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M Volm

Publications and source records attributed to M Volm.

At least 19 recordsLinked to original sources
PubMed2002

Protein expression profiles indicative for drug resistance of non-small cell lung cancer.

Data obtained from multiple sources indicate that no single mechanism can explain the resistance to chemotherapy exhibited by non-small cell lung carcinomas. The multi-factorial nature of drug resistance implies that the analysis of comprising expression profiles may predict drug resistance with higher accuracy than single gene or protein expression studies. Forty cellular parameters (drug resistance proteins, proliferative, apoptotic, and angiogenic factors, products of proto-oncogenes, and suppressor genes) were evaluated mainly by immunohistochemistry in specimens of primary non-small cell lung carcinoma of 94 patients and compared with the response of the tumours to doxorubicin in vitro. The protein expression profile of non-small cell lung carcinoma was determined by hierarchical cluster analysis and clustered image mapping. The cluster analysis revealed three different resistance profiles. The frequency of each profile was different (77, 14 and 9%, respectively). In the most frequent drug resistance profile, the resistance proteins P-glycoprotein/MDR1 (MDR1, ABCB1), thymidylate-synthetase, glutathione-S-transferase-pi, metallothionein, O6-methylguanine-DNA-methyltransferase and major vault protein/lung resistance-related protein were up-regulated. Microvessel density, the angiogenic factor vascular endothelial growth factor and its receptor FLT1, and ECGF1 as well were down-regulated. In addition, the proliferative factors proliferating cell nuclear antigen and cyclin A were reduced compared to the sensitive non-small cell lung carcinoma. In this resistance profile, FOS was up-regulated and NM23 down-regulated. In the second profile, only three resistance proteins were increased (glutathione-S-transferase-pi, O6-methylguanine-DNA-methyltransferase, major vault protein/lung resistance-related protein). The angiogenic factors were reduced. In the third profile, only five of the resistance factors were increased (MDR1, thymidylate-synthetase, glutathione-S-transferase-pi, O6-methylguanine-DNA-methyltransferase, major vault protein/lung resistance-related protein).

Carcinoma, Non-Small-Cell Lung↗
PubMed2001

Effect of highly active antiretroviral therapy on survival in patients with AIDS-associated pulmonary Kaposi's sarcoma treated with chemotherapy.

PURPOSE: Kaposi's sarcoma (KS) is the most common AIDS-related malignancy. Pulmonary involvement by KS (PKS) has carried a poor prognosis with median reported survival ranging from 3 to 10 months. We studied whether the introduction of highly active antiretroviral therapy (HAART; triple antiretroviral therapy including a protease inhibitor and two reverse transcriptase inhibitors) has been associated with improved survival for AIDS patients with PKS. PATIENTS AND METHODS: A retrospective study was performed of 37 consecutive patients with PKS and human immunodeficiency virus infection in the tumor registry at a large municipal hospital in New York City between 1994 to 1997. There were 16 patients from 1994 to 1995 (pre-HAART period) and 21 patients from 1996 to 1997 (post-HAART period). The primary end point was survival, which was defined as time from start of chemotherapy until death from any cause. RESULTS: Patients were analyzed by the date of diagnosis (pre- v post-HAART period) and whether or not they received HAART. Kaplan-Meier analysis showed significantly better survival in patients diagnosed in the post-HAART period (P =.0025). Additional Kaplan-Meier analysis indicated that patients on HAART had substantially better survival (P <.0001). Cox multivariate analyses showed that HAART therapy was associated with a reduced risk of death (hazard ratio = 0.09; 95% confidence interval, 0.03 to 0.69). CONCLUSION: In patients with AIDS-associated PKS and undergoing chemotherapy, administration of HAART was associated with increased survival.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Nonsteroidal and steroidal aromatase inhibitors in breast cancer.

Anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are members of the third generation of aromatase inhibitors that has now replaced aminoglutethimide (Cytadren), the progestins, and tamoxifen (Nolvadex) as the hormonal therapy of choice in estrogen-receptor-positive, postmenopausal, metastatic breast cancer. This article will review the role of aromatase in the pathogenesis of breast cancer and the results of recent studies that have established the role of its inhibitors in estrogen-receptor-positive breast cancer. We will also briefly outline the rationale and design of ongoing studies.

Anastrozole↗
PubMed2001

Vascular endothelial growth factor in newly diagnosed and recurrent childhood acute lymphoblastic leukemia as measured by real-time quantitative polymerase chain reaction.

