1,354,145 research outputs found
CELL OF ORIGIN MARKERS IDENTIFY DIFFERENT PROGNOSTIC SUBGROUPS OF LUNG ADENOCARCINOMA PATIENTS
No full textPur essendo il carcinoma del polmone la causa principale di morte per cancro a livello mondiale, non ci sono ancora marcatori affidabili in grado di stratificare da un punto di vista prognostico i pazienti affetti da adenocarcinoma del polmone. Né l’aspetto istologico né fingerprint genetici sono in grado di fornire una stratificazione prognostica dei pazienti che sia riproducibile e clinicamente utile. Per questo motivo, abbiamo costruito un pannello ad hoc di 6 marcatori immunoistochimici (TTF1, SP-A, Napsin A, MUC5AC, CDX2 e CK5). Testando questi marcatori, che sono fortemente correlati con le "cellule di origine" putative dell’adenocarcinoma polmonare (TTF1, SP-A e Napsin A indicano un'origine alveolare, mentre MUC5AC, CDX2 e CK5 indicano un'origine bronchiolare), ci proponiamo di identificare diversi sottogruppi prognostici tra i pazienti affetti da adenocarcinoma del polmone. Come secondo obiettivo, abbiamo correlato l’espressione di questi marcatori con le comuni mutazioni genetiche e l’aspetto istologico degli adenocarcinomi polmonari testati. A tal fine, abbiamo raccolto un'ampia coorte di pazienti sottoposti a intervento chirurgico per adenocarcinoma polmonare e, usando i tessuti fissati in formalina e inclusi in paraffina , abbiamo studiato: i) il pattern di crescita istologico (lepidico, acinare, papillare, micropapillare, solido e mucinoso) al microscopio ottico, ii) la presenza di mutazioni "hot spot" di geni candidati (ad esempio EGFR, KRAS, PI3K) tramite tecnologia Sequenom e iii) il pannello di 6 marcatori immunoistochimici. Le differenze tra i gruppi così ottenuti sono state valutate con il test di Mann-Whitney per le variabili continue e il test del chi-quadrato o test esatto di Fisher per le variabili categoriali. Per rilevare possibili fattori predittivi di sopravvivenza, abbiamo usato il modello di rischio proporzionale di Cox per descrivere rischi proporzionali con intervalli di confidenza al 95%. Come importante risultato, abbiamo identificato 4 sottogruppi differenti basati sull’espressione del pannello immunoistochimico: alveolari, bronchiolari, misti e tipo "nullo", che risultano fortemente correlati con diversi parametri clinico-patologici e soprattutto con la sopravvivenza globale. In particolare, se gli adenocarcinomi a fenotipo alveolare sorgono con maggiore frequenza nei pazienti giovani e nel sesso femminile e presentano più frequentemente mutazioni del gene EGFR, le neoplasie a fenotipo bronchiolare sono maggiormente associate alla presenza di invasione vascolare, istologia mucinosa e mutazioni del gene KRAS; infine, i fenotipi bronchiolari e “nulli” sono associati con una prognosi peggiore. In assenza di marcatori prognostici clinici, la stratificazione prognostica basata sulla "cellula di origine" è risultata più predittiva della prognosi dei parametri isto-morfologici e del fingerprint genetico e rappresenta un parametro predittivo indipendente di sopravvivenza nell'analisi multivariataLung carcinoma is the leading cause of cancer related-death worldwide, but reliable prognostic markers to correctly stratify the prognosis of patients with lung adenocarcinoma are still lacking. Neither morphology nor genetic fingerprints can fully achieve consistent and clinically informative stratifications. We aimed to evaluate a new immunohistochemical panel composed by 6 markers (TTF1, SP-A, Napsin A, MUC5AC, CDX2 and CK5). Using these markers, that are strongly correlated with the two possible putative “cell of origin” of lung adenocarcinoma (TTF1, SP-A and Napsin A indicate an alveolar origin, whereas MUC5AC, CDX2 and CK5 indicate a bronchiolar origin), we aim at identifying different prognostic subgroups among patients with such tumors. As a second aim, we have correlated these markers with common genetic mutations and classical morphology. We collected a large cohort of adenocarcinoma patients and, using formalin-fixed paraffin-embedded tissue, we have studied: i) the morphological appearance (lepidic, acinar, papillary, micropapillary, solid and mucinous) by light microscopy, ii) the presence of “hot spot” mutations of candidate genes (i.e. EGFR, KRAS, PI3K) by Sequenom technology and iii) the 6 immunohistochemical markers panel. Between-group differences were evaluated using the Mann–Whitney U test for continuous variables and the chi-square test or Fisher’s exact test for categorical variables. To detect possible predictors of survival, we used the Cox proportional hazard model to describe proportional hazards with 95% confidence intervals. As major finding, we