[Methods to increase participation in cancer screening programmes]. / Metodi per aumentare la partecipazione ai programmi di screening oncologici.

OBJECTIVE: to synthesize scientific evidences about methods to increase cervical, breast and colorectal cancer screening participation. METHODS: a multidisciplinary working group has been set up to define the scope of the report and to conduct the evaluation. The scope and the final evaluation have been submitted to a stakeholder committee, including the Ministry of Health, the National Screening Observatory, regional screening program coordinators, scientific societies, and Lega Italiana Lotta ai Tumori, for comments and integrations. A systematic review of the principal biomedical and social literature databases was conducted to identify experimental and observational studies, updating the existing review by Jepson and coll. (Health Technol Assess. 2000;4(14):i-vii, 1-133). RESULTS: 5900 have been identified, 900 relevant for the topic.Among those, 148 reported quantitative information on intervention efficacy, other 90 came from the previous review. Organised screening programmes, based on invitation letter or on GP involvement,were consistently effective in increasing participation compared to spontaneous screening. Interventions are classified according to their target: individual, community, test simplification, health operators, health service organization. The report presents meta-analyses on efficacy, analyses of cost-effectiveness, impact on organisation and social inequality, and ethical and legal issues, of all the intervention reported in the literature. CONCLUSIONS: there are several interventions consistently effective in any context, some of them have minimal impact on costs and health service resources.

Development of multitargeted inhibitors of both the insulin-like growth factor receptor (IGF-IR) and members of the epidermal growth factor family of receptor tyrosine kinases.

Emerging clinical and pre-clinical data indicate that both insulin-like growth factor receptor (IGF-IR) and members of the epidermal growth factor (EGF) family of receptor tyrosine kinases (RTKs) exhibit significant cross-talk in human cancers. Therefore, a small molecule that successfully inhibits the signaling of both classes of oncogenic kinases might provide an attractive agent for chemotherapeutic use. Herein, we disclose the structure activity relationships that led to the synthesis and biological characterization of 14, a novel small molecule inhibitor of both IGF-IR and members of the epidermal growth factor family of RTKs.

Epidemiology and costs of cervical cancer screening and cervical dysplasia in Italy.

BACKGROUND: We estimated the number of women undergoing cervical cancer screening annually in Italy, the rates of cervical abnormalities detected, and the costs of screening and management of abnormalities. METHODS: The annual number of screened women was estimated from National Health Interview data. Data from the Italian Group for Cervical Cancer Screening were used to estimate the number of positive, negative and unsatisfactory Pap smears. The incidence of CIN (cervical intra-epithelial neoplasia) was estimated from the Emilia Romagna Cancer Registry. Patterns of follow-up and treatment costs were estimated using a typical disease management approach based on national guidelines and data from the Italian Group for Cervical Cancer Screening. Treatment unit costs were obtained from Italian National Health Service and Hospital Information System of the Lazio Region. RESULTS: An estimated 6.4 million women aged 25-69 years undergo screening annually in Italy (1.2 million and 5.2 million through organized and opportunistic screening programs, respectively). Approximately 2.4% of tests have positive findings. There are approximately 21,000 cases of CIN1 and 7,000-17,000 cases of CIN2/3. Estimated costs to the healthcare service amount to 158.5 million euro for screening and 22.9 million euro for the management of cervical abnormalities. CONCLUSION: Although some cervical abnormalities might have been underestimated, the total annual cost of cervical cancer prevention in Italy is approximately 181.5 million euro, of which 87% is attributable to screening.

Incidence of invasive cervical cancer and direct costs associated with its management in Italy.

