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Aims and Background: The quantification and molecular characterization of circulating free DNA (cfDNA) have attracted much interest as new and promising, noninvasive means of detecting and monitoring the presence of surgical resectable colorectal cancer (CRC). Instead, the role of cfDNA in the early detection of malignant and premalignant colorectal lesions is still unclear. The aim of this study was to evaluate the predictive power of the quantification and KRAS status of cfDNA in detecting early colorectal lesions in plasma from healthy high-risk subjects., Methods: The study population consisted of 170 consecutive healthy high-risk subjects aged >50 years who participated in the screening program promoted by the Local Health Service (ASL-Milano) for early CRC detection and who underwent endoscopic examination after being found positive at fecal occult blood test (FOBT). Thirty-four participants had malignant lesions consisting of 12 adenocarcinomas (at an early stage in half of the cases) and 22 instances of high-grade intraepithelial neoplasia (HGIN) in adenomas; 73 participants had premalignant lesions (adenomas and hyperplasia), and 63 participants had no lesions. Plasma cfDNA was quantified by quantitative real-time PCR and analyzed for KRAS mutations by a mutant-enriched PCR. KRAS status was assessed also in matched adenocarcinoma and HGIN tissues. The distribution of cfDNA concentrations among FOBT-positive subjects with diagnosed lesion (cases) was compared with that of FOBT-positive subjects without lesions (controls) and its predictive capability (AUC) was assessed., Results: The predictive capability of cfDNA levels was satisfactory in predicting adenocarcinomas (AUC 0.709; 95% CI, 0.508-0.909) but not HGIN and premalignant lesions. The rate of KRAS mutations in plasma was low (5/170 = 3%) compared with the rate observed in the matched adenocarcinoma and HGIN tissues (45%)., Conclusions: The use of cfDNA quantification to predict adenocarcinoma at an early stage in high-risk (aged >50 years and FOBT positive) subjects seems to be promising but needs more sensitive methods to improve cfDNA detection.

Aims and Background: Colorectal carcinoma patients from hereditary non-polyposis colorectal cancer families are suggested to have a better prognosis than sporadic colorectal carcinoma cases. Since the majority of hereditary non-polyposis colorectal cancer-related colorectal carcinomas are characterized by microsatellite instability due to germline mutations in DNA mismatch repair genes, this is consistent with the prolonged survival observed in sporadic microsatellite instability-positive colorectal carcinoma compared to microsatellite stable cases. However, a fraction of colorectal carcinoma cases belongs to families that, despite fulfilling the clinical criteria for hereditary non-polyposis colorectal cancer, do not carry mismatch repair gene mutations. Our aim was to verify to what extent the genotypic heterogeneity influences the prognosis of hereditary non-polyposis colorectal cancer patients., Methods: A survival analysis was performed on 526 colorectal carcinoma cases from 204 Amsterdam Criteria-positive hereditary non-polyposis colorectal cancer families. Enrolled cases were classified as MLH1-positive, MSH2-positive and mutation-negative, according to the results of genetic testing in each family., Results: Five-year survival rates were 0.73 (95% CI, 0.66-0.80), 0.75 (95% CI, 0.66-0.84) and 0.62 (95% CI, 0.55-0.68) for MLH1-positive, MSH2-positive and mutation-negative groups, respectively (logrank test, P = 0.01). Hazard ratio, computed using Cox regression analysis and adjusted for age, sex, tumor site and stage, was 0.71 (95% CI, 0.51-0.98) for the mutation-positive compared to the mutation-negative group. Moreover, in the latter group, patients with microsatellite instability-positive colorectal carcinomas showed a better outcome than microsatellite stable cases (5-year survival rates, 0.81 and 0.60, respectively; logrank test, P = 0.006)., Conclusions: Our results suggest that the prognosis of hereditary non-polyposis colorectal cancer-related colorectal carcinoma patients depends on the associated constitutional mismatch repair genotype.

