1,720,998 research outputs found
The predictive role of the immune system for response to therapy and survival in patients with solid tumors.
No full textFirst of all I used an in silico approach (cBioPortal) to investigate possible correlations between survivals of patients with solid tumors and genomic alterations, using the gene list from the 770 immune-related PanCancer IO 360TM panel.
Secondly through an in vitro analysis, 62 Paraffin-embedded formalin fixed (PEFF) samples of MMe were analysed for TILs and PD-L1 expression. Patients were divided in 4 groups according to a cut-off of the percentage of TILs found per sample as measured by means of immunohistichemistry: “0” or absent (between 0% and 5%), “1” or low (between 6% and 25%), “2” or moderate (between 26% and 50%) and “3” or high (between 51% and 75%). Higher expression of peritumoral TILs (Group 2 + 3) versus Group 0 and 1 correlated with improved OS (p-value = 0,02). On the contrary, PD-L1 expression seemed to be inversely correlated with clinical outcomes, even in the absence of statistical significance (HR: 1.76; p=0.083 95% IC: 0.92-3.36 in areas within the tumour; HR: 1.60; p= 0.176 95%; IC: 0.80-3.19 in areas within the stroma). No relationship between TILs and PD-L1 expression was identified.
Thirdly we investigated the correlation between the prognosis of 12 PDAC patients and the presence of TILs through IHC and the expression of 521 immune system genes using Nanostring nCounter Vantage and related bioinformatics. Twenty immune system genes were significantly differentially expressed in patients with a good prognosis relative to patients with a worse prognosis: TLR2 and TLR7 (Toll-like receptor superfamily); CD4, CD37, FOXP3, PTPRC (B cell and T cell signalling); IRF5, IRF8, STAT1, TFE3 (transcription factors); ANP32B, CCND3 (cell cycle); BTK (B cell development); TNF, TNFRF1A (TNF superfamily); HCK (leukocyte function); C1QA (complement system); BAX, PNMA1 (apoptosis); IKBKE (NFκB pathway). Differential expression was more than twice log 2 for TLR7, TNF, C1QA, FOXP3, and CD37.
To find a biomarker that could be a good prognostic factor and a predictor of response to anti-cancer treatments for predicting survival of breast cancer patients I have reviewed the literature and implemented a meta-analysis on the role of PIK3CA mutational status in randomized clinical trials. Overall 1929 BC cases were included. The pooled analysis confirmed that the presence of a PIK3CA mutational status represents an independent negative prognostic factor (HR = 1.67, 95% CI: 1.15-2.43; p = 0.007) in BC, as previously reported. To investigate immune-related biomarkers for predicting response to everolimus therapy in HR+/HER2- in vitro, I have analysed neutrophil and platelet to-lymphocyte ratios (NLR and PLR), immune pathways, and TILs in clinically and molecularly characterized HR+/HER2- BC and explored a correlation with the therapeutic strategy targeting mTOR through everolimus in 2131 metastatic patients from the BALLET study, in 23 patients receiving neoadjuvant everolimus and in 15 metastatic patients at the local institution, respectively. In the BALLET study quartiles of patients with lower NLR levels in the blood had higher survivals compared to patients with higher NLR: NLR ≤ 2.3 vs. NLR >2.3; NLR ≤ 3.2 vs. NLR > 3.2; and NLR ≤ 4.4 vs. NLR >4.4 (p=0.19, p=0.12 and p=0.01). In the smaller population of 15 metastatic patients, FACs analyses showed that everolimus responders vs. non-responders had higher levels of CD3+ T-lymphocytes at baseline (p=0.0343) and during treatment (p=0.0233), higher levels CD8+ and CD4+ T-lymphocytes at baseline (p=0.0172, p=0.0005, respectively) and during treatment (p=0.0102, p=0.0032, respectively); while they had slightly lower levels of regulatory T-lymphocytes and NKs (p=0.0588 and p=0.0411, respectively).
