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ABSTRACT: The prognosis of patients affected by metastatic renal cell carcinoma (mRCC) has improved markedly with targeted therapies. Unfortunately, 20-25% of the patients are refractory to treatment at the first response assessment and most patients will acquire drug resistance during the treatment. Moreover, current data on the clinical activity of targeted agents in poor risk or non-clear-cell mRCC patients are inconclusive because of the absence of prospective trials. Therefore, there are still several patients in need of new therapeutic approaches to improve clinical outcomes. Kidney cancer is historically considered resistant to chemotherapy on the basis that the results of phase II trials have not always been promising. We carried out a systematic review of both monochemotherapy and polychemotherapy alone or combined with immunotherapy or targeted agents in mRCC to define the state of the art and to evaluate further clinical research fields. All retrospectives, phase I/dose finding, phase II and phase III studies on chemotherapy in mRCC, published in the literature from January 2003 to November 2012, with at least 20 patients enrolled, were evaluated. Although the results of clinical trials have often been disappointing, in selected cases of mRCC, chemotherapy may have a promising antitumor activity, particularly when there are sarcomatoid differentiation features, or in highly progressive disease where the combination of doxorubicine plus gemcitabine or capecitabine has yielded interesting results. Chemotherapy may play a role in mRCC, whereas targeted agents and immunotherapy have not yielded durable and satisfactory results; further studies are needed.
Anti-cancer drugs 04/2013; · 2.23 Impact Factor
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ABSTRACT: Renal cell carcinoma (RCC) is one of the ten most frequent solid tumors worldwide. Recent innovations in the treatment of metastatic disease have led to new therapeutic approaches being investigated in the adjuvant setting. Observation is the only current standard of care after radical nephrectomy, although there is evidence of efficacy of adjuvant use of vaccine among all the strategies used. This article aims to collect published experiences with systemic adjuvant approaches in RCC and to describe the results of past and ongoing phase III clinical trials in this field. We explored all the systemic treatments, including chemotherapy, immunotherapy and targeted drugs while alternative approaches have also been described. Appropriate selection of patients who would benefit from adjuvant therapies remains a crucial dilemma. Although the international guidelines do not actually recommend any adjuvant treatment after radical surgery for RCC, no conclusions have yet been drawn pending the results of the promising ongoing clinical trials with the target therapies. The significant changes that these new drugs have made on advanced disease outcome could represent the key to innovation in terms of preventing recurrence, delaying relapse and prolonging survival after radical surgery for RCC.
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ABSTRACT: BACKGROUND: Soft tissue sarcomas are a heterogeneous group of malignant neoplasms including several distinct entities with different cell differentiation and clinical prognosis, but which are often treated as a single disease. Case Report: We report the case of a male patient, heavily treated for a metastatic well-differentiated liposarcoma occurring in the left lateral neck. He received radiotherapy and different lines of standard chemotherapy with local progression and lung metastasis. In November 2009, on the basis of a phase II study demonstrating the efficacy of sunitinib in patients with liposarcoma, the patient was treated with sunitinib at 37.5 mg daily in 4-week cycles on a compassionate use basis. Until November 2012 he received a total of 23 cycles of sunitinib treatment achieving a stable disease in all sites. Therapy with sunitinib is still ongoing without side effects. CONCLUSION: Our findings confirm that sunitinib may be a useful therapeutic tool in the treatment of some cases of pre-treated liposarcoma.