PURPOSE: Overexpression of vascular endothelial growth factor (VEGF) is associated with increased angiogenesis, growth, and metastasis in solid tumors, but to date the significance of VEGF in leukemia has received only limited attention. Therefore, this study examined the cellular VEGF levels in 31 newly diagnosed and 22 recurrent cases of childhood acute lymphoblastic leukemia (ALL). EXPERIMENTAL DESIGN: VEGF was determined with real-time quantitative PCR methods. Kaplan-Meier statistical analyses were conducted for the relapse-free intervals and the overall survival times. The groups were compared by log-rank and rank-sum tests. RESULTS: The VEGF levels were significantly higher in recurrent ALL compared with newly diagnosed ALL (28.0 versus 3.1 units; P = 0.001). Kaplan-Meier estimates were conducted to analyze the prognostic value of VEGF levels in newly diagnosed ALL with regard to the relapse-free intervals and the overall survival times. In this analysis, the median relapse-free interval of patients with low VEGF levels was more than 10 years, whereas the relapse-free interval of patients with high VEGF expression was only 1.2 years. The median overall survival time for the collective with low VEGF levels was >10 years, whereas the survival of the group of patients with high VEGF levels was 3.9 years. This difference was not statistically significant. This may be attributable to the small number of patients involved. CONCLUSION: Our data suggest that VEGF may play an important role in the pathophysiology of ALL. The expression of VEGF raises the possibility of using angiogenesis inhibitors as a novel therapeutic strategy in childhood ALL.

Adolescent↗
PubMed2000

Relevance of proliferative and pro-apoptotic factors in non-small-cell lung cancer for patient survival.

This investigation first set out to analyse which cellular proliferative and apoptotic factors, in addition to the clinical prognostic factors, are most predictive in patients with non-small-cell lung carcinomas (NSCLC). To this purpose, we related the proliferative factors proliferating cell nuclear antigen (PCNA), cyclin A, cyclin D1, cyclin-dependent kinase 2 (cdk2), cdk4 and the proportion of cell cycle phases in NSCLC to the survival times of 150 patients. Additionally, we associated the expressions of Fas, Fas ligand and caspase-3 in NSCLC to patient survival. Immunohistochemistry was used to determine the proteins and flow cytometry to assess the proportion of cell cycle phases. Patients with PCNA-positive carcinomas had significantly shorter survival times than patients with PCNA-negative carcinomas (median survival times: 51 vs 89 weeks). Corresponding results were obtained with the factor cyclin A (64 vs 92 weeks), with the factor cdk2 (76 vs 89 weeks), with the factor cdk4 (62 vs 102 weeks) and with the proportion of S phases (86 vs 121 weeks). Patients with an expression of the apoptotic factors had a more favourable prognosis than patients with negative carcinomas. The median survival times of cancer patients with Fas expression was 86 weeks and of those without Fas expression only 69 weeks. Corresponding results were obtained with the Fas ligand (87 vs 41 weeks) and caspase 3 (87 vs 34 weeks). In order to determine whether a combination of factors can yield improved prognostic information, we investigated all possible combinations of the proliferative and apoptotic factors. Patients with tumours having a high proliferative activity, but which did not express apoptotic factors had the shortest survival times while patients with a low proliferative activity and a high expression of apoptotic factors had the most favourable outcome. A multivariate analysis (Cox model) of the cellular and clinical prognostic factors indicated that stage, lymph node involvement, Fas, PCNA and cyclin A are the most important prognostic factors for the clinical outcome of patients with non-small-cell lung carcinomas.

Adenocarcinoma↗
PubMed2000

nm23-H1 expression defines a high-risk subpopulation of patients with early-stage epithelial ovarian carcinoma.

The role of the nm23 gene in human ovarian cancer is still controversial. We studied the expression of the nm23-H1 gene in 247 human epithelial ovarian carcinomas. The patients were followed-up until their death, or for a minimum of 5 years if they survived. The expression of the gene was studied by means of immunohistochemistry and a semiquantitative scoring system considering the staining intensity and the number of reactive tumour cells. Patients carrying tumours with higher expression scores (4-6 on a scale from 0 to 6) had a significantly lower survival (P = 0.01) than the rest. Further stratified statistical analysis revealed that this effect was mainly attributable to the subgroup of patients with early-stage (I and II), well- and moderately differentiated tumours. In fact, a multivariate analysis carried out for this subset of patients showed nm23-overexpression to be the only significant independent predictor of an ominous prognosis. The association of nm23-overexpression with a worse prognosis was most probably not due to mutation of the nm23 gene, since mutational analysis in 60 tumours by means of single-strand conformational polymorphism and direct sequencing disclosed only one mutation, which was located outside the open reading frame. Our results seem to indicate that nm23 expression is associated with a significantly worse prognosis in early-stage, well-differentiated epithelial ovarian carcinoma, a finding with important clinical implications, considering that many patients with ovarian cancers showing these features do not undergo any further treatment beyond surgical staging. If confirmed, they could help in tailoring the treatment of these patients in the future.

