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Francescangeli F.,Oncology and Molecular Medicine | Patrizii M.,Oncology and Molecular Medicine | Signore M.,Oncology and Molecular Medicine | Federici G.,Oncology and Molecular Medicine | And 8 more authors.
Stem Cells | Year: 2012

Tumor-initiating cells are responsible for tumor maintenance and relapse in solid and hematologic cancers. Although tumor-initiating cells were initially believed to be mainly quiescent, rapidly proliferating tumorigenic cells were found in breast cancer. In colon cancer, the proliferative activity of the tumorigenic population has not been defined, although it represents an essential parameter for the development of more effective therapeutic strategies. Here, we show that tumorigenic colon cancer cells can be found in a rapidly proliferating state in vitro and in vivo, both in human tumors and mouse xenografts. Inhibitors of polo-like kinase1 (Plk1), a mitotic kinase essential for cell proliferation, demonstrated maximal efficiency over other targeted compounds and chemotherapeutic agents in inducing death of colon cancer-initiating cells in vitro. In vivo, Plk1 inhibitors killed CD133 + colon cancer cells leading to complete growth arrest of colon cancer stem cell-derived xenografts, whereas chemotherapeutic agents only slowed tumor progression. While chemotherapy treatment increased CD133+ cell proliferation, treatment with Plk1 inhibitors eliminated all proliferating tumor-initiating cells. Quiescent CD133+ cells that survived the treatment with Plk1 inhibitors could be killed by subsequent Plk1 inhibition when they exited from quiescence. Altogether, these results provide a new insight into the proliferative status of colon tumor-initiating cells both in basal conditions and in response to therapy and indicate Plk1 inhibitors as potentially useful in the treatment of colorectal cancer. © AlphaMed Press.

Lopez M.,Istituto Nazionale Tumori Regina Elena
Clinica Terapeutica | Year: 2011

Gastrointestinal stromal tumors (GIST) are the most common sarcomas of the gastrointestinal tract, known to be resistant to chemotherapy and radiotherapy. The recognition that KIT mutations were present in the majority of patients with GIST led to clinical trials of imatinib in this disease. Indeed, imatinib inhibits KIT kinase activity and represents the best drug for the treatment of unresectable and advanced GIST, achieving a partial response or stable disease in 85-90% of patients with metastatic disease. KIT activation is generally linked to somatic mutations, usually involving exon 11 or 9. Other less often involved genes are PDGFRA or BRAF. The presence and the type of KIT or PDGFRA mutation status are predictive of response to imatinib therapy in patients with advanced or metastatic GIST, as well as prognostic for relapse-free survival (RFS) after surgical resection of primary GIST. Defined risk factors for recurrent disease are mainly based on GIST size, location, and mitotic rate and provide useful guidelines for selecting patients for adjuvant therapy. Neoadjuvant therapy with imatinib has several potential advantages, including tumor downsizing to provide the opportunity for decreasing the morbidity of surgical resection as well as to decrease risk of intraoperative tumor rupture. Based on the results of ACOSOG Z9001 trial, in December 2008, the FDA approved imatinib for postoperative treatment of patients with resected KIT-positive GIST; optimum duration of adjuvant treatment was not stated. Recently, the final results of the SSGXVIII/AIO trial showed that 36 months compared to 12 months of adjuvant imatinib were significantly better in extending RFS and overall survival in patients with operable GIST with a high risk of recurrence (NIH classification). Treatment was generally well tolerated. During the last decade, striking advances have been made in the understanding, characterization, and treatment of GIST, which have emerged as a leading paradigm for genotype-driven targeted therapy. Continuing research in this field will hopefully lead to design clinical trials that more carefully select patients based on the tumor genetic features that have a significant pathogenetic role.