Anticancer research 03/2013; 33(3):1061-1063. · 1.73 Impact Factor
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Antonio Marchetti, Andrea Ardizzoni,
Mauro Papotti,
Lucio Crinò,
Giulio Rossi,
Cesare Gridelli,
Massimo Barberis,
Eugenio Maiorano,
Nicola Normanno,
Gian Luigi Taddei,
Giorgio Scagliotti,
Claudio Clemente,
Carmine Pinto
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ABSTRACT: INTRODUCTION:: Recent clinical trials led to the approval of crizotinib (PF-02341066; Pfizer) by the U.S. Food and Drug Administration for the treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC) patients whose tumors are positive for anaplastic lymphoma kinase (ALK) alterations. The European Medicines Agency accepted the regulatory submission of crizotinib for the treatment of these patients. Therefore, ALK gene testing has become mandatory to choose the most appropriate therapy. METHODS:: To help physicians, involved in the management of NSCLC patients to be treated with ALK inhibitors in Italy, the Italian Association of Medical Oncology and the Italian Society of Pathology and Cytopathology identified a large panel of Italian medical oncologists and pathologists that outlined recommendations for ALK testing in NSCLC patients. RESULTS:: The guidelines produced include specific information on the target patient population, the biological material for molecular analysis, a section dedicated to the histocytopathologic diagnosis of NSCLC, and the methods for the assessment of ALK alterations that are summarized in this article. CONCLUSIONS:: Clinicopathologic recommendations were produced to guide the management of NSCLC patients who need to be tested for ALK rearrangements before treatment with ALK inhibitors.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 03/2013; 8(3):352-358. · 4.55 Impact Factor
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Elisa Fontana,
Francesca Pucci,
Roberta Camisa,
Simona Bui,
Salvatore Galdy,
Francesco Leonardi,
Francesca Virginia Negri,
Elisa Anselmi,
Pier Luigi Losardo,
Luigi Roncoroni,
Paolo Dell'abate,
Pellegrino Crafa,
Stefano Cascinu, Andrea Ardizzoni
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ABSTRACT: Aim: To evaluate the activity, safety and long-term survival of patients after preoperative oxaliplatin and 5-fluorouracil chemoradiation therapy in locally advanced rectal cancer (LARC).
Patients with resectable, T3-4 and/or nodal involvement rectal adenocarcinoma were treated with oxaliplatin 60 mg/m(2) weekly and 5-fluorouracil 200 mg/m(2)/d infused continuously for five days, over a period of five weeks, and radiotherapy (45 Gy/25 fractions). The primary end-point was pathological complete response (ypCR). Safety, overall survival (OS) and relapse-free survival (RFS) were secondary end-points.
Sixty-six patients were treated. Grade 1-2 diarrhea was the most common adverse event. The ypCR rate was 16.7% (95% confidence interval=7.7-25.7%). After a median follow-up of 73.5 months, 23 patients (34.8%) had experienced relapse. Five-year actuarial RFS and OS rates were 64% and 73%, respectively. Five-year actuarial RFS was 91.7% in the ypCR group versus 57.8% in non-ypCR cases.
Long-term local control and survival after this very well-tolerated regimen appear encouraging.
Anticancer research 02/2013; 33(2):725-30. · 1.73 Impact Factor
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Cecilia Bozzetti,
Nadia Naldi,
Rita Nizzoli,
Cinzia Azzoni,
Beatrice Bortesi,
Valentina Zobbi,
Lorena Bottarelli,
Marcello Tiseo,
Donatello Gasparro,
Maria Majori,
Massimo De Filippo, Andrea Ardizzoni
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ABSTRACT: INTRODUCTION: Molecular profiling of advanced non-small cell lung cancer (NSCLC) has become essential for predicting customized medical treatment decision. In light of recent advances in non-invasive diagnostic procedures in NSCLC, we aimed to demonstrate the reliability of assessing molecular tests for epidermal growth factor receptor (EGFR) and KRAS genes on cytological samples by comparing the molecular profile obtained on cells from scraped smears with that on paired needle washing in a series of NSCLC cases. METHODS: Thirty-two cytological specimens obtained by fine-needle aspiration biopsy procedures from primary or metastatic lesions of NSCLCs were Giemsa stained for a rapid on-site evaluation and, in case of an adequate sampling, the cellular material obtained from needle washing was collected into a saline solution. Scraped smears and needle washings were tested for EGFR and KRAS by polymerase chain reaction followed by direct sequencing. RESULTS: The concordance between EGFR and KRAS mutational status in 29 paired scraped smears and needle washing was 100%, with 7 paired samples showing the same EGFR mutation (4 L858R mutation, 2 E746_A750 deletion and 1 A767_V769 duplication) and 8 paired samples showing the same KRAS mutations (4 G12D, 1 G12A, 1 G12V and 2 G12C). Three scraped smears, uninformative for poor DNA quality, resulted EGFR mutated on paired needle washings. CONCLUSIONS: Needle washing obtained in the course of NSCLC non-invasive fine needle diagnostic procedures allows reliable mutation testing and can be regarded as an additional important source of biological material for molecular profiling of advanced NSCLC.
