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Catucci I.,IFOM | Peterlongo P.,IFOM | Ciceri S.,IFOM | Colombo M.,Unit of Molecular Bases of Genetic Risk and Genetic Testing | And 20 more authors.
Genetics in Medicine | Year: 2014

Purpose:Monoallelic germ-line deleterious mutations of PALB2 (partner and localizer of BRCA2) are associated with breast cancer risk and have been found in several populations, with carrier frequencies of ∼1-2%. Initially, these mutations were considered to have moderate penetrance, but accumulating evidence now indicates that they are associated with much higher risk.Methods:In this study, we sequenced the PALB2 coding regions unlinked to BRCA (breast cancer) genes in 575 probands from Italian breast cancer families recruited in Milan.Results:We found 12 carriers (2.1%) of deleterious mutations, and none of the mutations was found in 784 controls collected in Milan. One of these mutations, the c.1027C>T (p.Gln343X), was found to be recurrent in the province of Bergamo in northern Italy, being detected in 6/113 (5.3%) familial breast cancer cases and 2/477 (0.4%) controls recruited in this area (Fisher's exact test: P < 0.01).Conclusions:Our data provide confirmatory findings that, in the Italian population also, deleterious mutations of PALB2 are relatively frequent predisposing factors for breast cancer and may be associated with high risk of the disease.Genet Med 16 9, 688-694. © American College of Medical Genetics and Genomics.

Miceli R.,Unit of Medical Statistics | Tomasello G.,Azienda Istituti Ospitalieri di Cremona | Bregni G.,Fondazione Istituto Nazionale Tumori | Di Bartolomeo M.,Fondazione Istituto Nazionale Tumori | Pietrantonio F.,Fondazione Istituto Nazionale Tumori
World Journal of Gastroenterology | Year: 2014

Gastric cancer still represents one of the major causes of cancer mortality worldwide. Patients survival is mainly related to stage, with a high proportion of patients with metastatic disease at presentation. Thus, the cure rate largely depend upon surgical resection. Despite the additional, albeit small, benefit of adjuvant chemotherapy has been clearly demonstrated, no general consensus has been reached on the best treatment option. Moreover, the narrow therapeutic index of adjuvant chemotherapy (i.e., limited survival benefit with considerable toxicity) requires a careful assessment of expected risks and benefits for individual patients. Treatment choices vary widely based on the different geographic areas, with chemotherapy alone more often preferred in Europe or Asia and chemoradiotherapy in the United States. In the present review we discuss the current evidence and future challenges regarding adjuvant chemotherapy in curatively resected gastric cancer with particular emphasis on the recently completed landmark studies and meta-analyses. The most recent patient-level meta-analysis demonstrated the benefit of adjuvant chemotherapy over curative surgery; the same Authors also showed that diseasefree survival may be used as a surrogate end-point for overall survival. We finally discuss future research issues such as the need of economic evaluations, development of prognostic or predictive biomarkers, and the unmet clinical need of trials comparing perioperative chemotherapy with adjuvant treatment. © 2014 Baishideng Publishing Group Co., Limited. All rights reserved.

Giganti M.O.,Prostate Program | Mariani L.,Unit of Medical Statistics | Salvioni R.,Urologic | Nicolai N.,Urologic | And 2 more authors.
BJU International | Year: 2011

OBJECTIVE To assess the efficacy of ketoconazole in patients with castration-resistant prostate cancer (CRPC). PATIENTS AND METHODS From April 2008 to November 2009, 37 patients with CRPC have been treated with ketoconazole. The primary endpoint was the prostate-specific antigen (PSA) response; the secondary endpoints were progression-free survival and safety profile. Ketoconazole was administered by oral route at a dose of 200 mg every 8 h continuous dosing until the onset of serious adverse events or disease progression. The study was based on a two-step design with an interim efficacy analysis carried out on the first 12 patients accrued. RESULTS Main characteristics of population were: median age 75 years (range 60-88); baseline mean PSA 28.8 ng/mL (4.3-1000); 30 patients previously challenged with at least two lines of hormone therapy; 15 patients previously treated with chemotherapy. Biochemical responses accounted for: two complete responses (5%), six partial responses (16%), 13 patients with stable disease (35%), and 14 with progressive disease (38%). Of 15 patients resistant to chemotherapy, overall disease control (complete plus partial responses plus stable disease) was recorded in seven of them. Treatment was feasible without inducing grade 3-4 adverse events. The most common grade 1-2 adverse events were asthenia (27%), vomiting (8%) and abdominal pain (8%). CONCLUSION Treatment with low-dose ketoconazole is feasible and well tolerated. The efficacy was satisfactory in patients previously treated with chemotherapy. © 2010 BJU INTERNATIONAL.