identified 4 different subgroups based on markers’ expression: “alveolar” type, “bronchiolar” type, “mixed” type and “null” type, that resulted strongly correlated with different clinic-pathological parameters and above all with Overall Survival (OS). Particularly, if the alveolar-type arose more in young and female patients, and harbor typically EGFR mutations, bronchiolar-type tumors were more frequently associated with vascular invasion, a mucinous histology and KRAS mutations; at last, Bronchiolar and Null types were associated with a worse prognosis. In the absence of reliable prognostic markers, our 6 “cell of origin” markers’ classifier appears more predictable than the classical morphologic parameters and the genetic fingerprint, and is an independent predictor of survival in a multivariate analysis
Esposizione nell’infanzia ed asma nell’adulto
No full textEsposizione nell’infanzia ed asma nell’adult
The Roles of Chromatin Remodeling Genes in Pancreatic-Biliary Malignancies
No full textRecent studies have definitively established that chromatin remodeling is a crucial epigenetic mechanism not only in physiological conditions but also in influencing cancer biology. It is a dynamic process in which the chromatin, the functional entity of DNA, can undergo specific modifications by obtaining transcriptional activation or transcriptional silencing. One of the most important recent discoveries in cancer genetics and genomics is that the genes involved in the establishment of chromatin structure, the so called chromatin remodelers, are frequently mutated in different types of human cancer. This review aims to summarize the main novelties related to this topic, describing also the contribution of such genes during oncogenesis. Particularly, we focus on the switch/sucrose non-fermentable complexes and on three of the most important chromatin remodeling genes in biliary and pancreatic cancer: ARID1A, PBRM1, and BAP1
Performance Evaluation of Mobile Processes via Abstract Machines
No full textWe use a structural operational semantics which drives us in inferring quantitative measures on system evolution. The transitions of the system are labelled and we assign rates to them by only looking at these labels. The rates re ect the possibly distributed architecture on which applications run. We then map transition systems to Markov chains, and performance evaluation is carried out using standard tools. As a working example, we compare the performance of a conventional uniprocessor with a prefetch pipeline machine. We also consider two case studies from the literature involving mobile computation to show that our framework is feasible
Comparative efficacy and safety of trastuzumab biosimilars to the reference drug: a systematic review and meta-analysis of randomized clinical trials
No full textPurpose: To assess efficacy and safety of trastuzumab biosimilars in comparison to the reference drug through a systematic review and meta-analysis of randomized controlled trials (RCTs). Methods: A comprehensive search was conducted using PubMed, Web of Science, Cochrane library, Open Grey and ClinicalTrials.gov databases. Dichotomous data for efficacy and safety outcomes were pooled to obtain the relative risk (RR) and 95% confidence intervals (CIs). Meta-analysis was performed with the Mantel–Haenszel method using Revman 5.3 software. Results: Eight phase III RCTs including a total of 3913 patients with HER2 + breast cancer were identified that met the inclusion criteria. The pooled results for the comparison of trastuzumab biosimilars to the reference drug showed no differences of objective response rate (ORR) (RR 1.05, 95% CI 0.98–1.12, P = 0.20) or overall survival (RR 0.82, 95% CI 0.61–1.09, P = 0.17) in the intention-to-treat population, as well as no difference of ORR (RR 1.03, 95% CI 0.97–1.10, P = 0.30) in the per-protocol population. Similarly, no significant difference was detected in any type of adverse event reported in at least three RCTs, including any serious treatment-emergent adverse effects (RR 0.97, 95% CI 0.76–1.25, P = 0.83), heart failure (RR 1.47, 95% CI 0.69–3.14, P = 0.32), neutropenia (RR 1.05, 95% CI 0.96–1.15, P = 0.26), and infusion-related reaction (RR 1.10, 95% CI 0.89–1.36, P = 0.38). Conclusion: This meta-analysis provides compelling evidence of clinical comparability between trastuzumab biosimilars and the originator product in terms of both efficacy and safety for the treatment of HER2 + breast cancer
Complete Cerebrospinal Fluid Response to T-DM1 in HER2 Positive Metastatic Breast Cancer: A Case Report