Lung cancer (Amsterdam, Netherlands) 01/2013; · 3.14 Impact Factor
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Elena Galvani,
Elisa Giovannetti,
Francesca Saccani,
Andrea Cavazzoni,
Leticia G Leon,
Henk Dekker,
Roberta Alfieri,
Caterina Carmi,
Marco Mor, Andrea Ardizzoni,
Pier Giorgio Petronini,
Godefridus J Peters
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ABSTRACT: Overcoming the emergence of acquired resistance to clinically approved epidermal growth factor receptor (EGFR) inhibitors is a major challenge in the treatment of advanced non-small cell lung cancer (NSCLC). The aim of this study was to investigate the effects of a series of novel compounds affecting viability of NSCLC NCI-H1975 cells (carrying the EGFR T790M mutation). The inhibition of the autophosphorylation of EGFR occurred at nanomolar concentrations and both UPR1282 and UPR1268 caused a significant induction of apoptosis. Targeting of EGFR and downstream pathways was confirmed by a peptide substrate array, which highlighted the inhibition of other kinases involved in NSCLC cell aggressive behavior. Accordingly, the drugs inhibited migration (about 30% vs. control), which could be, in part, explained also by the increase of E-cadherin expression. Additionally, we observed a contraction of the volume of H1975 spheroids, associated with the reduction of the cancer stem-like cell hallmark CD133. The activity of UPR1282 was retained in H1975 xenograft models where it determined tumor shrinkage (P < .05) and resulted well tolerated compared to canertinib. Of note, the kinase activity profile of UPR1282 on xenograft tumor tissues showed overlapping results with respect to the activity in H1975 cells, unraveling the inhibition of kinases involved in pivotal proliferation and invasive signaling pathways. In conclusion, UPR1282 and UPR1268 are effective against various processes involved in malignancy transformation and progression and may be promising compounds for the future treatment of gefitinib-resistant NSCLCs.
Neoplasia (New York, N.Y.) 01/2013; 15(1):61-72. · 5.48 Impact Factor
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Andrea Cavazzoni,
Roberta R Alfieri,
Daniele Cretella,
Francesca Saccani,
Luca Ampollini,
Maricla Galetti,
Federico Quaini,
Gallia Graiani,
Denise Madeddu,
Paola Mozzoni,
Elena Galvani,
Silvia La Monica,
Mara Bonelli,
Claudia Fumarola,
Antonio Mutti,
Paolo Carbognani,
Marcello Tiseo,
Elisabetta Barocelli,
Pier Giorgio Petronini, Andrea Ardizzoni
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ABSTRACT: BACKGROUND: The epidermal growth factor receptor (EGFR) is an established target for anti-cancer treatment in different tumour types. Two different strategies have been explored to inhibit this pivotal molecule in epithelial cancer development: small molecules TKIs and monoclonal antibodies. ErbB/HER-targeting by monoclonal antibodies such as cetuximab and trastuzumab or tyrosine-kinase inhibitors as gefitinib or erlotinib has been proven effective in the treatment of advanced NSCLC. RESULTS: In this study we explored the potential of combining either erlotinib with cetuximab or trastuzumab to improve the efficacy of EGFR targeted therapy in EGFR wild-type NSCLC cell lines. Erlotinib treatment was observed to increase EGFR and/or HER2 expression at the plasma membrane level only in NSCLC cell lines sensitive to the drug inducing protein stabilization. The combined treatment had marginal effect on cell proliferation but markedly increased antibody-dependent, NK mediated, cytotoxicity in vitro. Moreover, in the Calu-3 xenograft model, the combination significantly inhibited tumour growth when compared with erlotinib and cetuximab alone. CONCLUSION: Our results indicate that erlotinib increases surface expression of EGFR and/or HER2 only in EGFR-TKI sensitive NSCLC cell lines and, in turns, leads to increased susceptibility to ADCC both in vitro and in a xenograft models. The combination of erlotinib with monoclonal antibodies represents a potential strategy to improve the treatment of wild-type EGFR NSCLC patients sensitive to erlotinib.