Comprehensive cancer control is defined as an integrated and coordinated approach to reducing cancer incidence, morbidity, and mortality across the cancer control continuum from primary prevention to end-of-life care. This approach assumes that when the public sector, non-governmental organizations, academia, and the private sector share with each other their skills, knowledge, and resources, a country can take advantage of all its talents and resources to more quickly reduce the burden of cancer for all its population. One critical issue for comprehensive cancer control is the extent to which the private sector can contribute to cancer prevention and control programs and policies that have historically been lead by the public health sector, and similarly how can the public sector increase its investment and involvement in clinical research and practice issues that are largely driven by the private sector worldwide? In addition, building capacity to integrate research that is appropriate to the culture and context of the population will be important in different settings, in particular research related to cancer control interventions that have the capacity to influence outcomes. To whatever extent cancer control research is ultimately funded through the private and public sectors, if investments in research discoveries are ultimately to benefit the populations that bear the greatest burden of disease, then new approaches to integrating the lessons learned from science with the lessons learned from service (public health, clinical, and public policy) must be found to close the gap between what we know and what we do. Communities of practice for international cancer control, like the ones fostered by the first three International Cancer Control Congresses, represent an important forum for knowledge exchange opportunities to accelerate the translation of new knowledge into action to reduce the burden of cancer worldwide.

Aims and Background: Italian performance in cancer research from 2000 to 2007 was assessed and compared to that of the other 19 wealthiest countries in the world which carry out the bulk of cancer research., Methods: Performance was evaluated quantitatively as the number of publications in 125 journals indexed as 'oncological' by Journal Citation Reports and qualitatively as the total impact factor (TIF). Number of publications and TIF were adjusted for the population and gross domestic product (GDP) of each country. The Scopus database was used as publication source., Results: Italy ranked 5th, with the US ranking 1st, over the entire study period for number of cancer publications, which increased over that period. Italy ranked 4th in 2006-2007 for GDP-adjusted and 5th for population-adjusted publication number, loosing ground in the GDP-adjusted ranking and gaining ground in the population-adjusted ranking over the study period. When the quality of research publications was considered, in 2006-2007 Italy was in 5th place for crude TIF (US 1st), in 4th place for GDP-adjusted TIF (Sweden 1st), and in 6th place for population-adjusted TIF (Sweden 1st). Over the study period, Italy was stable for crude and population-adjusted TIF but declined somewhat for GDP-adjusted TIF., Conclusions: Italy's performance in cancer research over the eight years to 2008 was better than expected considering its GDP and population. Nevertheless, the slight decline evidenced by the present study should induce scientists and policy makers to find ways to reverse the situation.

Even though the increasing incidence of cancer is mainly a consequence of a population with a longer life span, part of this augmentation is related to the increasing prevalence of patients living with a chronic cancer disease. To fight the problem, improved preventive strategies are mandatory in combination with an innovative health care provision that is driven by research. To overcome the weakness of translational research the OECI is proposing a practical approach as part of a strategy foreseen by the EUROCAN+PLUS feasibility study, which was launched by the EC in order to identify mechanisms for the coordination of cancer research in Europe.

"There is Plenty of Room at the Bottom"--not just "There is Room at the Bottom."What I have demonstrated is that there is room--that you can decrease the size of things in a practical way. I now want to show that there is plenty of room. Richard Feynman, December 29, 1959. More than 30 years ago Richard Feynman pointed out that physicists knew no limits to prevent us from doing engineering at the level of atoms. Until recently, though, while the lack of physical limits was accepted as commonplace, molecular engineering was thought of as impractical, unnecessary, or requiring breakthroughs in knowledge and technique that placed it somewhere in the distant future. Many visionaries intimately familiar with the development of silicon technology still forecast it would take between 20 and 50 years before molecular engineering became a reality. This is well beyond the planning horizon of most companies. But recently, everything has begun to change. After the industrial revolution and the "computer age", are we really facing a new era?

Medullary thyroid carcinoma (MTC) responds very poorly to chemotherapy. Mutations in the RET gene are critical for MTC pathogenesis. RET therefore represents a rational target for the development of novel MTC therapies. The accumulation of evidence from laboratory studies strongly suggests that PP1 inhibitor is a cytostatic agent for cells expressing RET oncoproteins. PP1 functions as a potent and selective inhibitor of RET oncoprotein phosphorylation, promoting its proteasomal degradation.

Significant alterations in gene sequences, expression levels and protein structures have been associated with specific types of thyroid epithelial tumorigenesis. Recent revolutionary changes in molecular biology have spanned the disciplines of genomics and proteomics, which systematically generate and analyze the information about genomes, gene transcripts, proteins and their functions in a global, comprehensive manner. The application of these approaches will better discriminate between thyroid tumor subtypes that are not recognizable when traditional pathological criteria are used.

