Antivascular agents for non-small-cell lung cancer: current status and future directions.

BACKGROUND: Despite improvements in surgery and chemo(radio)therapy which have allowed for modest advances in the treatment of patients with non-small-cell lung cancer (NSCLC), survival remains poor and further improvements are needed. Attention over recent years has focused, therefore, on targeted therapies, with notable success in the development of antivascular drugs. OBJECTIVE: To summarize the current knowledge on antivascular therapy in patients with NSCLC. METHOD: Review of randomized controlled trials exploring treatment of NSCLC patients with antivascular drugs. RESULTS/CONCLUSION: Bevacizumab, a humanized monoclonal antibody against the vascular endothelial growth factor (VEGF), when added to cytotoxic chemotherapy, was the first treatment to prolong the overall survival of patients with advanced NSCLC beyond 12 months, a significant breakthrough in the management of advanced NSCLC. Small-molecule tyrosine kinase inhibitors and alternative antivascular strategies such as VEGF-trap and vascular disrupting agents are also being investigated and have shown promise in clinical trials. This review summarizes the most recent and important findings in antivascular agents in NSCLC.

Apoptosis regulation and spontaneous apoptosis index of testicular germ cell tumors are associated with differentiation and resistance to systemic treatment.

BACKGROUND: Cisplatin-based chemotherapy can cure more than 80% of metastatic germ cell testicular tumors (GCT). Germ cells are particularly susceptible to apoptosis and it is reasonable to presume that GCTs are curable because of an intact and effective apoptotic pathway. PATIENTS AND METHODS: The expression of p53 and p21 was investigated in conjunction with the spontaneous apoptotic index in 20 refractory and 50 chemosensitive GCTs, with a complete follow-up. To detect a differentiation-dependent alteration in the apoptotic pathway, all of the histological tumor types were examined separately. RESULTS: Embryonal carcinoma components showed significantly higher p53 expression compared to other histological subtypes of GCTs. p21 was barely detectable in the majority of tumors. Seminomatous components showed no p21 expression. Mature teratomas and syncytiotrophoblasts showed significantly higher p21 expression than other tumor subtypes. Embryonal carcinomas showed significantly higher apoptotic indices than other non-seminomatous components. On the other hand, choriocarcinomas and mature teratomas showed the lowest spontaneous apoptotic potential. The apoptotic index correlated with the fraction of p53-positive cells, but not with the p21 expression rate. The refractory group showed significantly lower p53 expression, higher p21 expression and a higher apoptosis index than the sensitive group. CONCLUSION: Our results suggest that the p53 and p21 expression levels and the apoptosis index seem to be important factors in the issue of the chemosensitivity of GCTs. The protein expression pattern reflects a differentiation-dependent preference for G1/S-phase arrest in terminally differentiated syncytiotrophoblasts and mature teratoma cells, while p53 mediated apoptosis induction is meaning to less differentiated tumor types.

Reversal of multidrug resistance of cancer cells in vitro: modification of drug resistance by selected carotenoids.

The development of multidrug resistance (MDR) causes difficulties in the chemotherapy of of human cancer. Investigation of the possibility of reversal of MDR has been greatly aided by the use of cell lines with acquired resitance to anticancer agents in vitro or transfected with the mdrl gene. The aim of this study was to examine new perspectives of chemotherapy focused on natural, carotenoid compounds, in connection with the modification of MDR. The function of the MDR protein was examined via the R123 drug accumulation of both cell lines in the presence of carotenoids. The fluorescence of the cell population was measured by flow cytometry. The most effective resistance modifiers Monoepoxy-beta-carotene, (SS, 8S)-capsochrome, (8'S) Luteoxanthin, (9Z)-Violaxanthin, (9Z)-Zeaxanthin, (13Z)-Zeaxanthin were assayed for their antiproliferative effects in combination with the anti-cancer drug epirubicin. (13Z)-Zeaxanthin was able to enhance the antiproliferative effect on human mdrl gene transfected mouse lymphoma and anthracycline resistant human breast cancer cell line MCF7. (8'S)-luteoxanthin, (5S, 8S)-capsochrome and (9Z)-zeaxanthin treatment revealed synergism with epirubicin on resistant mouse lymphoma. The enhanced antiproliferative activity of epirubicin combinated with (9Z)-Violaxanthin was more significant on MCF7 cells resistant to anthracycline.

Influence of hMLH1 methylation, mismatch repair deficiency and microsatellite instability on chemoresistance of testicular germ-cell tumors.