Aged↗
PubMed2000

Association of telomerase expression with successful heterotransplantation of lung cancer.

This study analyzed whether the expression of telomerase may serve as prognostic factor for the aggressiveness of human non-small cell lung carcinomas. To this purpose the expression of telomerase measured by immunohistochemistry was compared with the take rate of the primary tumors that were heterotransplanted into nude mice. Formalin-fixed, paraffin-embedded specimens of 97 non-small cell lung carcinomas from primarily untreated patients were analyzed for the expression of telomerase by a goat polyclonal antibody (clone C-20). Moderate or strong telomerase-staining was found in 78 (80%) cases. Age, gender, stage and histology had no influence on the telomerase expression. It was discovered that of the 19 telomerase-negative carcinomas only five (26%) exhibited growth in nude mice while of the 78 telomerase-positive cases 37 (47%) were successfully transplanted. To confirm these results, alcohol-fixed, paraffin-embedded cancer specimens from another group of patients (n=58) were analyzed for telomerase expression by a rabbit polyclonal antibody (clone H-231). Corresponding results were obtained. The take rate of telomerase-negative carcinomas was only 36%; the take rate of telomerase-positive carcinomas was 59%. These data suggest that high telomerase expression does indeed correlate with the aggressiveness of non-small cell lung carcinomas.

Animals↗
PubMed2000

Angiostatin expression in non-small cell lung cancer.

Angiostatin, a potent inhibitor of angiogenesis, tumor growth, and metastasis, was examined in a panel of human lung cancer cell lines with Western blot analysis and in 143 primary non-small cell lung carcinomas with immunohistochemistry. Thirty-four of 143 cases (24%) stained positively. Patients with angiostatin-positive tumors survived longer (146 weeks) than patients with angiostatin-negative tumors (77 weeks; log-rank test: P = 0.07; rank-sum test: P = 0.02). To determine whether combining stimulating and inhibiting factors might improve the prognostic capability, both angiostatin and vascular endothelial growth factor (VEGF) were analyzed together with respect to patient survival. The median survival time of patients with angiostatin-positive/VEGF-negative carcinomas was 184 weeks, whereas the median survival time of patients with angiostatin-negative/VEGF-positive tumors was only 52 weeks. The angiostatin-positive tumors exhibited an increased incidence of apoptosis and a reduced capability to be transplanted into nude mice, but these differences did not reach or were only of borderline statistical significance.

Angiostatins↗
PubMed1999

Association of cyclin D1 expression in lung cancer and the smoking habits of patients.

This study examined whether or not cyclin D1 expression is associated with the smoking habits of patients with non-small cell lung carcinomas (NSCLC). Immunohistochemistry was used to analyze 181 NSCLC samples for the expression of cyclin D1. Expression of cyclin D1 protein was found in 130 out of 181 cases (72%). A significant relationship between cyclin D1 expression and stage or histological classification was not observed. The carcinomas of smokers expressed cyclin D1 in 77% of the cases while carcinomas of non-smokers expressed this protein only 57% of the time (P < 0.01, Fisher's exact test). The correlation between smoking and cyclin D1 expression was maintained when the analysis was limited to squamous cell lung carcinomas. However, no correlation was found between cyclin D1 expression and the smoking habits of patients with adenocarcinomas. This can be explained by the fact that the development of adenocarcinomas--in contrast to squamous cell lung carcinomas--is not closely related to tobacco smoke.

Adenocarcinoma↗
PubMed1999

Expression of Fas (CD95/APO-1) and Fas ligand in lung cancer, its prognostic and predictive relevance.