Aims: Circumstantial evidence suggests that genetic changes may lead to tumor progression within the myxoid liposarcoma tumors (MLTs) carrying non-random chromosomal translocation t(12;16)., Methods: To address this subject an immunophenotypic analysis, applying antibodies against proteins encoded by TP53, MDM2 and CDK4 genes, complemented by molecular analysis of eight suitable cases, was performed on 104 consecutive cases. Chromosomal translocations were assessed either by cytogenetic analysis or by RT-PCR in 9 suitable cases and chimeric transcripts were found in all cases but two pleomorphic liposarcomas., Results: Based on immunophenotyping and tumor site, the case material consisted of three groups. The first one was made up of 92 non-retroperitoneal cases carrying a null p53, mdm2, cdk4 immunophenotype, which remained unchanged over the time of recurrences and along the gamut of histologic subtypes. The second group was represented by five p53+, mdm2-, cdk4- non-retroperitoneal cases, 4 of which were further analysed by PCR-SSCP for p53 mutation. The immunophenotypic profile of these cases, complemented by the molecular findings, supported a role of TP53 in tumor progression in three high-grade MLTs. The third group, consisting of 7 retroperitoneal cases, showed a heterogeneous immunophenotype, sharing immunophenotypic and molecular features with the well-differentiated/evoluted (dedifferentiated) liposarcoma group., Conclusions: TP53 mutations seem to play a role in tumor progression in a few cases of MLTs (2.8%) showing more aggressive histologic characteristics. The unexpected finding that a number of retroperitoneal LMTs display the immunophenotypic profile of the well differentiated/evoluted (dedifferentiated) liposarcomas, deserves further investigation.

The murine inbred strain C3H provides an experimental model of inherited predisposition to hepatocellular cancer. Hepatocellular neoplastic lesions induced by chemical carcinogens reach a volume 10-100-fold greater in C3H mice than in genetically resistant strains. However, the huge strain differences in tumor size are explained by relatively small differences (10%-30%) in tumor cell kinetics. Genetic linkage experiments in different crosses demonstrated that six unlinked hepatocarcinogen sensitivity (Hcs) and two hepatocarcinogen resistance (Hcr) loci determined quantitative variations in susceptibility to hepatocarcinogenesis. Such results provide the genetic basis for the strain variations in susceptibility to hepatocarcinogenesis and demonstrate a new model of polygenic inheritance of predisposition to cancer.

The analysis of the molecular mechanisms governing multistep carcinogenesis became experimentally approachable since the identification and characterization in tumor cells of altered or activated versions of cellular genes (oncogenes) that normally control cell growth and differentiation. The activating mutations confer new properties to the oncogene products and should therefore be considered as gain of function mutations. In addition, the oncogenes appear to act as dominant genetic traits since they act also in the presence of the homologous wild-type allele. However, the concept of a dominance of the transformed phenotype has been challenged by early experiments with somatic cell hybrids which showed that the fusion of normal and malignant cells may suppress the tumorigenic phenotype. The suppression or reversion of the malignant phenotype by the introduction of a normal chromosome into a tumor cell line has lent support to the idea that a family of cellular genes are coding for factors capable to interact with the cell-growth control machinery. These genes seem to reconstitute the normal control of cell growth even in the presence of an activated oncogene. In addition, a two-mutation model has been proposed to explain the epidemiological and clinical features of childhood cancers. According to the model, the development of these malignancies can be caused by the loss or inactivation of both alleles of cellular genes, as suggested by the somatic cell hybrid experiments where the function of the inactivated genes is restored by the contribution of those derived from the normal parental cells. This family of genes is designated as onco-suppressor genes since their product is necessary for the normal regulated cell growth and is lacking or inactivated in malignant cells. At gene level they should be considered as recessive genetic traits, since the tumor phenotype appears when both alleles of an onco-suppressor gene are inactivated. The mutations affecting their normal functions belong to the type "loss of function". The molecular analysis of retinoblastoma has led to the cloning and sequencing of the related onco-suppressor gene (RB gene) whose product displays the features of a gene-regulatory protein. In addition, a binding between the RB product and various viral onco-proteins (E1A, large T, E7) has been demonstrated, thus suggesting a mechanism of RB inactivation by which some DNA viruses can transform the host cell.(ABSTRACT TRUNCATED AT 400 WORDS)