Molecular Cancer 12/2012; 11(1):91. · 3.99 Impact Factor
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Carmine Pinto,
Silvia Novello,
Valter Torri, Andrea Ardizzoni,
Pier Giacomo Betta,
Pier Alberto Bertazzi,
Gianni Angelo Casalini,
Cesare Fava,
Bice Fubini,
Corrado Magnani,
Dario Mirabelli,
Mauro Papotti,
Umberto Ricardi,
Gaetano Rocco,
Ugo Pastorino,
Gianfranco Tassi,
Lucio Trodella,
Maurizio Zompatori,
Giorgio Scagliotti
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ABSTRACT: Malignant pleural mesothelioma (MPM) is a relevant public health issue. A large amount of data indicate a relationship between mesothelioma and asbestos exposure. MPM incidence has considerably and constantly increased over the past two decades in industrialized countries and is expected to peak in 2010-2020. In Italy, the standardized incidence rate in 2008 was 3.6 and 1.3 per 100,000 in men and women respectively, with wide differences from one region to another. The approach to this disease remains difficult and complex in terms of pathogenic mechanism, diagnosis, staging and treatment thus an optimal strategy has not yet been clearly defined. The Second Italian Multidisciplinary Consensus Conference on Malignant Pleural Mesothelioma was held in Turin (Italy) on November 24-25, 2011: recommendations on MPM management for public health institutions, clinicians and patients are presented in this report.
Cancer treatment reviews 12/2012; · 5.30 Impact Factor
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Andrea Ardizzoni,
Marcello Tiseo,
Luca Boni,
Andrew D Vincent,
Rodolfo Passalacqua,
Sebastiano Buti,
Domenico Amoroso,
Andrea Camerini,
Roberto Labianca,
Giovenzio Genestreti, [......],
Antonio Santo,
Antonio Pazzola,
Fausto Barbieri,
Nicoletta Zilembo,
Ida Colantonio,
Carmelo Tibaldi,
Rodolfo Mattioli,
Mara A Cafferata,
Roberta Camisa,
Egbert F Smit
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ABSTRACT: PURPOSETo compare efficacy of pemetrexed versus pemetrexed plus carboplatin in pretreated patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS
Patients with advanced NSCLC, in progression during or after first-line platinum-based chemotherapy, were randomly assigned to receive pemetrexed (arm A) or pemetrexed plus carboplatin (arm B). Primary end point was progression-free survival (PFS). A preplanned pooled analysis of the results of this study with those of the NVALT7 study was carried out to assess the impact of carboplatin added to pemetrexed in terms of overall survival (OS).ResultsFrom July 2007 to October 2009, 239 patients (arm A, n = 120; arm B, n = 119) were enrolled. Median PFS was 3.6 months for arm A versus 3.5 months for arm B (hazard ratio [HR], 1.05; 95% CI, 0.81 to 1.36; P = .706). No statistically significant differences in response rate, OS, or toxicity were observed. A total of 479 patients were included in the pooled analysis. OS was not improved by the addition of carboplatin to pemetrexed (HR, 90; 95% CI, 0.74 to 1.10; P = .316; P heterogeneity = .495). In the subgroup analyses, the addition of carboplatin to pemetrexed in patients with squamous tumors led to a statistically significant improvement in OS from 5.4 to 9 months (adjusted HR, 0.58; 95% CI, 0.37 to 0.91; P interaction test = .039). CONCLUSION
Second-line treatment of advanced NSCLC with pemetrexed plus carboplatin does not improve survival outcomes as compared with single-agent pemetrexed. The benefit observed with carboplatin addition in squamous tumors may warrant further investigation.