The knowledge produced helps to define key immune-related pathways in solid tumors. Further refining a panel of immune-system markers could help guiding clinicians in the decision-making step for giving mTOR inhibitor everolimus in HR+/HER2- BC
Circulating cell-free nucleic acids as prognostic and therapy predictive tools for metastatic castrate-resistant prostate cancer
Full text linkMetastatic castrate-resistant prostate cancer remains a disease hard to cure, and for this reason predictive tools to monitor disease progression and therapy response are an urgent need. In this respect, liquid biopsy on circulating cell-free nucleic acids represents an interesting strategy based on robust data. The low invasiveness and the possibility to target circulating cell-free tumor
deoxyribonucleic acid underline the high specificity, sensitivity and clinical usability of the technique. Moreover, it has been observed that the cell-free tumor deoxyribonucleic acid of metastatic castrate-resistant prostate cancer patients can be representative of the tumor heterogeneity. Cell-free tumor deoxyribonucleic acids express the same behaviors as mutations: Variation in gene copy number or the methylation rate of the tumor tissue. Recently, circulating cell-free ribonucleic acid molecules have emerged as interesting markers to stratify the disease. Due to high-throughput technologies, liquid biopsy on circulating cell-free nucleic acids will soon be utilized in the clinical management of metastatic castrate-resistant prostate cancer patients
Bevacizumab in small cell lung cancer
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Italian, Multicenter, Phase III, Randomized Study of Cisplatin Plus Etoposide With or Without Bevacizumab as First-Line Treatment in Extensive-Disease Small-Cell Lung Cancer: The GOIRC-AIFA FARM6PMFJM Trial. [J Clin Oncol. 2017
PAK6-Associated Support Vector Machine Classifier: A New Way to Evaluate Response and Survival of Gastric Cancer Treated by 5-FU/Oxaliplatin Chemotherapy
Full text linkGastric cancer (GC) is the 4th most common human malignant disease and the second-leading cancer-related deaths in the world(DeManzoni et al., 2016). Treatment with 5-fluorouracil/oxaliplatin (5-FU/oxaliplatin) chemotherapy has proven to significantly improve survivalof patients with metastatic G
Current status of androgen receptor-splice variant 7 inhibitor niclosamide in castrate-resistant prostate-cancer
Full text linkCastrate-Resistant Prostate-Cancer (CRPC) is one of the most common malignancies occurring in men. Unfortunately, even if several recently approved agents clinically improved the outcome of CRPC patients, none of these is curative especially for a splice version of the Androgen Receptor (AR) AR-V7, which is a variant of the receptor constitutively activated and does not require the presence of androgens for the activation AR down-stream pathways. Since high AR-V7 expression is one of the most common features of CRPC, targeting this receptor variant is considered as one of the most promising strategies for treating this disease. Therefore anti-AR-V7 molecules could lead to a potential shift in paradigm in the treatment of CRPC. Niclosamide, an already FDA-approved anti-helminthic drug, was identified as a potent AR-V7 inhibitor in prostate cancer cells. Due to the recent positive preclinical results, niclosamide may be an interesting and novel type of targeted treatments for CRPC. This mini-review outlines the most recent pre- and clinical- data on the current status of niclosamide in the treatment of ARV7-positive CRPC patients
Future AI Will Most Likely Predict Antibody-Drug Conjugate Response in Oncology: A Review and Expert Opinion
Full text linkThe medical research field has been tremendously galvanized to improve the prediction of therapy efficacy by the revolution in artificial intelligence (AI). An earnest desire to find better ways to predict the effectiveness of therapy with the use of AI has propelled the evolution of new models in which it can become more applicable in clinical settings such as breast cancer detection. However, in some instances, the U.S. Food and Drug Administration was obliged to back some previously approved inaccurate models for AI-based prognostic models because they eventually produce inaccurate prognoses for specific patients who might be at risk of heart failure. In light of instances in which the medical research community has often evolved some unrealistic expectations regarding the advances in AI and its potential use for medical purposes, implementing standard procedures for AI-based cancer models is critical. Specifically, models would have to meet some general parameters for standardization, transparency of their logistic modules, and avoidance of algorithm biases. In this review, we summarize the current knowledge about AI-based prognostic methods and describe how they may be used in the future for predicting antibody-drug conjugate efficacy in cancer patients. We also summarize the findings of recent late-phase clinical trials using these conjugates for cancer therapy
Cyclin dependent kinase 4 and 6 inhibitors as novel therapeutic agents for targeted treatment of malignant mesothelioma