BACKGROUND: Cisplatin-based chemotherapy can cure more than 80% of metastatic germ-cell testicular tumors (GCTs). The response to cisplatin-based chemotherapy has been related to Microsatellite Instability (MSI), which is caused by genetic or epigenetic changes in genes of the DNA Mismatch Repair (MMR) pathway. PATIENTS AND METHODS: We investigated 15 refractory and 36 chemosensitive GCTs for immunohistochemical loss of hMLH1, hMSH2 and hMSH6 protein expressions, in conjunction with hMLH1 gene methylation and MSI of GCTs, with a complete follow-up. RESULTS: A loss of either of the MMR protein expressions was detected in 14 cases (27.5%). Pathological hMLH1 protein expression was seen in 10 cases (19.6%). hMLH1 methylation was found in 11 cases (21.60%) and was highly correlated with loss of hMLH1 expression (p < 0.0001) and with immunohistochemically-detected MMR deficiency (p = 0.0005). MSI was found in 16 cases (31.4%). There was no correlation between hMLH1 methylation and MSI. Neither hMLH1 methylation status, nor MSI correlated with any of the clinicopathological parameters investigated (tumor stage, histology, resistance to systemic treatment). CONCLUSION: hMLH1 gene methylation was detected as a common alteration in GCTs, and correlated with the loss of hMLH1 protein expression (p < 0.0001). Neither hMLH1 gene methylation, MMR deficiency, nor MSI showed a relationship with the relevant clinicopathological parameters.

Investigation of HER2 overexpression in non-small cell lung cancer.

Lung cancer is the leading cause of mortality worldwide. The median survival of advanced disease is in the range of 8 to 10 months. Intrinsic or acquired drug resistance pose major challenges to the success of chemotherapy. The HER2 gene, also known as c-erbB-2 or neu, is a proto-oncogene that encodes a membrane-bound receptor tyrosine kinase of the epithelial growth factor receptor (EGFR) family. It has a possible role in tumor cell proliferation, tumor invasion, tumor metastasis and drug resistance. We retrospectively investigated 88 samples of non-small cell lung cancer (NSCLC) and assessed the correlation between HER2 expression and tumor histology. The expression of HER2 protein was analyzed by immunohistochemical staining (IHC) and HER2 DNA amplification was detected by using fluorescence in situ hybridization (FISH). HER2 overexpression (2+, 3+) was detected in 5 (5.7%) out of 88 specimens. All of the HER2-overexpressing tumors histologically proved to be squamous cell carcinoma (SCC). Cases with 2+ HER2 immunoreactivity showed either no amplification (3.875 and 2.525), or borderline amplification (4.75). Cases with 3+ HER2 immunoreactivity showed moderate amplification (7.35) and strong amplification (15-20 - cluster), respectively. The HER2 expression in NSCLC was relatively low in the selected Hungarian population; consequently, there is no indication for introduction of trastuzumab for the treatment of lung cancer.

[The "gray zone" in fine needle aspiration cytology of the breast]. / Az ún. "szürke zóna" az emlobetegségek vékonytu aspirációs citológiájában.

Fine needle aspiration cytology (FNAC) is an essential procedure in the diagnosis of premalignant and malignant lesions of the breast. A "gray zone" exists between benign and malignant lesions in FNAC of breast; there an unequivocal diagnosis cannot be reached. Lesions in "gray zone" are categorized as "probably benign with atypia" (C3) and "probably malignant" (C4). Authors compared the cytology with histopathology and clinical follow-up of "gray zone" breast lesions, classified either as C3 or as C4 by FNAC. Amongst the total of 1679 FNACs, 85 (5%) were diagnosed as C3, whereas 101 (6%) were diagnosed as C4. Of the C3 cases, 48 patients underwent surgical biopsy. Histology proved malignancy in 21 (44%) cases, and was benign in 27 (56%) cases. Eighty-five open biopsies were performed out of the C4 cases. The histology was malignant in 76 (89%) cases, and benign in 9 (11%) cases. Lesions belong to "gray zone" should be taken into consideration in the FNAC of the breast and patients must be informed regarding this fact.

Clinical relevance of HER-2/neu expression in germ-cell testicular tumors.

BACKGROUND: Amplification and/or overexpression of HER-2/neu are associated with poor clinical outcome in several epithelial tumors. However, the exact prognostic role of HER-2/neu expression in testicular germ-cell tumors is equivocal. PATIENTS AND METHODS: Since teratomas are relatively chemoresistant tumors, we evaluated the HER-2/neu alterations of 59 primary testicular teratomas and mixed germ-cell tumors containing teratomatous components using the standardized immunohistochemical method (IHC) (HercepTest) and Fluorescence in Situ Hybridization (FISH). RESULTS: HER-2/neu overexpression was detected in 14 (24%) out of 59 specimens. With IHC, teratomatous and choriocarcinoma components showed significantly higher HER-2/neu expression compared to other histological subtypes of GCTs (p=0.0095). A statistically significant correlation (p=0.0004) can be established between HER-2/neu status and clinical stage of the disease. Similarly, a significant correlation was observed between HER-2/neu overexpression and clinical outcome (p=0.0077). None of the specimens had definite HER-2/neu gene amplification. CONCLUSION: Our results suggest that HER-2/neu overexpression is associated with an adverse clinical outcome and has a prognostic role in testicular germ-cell tumors. Further studies are needed to evaluate the exact background of HER-2/neu overexpression in germ-cell tumors and the role of anti-HER-2/neu antibodies in the treatment regimens for this malignancy.