Silvestrini R.,Biomarkers Unit | Martelli G.,Breast Unit | Miceli R.,Unit of Medical Statistics | Agresti R.,Breast Unit | And 2 more authors.
International Journal of Biological Markers | Year: 2013

The present study investigated whether tumor markers such as cell proliferation and steroid receptor status, which have been shown to have relevance for important endpoints (relapse-free and overall survival), can also predict axillary disease in elderly patients with breast cancer. We evaluated 351 consecutive elderly women with breast cancer ≥70 years of age with estrogen receptor (ER) positive tumors with no palpable axillary nodes, for whom information on cell proliferation determined by the 3H-thymidine labeling index (TLI) and progesterone receptor (PgR) was available. Patients underwent quadrantectomy (70.1%) or quadrantectomy plus radiotherapy (29.9%) without axillary node dissection, followed by adjuvant tamoxifen for at least 2 years. Univariable (cumulative incidence curves) and multivariable analyses (Fine and Gray models) were carried out. After a median follow-up of 16 years, ipsilateral axillary relapse was not related to PgR status but was strongly associated with tumor cell proliferation in both small (pT1) and large (pT2-4b) tumors. Axillary relapse cumulative incidence increased from 1% in patients with low-TLI (≤3%), PgR-positive and pT1 tumors to a maximum of 20% in patients with high-TLI, PgR-negative and pT2-4b tumors. Tumor cell proliferation, determined by TLI at primary surgery, is an important predictor of axillary relapse in elderly ER-positive breast cancer patients and could help to identify patients who should undergo axillary surgery. © 2013 Wichtig Editore.

Colombo C.,Sarcoma Service | Ronellenfitsch U.,University of Mannheim | Yuxin Z.,Harvard University | Yuxin Z.,Chinese Academy of Sciences | And 6 more authors.
Annals of Surgical Oncology | Year: 2012

Background. The duodenum is a rare site of primary gastrointestinal stromal tumor (GIST). Overall (OS) and disease-free survival (DFS) after limited resection (LR) versus pancreaticoduodenectomy (PD) were studied. Methods. All patients who underwent surgery for primary, localized duodenal GIST between 2000 and 2011 were identified from four prospective institutional databases. OS and DFS were calculated by Kaplan-Meier method. Univariate analysis was performed. Results. Eighty-four patients (median follow-up 42 months) underwent LR (n = 56, 67 %) or PD (n = 28, 33 %). Patients in the PD group had a larger median tumor size (7 cm vs. 5 cm, p = 0.024) and higher mitotic count (39 % vs. 19 % >5/50 high-power fields, p = 0.05). Complications were observed in five patients (9 %) in the LR group and ten patients (36 %) in the PD group. OS and DFS for the entire cohort were 89 % and 64 % at 5 years, respectively. No difference in outcome between LR and PD were observed. Eleven patients were treated with preoperative IM. A major RECIST response was obtained in nine (80 %), whereas two had stable disease. Twenty-three patients received postoperative Imatinib (IM). A trend toward a better OS in IM-treated patients could be detected only in the high-risk group. Conclusions. Type of duodenal resection does not impact outcome. The choice should be determined by duodenal site of origin and tumor size. IM may be considered in cases at high risk of recurrence; in neoadjuvant setting, IM might facilitate resection and possibly increase the chance of preserving normal biliary and pancreatic anatomy. © Society of Surgical Oncology 2012.

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