico , MicroRNAs/metabolismo , Regulação para Cima , Regulação para Baixo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genéticaRESUMO
New treatment modalities have been recently introduced in the management of ovarian cancer (OC). Herein, we sought to investigate their implementation in routine clinical practice and examine the real-world management of OC in Greece. EpOCa was a non-interventional, multicenter, retrospective study in patients with advanced epithelial OC. The primary outcome was to estimate the proportions of the different treatment regimens used per line of therapy, while progression-free survival (PFS) and overall survival (OS) were the key secondary endpoints. A total of 154 patients were enrolled in the study, among whom, 40% were tested for BRCA mutations and 30% were found to be positive. Nearly 90% of patients underwent debulking surgery at diagnosis, with few operations being also recorded upon relapse. Platinum-based chemotherapy (CT) was predominantly used in the first line with half of patients also receiving angiogenesis inhibitor (AI), while non-platinum-based CT was preferred in later lines. The median PFS was 18.2 and 8.8 months in the first- and second-line setting, respectively, whereas the median OS was approximately 50 months. Our study adds to the available, but limited, real world data on the management of ovarian cancer providing evidence regarding the applied treatment strategies and outcomes of patients in Greece.