1,721,232 research outputs found
Le neoplasie eredo-familiari della mammella, dell'ovaio e del colon retto. Aspetti clininci, diagnostici e teraputici.
No full textBreast cancer prevention with fenretinide in young women at gentic and familial risk. A phase III randomized clinical trial
No full textThe aim of the proposed trial is to assess the efficacy of fenretinide (4-hydroxyphenylretinamide, 4-HPR), a vitamin A derivative, in reducing the incidence of breast cancer (BC) in healthy young premenopausal women at increased familial/genetic risk for BC (i.e., BRCA1 or BRCA2 mutation carriers or women with a significant family risk) The primary endpoint is the incidence of invasive BC and ductal intraepithelial neoplasia (DIN).Secondary endpoints are the incidence of other non-invasive breast disorders (i.e., lobular intraneoplasia, atypical hyperplasia), ovarian cancer and other cancers. These clinical endpoints require a long follow-up.
During the study we will study also several intermediate biomarkers. The biological effects of fenretinide will be assessed to provide data on its activity investigating different pathways where fenretinide may be involved. We intend to measure circulating levels of several hormones and growth factors and lipid profile parameters correlated to BC risk and metabolic syndrome, which may be indirectly involved in the carcinogenesis process and insulin resistance. In particular, we will measure circulating levels of insulin-like growth factor-I (IGF-I), its main binding protein (IGFBP-3), testosterone, insulin, glycemia, total and HDL cholesterol and triglycerides.
Fenretinide and its metabolites and retinol binding protein will also be measured to investigate drug bioavailability and compliance.
Furthermore we will quantify cell-free circulating DNA in plasma samples
Studio osservazionale sorveglianza diagnostica di donne ad alto rischio genetico-familiare di tumore mammario (ISSIN-HIBCR)
No full textLa maggior parte dei casi di carcinoma mammario (CM) è considerata a carattere “sporadico”. In alcune famiglie l’incidenza di CM è superiore a quella attesa nella popolazione generale, per un totale delle forme ereditarie e familiari di circa il 15% dei casi. Si stima che circa il 5% dei CM siano clusterizzati in famiglie ad alto rischio con predisposizione ereditaria multifattoriale che determina un lifetime risk maggiore del 50-60%, associato a precoce esordio della malattia, tipicamente in età premenopausale. Circa un 50% di questi CM sono determinati da mutazioni patogeniche dei geni BRCA1 o BRCA2 (allocati su 17q21 e 13q12, rispettivamente) con trasmissione autosomica dominante a penetranza incompleta. Tali tumori si associano a prognosi più sfavorevole.
I test genetici consentono l’identificazione di soggetti con dimostrato alto rischio genetico. Tuttavia, donne con alta familiarità e tumore diagnosticato o pregresso possono avere un risultato “non conclusivo” al test genetico in una elevata frazione di casi (anche oltre il 50%), probabilmente a causa della presenza di una o più mutazioni non ancora identificate. Inoltre, una donna con alta familiarità potrebbe non trovare una familiare affetta che accetti di sottoporsi al test o potrebbe desiderare di non conoscere il suo stato mutazionale. La sorveglianza delle donne ad alto rischio non può avvalersi dei modelli sperimentati e noti per lo screeening di popolazione, basato in Europa sulla sola mammografia a cadenza biennale dopo i 50 anni. Nei soggetti ad alto rischio si ritiene oggi opportuno adottare programmi di sorveglianza con esordio più precoce (con conseguente necessità di tecniche di imaging meno dipendenti dalla densità ghiandolare rispetto alla mammografia) e intervalli più brevi tra un round e il successivo. Infatti, la mammografia annuale si è dimostrata non sufficientemente sensibile nelle donne ad alto rischio, con un tumore ogni due diagnosticato come cancro d’intervallo. Inoltre, i soggetti portatori di mutazione BRCA sono probabilmente più sensibili alle radiazioni ionizzanti, come già dimostrato per BRCA2 in un modello animale.