Journal of Clinical Oncology 10/2012; · 18.37 Impact Factor
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Elena Galvani,
Roberta Alfieri,
Elisa Giovannetti,
Andrea Cavazzoni,
Silvia La Monica,
Maricla Galetti,
Claudia Fumarola,
Mara Bonelli,
Marco Mor,
Marcello Tiseo,
Godefridus J Peters,
Pier Giorgio Petronini, Andrea Ardizzoni
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ABSTRACT: Conventional chemotherapeutic regimens have reached an efficacy plateau against most solid tumors and deal with significant toxicity. Recently, the goal of the oncologic research to improve outcome and reduce treatment-related side-effects has led to the development of novel anticancer treatments targeting specific proteins or genes involved in cancer growth and progression. In particular, the tyrosine-kinase inhibitors (TKIs) gefitinib and erlotinib targeting the epidermal growth factor receptor (EGFR) have been approved for the treatment of non-small-cell lung cancer (NSCLC). Their clinical activity has been related to different clinical and biological parameters, such as the presence of activating mutations in the kinase domain of the target. Disappointingly, their clinical efficacy is limited by the development of resistance which is caused in more than 50% of the cases by the emergence of a secondary point-mutation (T790M) in the ATP-binding cleft of EGFR. Several novel EGFR inhibitors, able to covalently bind the target and prolong its inactivation, have been developed with the aim to overcome such resistance and are evaluated in ongoing clinical studies. However, not all clinical outcomes, including tolerability, are explained, and the identification/validation of novel biomarkers of sensitivity or resistance to such agents is a viable area of research to improve their clinical use. This review summarizes the current knowledge on the functional role of activating mutations of EGFR, pivotal primary/acquired resistance mechanisms as well as clinical data of small molecule EGFR-TKIs, and discusses the future of such therapeutic approach in NSCLC.
Current pharmaceutical design 09/2012; · 4.41 Impact Factor
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ABSTRACT: Aims and background. The incidence of asymptomatic pulmonary embolism in cancer patients is unknown and strictly related to the imaging used for tumor assessment. Recent findings suggest a similar clinical outcome of asymptomatic pulmonary embolism events compared to symptomatic events with a significant impact on survival. The aim of the present study was to determine the prevalence of asymptomatic pulmonary embolism in a population of lung cancer outpatients and to investigate its clinical features. Methods. Outpatients with a diagnosis of lung carcinoma undergoing chemotherapy were selected from October 2006 to June 2009. Disease and patient characteristics, risk factors and treatment modalities were collected. All the computed tomography images performed for each patient during the study period were retrospectively reviewed to identify pulmonary embolism. Results. A total of 141 consecutive patients were included and 657 computed tomography scans were completely reviewed (from two to six consecutive scans for each patient). Asymptomatic pulmonary embolism in the study population had a prevalence of 14.9% (21 patients). Most of the events occurred in patients with adenocarcinoma, advanced stage and poor performance status, during the early phases of first-line chemotherapy or at the same time of the cancer diagnosis. Compared with the symptomatic pulmonary embolism events (5 patients), asymptomatic events occurred earlier (time from cancer diagnosis to pulmonary embolism of 3.5 [95% CI, 2.0-4.9] versus 12.1 months [95% CI, 6.3-17.9; P = 0.02]) and had a better prognosis (survival from PE of 7.5 [95% CI, 3.4-11.6] versus 1.9 months [95% CI, 0-3.9; P = 0.04]). Conclusions. Our findings indicate an underestimation of embolic events among lung cancer outpatients due to their frequent asymptomatic natur. Such a high prevalence suggests the importance to pay more attention to pulmonary embolism prevention in this population.
Tumori. 09/2012; 98(5):594-600.
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Marcello Tiseo,
Elisa Giovannetti,
Carmelo Tibaldi,
Andrea Camerini,
Francesco Di Costanzo,
Fausto Barbieri,
Jacobus A Burgers,
Andrew Vincent,
Godefridus J Peters,
Egbert F Smit, Andrea Ardizzoni
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ABSTRACT: To correlate candidate polymorphisms affecting pemetrexed and carboplatin activity with clinical outcome of patients with advanced non-small cell lung cancer (NSCLC) treated in second-line with pemetrexed or pemetrexed plus carboplatin.
Functional polymorphisms in thymidylate synthase (TS), reduced folate carrier (RFC), gamma-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR) and xeroderma pigmentosum group D (XPD) genes were evaluated in 208 patients either treated within randomized phase II trials NVALT-7 and GOIRC-02.2006, comparing second-line pemetrexed with pemetrexed plus carboplatin, or with the same regimens outside of these trials. Univariate and multivariate analyses correlated genotyping data with response, clinical benefit, toxicity, progression-free (PFS) and overall survival (OS) using Pearson-χ(2) test, log-rank test and Cox proportional hazards model.