In order to examine whether or not the expression of the apoptosis-related receptor Fas (CD-95/APO-1) and its ligand (FasL) has relevance for patient survival, immunohistochemistry was used to analyze the proteins of both factors in 164 non-small cell lung carcinomas. Patients with Fas-positive tumors exhibited significantly longer survival times than patients with Fas-negative carcinomas. In contrast, FasL did not significantly influence patient survival time. A multivariate analysis of clinical and biological factors indicated that lymph node status and Fas expression were significant prognostic factors. Carcinoma patients who were negative for both Fas and FasL had a significantly higher incidence of lymph node involvement than did carcinoma patients who were positive for Fas and FasL. Carcinomas that were positive for Fas and FasL demonstrated a greater sensitivity to doxorubicin in vitro.

Adult↗
PubMed1999

Concurrent paclitaxel and radiation therapy for breast cancer.

Few studies have evaluated the role of concurrent chemoradiation therapy in the management of locally advanced breast cancer. The availability of radiosensitizing chemotherapeutic agents that are effective in breast cancer and the encouraging results achieved by concurrent chemoradiation in other malignancies have prompted us to investigate this approach. Paclitaxel is a promising agent for use with concurrent radiotherapy because of its single-agent efficacy profile and its radiosensitizing effects. A clinical protocol of preoperative paclitaxel and radiation in locally advanced breast cancer is ongoing at our institution to test feasibility, measure pathologic response at mastectomy, and explore association of pathologic response with molecular tumor markers. Initially, the study was designed to test weekly paclitaxel at a dose of 60 mg/m2 during radiation therapy, delivered 5 days a week at 200 cGy fractions to a total dose of 50 Gy over 5 weeks. Due to severe skin toxicity in the first two patients, the protocol was amended to change the scheduling of paclitaxel to 30 mg/m2 twice weekly and to reduce the radiation to 180 cGy fractions to a total dose of 45 Gy, delivered 5 days a week over 5 weeks. Presently, 13 patients have been accrued; preliminary data indicate good tolerance to twice-weekly paclitaxel, and four of eight evaluable patients have achieved pathologic response (one patient who received the weekly regimen and three who received the twice-weekly regimen). In addition, sequential fine-needle aspirations of palpable breast cancers were obtained in patients enrolled in a parallel study of preoperative single-agent paclitaxel (200 mg/m2 every 2 weeks, for a total of four cycles before breast surgery). Preliminary results suggest that a steep increase in the mitotic index occurs during the first day after paclitaxel administration and plateaus between the second and the third day, then decreases to pretreatment values. The peak apoptotic index occurs at approximately 72 hours after paclitaxel administration and decreases at approximately 98 hours. These initial findings suggest that twice-weekly dosing of paclitaxel may optimize recruitment of cells into the G2/M phase of the cell cycle, the most radiosensitive phase.

Antineoplastic Agents, Phytogenic↗
PubMed1999

Biological characterization of subgroups of squamous cell lung carcinomas.

Recently, Pezzella et al. (Am. J. Pathol., 1997, 151: 1417-1423, 1997) reported on a subgroup of non-small cell lung carcinomas that had no morphological evidence of neoangiogenesis but appeared to grow and were highly aggressive. In this investigation, we subdivided 87 squamous cell lung carcinomas into four subgroups according to angiogenesis (low and high vessel density) and tumor growth (low and high tumor cell proliferation). The aim was to find differences, if any, in the angiogenic status and clinical behavior between these subgroups. We identified a group of tumors with low angiogenesis and high tumor cell proliferation that was characterized by high expression of vascular endothelial growth factor, low expression of basic fibroblast growth factor, reduced apoptosis, increased incidence of metastases, and short survival times. These data show that even squamous cell lung carcinomas are a heterogeneous group of tumors that can be subdivided in tumors with different biological properties and different clinical behaviors.

Adult↗
PubMed1998

O6-methylguanine-DNA methyltransferase activity and sensitivity to cyclophosphamide and cisplatin in human lung tumor xenografts.

The DNA repair protein O6-methylguanine-DNA methyl-transferase (MGMT) is a main determinant of resistance of cells to the cytostatic effects of O6-alkylguanine-generating alkylating agents. The purpose of our study was to assay MGMT activity in cells of lung cancers and to correlate MGMT levels with chemotherapy response to cyclophosphamide (CTX) and cisplatin (DDP). MGMT levels were determined in 14 human lung tumor xenografts. There was a wide variation of MGMT expression in these tumors, ranging from 10 to 984 fmol/mg protein. There was also a wide range in the sensitivity of the xenografts to CTX and DDP, as measured by specific growth delay. When the MGMT levels of the different xenograft lines were compared with the corresponding responses to CTX and DDP, a close correlation was found between MGMT activity and CTX (lin reg., r = -0.83, p < 0.05). The higher the MGMT activity, the less pronounced was the growth-inhibiting effect of CTX. With DDP, no such correlation was found. Our results indicate that the in vivo response of tumors to CTX is related to the level of MGMT expression.

