Lentiviral vectors and cardiovascular diseases: a genetic tool for manipulating cardiomyocyte differentiation and function.

Engineered recombinant viral vectors are a powerful tool for vehiculating genetic information into mammalian cells. Because of their ability to infect both dividing and non-dividing cells with high efficiency, lentiviral vectors have gained particular interest for basic research and preclinical studies in the cardiovascular field. We review here the major applications for lentiviral-vector technology in the cardiovascular field: we will discuss their use in trailing gene expression during the induction of differentiation, in protocols for the isolation of cardiac cells and in the tracking of cardiac cells after transplantation in vivo; we will also describe lentivirally-mediated gene delivery uses, such as the induction of a phenotype of interest in a target cell or the treatment of cardiovascular diseases. In addition, a section of the review will be dedicated to reprogramming approaches, focusing attention on the generation of pluripotent stem cells and on transdifferentiation, two emerging strategies for the production of cardiac myocytes from human cells and for the investigation of human diseases. Finally, in order to give a perspective on their future clinical use we will critically discuss advantages and disadvantages of lentivirus-based strategies for the treatment of cardiovascular diseases.

CA 15.3 determination in patients with breast cancer: clinical utility for the detection of distant metastases.

In 81 healthy women, 26 pregnant women, 25 patients with fibrocystic disease and 144 breast cancer patients, the overall diagnostic sensitivity and specificity of the CA 15.3 test was 27 and 97%, respectively. The positive and negative predictive values were 93 and 43%. In 150 node-negative patients taking part in a chemoprevention trial CA 15.3 was assayed at baseline and every 4 months for a median follow-up of 24 months (range 4-48). In these patients, 5 had local recurrences, 1 had a regional recurrence, 9 had distant metastases and 3 developed cancer in the contralateral breast. Among the patients with recurrences, those with distant metastases showed the highest ratio of CA 15.3 increase (8/9); in local and regional recurrences, this ratio was lower (2/6). The patients with contralateral breast cancer had no significant increase in CA 15.3. Patients in whom metastases were detected showed an increase in CA 15.3 4-48 months before clinical or instrumental detection of the metastases.

Prognostic factors in resectable breast cancer.

The traditional unfavorable clinicopathologic features in operable breast cancer are large tumor size, number of axillary node metastases, poorly differentiated grade, presence of lymphatic tumor emboli near to the primary malignancy, blood vessel invasion, tumor necrosis, intense lymphoplasmocytic reaction around the tumor and perimenopausal status. Current multidisciplinary approach is still based on two major clinico-pathologic findings such as tumor size and number of infiltrated axillary nodes. Only in recent years the presence or absence of estrogen receptors was taken into consideration to administer adjuvant tamoxifen or adjuvant chemotherapy, respectively. Since the fundamental prognostic indicators in breast cancer are the total tumor cell number and its inherent biological aggressiveness, it is important to assess the clinical role of the proposed new determinants as a guide to prognosis in series of consecutive patients staged and managed according to uniform treatment programs. Properties such as hormone receptor status, ploidy and tumor cell kinetics (3H-TdR labeling index and percent of S-phase cell) as well as oncogenes should be evaluated also as expression of tumor cell burden and/or indicators of clinical aggressiveness. Recent results from retrospective case series strongly suggest that tumor cell proliferative activity, in particular labelling index, is a prognostic factor independent of axillary nodes, tumor size, and receptor status for the relapse-free survival of node-positive and node-negative tumors. This new prognostic factor should be taken into consideration in the selection of candidates for adjuvant chemotherapy.

New prognostic indicators in resectable breast cancer (review).

Despite advances in early diagnosis and primary treatment of breast cancer with surgery, radiation therapy or both modalities, more than one-third of newly diagnosed patients will develop recurrent or systemic disease and ultimately die. In recent years, systemic adjuvant treatment has shown positive results in high-risk women and tumor mortality has significantly decreased in patients entered clinical trials. This review outlines old and new prognostic indicators which will enable clinicians to improve the selection of patients who are real candidates to adjuvant chemotherapy and/or hormonal therapy.

Prognostic factors in Hodgkin's disease: implications for modern treatment (review).

This review outlines the major prognostic factors as derived from the analysis of recent prospective trials. Disease extent, systemic symptoms, age, sex, and achievement of complete remission lasting longer than 12 months following chemotherapy, as well as certain treatment-related complications (e.g. acute leukemia), constitute the major variables affecting survival. Bulky lymphoma and inadequate primary irradiation are factors which have influence on relapse-free but not necessarily on total survival. Recent reports provide no evidence that minimalizing treatment (except salvage treatment), will demonstrably reduce treatment-related complications. Optimal treatment, giving patients the best chance to enter first durable complete remission, still seems to represent the best strategic approach. However, in given patient subsets, the impact of various treatment strategies on the 5-, 10-, and 15-year results is now being balanced against delayed morbidity, such as organ damage and second malignancies, produced by the intensity of treatment or the prolonged delivery of certain drugs.

Prognostic factors and response to treatment in non-Hodgkin's lymphomas (review).

