Giuseppe Toscano

A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives

The discovery of Epidermal Growth Factor Receptor (EGFR) mutations in Non Small Cell Lung Cancer (NSCLC) launched the era of personalized medicine in advanced NSCLC, leading to a dramatic shift in the therapeutic landscape of this disease. After ten years from the individuation of activating mutations in the tyrosine kinase domain of the EGFR in NSCLC patients responding to the EGFR tyrosine kinase inhibitor (TKI) Gefitinib, several progresses have been done and first line treatment with EGFR TKIs is a firmly established option in advanced EGFR-mutated NSCLC patients. During the last decade, different EGFR TKIs have been developed and three inhibitors have been approved so far in these selected patients. However, despite great breakthroughs have been made, treatment of these molecularly selected patients poses novel therapeutic challenges, such as emerging of acquired resistance, brain metastases development or the need to translate these treatments in earlier clinical settings, such as adjuvant therapy. The aim of this paper is to provide a comprehensive review of the major progresses reported so far in the EGFR inhibition in this molecularly-selected subgroup of NSCLC patients, from the early successes with first generation EGFR TKIs, Erlotinib and Gefitinib, to the novel irreversible and mutant-selective inhibitors and ultimately the emerging challenges that we, in the next future, are called to deal with.

Emerging Targeted Therapies for Castration-Resistant Prostate Cancer

Until recently, few therapeutic options were available for patients with castration-resistant prostate cancer (CRPC). Since 2010, four new molecules with a demonstrated benefit (sipuleucel-T, cabazitaxel, abiraterone, and denosumab) have been approved in this setting, and to-date several other agents are under investigation in clinical trials. The purpose of this review is to present an update of targeted therapies for CRPC. Presented data are obtained from literature and congress reports updated until December 2011. Targeted therapies in advanced phases of clinical development include novel androgen signaling inhibitors, inhibitors of alternative signaling pathways, anti-angiogenic agents, inhibitors that target the bone microenvironment, and immunotherapeutic agents. Radium-223 and MDV3100 demonstrated a survival advantage in phase III trials and the road for their introduction in clinical practice is rapidly ongoing. Results are also awaited for phase III studies currently underway or planned with new drugs given as monotherapy (TAK-700, cabozantinib, tasquinimod, PROSTVAC-VF, ipilimumab) or in combination with docetaxel (custirsen, aflibercept, dasatinib, zibotentan). The optimal timing, combination, and sequencing of emerging therapies remain unknown and require further investigation. Additionally, the identification of novel markers of response and resistance to these therapies may better individualize treatment for patients with CRPC.

Clinical significance of circulating interleukin‐23 as a prognostic factor in breast cancer patients

Little is known about specific IL‐23 alterations associated with breast cancer and the data available are still controversial. Therefore, the evaluation of changes in serum IL‐23 levels may add further information on the role of this cytokine in breast cancer patients. The aim of this study was to evaluate prospectively the prognostic importance of circulating IL‐23 in patients with untreated breast cancer, respect to healthy controls, and the association with clinico‐pathological variables. The study involved 50 women diagnosed with stages I–IV breast cancer and 38 healthy controls. Of the 50 breast cancer patients, 37 women were recruited prior to their initial adjuvant chemotherapy and 13 prior to receive first line chemotherapy for metastatic disease. Adjuvant chemotherapy patients were at least in their 4th week post‐surgery. IL‐23 serum concentrations were measured by a quantitative enzyme immunoassay technique. We found a statistically significant higher systemic cytokine value in women with cancer in comparison with the control group (14.52 ± 11.39 pg/ml vs. 6.35 ± 4.63 pg/ml, P < 0.0001). Patients with shorter overall survival presented higher IL‐23 values, suggesting a negative prognostic correlation. There was no significant differences in IL‐23 levels among patients according to the biomolecular characteristics, the different subtypes and the presence of metastatic disease. This work investigated, for the first time, the role of IL‐23 in breast cancer patients showing a significant increase respect the control group. However, further validations are needed in larger studies to better investigate the implications of IL‐23 increase in these patients. J. Cell. Biochem. 113: 2122–2125, 2012.