No full textLeptomeningeal carcinomatosis is a rare but serious consequence of pre-existing tumors, such as breast, lung, and gastrointestinal carcinomas. Further, leptomeningeal carcinomatosis is more frequently diagnosed with breast cancers, if only because breast cancers are diagnosed far more often than any other carcinomas. In this paper, we present the case of a leptomeningeal carcinomatosis patient who experienced complete remission following therapy targeted at the Her-2 (human epidermal growth factor receptor 2-positive) receptor. This patient’s diagnosis was complicated by the fact that brain and column MRI imaging were clear, but analysis of the cerebrospinal fluid led to the conclusion of leptomeningeal carcinomatosis. The tests were requested because the patient, under chemotherapy for advanced breast cancer at the time, reported some neurological symptoms. Following the diagnosis of leptomeningeal carcinomatosis and subsequent T-DM1 Her-2 receptor therapy, the patient showed a complete response to leptomeningeal carcinomatosis within 30 days and survived for another 16 months. This case offers compelling evidence that the effect TDM1 Her-2 receptor therapy has on a patient’s remission and long-term survivability is considerably better than other therapies for similar pre-existing conditions diagnosed with leptomeningeal carcinomatosis. Further prospective studies should confirm these findings
Female-specific association among I, J and K mitochondrial genetic haplogroups and cancer: A longitudinal cohort study
No full textRecent studies highlighted the role of mitochondrial dysregulation in cancer, suggesting that the different mitochondrial haplogroups might play a role in tumorigenesis and risk of cancer development. Our aim is to investigate whether any mitochondrial haplogroups carried a significant higher risk of cancer development in a large prospective cohort of North American people. The haplogroup assignment was performed by a combination of sequencing and PCR-RFLP techniques. Our specific outcome of interest was the incidence of any cancer during follow-up period. Overall, 3222 participants were included in the analysis. Women having I, J, K haplogroup reported a significant higher incidence of cancer compared to people with other haplogroups (p < 0.0001), whilst in men non association was found. In the multivariate analysis, women having I, J, K mitochondrial haplogroup reported a 50% increased risk of cancer (HR = 1.50; 95%CI: 1.04–2.16; p = 0.03). This gender-linked association may be partly explained by the role of mitochondrial function in female-specific (e.g. BRCA-driven) oncogenesis, but further studies are needed to better understand this potential correlation. Our findings may have important implications for cancer epidemiology and prevention
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Comparative efficacy and safety of trastuzumab biosimilars to the reference drug: a systematic review and meta-analysis of randomized clinical trials
No full textPurpose To assess efficacy and safety of trastuzumab biosimilars in comparison to the reference drug through a systematic review and meta-analysis of randomized controlled trials (RCTs). Methods A comprehensive search was conducted using PubMed, Web of Science, Cochrane library, Open Grey and ClinicalTrials.gov databases. Dichotomous data for efficacy and safety outcomes were pooled to obtain the relative risk (RR) and 95% confidence intervals (CIs). Meta-analysis was performed with the Mantel-Haenszel method using Revman 5.3 software. Results Eight phase III RCTs including a total of 3913 patients with HER2 + breast cancer were identified that met the inclusion criteria. The pooled results for the comparison of trastuzumab biosimilars to the reference drug showed no differences of objective response rate (ORR) (RR 1.05, 95% CI 0.98-1.12,P = 0.20) or overall survival (RR 0.82, 95% CI 0.61-1.09,P = 0.17) in the intention-to-treat population, as well as no difference of ORR (RR 1.03, 95% CI 0.97-1.10,P = 0.30) in the per-protocol population. Similarly, no significant difference was detected in any type of adverse event reported in at least three RCTs, including any serious treatment-emergent adverse effects (RR 0.97, 95% CI 0.76-1.25,P = 0.83), heart failure (RR 1.47, 95% CI 0.69-3.14,P = 0.32), neutropenia (RR 1.05, 95% CI 0.96-1.15,P = 0.26), and infusion-related reaction (RR 1.10, 95% CI 0.89-1.36,P = 0.38). Conclusion This meta-analysis provides compelling evidence of clinical comparability between trastuzumab biosimilars and the originator product in terms of both efficacy and safety for the treatment of HER2 + breast cancer
Variations on the Author
No full text“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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