SESy-Europe: a multi-language database dedicated to cancer screening monitoring.

Cancer is the second cause of death in developed countries. Many efforts to educate the public to more tumor free life-style and screening practice have been therefore adopted. Considering the high costs of diagnostic procedures and educational programs a cancer prevention/screening practice monitoring system is required to reduce costs, to assist health making policy decisions, and to tailor more targeted interventions whenever indicated. We, therefore, realized a computerized data-base able to assist medical personnel in health intervention monitoring and making policy at community level with a focus on the European region. An international medical board provided the translation of medical-related contents in English, French, German, Greek, Italian, Rumanian, Spanish and Turkish. The electronic system recognizes and finds relationships between screening events or secondary prevention tests and various causes of medical examinations (symptoms, diseases, professions, presence and type of health insurance, sex, age, medical history, family history, educational level, knowledge about cancer screening and prevention, patient location, type of community, region of provenance, etc). Due to its multi-language standardized characteristics its application may bridge European countries in cancer screening monitoring policy.

Primary fallopian tube adenocarcinoma: preoperative diagnosis, treatment and follow-up.

Preoperative diagnosis of fallopian tube carcinoma is difficult due to the rarity and silent course of this neoplasm. We present herein the case of a 58-year-old woman with primary fallopian tube carcinoma that was diagnosed preoperatively on the basis of a positive for adenocarcinoma Papanicolaou vaginal smear, repeated episodes of vaginal bleeding, negative endocervical and endometrial curettage, characteristic features on ultrasonography and elevated CA-125 levels. The patient was treated by total abdominal hysterectomy, bilateral salpigno-oophorectomy and omentectomy. Pathologic confirmation of primary serous papillary adenocarcinoma of the left fallopian tube was made. Peritoneal washings were positive for malignancy. FIGO stage was considered as IIIb and the patient received six courses of combined carboplatin-taxol chemotherapy. At two years from onset of therapy the patient underwent a modified radical mastectomy and lymphadenectomy because of primary carcinoma of the right breast. The patient was started on tamoxifen therapy, which she is still taking. At 60 months after initial surgery, the patient is alive and well. In conclusion, our study suggests an association between fallopian tube carcinoma and breast cancer and a good response of the patient to platinum-based chemotherapy.

Primary ovarian carcinosarcoma: a case report and review of the literature.

Primary ovarian carcinosarcoma is characterized by an admixture of malignant epithelial and stromal elements. This neoplasm is extremely rare with fewer than 400 cases reported in the English literature. Its histogenesis, clinical features and optimal treatment remain unclear because of the rarity of primary ovarian carcinosarcoma. This study focuses on the clinical, pathological, immunohistochemical features and survival of a 73-year-old patient with primary ovarian carcinocarcoma. The patient was treated with surgery followed by combined chemotherapy with carboplatin and taxol and assigned to FIGO Stage IIIc. She died from the disease 17 months after surgery. In conclusion, ovarian carcinosarcoma is a very aggressive tumor, especially when it is diagnosed at advanced stage.

G-CSF induces elevation of circulating CA 15-3 in breast carcinoma patients treated in an adjuvant setting.

BACKGROUND: Cancer antigen 15-3 (CA 15-3), a circulating marker that determines secreted products of the polymorphic MUC1 gene, has been established as a convenient tool for monitoring breast carcinoma patients. METHODS: The authors investigated alterations of soluble CA 15-3 in 57 postoperative breast carcinoma patients while they were receiving intensified adjuvant chemotherapy with granulocyte colony stimulating factor (G-CSF) support; 26 patients had American Joint Committee on Cancer (AJCC) Stage II, and 31 patients had AJCC Stage III breast carcinoma. Serial CA 15-3 values recorded thoughout the treatment were compared with baseline values, analyzed for correlation with hematologic and biochemical parameters, and compared with clinicopathologic characteristics and patient outcome. At a median follow-up time of 32 months, 47 of these patients remained relapse-free. RESULTS: A twofold increase of CA 15-3 was detected at the end of the second week of treatment, remained significantly elevated in most patients at above the cutoff level of 30 U/mL throughout the treatment period (P < 0.0001), and subsided to pretreatment values 1-2 months after treatment cessation. CA 15-3 values were found to be associated strongly with absolute neutrophil count, serum lactate dehydrogenase, and alkaline phosphatase. The median values and the kinetics of tumor markers did not differ over time in regard to hormonal receptor status and disease recurrence. CONCLUSIONS: These data provide strong evidence that G-CSF administration can induce elevation of CA 15-3 and indicate that false-positive results should be considered when evaluating CA 15-3 in patients who are receiving G-CSF. It is speculated that this phenomenon occurs through the induction of MUC1 antigen of unknown origin by G-CSF. Experimental investigation of this clinical observation is warranted.

Sequence dependent effect of paclitaxel on gemcitabine metabolism in relation to cell cycle and cytotoxicity in non-small-cell lung cancer cell lines.