Combined epirubicin and interleukin-2 regimen in the treatment of malignant mesothelioma: A multicenter phase II study of the Italian group on rare tumors

The Italian Group on Rare Tumors undertook a phase II study of a combination of epirubicin and interleukin-2 in 21 chemotherapy-naive patients with malignant mesothelioma. All patients had bidimensionally measurable disease at CT scan. Treatment included intravenous administration of epirubicin at a dose of 110 mg/m2 i.v. on day 1, and interleukin-2 at a dose of 9 MU subcutaneously from day 8 to day 12 and from day 15 to day 19. Cycles were repeated every three weeks, up to six times in the absence of progressive disease. Treatment response was evaluated after two cycles of therapy. Only one patient achieved a partial response, resulting in an overall response rate of 5% (1/21) with a median progression-free and overall survival of 5 and 10 months, respectively. Toxicity was relevant and caused treatment discontinuation in many patients. These results do not support the use of such a combination in the management of malignant mesothelioma.

Oxaliplatin and raltitrexed in the treatment of inoperable malignant pleural mesothelioma: Results of a pilot study

Aims and Background The treatment of inoperable malignant pleural mesothelioma is a challenge for the oncologist. Available chemotherapy regimens achieve poor results, therefore new agents or combinations are needed. In a phase I study, the combination of oxaliplatin and raltitrexed was shown to be active against malignant pleural mesothelioma. We herein report the results of a pilot study about the treatment of this disease. Methods From April 1999 to June 2000, we enrolled 11 chemotherapy-naïve patients with inoperable malignant pleural mesothelioma suitable to receive the following combination chemotherapy: raltitrexed, 3 mg/m2 iv, and oxaliplatin, 130 mg/m2, as a 2-hr infusion every 3 weeks. Results Four partial responses, 1 regression of disease (objective response rate, 45%; 95% Cl, 15.6-74.4%), 4 stable diseases and 2 progressions of disease were observed. An improvement in disease-related symptoms was recorded in all responders and in 2 patients with stable disease. Toxicity was mild, with no toxic-related death and only 1 episode of grade 4 neurotoxicity. Conclusions We consider the combination promising and worthy of further studies.

Cisapride and dexamethasone in the prevention of delayed emesis after cisplatin administration

Abstract Management of delayed emesis (DE) remains unsatisfactory, and only 50% of the patients achieve complete protection. Cisapride is a strong prokinetic gastrointestinal drug that could have a role in the prevention of DE. We enrolled 31 adult naive outpatients who were scheduled to receive cisplatin chemotherapy at doses of ≥75 mg/m2. All patients received the same prophylactic treatment for acute emesis (20 mg dexamethasone and 8 mg ondansetron i.v.) and, as preventive therapy for DE, oral cisapride, 10 mg every 8 h on days 2–4, combined with dexamethasone i.m., 8 mg twice daily on days 2 and 3, and 4 mg twice daily on day 4. All patients were evaluable for activity. Complete protection from acute vomiting was 80.7%, from nausea 71% and from nausea/vomiting 64.5%. The overall protection from DE (days 2–4) was 74.1% for vomiting, 64.5% for nausea and 58% for nausea/vomiting. In our study the combination of cisapride and dexamethasone was effective, giving 58% of complete protection from DE, and it is therefore worthy of further studies.

Imatinib mesylate treatment in a patient with chemoresistant Ph+ acute myeloid leukemia: possible role of Wilms' tumor gene 1.

than 8 months 1 . Imatinib mesylate, an effective and selective inhibitor of BCR-ABL tyrosine kinase activity, is commonly used in the treatment of Ph-positive chronic myeloid leukemia (CML), also in the blastic phase, whereas its role in the treatment of Ph+ AML is not yet well understood. To our knowledge, few cases of Ph + AML have been treated with imatinib mesylate 2,3 .

The Principle of Nullum Crimen Sine Lege in the Construction of European Criminal Law

This paper investigates the role played by the rule of law in the construction of an EU criminal law. The analysis, also from a historical perspective, of the rule of law shows how it is tremendously flexible and adaptable to the changing socioinstitutional contexts in which it is considered. It is necessary to assess whether the process of Europeanization can be considered a “risk factor” for its stability or whether, on the contrary, it requires only simple adaptations that do not detract from its essence.