No full textMalignant Mesothelioma (MM) is a rare and aggressive form of tumour that affects the lining of the internal organs for which current treatments have not been proven to be very effective. P16(INK4A) tumour suppressor encoding CDKN2A gene is often downregulated in MM. This protein is a cyclin dependent kinase 4 and 6 inhibitor, that normally phosphorylates RB1, which has to be un-phosphorylated in order to block cell-cycle at G1 in normal cells. Adding CDK inhibitor molecules to MM in pre-clinical studies has been proven to restore the normal function of p16(INK4A), blocking thereby MM cell cycle at G1. Future randomised phase III studies with CDK4/6 inhibitors in MM carrying relevant CDK4/6, cyclin D1/3 or p16 aberrations will be warranted
Targeting Aberrant FGFR Signaling to Overcome CDK4/6 Inhibitor Resistance in Breast Cancer
Full text linkBreast cancer (BC) is the most common cause of cancer-related death in women worldwide. Therapies targeting molecular pathways altered in BC had significantly enhanced treatment options for BC over the last decades, which ultimately improved the lives of millions of women worldwide. Among various molecular pathways accruing substantial interest for the development of targeted therapies are cyclin-dependent kinases (CDKs)—in particular, the two closely related members CDK4 and CDK6. CDK4/6 inhibitors indirectly trigger the dephosphorylation of retinoblastoma tumor suppressor protein by blocking CDK4/6, thereby blocking the cell cycle transition from the G1 to S phase. Although the CDK4/6 inhibitors abemaciclib, palbociclib, and ribociclib gained FDA approval for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative BC as they significantly improved progression-free survival (PFS) in randomized clinical trials, regrettably, some patients showed resistance to these therapies. Though multiple molecular pathways could be mechanistically responsible for CDK4/6 inhibitor therapy resistance, one of the most predominant ones seems to be the fibroblast growth factor receptor (FGFR) pathway. FGFRs are involved in many aspects of cancer formation, such as cell proliferation, differentiation, and growth. Importantly, FGFRs are frequently mutated in BC, and their overexpression and/or hyperactivation correlates with CDK4/6 inhibitor resistance and shortened PFS in BC. Intriguingly, the inhibition of aberrant FGFR activity is capable of reversing the resistance to CDK4/6 inhibitors. This review summarizes the molecular background of FGFR signaling and discusses the role of aberrant FGFR signaling during cancer development in general and during the development of CDK4/6 inhibitor resistance in BC in particular, together with other possible mechanisms for resistance to CDK4/6 inhibitors. Subsequently, future directions on novel therapeutic strategies targeting FGFR signaling to overcome such resistance during BC treatment will be further debated
Advances in anti-BRAF therapies for lung cancer
No full text: Non-small cell lung cancer (NSCLC) is one of the most frequent causes of mortality in the western world. v-raf murine sarcoma viral oncogene homolog B (BRAF) is a member of the Raf kinase family and plays a critical role in cellular growth, proliferation, and differentiation through the mitogen-activated protein kinase pathway. The incidence of BRAF mutations in NSCLC is low, accounting for 0-3% of all cases of lung cancer. Given the results obtained in metastatic melanoma, several studies have reported the efficacy of anti-BRAF therapies in NSCLC treatment. In this review, we describe changes in the landscape of BRAF-mutated lung cancer treatment and analyze insights from major clinical trials in the context of future therapeutic prospects
PROGNOSTIC ROLE OF TUMOR INFILTRATING LYMPHOCITES (TILS) IN EPITHELIOID PLEURAL MESOTHELIOMA
No full textObjective. The inflammation is known to be essential in the neoplastic progression, nevertheless this host-tumor interaction has not been yet clarified. Whilst neoangiogenesis might stimulate the tumor progression, simultaneously this process could interfere with tumor growth. The aim of this study was to evaluate the prognostic value of intra- and peri- tumor infiltrating lymphocites (TILs) and correlate this parameter with the overall survival.
Material and Methods. We retrospectively collected 50 cases of epithelioid pleural mesthelioma analyzed from 2005 until 2016 by UCO di Anatomia e Istologia Patologica di Trieste. Immunohistochemistry staining of CD3 was performed to define intra-tumor lymphocites count. Intraepithelial, stromal and peritumoral TILs was assessed using the following scoring system: score 1 when TILs percentage ranges between 6 and 25%; score 2 when TILs percentage ranges between 26 and 50% and score 3 between 51% and 75%. Data were statistically analyzed by Kaplan-Meier method using a dedicated software (Statistical Package for Social Sciences, SPSS Inc., Chicago, IL, USA). The level of significance was p < 0.05.
Results. In this sample the average and median age were 70 and 71 respectively. The 4-years OS was 16% (n=8) with 42 deaths due to mesothelioma and the event occurred after an average period 14.97 months long. Neither intraepithelial nor stromal TILs scores correlated with OS (p>0.05). On the contrary, high scores (2+3 score) of peritumoral TILs significantly correlates with improved OS (p=0.02).
Conclusions. In our experience, peritumoral TILs was a positive prognostic factor in epithelioid pleural mesothelioma. This result suggests to include an immunological analysis in the therapeutical approach to mesothelioma because it has to be clarify how immune elements take part in the tumor progression. Aiming to stimulate a specific antitumor immune response,further studies are needed to optimize the immunotherapy
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