Patients harboring the MTHFR-T667T variant had significantly longer PFS (5.4 versus 3.4 months; p=0.012) and OS (16.4 versus 8.5 months; p=0.026) than patients with CC-CT genotypes. No correlation was observed for other polymorphisms, except for XPD-Gln751Gln, which was associated with shorter PFS (p=0.021) and OS (p=0.044) in the subgroup of patients treated with pemetrexed plus carboplatin. Multivariate analysis confirmed the independent prognostic significance of MTHFR-C677T both in risk of disease progression (CC-CT genotypes hazard ratio [HR] 1.94, 95%CI 1.15-3.28; p=0.012) and of death (HR 2.00, 95%CI 1.12-3.54; p=0.018).
MTHFR-C667T polymorphisms appear to predict survival differences in pemetrexed-treated NSCLC. These results should be validated in larger and adequately designed prospective studies using pemetrexed.
Lung cancer (Amsterdam, Netherlands) 08/2012; 78(1):92-9. · 3.14 Impact Factor
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Cecilia Bozzetti,
Francesca V Negri,
Cinzia Azzoni,
Nadia Naldi,
Rita Nizzoli,
Beatrice Bortesi,
Valentina Zobbi,
Lorena Bottarelli,
Marcello Tiseo,
Enrico Maria Silini, Andrea Ardizzoni
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ABSTRACT: Epidermal growth factor receptor (EGFR) and Kras gene mutations are crucial for discriminating patients responsive to anti-EGFR drugs in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC), respectively. The majority of NSCLCs come to clinical attention at an advanced stage when surgery is no longer recommended and a considerable number of them are diagnosed by cytology only. A large number of metastatic CRCs are also diagnosed by imaging and minimally invasive techniques such as fine-needle aspiration biopsy. Here, we report our experience in the mutation analysis of EGFR and Kras on cytological material obtained from superficial and deep lesions of NSCLC and CRC. Our series included 63 cytological specimens from primary or metastatic lesions of 42 NSCLCs and 21 CRCs. The cytological material was adequate for the mutation analysis in 39/42 (93%) NSCLCs and in 20/21(95%) CRCs. EGFR and Kras mutations were found in 9 (23%) and 9 (23%) NSCLC cases, respectively. Kras mutations were found in 9/20 (45%) CRC specimens. Histological samples from the primary tumors were available in 9/42 NSCLCs and in 17/21 CRCs. The agreement of EGFR and Kras mutational status in cytological vs. histological samples was 100% for NSCLC and 88% for CRC. Our results suggest that standard cytology provides adequate material for the assessment of EGFR and Kras mutational status in NSCLC and CRC patients and could be specifically indicated in patients not eligible for surgery but candidate to anti-EGFR therapy. Diagn. Cytopathol. 2012 © 2012 Wiley Periodicals, Inc.
Diagnostic Cytopathology 07/2012; · 1.16 Impact Factor
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Andrea Ambrosini-Spaltro,
Nicoletta Campanini,
Beatrice Bortesi,
Cinzia Azzoni,
Nadia Naldi,
Luca Ampollini,
Marcello Tiseo, Andrea Ardizzoni,
Michele Rusca,
Paolo Carbognani,
Enrico M Silini
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ABSTRACT: Epidermal growth factor receptor (EGFR) gene mutations are usually detected by direct sequencing to identify patients with advanced pulmonary adenocarcinomas as candidates for tyrosine kinase inhibitor therapy. The aim of the study was to evaluate the efficacy of EGFR mutation-specific antibodies in identifying EGFR-mutated adenocarcinomas.
Thirty-three consecutive cases of pulmonary adenocarcinomas sequenced for EGFR mutations were retrieved from our files. Immunohistochemistry was performed with the rabbit monoclonal antibodies E746-A750del (6B6) and L858R (43B2). The results obtained using the 2 procedures were statistically compared by Coehn κ and by calculation of sensitivity and specificity.