AIM AND BACKGROUND: Cervical cancer is the second most common cancer in European women aged 15-44 years. The aim of this study was to estimate the direct cost of managing invasive cervical cancer in Italy. METHODS: Data from the Italian Network of Cancer Registries were used to estimate the annual number of new cervical cancer cases. To assess the management costs, a typical management pathway for each FIGO (Fédération Internationale de Gynécologie et d'Obstétrique) cervical cancer stage was derived from published guidelines. Data from the Modena Cancer Registry were used to estimate the proportion of patients by FIGO stage. This algorithm was combined with tariffs for outpatient and inpatient procedures to obtain a mean cost for each FIGO stage. RESULTS: An estimated 2,927 new cases of cervical cancer occurred in Italy in 2005 (crude incidence 9.7/100,000; world age-standardized incidence 6.0/100,000). The estimated numbers of new cases by FIGO stage were: FIGO I, 1,927; FIGO II, 556; FIGO III, 259; and FIGO IV, 185. Costs for the most frequent procedures were estimated as: Euro 6,041 for radical hysterectomy or other surgery; Euro 4,901 for radio-chemotherapy; Euro 1,588 for brachytherapy; and Euro 3,795 for palliative chemotherapy. Mean management costs for incident cases (including 10 years of follow-up) were estimated at: FIGO I, Euro 6,024; FIGO II, Euro 10,572; FIGO III, Euro 11,367; FIGO IV, Euro 8707; and Euro 5,854 for the terminal phase (1 month). The total direct management cost was estimated at Euro 28.3 million per year. CONCLUSIONS: This is one of the first studies to estimate the direct cost of treating patients newly diagnosed with invasive cervical cancer in Italy. Although according to current management pathways real treatment costs are likely to be underestimated, this information is necessary to design evidence-based vaccination policies able to harmonize primary and secondary prevention of cervical cancer.

Discovery and optimization of anthranilic acid sulfonamides as inhibitors of methionine aminopeptidase-2: a structural basis for the reduction of albumin binding.

Methionine aminopeptidase-2 (MetAP2) is a novel target for cancer therapy. As part of an effort to discover orally active reversible inhibitors of MetAP2, a series of anthranilic acid sulfonamides with micromolar affinities for human MetAP2 were identified using affinity selection by mass spectrometry (ASMS) screening. These micromolar hits were rapidly improved to nanomolar leads on the basis of insights from protein crystallography; however, the compounds displayed extensive binding to human serum albumin and had limited activity in cellular assays. Modifications based on structural information on the binding of lead compounds to both MetAP2 and domain III of albumin allowed the identification of compounds with significant improvements in both parameters, which showed good cellular activity in both proliferation and methionine processing assays.

Apoptosis induction and mitochondria alteration in human HeLa tumour cells by photoproducts of Rose Bengal acetate.

The aim of this work was to investigate the apoptosis induction and mitochondria alteration after photodamage exerted by incubation of HeLa cells with Rose Bengal acetate-derivative (RBAc) followed by irradiation for a total dose of 1.6 J/cm2. This treatment was previously demonstrated to reduce cell viability under mild treatment conditions, suggesting the restoration of the photoactive molecule in particularly sensitive cell sites. Indeed, Rose Bengal (RB) is a very efficient photosensitizer, whose photophysical properties are inactivated by addition of the quencher group acetate. The RBAc behaves as a fluorogenic substrate by entering easily the cells where the original, photoactive molecule is restored by specific esterases. Different intracellular sites of photodamage of RB are present. In particular, fluorescence imaging of Rodamine 123 and JC-1 labelled cells showed altered morphology and loss of potential membrane of mitochondria. MTT and NR assays gave indications of alteration of mitochondrial and lysosomal enzyme activities. These damaged sites were likely responsible for triggering apoptosis. Significant amount of apoptotic cell death (about 40%) was induced after light irradiation followed RBAc incubation as revealed by morphological (modification of cell shape and blebs formation), cytochemical (FITC-Annexin-V positive cells) and nuclear fragmentation assays.

E-DIMEM: an economic model to estimate the costs of e-disease management.

In order to estimate the cost of generic clinical guidelines based on telemedicine services for chronic patients, an economic model (E-DIMEM) has been defined. This model is designed to help health suppliers and managers to plan for the future. It is essentially a workflow composed by diagnosis and therapeutic activities. The cost of each workflow activity is related to healthcare providers (activity agents), drugs, instruments, telemedicine services, and type of specialized healthcare centers used (hospital, clinics, etc.). This model performs multidimensional analysis. A web service based on the E-DIMEM has been implemented.

Pyrazolo[3,4-d]pyrimidines as potent inhibitors of the insulin-like growth factor receptor (IGF-IR).

A high throughput screen of Abbott's compound repository revealed that the pyrazolo[3,4-d]pyrimidine class of kinase inhibitors possessed moderate potency for IGF-IR, a promising target for cancer chemotherapy. The synthesis and subsequent optimization of this class of compounds led to the discovery of 14, a compound that possesses in vivo IGF-IR inhibitory activity.

Synthesis and structure activity relationship of guanidines as NPY Y5 antagonists.

A series of bis-aryl substituted guanidines have been discovered as potent NPY Y5 antagonists. The SAR and in vitro metabolic stability of these compounds are discussed.