Animals↗
PubMed1998

Clinical implications of cyclins, cyclin-dependent kinases, RB and E2F1 in squamous-cell lung carcinoma.

In the search for new risk factors at the molecular and cellular levels, clinical data [lymph-node involvement(LN)and stage] were used and 104 squamous-cell lung carcinomas were analyzed by immuno-histochemistry for expression of cyclin D1, cyclin A, cdk2, cdk4, RB, and E2F1. The results of the univariate analysis of all 8 factors showed that cyclin A and cdk2 gave the best prognostic information, while no prognostic value could be found associated with cyclin D1, cdk4, RB and E2F1. The subsequent multivariate analysis of all possible combinations of the important factors showed that the pairs LN/cyclin A, LN/cdk2 and cyclin A/cdk2, and the triplet LN/cyclin A/cdk2 yielded the best prognostic information. It was essentially better than the information given by a single factor.

Carcinoma, Squamous Cell↗
PubMed1998

Tissue-factor expression in human non-small-cell lung carcinoma measured by immunohistochemistry: correlation between tissue factor and angiogenesis.

Tissue factor (TF) is the physiological initiator of blood coagulation. It has been suggested that TF also regulates tumor growth and angiogenesis. We therefore used immunohistochemistry to analyze the expression of TF and angiogenesis in non-small-cell lung carcinomas of 191 patients. A significant association was found between TF expression and microvessel density (MVD): TF-negative carcinomas more frequently exhibited low MVD. Additionally, a significant relationship between TF expression and the expression of vascular endothelial growth factor (VEGF) was discovered. TF was also compared with the resistance of the carcinomas to doxorubicin, as measured in vitro: TF-negative tumors were more frequently resistant to doxorubicin than were TF-positive tumors. Kaplan-Meier survival analysis revealed that survival times were longer in patients with TF-negative tumors than in patients with TF-positive tumors. These data suggest that TF functions as an additional angiogenic factor that could be used as a new prognostic and predictive factor for non-small-cell lung carcinomas.

Carcinoma, Non-Small-Cell Lung↗
PubMed1998

Association between nm23-H1 expression, proliferation and apoptosis in non-small cell lung carcinomas.

Twelve non-small cell lung carcinomas and adjacent normal lung tissues were examined for mutations of the nm23-H1 gene by using SSCP analysis and for an expression of the nm23-H1 protein by immunohistochemistry. No mutations could be found in either the carcinomas or in the adjacent normal tissues. In contrast, six of 12 carcinomas showed protein expression while only one adjacent normal lung tissue yielded a positive staining result. Therefore, the expression of nm23-H1 protein was analysed in a larger group of non-small cell lung carcinomas (n = 185) to determine whether or not the expression of nm23 protein may be of prognostic relevance. Only a weak relationship between nm23-H1 expression and lymph node involvement was observed. However, a significant correlation between proliferation and nm23-H1 expression was detected. Additionally, a direct correlation between apoptosis and nm23-H1 expression or between myc and nm23-H1 expression was found. Finally, non-small cell lung carcinomas that expressed nm23-H1 protein were more frequently sensitive to doxorubicin than carcinomas that did not express this protein.

Apoptosis↗
PubMed1998

Prognostic value of ERBB-1, VEGF, cyclin A, FOS, JUN and MYC in patients with squamous cell lung carcinomas.

Patients with previously untreated squamous cell lung carcinomas were evaluated to see if combining the expression of molecular and cellular factors with the most important clinical prognostic factors could improve the diagnostic ability to predict prognosis. For this reason, immunohistochemistry was used to examine the squamous cell lung carcinomas from 121 patients for their expression of ERBB-1, vascular endothelial growth factor (VEGF), cyclin A, FOS, JUN and MYC. Median survival was shorter for patients with ERBB-1-, VEGF-, cyclin A-, FOS-, or JUN-positive tumours. For those patients with positive lymph node involvement, the survival times were also shorter in the VEGF-positive, cyclin A-positive and FOS-positive groups. Multivariate analysis independently demonstrated a significant prognostic value for lymph node involvement, VEGF and FOS.

Adult↗