Expression and prognostic value of the lung resistance-related protein (LRP) in germ cell testicular tumors.

BACKGROUND: Lung resistance-related protein (LRP) was first detected in a non-P-glycoprotein-mediated multidrug-resistant lung cancer cell line and has been shown to be the major human vault protein. The aim of this study was to evaluate the expression of LRP in germ cell testicular tumors (GCT) and to determine the correlation between LRP expression and the clinical outcome of these tumors. PATIENTS AND METHODS: Seventy cases of primary testicular tumors were investigated. LRP protein was detected by immunohistochemistry and Western blotting methods. LRP mRNA was determined with RT-PCR. Patients' clinical parameters and tumor response to treatment were recorded. RESULTS: With immunohistochemistry, LRP was detected in 29 (41%) out of 70 primary testicular tumors. Twenty-two (63%) out of 35 tumors expressed LRP mRNA and LRP protein on examination by RT-PCR and Western blotting, respectively. Pure teratomas showed significantly higher LRP expression compared to other types of GCTs (p=0.0418). No relationship was demonstrated between the LRP immunostaining and stage of disease (p=0.2263). A significantly higher proportion of patients with LRP-negative tumors achieved complete response than those with LRP-positive tumors (p=0.0155). Patients whose tumors showed expression of LRP had significantly shorter overall survival (p=0.0428) than LRP-negative patients. CONCLUSION: Immunohistochemistry is a reliable method to evaluate LRP expression in testicular germ cell tumors. A positive correlation was found between LRP immunostaining and pure teratomas. LRP expression was associated with an adverse clinical outcome and shorter overall survival. Our findings suggest that LRP has prognostic value in testicular germ cell tumors and can predict clinical outcome.

Expression of HER-2/neu in testicular tumors.

BACKGROUND: Although the overexpression of the Epidermal Growth Factor Receptor 2 (EGFR-2, HER-2/neu, c-erbB-2) in malignancies might predict chemoresistance and poor prognosis, its clinical relevance has not been widely studied and determined in testicular tumors. PATIENTS AND METHODS: Since teratomas are relatively chemoresistant tumors, we evaluated the HER-2/neu receptor status of 28 primary testicular tumors (7 pure teratomas, 21 mixed germ cell tumors containing teratomatous components) using a standardized immunohistochemical method (HercepTest Kit). RESULTS: Seven (25%) out of 28 non-seminomatous germ cell tumors showed HER-2/neu positivity. The teratomatous components of mixed GCTs showed HER-2/neu overexpression in 5 cases. Three of the 5 choriocarcinoma components of mixed tumors overexpressed HER-2/neu. In one case (teratoma + choriocarcinoma) both components showed HER-2/neu overexpression. No HER-2/neu overexpression was detected in other, less differentiated histological subtypes. Among the HER-2/neu-positive cases, 3 patients are in complete remission, 3 patients are in partial remission and one patient died after primary chemotherapy. CONCLUSION: Twenty-five percent of the non-seminomatous germ cell tumors which contain teratomatous components overexpress HER-2/neu protein. The overexpression is restricted to the more differentiated histotypes. Further molecular investigations and clinicopathological studies are necessary to determine the correlation between HER-2/neu overexpression and clinical resistance of testicular tumors.

[Lung resistance protein analysis in testicular cancer]. / A lung rezisztencia protein (LRP) expressziójának vizsgálata hererákokban.

Germ cell testicular cancers are well-curable neoplasms, because total remission can be achieved in about 80% of the cases. However, 15-20% of the patients die due to drug resistance (DR). A number of mechanisms of the multidrug resistance phenotype are known, including MDR/P-glycoprotein (P-gp) and the so-called multidrug resistance associated protein (MRP). Lung Resistance Protein (LRP) is an ATP dependent membrane transporter protein associated with MDR. In our present work we studied the expression of LRP in testicular cancers. LRP expression was determined by immunohistochemistry (IH), Western blot (WB) and RT-PCR techniques. Clinical resistance was defined in accordance with the clinical oncologic rules. In 29 (41%) of 70 primary testicular tumours and in 22 (63%) of 35 cases, elevated LRP levels were established by IH and WB, respectively. In the latter 63%, the LRP mRNA levels were elevated as well. Six cases of the 15 seminomas and 23 cases of the nonseminomatous germ cell tumours (NSGCT) proved to be positive. No relationship was demonstrated between LRP expression and the stage of the disease. Despite the LRP positivity of 6 tumour samples, all of the seminomas proved sensitive. Of the 39 sensitive NSGCT, 27 cases were LRP-negative, whereas 11 tumour samples of 16 patients belonging to the resistant group proved LRP-positive (p=0.04). The authors concluded that the expression of LRP is responsible for clinical drug resistance in non-seminomatous testicular cancer patients.