There were 21 women and 12 men, ranging in age from 48 to 78 years. All cases were lung adenocarcinomas, 23 primaries and 10 metastatic. The mutational spectrum was as follows: 12 cases mutated in exon 19 (9 with E746-A750del, 1 with homozygote L747-T751del, 1 with L747-P753del, 1 with E747-S752del), 6 in exon 21 (5 with L858R, 1 with L861Q+L862L), and 15 EGFR wild type. Immunohistochemistry detected 6/9 cases with an E746-A750del mutation (κ=0.744, sensitivity: 66.7%, specificity: 100%) and 5/5 cases with an L858R mutation (κ=1, sensitivity: 100%, specificity: 100%). Four cases showed faint and focal immunostaining and were interpreted as negative. All other cases were negative. Overall, the 2 antibodies had 61.1% sensitivity and 100% specificity for EGFR mutations.
EGFR mutation-specific antibodies may represent a first-line screening tool to identify patients as candidates for tyrosine kinase inhibitor therapy.
Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 07/2012; 20(4):356-62. · 1.63 Impact Factor
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ABSTRACT: To determine whether human epidermal growth factor receptor 2 (HER2) -positive status is associated with risk of breast cancer diagnosis in the interval between mammographic screening, we estimated the distribution of features of aggressive tumor behavior in a general population with newly diagnosed breast cancer and known screening status.
We evaluated all invasive breast cancers (N = 641) that were systematically collected by the Parma Province Cancer Registry and diagnosed in women age 50 to 69 years from 2004 to 2007. From this population, 292 screen-detected cancers and 48 interval cases with negative screening mammograms on expert rereading (true interval cancers) were selected for study purposes. Unconditional logistic regression adjusted for age and tumor size was used to determine whether interval cancers were associated with selected clinicobiologic characteristics.
Tumors with a high histologic grade (odds ratio [OR], 1.8; 95% CI, 1.2 to 3.8), high proliferative rate (OR, 2.4; 95% CI, 1.2 to 4.5), negative estrogen receptor status (OR, 1.6; 95% CI, 1.1 to 3.1), or HER2-positive status (OR, 3.4; 95% CI, 1.7 to 7.1) were more likely to be diagnosed in the interval between screening. Women age less than 60 years with HER2-positive breast cancer were four times more likely to be diagnosed in the interval between screening compared with only a two-fold increased risk for older women.
This population-based cancer registry study demonstrated that HER2-positive tumors account for a substantial proportion of mammographic screening failure. The distribution of biologic characteristics in screen-detected cancers differs from that observed in interval cancers and may account in part for the more aggressive behavior of interval-detected cases.
Journal of Clinical Oncology 05/2012; 30(19):2362-8. · 18.37 Impact Factor
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Caterina Carmi,
Elena Galvani,
Federica Vacondio,
Silvia Rivara,
Alessio Lodola,
Simonetta Russo,
Stefania Aiello,
Fabrizio Bordi,
Gabriele Costantino,
Andrea Cavazzoni,
Roberta R Alfieri, Andrea Ardizzoni,
Pier Giorgio Petronini,
Marco Mor
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ABSTRACT: Irreversible epidermal growth factor receptor (EGFR) inhibitors contain a reactive warhead which covalently interacts with a conserved cysteine residue in the kinase domain. The acrylamide fragment, a commonly employed warhead, effectively alkylates Cys797 of EGFR, but its reactivity can cause rapid metabolic deactivation or nonspecific reactions with off-targets. We describe here a new series of irreversible inhibitors containing a 3-aminopropanamide linked in position 6 to 4-anilinoquinazoline or 4-anilinoquinoline-3-carbonitrile driving portions. Some of these compounds proved to be as efficient as their acrylamide analogues in inhibiting EGFR-TK (TK = tyrosine kinase) autophosphorylation in A549 lung cancer cells. Moreover, several 3-aminopropanamides suppressed proliferation of gefitinib-resistant H1975 cells, harboring the T790M mutation in EGFR, at significantly lower concentrations than did gefitinib. A prototypical compound, N-(4-(3-bromoanilino)quinazolin-6-yl)-3-(dimethylamino)propanamide (5), did not show covalent binding to cell-free EGFR-TK in a fluorescence assay, while it underwent selective activation in the intracellular environment, releasing an acrylamide derivative which can react with thiol groups.