Gemcitabine and paclitaxel are active agents in the treatment of non-small-cell lung cancer (NSCLC). To optimize treatment drug combinations, simultaneously and 4 and 24 h intervals, were studied using DNA flow cytometry and multiple drug effect analysis in the NSCLC cell lines H460, H322 and Lewis Lung. All combinations resulted in comparable cytotoxicity, varying from additivity to antagonism (combination index: 1.0-2.6). Gemcitabine caused a S (48%) and G1 (64%) arrest at IC-50 and 10 x IC-50 concentrations, respectively. Paclitaxel induced G2/M arrest (70%) which was maximal within 24 h at 10 x IC-50. Simultaneous treatment increased S-phase arrest, while at the 24 h interval after 72 h the first drug seemed to dominate the effect. Apoptosis was more pronounced when paclitaxel preceded gemcitabine (20% for both intervals) as compared to the reverse sequence (8%, P = 0.173 for the 4 h and 12%, P = 0.051 for the 24 h time interval). In H460 cells, paclitaxel increased 2-fold the accumulation of dFdCTP, the active metabolite of gemcitabine, in contrast to H322 cells. Paclitaxel did not affect deoxycytidine kinase levels, but ribonucleotide levels increased possibly explaining the increase in dFdCTP. Paclitaxel did not affect gemcitabine incorporation into DNA, but seemed to increase incorporation into RNA. Gemcitabine almost completely inhibited DNA synthesis in both cell lines (70-89%), while paclitaxel had a minor effect and did not increase that of gemcitabine. In conclusion, various gemcitabine-paclitaxel combinations did not show sequence dependent cytotoxic effects; all combinations were not more than additive. However, since paclitaxel increased dFdCTP accumulation, gemcitabine incorporation into RNA and the apoptotic index, the administration of paclitaxel prior to gemcitabine might be favourable as compared to reversed sequences.

Drug-induced apoptosis in lung cnacer cells is not mediated by the Fas/FasL (CD95/APO1) signaling pathway.

Anticancer drugs exert at least part of their cytotoxic effect by triggering apoptosis. We previously identified chemotherapy-induced apoptosis in lung cancer cells and suggested a role for p53 alternative or complementary pathways in this process. Recently, a role for the Fas/FasL (CD95/Apo1) signaling system in chemotherapy-induced apoptosis was proposed in some cell types. In the present work, the involvement of the Fas/FasL system in drug-induced apoptosis in lung cancer cells was investigated upon exposure to four cytotoxic drugs (cisplatin, gemcitabine, topotecan, and paclitaxel). We assessed the expression of Fas and FasL and the function of the Fas pathway in six lung cancer cell lines (H460, H322, GLC4, GLC4/ADR, H187, and N417). All lung cancer cell lines expressed Fas and FasL at RNA and protein levels, and apoptosis could be induced in four of six cell lines upon exposure to the Fas agonistic monoclonal antibody (mAb) CLB-CD95/15. Nevertheless, after drug exposure, no significant FasL up-regulation was observed, whereas the Fas expression was increased in the wild-type p53 cell line H460, but not in the other lines, proved to be mutant p53 by direct gene sequencing. Moreover, no correlation was observed in lung cancer cell lines between sensitivity to drugs and to a Fas agonistic mAb, and preincubation of cells with either the Fas-antagonistic mAb CLB-CD95/2 or a FasL-neutralizing mAb did not protect from drug-induced apoptosis. Taken together, these observations strongly argue against a role of the Fas/FasL signaling pathway in drug-induced apoptosis in lung cancer cells. Interestingly, caspase-8 activation was observed upon drug exposure, independently from Fas/FasL signaling.

p53 and chemosensitivity.

BACKGROUND: Although hematologic malignancies and some solid tumors such as germ cell tumors and pediatric malignancies can be cured by cytotoxic treatment, the most prevalent solid tumors are relatively resistant to these interventions. Apoptosis is involved in the cell kill of anticancer drugs and p53 is believed to be of principal importance in this process. However p53 also plays a role in cell cycle arrest and DNA repair, cellular processes that can decrease the sensitivity to chemotherapy. Therefore, p53 may play a dual role after exposure to cytotoxic treatment, activating either mechanisms that lead to apoptosis or launching processes directing to DNA repair and survival of the cell. DESIGN: In this article, we review in details the p53 functions involved in the mediation of chemosensitivity. The preclinical and clinical data published in the recent years about the relation between p53 and chemosensitivity are discussed and the potential pitfalls associated to most of these studies, and that may account for the contradictory results produced so far are also mentioned.

Cell cycle disturbances and apoptosis induced by topotecan and gemcitabine on human lung cancer cell lines.