Negli ultimi cinque anni sono stati pubblicati alcuni studi concernenti l’utilizzo della risonanza magnetica (RM) con mezzo di contrasto (MdC) paramagnetico nella sorveglianza di donne ad alto rischio di tumore mammario, sia prospettici che retrospettivi. Tali studi hanno dimostrato che questa tecnica è più sensibile della visita clinica, della mammografia e dell’ecografia nella diagnosi di CM in soggetti ad alto rischio.
La valutazione metanalitica di cinque studi prospettici di soggetti ad alto rischio genetico-familiare sottoposti a sorveglianza con imaging convenzionale – mammografia, ecografia (in alcuni studi) e RM – fornisce il seguente quadro complessivo: su 3.571 donne sottoposte a screening e 9.652 round sono stati diagnosticati 168 casi di CM (155 screen-detected, 8 cancri d’intervallo e 5 casi esclusi dall’analisi) con un detection rate dell’1,7%. Tali tumori erano di piccole dimensioni (49% con diametro 10 mm), aggressivi (82% invasivi e 49% G3) ma con una modesta frequenza (19%) di metastasi linfonodali La sensibilità dei cinque studi è risultata del 16% per la visita clinica, del 40% per la mammografia, del 43% per l’ecografia e del 81% per la RM. Il valore predittivo positivo (calcolato sulla base del numero di procedure diagnostiche invasive dovute ai falsi positivi di ciascuna modalità diagnostica) è risultato 33%, 47%, 18% e 53%, rispettivamente.
In tale panorama internazionale l’Italia si è collocata fra i gruppi di ricerca più avanzati grazie al Trial multicentrico coordinato, a partire dal 1998, dall’Istituto Superiore di Sanità (High Breast Cancer Risk Italian Trial, HIBCRIT). I risultati preliminari (relativi al primo round su 105 soggetti arruolati) sono stati pubblicati nel 2002 mentre i risultati dell’interim analysis su 278 soggetti arruolati con una media di 1.4 round per soggetto sono stati pubblicati nel 2007. Sulla base di tale esperienza, il Ministero della Salute ha affidato all’Istituto Superiore di Sanità la conduzione di un progetto intitolato “Sorveglianza di donne ad alto rischio genetico-familiare di tumore mammario: sviluppo di un Network Nazionale Italiano”
New biomolecular prognostic and predictive factors of response to treatments in colorectal cancer
No full textLa candidata ha analizzato l'espressione di una serie di microRNA in campioni di tessuto derivati da neoplasie del retto localmente avanzate, trattate con radio-chemioterapia concomitante a scopo adiuvante. Un cluster di 14 microRNA erano sovraespressi nei pazienti che ottenevano una risposta completa patologica (Tumor Regression Grade 1) dopo il trattamento neoadiuvante (sensibilità 78%; specificità 80%
TESI DI DOTTORATO: Hereditary and familial breast and ovarian cancer: spectrum of related tumors. CANDIDATO: M.Pensabene. RELATORE: S.Pepe
No full textThis dissertation is focused on the evaluation of cancer spectrum related to
hereditary and familial breast cancer. In BRCA1 mutation carriers, mean
cumulative risk at age 70 years is 57% (95% CI, 47% to 66%) for breast cancer
and 40% (95% CI, 35% to 46%) for ovarian cancer. Moreover, in BRCA2
mutation carriers mean cumulative risk at age 70 years is 49% (95% CI, 40%
to 57%) for breast cancer and 18% (95% CI, 13% to 23%) for ovarian cancer.
Various studies reported contradictory data concerning risk of cancer at sites
different than breast and ovary in both of carriers of mutations in BRCA1 and
BRCA2 genes.
We selected families referred to “Screening and follow-up for hereditary
and familial cancers” Unit of University “Federico II” in Naples for
oncogenetic counseling. Families were analyzed in order to evaluate the cancer
spectrum related with inherited and familial breast and ovarian cancer. We
examined 104 pedigrees for a total of 4100 individuals (2117 females, 1983
males), all of Caucasian ethnicity. Based on family history of breast cancer
and/or ovarian cancer and on clinical characteristics at diagnosis, pedigrees
were classified according to Modena model in: hereditary with clustering (41
families; 39%), hereditary without clustering (27 families; 26%) and familial
(36 families; 35%).