The nature and some biological properties of the natural antitumor cytotoxins previously found in normal C3Hf serum, have been investigated. By immunoelectronmicroscopy study, employing rabbit hybrid antibodies with specificity for mouse Ig and ferritin, the C3Hf cytotoxins were shown to belong to immunoglobulins. By gel filtration, by inhibition experiments of the cytotoxic serum activity with monospecific anti-IgG and anti-IgM sera, and by 2-mercaptoethanol treatment of the C3Hf serum, the cytotoxic immunoglobulins were demonstrated to belong to the IgM class. They were not inactivated by heating until 60 degrees C and were able to activate guinea pig, rabbit, and human complement. The highest cytotoxic activity of the normal C3Hf serum was found when cells and serum were incubated at the low temperature, suggesting a low binding affinity of the cytotoxic IgM.

Crude membranes (CM) were obtained from in vivo subcutaneous nodules of the methylcholanthrene-induced BALB/c fibrosarcoma C-1 by forcing tumor fragments through a mechanical press and subsequent differential centrifugation. This immunogenic tumor has been previously shown to express both H-2d and extra H-2k-like antigens. Original H-2d and alien H-2k antigenic activities were present in CM C-1 as judged by the specific inhibition of the C'-dependent cytotoxicity of monospecific H-2 alloantisera on normal 51Cr-labelled lymphoid cells. Both K- and D-end private H-2d antigens (31 and 4), and H-2d public antigens 8, 29, 35 were detected in CM C-1. In addition, the alien H-2Kk.23 private specificity and the public H-2k.1, 5, and 25 were also found in CM C-1. A weak but reproducible activity attributable to the Dk private antigen 32 was also revealed in this material. A hierarchy in the expression of both H-2d and H-2k specificities was evident in CM C-1 which paralleled, although with an overall lower antigenic activity, those of two other BALB/c (H-2D) FIBROSARCOMAS AND OF A C3Hf (H-2k) lymphoma, respectively. CM from normal BALB/c and C3Hf spleens, while expressing higher amounts of all the tested H-2 antigens, displayed a hierarchy of the different specificities similar to that of neoplastic tissues. Crude soluble (CS) material was obtained from CM C-1 by deoxycholate treatment and was tested in the inhibition assay for the presence of H-2d and alien H-2k antigens. Only specificities with the highest expression in CM were found in CS, i.e. H-2.4 and 29 for H-2d and H-2.25 for H-2k. Both CM and CS from C-1, but not from another control BALB/c sarcoma, were able to significantly inhibit the activity of an oligospecific serum to the Kk-coded antigens.

Absorption experiments on C3Hf normal mouse sera followed by cytotoxic tests on EL4 lymphoma cells were done to investigate a possible identity between natural antilymphoma antibodies (NAA) and various types of autoantibodies known to be present in normal mouse sera. Single C3Hf normal sera were also tested both by cytotoxicity on EL4 cells and by radioimmune precipitation assay (RIP) on 125I-labelled AKR ecotropic virus to ascertain whether or not viral antigen are the target structures of the NAA activity. The study provides evidence that NAA coexist with autoanticorpal and antiviral activities although they are distinct entities.

In an earlier report we have shown that an allogeneic but not a syngeneic immunization of mice with lymphoma cells evoked a humoral complement-dependent cytotoxic response against lymphoma cells syngeneic with the serum. Here we report the results of an investigation, using the same experimental model, on the cellular antitumor response in vitro and the in vivo tumor resistance. Both the allogeneic and the syngeneic antitumor immunizations induced a cellular immune response that was detectable in vitro and that not inhibited by the correspondent antiserum that was obtained with the same type of immunization. The humoral and cellular immune responses evoked in our system seem, therefore, directed against different antigenic determinants. In the in vivo experiments the maximal antitumor protection was obtained in mice immunized syngeneically, whereas the allogeneic immunization gave a protection that was similar to that obtained in mice immunized with normal allogeneic thymus cells. However, mitomycin-C-blocked thymus cells were unable to induce any protection against the tumor challenge, whereas blocked allogeneic tumor cells conferred the same degree of protection as that obtained with untreated cells. The in vivo transfer in untreated mice of sera obtained with syngeneic or allogeneic antitumor immunization did not give any protection against the tumor challenge.