Annals of Oncology | Year: 2011
The clinical development of PARP inhibitors for the treatment of tumors deficient in BRCA1 or BRCA2 is based on the concept of synthetic lethality. From the initial proof of concept study with the PARP1 inhibitor olaparib (AZD2281) in BRCA mutation carriers, in which 28% of ovarian cancer patients achieved an objective response, the target population of ovarian patients potentially sensitive to treatment with PARP inhibitors has greatly increased. Objective responses have been observed in both platinum-sensitive and platinum-resistant BRCA mutation carriers but, more recently, also in BRCA negative 'BRCAness' patients, those with no BRCA mutations but with a dysfunction of the homologous recombination (HR) system, which makes them more sensitive to the antitumor agents which cause double strand breaks of DNA. The recent results achieved with olaparib, given as maintenance in platinum sensitive recurrent high grade serous ovarian cancer, in response after reinduction with platinum, confirm the antitumor effect of single agent olaparib in BRCAness patients. Main topics of investigations in this field are the identification of BRCAness phenotype and the definition of tests to identify BRCAness patients. More in general, additional preclinical studies are needed to further improve clinical results in order to define the optimal regimen of combination with PARP1 inhibitor and cytotoxics or molecular targeted agents (sequence of administration, interval between dosing of the agents, duration of treatment). © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Source
Christensen J.,Albert Ludwigs University of Freiburg |
El-Gebali S.,University of Bern |
Natoli M.,CNR Institute of Neuroscience |
Sengstag T.,RIKEN |
And 14 more authors.
BMC Genomics | Year: 2012
Background: The criteria for choosing relevant cell lines among a vast panel of available intestinal-derived lines exhibiting a wide range of functional properties are still ill-defined. The objective of this study was, therefore, to establish objective criteria for choosing relevant cell lines to assess their appropriateness as tumor models as well as for drug absorption studies.Results: We made use of publicly available expression signatures and cell based functional assays to delineate differences between various intestinal colon carcinoma cell lines and normal intestinal epithelium. We have compared a panel of intestinal cell lines with patient-derived normal and tumor epithelium and classified them according to traits relating to oncogenic pathway activity, epithelial-mesenchymal transition (EMT) and stemness, migratory properties, proliferative activity, transporter expression profiles and chemosensitivity. For example, SW480 represent an EMT-high, migratory phenotype and scored highest in terms of signatures associated to worse overall survival and higher risk of recurrence based on patient derived databases. On the other hand, differentiated HT29 and T84 cells showed gene expression patterns closest to tumor bulk derived cells. Regarding drug absorption, we confirmed that differentiated Caco-2 cells are the model of choice for active uptake studies in the small intestine. Regarding chemosensitivity we were unable to confirm a recently proposed association of chemo-resistance with EMT traits. However, a novel signature was identified through mining of NCI60 GI50 values that allowed to rank the panel of intestinal cell lines according to their drug responsiveness to commonly used chemotherapeutics.Conclusions: This study presents a straightforward strategy to exploit publicly available gene expression data to guide the choice of cell-based models. While this approach does not overcome the major limitations of such models, introducing a rank order of selected features may allow selecting model cell lines that are more adapted and pertinent to the addressed biological question. © 2012 Christensen et al.; licensee BioMed Central Ltd. Source
Mian M.,Azienda Ospedaliera S. Maurizio |
Ferreri A.J.M.,San Raffaele Scientific Institute |
Rossi A.,Ospedali Riuniti |
Conconi A.,University of Piemonte Orientale |
And 15 more authors.