A total of 587 independent events of cancer have been detected in the 104
families on study. In particular among the three major categories in which
individuals have been grouped, 294 cases (17.6%) of tumors were registered in
the category of hereditary with clustering constituted of a cohort of 1670
individuals, 103 cases (9.8%) of tumors in the category of hereditary without
clustering constituted of a cohort of 1053 individuals and 190 cases (13.8%) of
tumors in the familial category constituted of a cohort of 1377 individuals.
In the hereditary with clustering group a high frequency emerges for cancer
of ovary (2%), uterus (1,4%), prostate (1,4%) and lung (0,9%). A moderate
frequency emerges for colon-rectum (0,8%) and stomach (0,7%) cancers. In
the hereditary without clustering group a similar association has not been
revealed except for colon-rectum cancer ((0,8%). In the familial group a high
frequency has been registered for cancers of ovary (1,3%), uterus (2%), and
colon-rectum (1,3%). A moderate frequency has been registered for prostate
cancer (0,9%).
We also determined frequency of tumors in families with mutations of
BRCA1/2 genes. In the 10 families with BRCA1 mutations, 76 events of
cancers have been detected in a total of 486 individuals. It emerges a clustering
with ovarian (4.9%), uterine (1.2%) and bladder cancer (0.8%). In the 6
families with BRCA2 genotype, 33 events of cancers have been registered in a
total of 185 individuals. It emerges a clustering with ovarian (2.8%), uterine
(2,8%), colon-rectum (1%) and prostate cancers (2,6%).
At least, the statistical analysis have not revealed a typical cancer spectrum,
because differences of statistical value have not been gained for any specific
site other than breast in our series among risk categories and sex
TESI DI DOTTORATO:Gefitinib and Radiotherapy in patients with locally advanced inoperable squamous cell carcinoma of the head and neck. CANDIDATO: C.Romano. RELATORE: S.Pepe.
No full textIntroduction: Gefitinib, an orally active epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, induces growth arrest in squamous cancer cell carcinoma of head and neck (SCCHN) cell lines mainly by blocking cells in G1 and preventing them from entering the cell cycle. Clinical studies have demonstrated the activity of gefitinib monotherapy in SCCHN. Preclinical studies
have shown that the combination of radiotherapy (RT) and drugs interfering with the EGF pathway may result in radiosensitization in squamous cell carcinomas that over express EGFR.
Purpose: Two different doses of gefitinib, administered along with standard radiation therapy, were tested in locally advanced inoperable head and neck cancer who have neiver received radiotherapy or chemotherapy or undergone surgery for head and neck carcinoma, with the aim of finding the maximum
tolerated dose and assessing the toxicity and activity of the combination.
Patients and methods: The standard “3+3” design was used for the phase I study. Radiation therapy was given according to conventional dose and schedule. Gefitinib dose escalation was stopped if more than a third of patients of a given cohort had dose limiting toxicity (DLT).
Results: DLT was observed in 3 out of 4 patients treated at the dose of 500 mg and included grade 3 stomatitis in 3 patients and grade 3 liver toxicities in 1 patient. The dose level of 250 mg was recommended for the phase II study. Six confirmed objective responses were observed among 16 patients. Four patients
had a complete response, which was confirmed in three cases; eight patients had a partial response, which was not confirmed in six patients. Stable disease and disease progression were observed in one and three patients, respectively. Median
duration of response was 5.4 (range: 1–21) months. The observed stable disease lasted 7.4 months. The median progression free-survival was 6.7 months (95% CI: 4.5–12.1) and the median OS was 8.5 months.
Conclusion: Our results do not support further trials with gefitinib and radiation therapy, according to our schedule, in this patient population. Integration of gefitinib within chemoradiotherapy regimens and combination with other biological therapies may represent the next challenge
Quality control for the evaluation of the S-phase fraction by flow cytometry: a multicentric study.
No full text- …