Apoptosis is a major mode of cell death in response to cytotoxic drug treatment. A correlation between induction of apoptosis and chemosensitivity has been documented in some preclinical models. Topotecan (a topoisomerase I inhibitor) and gemcitabine (a deoxycytidine analogue), two active new drugs for the treatment of lung cancer, were evaluated for their growth inhibitory effect on human lung cancer cell lines and their effect on cell cycle perturbation, apoptosis and apoptosis-related genes. The cytotoxicities of topotecan and gemcitabine on the human lung cancer cell lines H460 (wild-type-p53) and H322 (mutant p53 were determined after 72 h drug exposure employing the MTT assay. The apoptotic index (AI) was assessed by three methods: analysis of morphological changes using May-Grünwald-Giemsa (MGG) staining, the TUNEL assay and FACS analysis. Cell cycle disturbances were studied by FACS and the number of cells expressing p53 and p21 were determined by immunohistochemistry. Both gemcitabine and topotecan had potent growth inhibitory effects in human lung cancer cell lines; combination treatment with these two drugs showed some additivity but no synergism. Induction of apoptosis after treatment was concentration- and time-dependent with both drugs and IC80 concentrations induced the highest values. The DNA histograms at 4, 24, 48 and 72 h indicate that topotecan at IC80 concentrations causes accumulation of cells in S and G2/M phases, whereas gemcitabine at IC80 concentrations causes, accumulation of cells in G1 phase. Both compounds induced p53 and p21 expression in the H460 cell line but not in the H322 cell line; the percentage of cells expressing p53 was highest at IC80 values, whereas the highest percentage of p21 positive cells could be induced with IC50 values. This could suggest that p53 induces cell cycle arrest at low drug concentrations, whereas p53 induces apoptosis at higher concentrations. In conclusion, p53-dependent and independent pathways of apoptosis exist in lung cancer cell lines. Activation of the p53 pathway depends on the induced cellular damage. Understanding the cell cycle disturbances induced by these drugs may help in the design of more rational treatment schedules.

Primary lymphoma of the pericardium: report on a "cured" case and review of the literature.

This report describes a 62-year-old man with a primary diffuse, immunohistochemically proven B-cell lymphoma of large non-cleaved cell (centroblastic) type of the pericardium. The patient responded completely to systemic chemotherapy and remains free of disease 30 months after diagnosis. The use of non-cardiotoxic drugs in divided doses as initial treatment is emphasized. In addition, the authors reviewed the literature of the last decade regarding the management and outcome of patients with primary cardiac lymphomas.

Growth inhibitory activity of S12363, a novel vinca alkaloid derivative on human melanoma cell lines.

The growth inhibitory activity of S12363, a new antineoplastic agent which belongs to the vinca alkaloid group incorporating an amino-phosphonate (bioester of valine), was studied on six human melanoma cell lines with different phenotypic characteristics and in vitro growth rates. S12363 was compared with vinblastine (VBL), vincristine (VCR) and vindesine (VDS) using the MTT assay. Inhibition was time- and dose-dependent. Overall, IC50 values ranged from 24-6770nM and 4.6-11.6 nM for the reference drugs and for S12363 respectively, after exposure for 1 hr. All the vinca alkaloids were more active when cells were exposed continuously for 72 hrs, inhibition by S12363 was greater than the reference drugs (p < 0.05 in 15/18 comparisons). The activities of VDS and S12363 were also compared using the clonogenic assay. IC50 values ranged from 45-500 nM and 17-75 nM respectively. On a molar basis, S12363 was significantly more active than VDS (ANOVA p < 0.0001). The shape of the cell survival curve obtained with S12363 was exponential, whereas that of VDS was of the exponential-plateau type. Furthermore, survival with higher concentrations of S12363 was inversely related to cells seeded. Cell cycle analysis showed these compounds to block cells in G2+M after exposure to their respective IC50 concentrations for 1 hr. This effect was obtained using a lower S12363 concentration. In summary, S12363 proved to be 18-83 times more active than the reference drugs in the MTT and 3-11 times more active than VDS in the clonogenic assay. Its high potency and dissimilar cell survival profile indicate that this compound possesses different biological properties, and therefore merits further in vivo evaluation.

Neglected cases of papillary and follicular thyroid carcinoma. Occurrence of subcutaneous scalp metastases.

Three cases, two follicular and one of papillary thyroid carcinoma are reported. All three patients presented with subcutaneous cystic scalp metastases; they had a long-standing history of thyroid cancer, although two had never sought medical attention. We discuss this unusual clinical manifestation in patients with untreated well differentiated thyroid carcinoma.

Is androgen substitution necessary in hypogonadal patients when they are treated with chemotherapy for malignant diseases?

A patient with hypogonadotropic hypogonadism owing to endogenous gonadotropin releasing hormone deficiency, who developed Hodgkin's disease is described. Chemotherapy administration caused prolonged and life-threatening myelosuppression; androgen substitution seemed to reverse bone marrow function and to maintain normal peripheral blood counts. Whether or not androgens are a necessary substitution in hypogonadal patients suffering from cancer and undergoing chemotherapy is discussed.