Leukemia and Lymphoma | Year: 2013
Consolidation radiotherapy (cRT) in patients with stage I/II diffuse large B-cell lymphoma of the Waldeyer's ring (WR-DLBCL) in complete remission (CR) after induction chemotherapy (CHT) is often associated with relevant acute and chronic toxicity, and its impact on survival remains to be defined. A total of 184 patients in CR after anthracycline-based chemotherapy were retrospectively analyzed: 62 underwent CHT alone (CHT group), while 122 (66%) patients were referred to cRT (CHT + RT group). After a median follow-up of 54 months, 36 patients (20%) experienced relapse: 19% in the CHT group and 20% in the CHT + RT group. At the time of analysis 47 (76%) CHT patients and 97 (80%) CHT + RT patients were alive. Five-year overall survival (OS), disease-free survival (DFS) and lymphoma-specific survival (LSS) were 80%, 74% and 86%, respectively. Five-year OS was significantly prolonged in the CHT + RT group, while DFS and LSS were similar between groups. This discrepancy was attributed to a high percentage of deaths due to unrelated causes in CHT patients. cRT does not prolong LSS in patients with early-stage WR-DLBCL in CR after anthracycline-containing chemotherapy. An international confirmatory trial is warranted. © 2013 Informa UK, Ltd. Source
High response rate and improvement of long-term survival with combined treatment modalities in patients with poor-risk primary thyroid diffuse large B-cell lymphoma: An international extranodal lymphoma study group and intergruppo Italiano linfomi study
Mian M.,Azienda Ospedaliera S. Maurizio |
Mian M.,Oncology Institute of Southern Switzerland IOSI |
Gaidano G.,University of Piemonte Orientale |
Conconi A.,University of Piemonte Orientale |
And 17 more authors.
Leukemia and Lymphoma | Year: 2011
The impact of different treatment modalities and prognostic factors on the clinical course of primary thyroid diffuse large B-cell lymphoma (PTDLBCL) is still the subject of research. This study was conducted to clarify these clinical aspects of this disorder. The clinical parameters of 48 patients with PTDLBCL at time of diagnosis were comparable to those of previous studies. Patients underwent either radiotherapy (RT) ±° surgery (SX), chemotherapy (CHT) alone or in combination with local treatments (RT or SX), or SX followed by CHT and RT. A 90% complete remission (CR) rate was observed among patients who underwent combined treatment modalities (CTM), compared to 76% among the others. The 5-year progression-free survival differed significantly between both groups (p = 0.028). Poor performance status and advanced age correlated with decreased survival. PTDLBCL is a curable disease prevalent in elderly patients. Combined treatment modalities were able to induce an elevated rate of CR, improving long-term survival in younger patients. However, the outcome in elderly patients still remains unsatisfactory. © 2011 Informa UK, Ltd. Source
Koeberle D.,Kantonsspital St. Gallen |
Betticher D.C.,Hopital Fribourgeois |
von Moos R.,Kantonsspital Chur |
Dietrich D.,Coordinating Center |
And 16 more authors.
Annals of Oncology | Year: 2015
Background: Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer (mCRC) patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after completing first-line chemotherapy. Patients and methods: In an open-label, phase III multicentre trial, patients with mCRC without disease progression after 4-6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned to continuing bevacizumab at a standard dose or no treatment. CT scans were done every 6 weeks until disease progression. The primary end point was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significance level of 10% and a statistical power of 85%. Results: The intention-to-treat population comprised 262 patients: median follow-up was 36.7 months. The median TTP was 4.1 [95% confidence interval (CI) 3.1-5.4] months for bevacizumab continuation versus 2.9 (95% CI 2.8-3.8) months for no continuation; HR 0.74 (95% CI 0.58-0.96). Non-inferiority could not be demonstrated. The median overall survival was 25.4 months for bevacizumab continuation versus 23.8 months (HR 0.83; 95% CI 0.63-1.1; P = 0.2) for no continuation. Severe adverse events were uncommon in the bevacizumab continuation arm. Costs for bevacizumab continuation were estimated to be ~30 000 USD per patient. Conclusions: Non-inferiority could not be demonstrated for treatment holidays versus continuing bevacizumab monotheray, after 4-6 months of standard first-line chemotherapy plus bevacizumab. Based on no impact on overall survival and increased treatment costs, bevacizumab as a single agent is of no meaningful therapeutic value. More efficient treatment approaches are needed to maintain control of stabilized disease following induction therapy. Clinical trial registration:: ClinicalTrials.gov, number NCT00544700. © The Author 2015. Source