Journal of Medicinal Chemistry 03/2012; 55(5):2251-64. · 4.80 Impact Factor
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Cesare Gridelli,
Filippo de Marinis,
Massimo Di Maio, Andrea Ardizzoni,
Chandra P Belani,
Federico Cappuzzo,
Fortunato Ciardiello,
Panagiotis Fidias,
Luis Paz-Ares,
Francesco Perrone,
Robert Pirker,
Luigi De Petris,
Rolf Stahel
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ABSTRACT: Several randomized trials have recently investigated the role of maintenance treatment for patients with advanced non-small-cell lung cancer (NSCLC) with responding or stable disease after completion of first-line chemotherapy. Maintenance strategy has relevant implications in terms of potential toxicity, logistics and costs, and all of these aspects should be taken into account, together with the magnitude of benefit for the patient. In order to assess the strengths and limitations of available evidence, to help clinical practice, and to suggest priorities for future clinical research, the Italian Association of Thoracic Oncology (AIOT) organized an International Experts Panel Meeting on maintenance treatment of advanced NSCLC, which took place in Sperlonga (Italy) in May 2011. Based on the available evidence, panelists agreed that maintenance therapy represents a treatment option in advanced NSCLC. Maintenance should be discussed with patients not progressed after 4-6 cycles of first-line chemotherapy, who are fit (performance status 0-1) and without persistent chemotherapy-induced toxicity. Patients need to be well informed about potential advantages and disadvantages of accepting additional therapy without a "treatment-free period". Two different strategies, switch or continuation maintenance, are supported by available evidence. At the moment, there is no direct comparison between switch maintenance and continuation maintenance. For future trials, the panel recommends the use of overall survival as the primary endpoint, with pre-defined second-line treatment. Translational research is essential to identify predictive factors, and should be performed, whenever feasible, in order to achieve treatment optimization with proper patient selection.
Lung cancer (Amsterdam, Netherlands) 01/2012; 76(3):269-79. · 3.14 Impact Factor
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ABSTRACT: Renal cell carcinoma (RCC) is one of the ten most frequent solid tumors worldwide. Recent innovations in the treatment of metastatic disease have led to new therapeutic approaches being investigated in the adjuvant setting. Observation is the only current standard of care after radical nephrectomy, although there is evidence of efficacy of adjuvant use of vaccine among all the strategies used. This article aims to collect published experiences with systemic adjuvant approaches in RCC and to describe the results of past and ongoing phase III clinical trials in this field. We explored all the systemic treatments, including chemotherapy, immunotherapy and targeted drugs while alternative approaches have also been described. Appropriate selection of patients who would benefit from adjuvant therapies remains a crucial dilemma. Although the international guidelines do not actually recommend any adjuvant treatment after radical surgery for RCC, no conclusions have yet been drawn pending the results of the promising ongoing clinical trials with the target therapies. The significant changes that these new drugs have made on advanced disease outcome could represent the key to innovation in terms of preventing recurrence, delaying relapse and prolonging survival after radical surgery for RCC.
Oncology Reviews 01/2012; 6(e18):145-152.
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ABSTRACT: Renal cell cancer incidence is fastly growing worldwide. In spite of major advances in the treatment of metastatic disease, to date there is no adjuvant therapy proven feasible in high risk patients after radical resection. An effective adjuvant agent against renal cell cancer should be relatively non toxic, have estabilished efficacy in the metastatic setting and have demonstrated effectiveness against the standard of care in randomized Phase III trials. The development of adjuvant therapy requires the proper identification of patients at highest risk of relapse; our ability to predict the recurrence has much room for improvement. To date, only an autologous vaccine has achieved a significant benefit in the adjuvant setting for renal cell carcinoma. The recent arrival of new drug classes, such as tyrosine kinase inhibitors and monoclonal antibodies, strongly improving overall and progression free survivals in the metastatic disease, has renewed the hopes on the adjuvant treatment of the disease. Several studies have been performed in the past using radiation treatment and systemic agents, including chemotherapy, immunotherapy and hormonal treatments, with adjuvant purpose; new trials are in progress to evaluate the effectiveness of antiangiogenic agents in this setting. An overall review of the completed and upcoming trials and patents on this issue shall be discussed here.
01/2012: pages 242-268;