This review outlines the major prognostic factors as derived from multivariate analysis of recent therapeutic studies in non-Hodgkin's lymphomas. Age at diagnosis (greater than or equal to 60 years vs less than or equal to 60 years), total number of involved sites, tumor bulk (mass size greater than or equal to 10 cm vs less than 10 cm), serum LDH (greater than or equal to 500 Units) and prompt achievement of complete remission following intensive combination regimens appear to be the most important variables predicting for cure in aggressive lymphomas. The clinical prognostic factors in follicular lymphomas were less extensively evaluated through Cox multiple regression analysis compared to large cell lymphomas. These factors include systemic symptoms, hepatosplenomegaly, anemia, as well as response to treatment. Treatment guidelines are provided in relation to high-risk and low-risk subsets rather than the classical stage assignment.

Circulating tumor markers in breast cancer (review).

The clinical application of circulating tumor markers remains a controversial subject in terms of useful methods and correct interpretation of findings. In particular and despite numerous investigations in the field, we do not have as yet specific or highly sensitive biological markers in breast cancer. Nevertheless, many oncologists often utilize circulating tumor markers in various phases of this malignancy to obtain additional information about disease extent and clinical course. For this reason, we have reviewed the present status of the most widely used serum tumor markers in this neoplasm. Both CEA and TPA are well known, but their organ specificity is not related to breast. Among novel biological markers identified by monoclonal antibodies, special attention has been devoted to circulating agents that are recognized by immunoreagents and that were obtained by immunization with breast-derived products. Both CA 15.3 and MCA are now being validated at the clinical level. From the present review it is clear that today we are still far from being able to make the diagnosis of breast cancer on the sole basis of laboratory findings. On the contrary, some of the available markers can be utilized as prognostic indicators of disease extent and treatment response. Their value greatly increases when combined with conventional diagnostic methods that can be prescribed on the basis of abnormal laboratory findings to confirm or rule out disease recurrence.

Lymphocyte subpopulations in Lynch syndrome II: an immunocytochemical study on gastrointestinal biopsies. Preliminary report.

Gastrointestinal biopsies from 18 members of a family with Lynch Syndrome II were evaluated and immunocytochemical studies were made to characterize the phenotypic expression of the tissue's immune populations. The intestinal findings suggest polyclonal B-cell activation related to the T-helper distribution. Our evaluation provides no specific information so far on the management of patients with Lynch Syndrome II.

Prognostic value of ploidy, cell proliferation kinetics, and conventional clinicopathologic criteria in patients with colorectal carcinoma: a prospective study.

PURPOSE: The aim of this study was to obtain additional biologic determinants that may be of use in segregating into subgroups with different prognosis patients with similarly staged colorectal cancers. METHODS: Between 1989 and 1991, a prospective study of prognostic factors has been performed in a group of 98 consecutive, unselected patients who underwent curative resections for primary untreated large bowel carcinoma. The fate of all patients is known at three years after operation. Clinical and pathologic data were recorded at the time of presentation and operation, and patients have been the subjects of regular follow-up. Tumor DNA content was determined by flow cytometry, and cell proliferative activity was determined by autoradiography with tritiated thymidine labeling index (LI). RESULTS: Univariate analysis revealed that the most important predictors of survival (P < 0.001) were the presence of positive lymph nodes, the presence of preoperative complications, Dukes stage, and LI. The multivariate analysis showed that Dukes stage (P < 0.002) and LI (P < 0.0001) were the only factors significantly related to survival. Disease-free survival was influenced significantly by Dukes stage (P < 0.001), LI, according to the classification in the two groups of high and low proliferative activity, respectively, (P < 0.0001), LI, calculated as a continuous variable (P < 0.0002), and the presence of lymph node metastases (P < 0.003). Outcome (favorable/unfavorable) was influenced significantly by Dukes stage (P < 0.0001) and LI (P < 0.0001). Concordance for each patient between Dukes stage and outcome was 73.1 percent and between LI, calculated as a continuous variable, and outcome was 74.1 percent. If, on the other hand, Dukes stage and LI are used together, concordance with outcome reaches 89.2 percent. CONCLUSION: We can conclude that, from a practical point of view, LI is an essential factor that must be combined with pathologic variables for a better prediction of patient outcome.

Tissue polypeptide antigen and carcinoembryonic antigen in colon tumors: serum levels and immunohistochemical localization.

Patients with malignant and benign colon disease (59 colon cancer and 96 polyps) were studied by means of tissue polypeptide antigen (TPA) and carcinoembryonic antigen (CEA) tests. The evaluation of the circulating levels of the markers showed that the overall sensitivity for the TPA test was 57.6% and for the CEA test was 55.9%. Their specificities were 89.5% and 94.7%, respectively. The analysis of results indicated no considerable difference between CEA and TPA in detecting individuals with malignant diseases. There was only a slight difference in Dukes stages: in stages A and B, TPA sensitivity was higher than CEA sensitivity. On the contrary, in the group of patients with polyps, more false-positive results were obtained with the TPA test than with the CEA test. Immunohistochemical studies on the small group of patients (12 colon cancers) allowed us to evaluate the relationship between the staining positivity for the anti-TPA and anti-CEA antibodies and the circulating levels of the markers. The staining in some cases was not correlated either with the stage of cancer or the circulating TPA or CEA levels. This fact further shows the need to investigate the mechanism that determines the blood levels of many tumor markers. All the specimens examined were positive for TPA and CEA staining, but they were composed of varying proportion of positive and negative tumor cells. The degree of positivity was frequently variable not only between the specimens but also within the same specimen.