Clemente S.,Centro Of Riferimento Oncologico Della Basilicata | Nigro R.,Azienda Sanitaria Locale Rieti | Oliviero C.,Centro Of Riferimento Oncologico Della Basilicata | Marchioni C.,Azienda Sanitaria Locale Rieti | And 9 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2015

The increasing use of moderate (<35 fractions) and extreme (<5 fractions) hypofractionated radiation therapy in prostate cancer is yielding favorable results, both in terms of maintained biochemical response and toxicity. Several hypofractionation (HF) schemes for the treatment of prostate cancer are available, although there is considerable variability in the techniques used to manage intra-/interfraction motion and deliver radiation doses. We performed a review of the published studies on HF regimens as a topic of interest for the Stereotactic Ablative Radiotherapy working group, which is part of the Italian Association of Medical Physics. Aspects of organ motion management (imaging for contouring, target volume definition, and rectum/bladder preparation) and treatment delivery (prostate localization, image guided radiation therapy strategy and frequency) were evaluated and categorized to assess outcome relative to disease control and toxicity. Despite the heterogeneity of the data, some interesting trends that emerged from the review might be useful in identifying an optimum HF strategy. © 2015 Elsevier Inc.

Schernhammer E.S.,Harvard University | Sperati F.,Istituto Nazionale Tumori Regina Elena | Razavi P.,University of Southern California | Agnoli C.,Nutritional Epidemiology Unit | And 10 more authors.
Breast Cancer Research | Year: 2013

Introduction: Previous studies showed that higher testosterone levels are associated with greater risk of breast cancer in premenopausal women, but the literature is scant and inconsistent.Methods: In a prospective nested case-control study of 104 premenopausal women with incident breast cancer and 225 matched controls, all characterized by regular menstrual cycles throughout their lifetime, we measured the concentration of estradiol, total and free testosterone (FT), progesterone, sex hormone-binding globulin (SHBG), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in blood samples collected on days 20 through 24 of their cycles.Results: In logistic regression models, the multivariate odds ratios (ORs) of invasive breast cancer for women in the highest tertile of circulating FT compared with the lowest was 2.43 (95% confidence interval (95% CI), 1.15 to 5.10; Ptrend= 0.03), whereas for total testosterone, the association had the same direction but was not statistically significant (OR, 1.27; 95% CI, 0.62 to 2.61; Ptrend= 0.51). Endogenous progesterone was not statistically associated with breast cancer (OR, 1.16; 95% CI, 0.60 to 2.27; Ptrend= 0.75), nor were the other considered hormones.Conclusions: Consistent with previous prospective studies in premenopausal women and our own earlier investigation, we observed that higher levels of FT are positively associated with breast cancer risk in women with regular menstrual cycles throughout their lifetimes. No evidence of risk was found associated with the other endogenous sex steroids. © 2013 Schernhammer et al.; licensee BioMed Central Ltd.

Telera S.,Istituto Nazionale Tumori Regina Elena | Fabi A.,Istituto Nazionale Tumori Regina Elena | Pace A.,Istituto Nazionale Tumori Regina Elena | Vidiri A.,Istituto Nazionale Tumori Regina Elena | And 6 more authors.
Journal of Neuro-Oncology | Year: 2013

Sterotactic radiosurgery (SRS) is an effective and commonly employed therapy for metastatic brain tumors. Among complication of this treatment, symptomatic focal cerebral radionecrosis (RN) occurs in 2-10 % of cases. The large diffusion of combined therapies as SRS followed by WBRT and/or CHT, has significantly amplified the number of patients who potentially might be affected by this pathology and neurosurgeons are increasingly called to treat suspected area of RN. Results of surgery of RN in patients with brain metastases are rarely reported in literature, a standardization of diagnostic work-up to correctly identify RN is still lacking and the timing and indications in favour of surgical therapy over medical treatments are not clear as well. In this retrospective study, we review current concept related to RN and analyze the outcome of surgical treatment in a series of 15 patients previously submitted to SRS for brain metastases and affected by suspected radionecrotic lesions. After surgery, all patients except one neurologically improved. No intra-operative complications occurred. Brain edema improved in all patients allowing a reduction or even suspension of corticosteroid therapy. Pure RN was histologically determined in 7 cases; RN and tumor recurrence in the other 8. Overall median survival was 19 months. An aggressive surgical attitude may be advisable in symptomatic patients with suspected cerebral RN, to have histologic confirmation of the lesion, to obtain a long-lasting relief from the mass effect and brain edema and to improve the overall quality of life, sparing a prolonged corticosteroid therapy. © 2013 Springer Science+Business Media New York.

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