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R Rosell

Publications and source records attributed to R Rosell.

At least 73 records · Page 4Linked to original sources
PubMed1999

The anti-apoptosis survivin gene and its role in human cancer: an overview.

Malignant transformation of cells is accompanied by multiple genetic abnormalities with aberrant expression of genes. By using the reverse transcriptase polymerase chain reaction (RT-PCR) assay, we have assessed the regulation of survivin gene expression in a prospectively collected series of 83 human non small-cell lung cancers. Survivin gene transcripts were identified in 71 (85.5%) of the tumor samples, while they were detected in only 10 (12%) of the paired histopathologically normal lung samples. Furthermore, a diminished overall survival was associated with survivin expression (Log-rank, P=0.01). This review discusses the structure, expression, and function of the survivin gene. It presents updated pooled data on survivin, analyzed by either immunochemistry or by RT-PCR, and the clinical correlates of aberrant expression in several tumors. We conclude that estimation of survivin gene transcripts by RNA techniques may have relevant applications in the prognostic and therapeutic assessment of lung cancer.

Journal Article↗
PubMed1999

Genetic susceptibility associated with rare HRAS1 variable number of tandem repeats alleles in Spanish non-small cell lung cancer patients.

The highly polymorphic HRAS1 variable number of tandem repeats (VNTR), which maps 1 kb downstream from the human H-ras1 gene, has been described as an inherited predisposing factor in many human cancers. Here, we investigated the association between the presence of rare HRAS1 minisatellite alleles and lung cancer in the population studied. Four hundred sixty-six HRAS1 VNTR alleles from 233 lung cancer patients and 892 alleles from 446 unaffected controls were typed using PCR-long agarose gel electrophoresis assay of peripheral blood lymphocyte DNA. Rare alleles were differentiated from common alleles (a1, a2, a3, and a4) by shifts in electrophoretic mobility. Odds ratio was calculated to evaluate increased risk of lung cancer associated to the presence of rare HRAS1 alleles. A higher percentage of rare HRAS1 VNTR alleles in lung cancer patients than in unaffected controls (32.7 versus 21.9%) was confirmed. The presence of rare alleles was associated with an increased risk of lung cancer (odds ratio = 1.68; P < or = 0.0001), indicating a genetic predisposition to lung cancer. No differences based on other clinicopathological variables were observed. Furthermore, a meta-analysis showed a higher distribution of rare alleles in our study of Caucasian Spaniards than was found in other studies of American and Northern European Caucasian populations. We conclude that the presence of rare HRAS1 VNTR alleles may be an inherited predisposing factor in lung cancer. This presence can be easily determined from peripheral blood samples by PCR-based methods. Furthermore, interracial variations in allele frequencies and variations between Caucasian subpopulations suggest that genetic variations may be involved in susceptibility to lung oncogenesis, especially in certain ethnic populations.

Alleles↗
PubMed1999

New approaches in the adjuvant and neoadjuvant therapy of non-small cell lung cancer, including docetaxel (Taxotere) combinations.

Among the issues debated in the therapy of early non-small cell lung cancer are whether postoperative chemotherapy improves survival, whether postoperative radiation therapy has some benefit either in local control or in the prevention of distant recurrence, and whether neoadjuvant treatment benefits patients with stage IIIA disease. The role of surgery is being investigated in the North American Intergroup Trial, in which concurrent chemoradiotherapy followed by surgery and postoperative chemotherapy is compared with concurrent chemoradiotherapy alone. Based on the evidence to date, surgery appears to benefit patients in whom complete resection is attained. However, even in these patients, the detection of tumor DNA in serum is a clear indication for postoperative chemotherapy. A trial undertaken by the Spanish Lung Cancer Group is currently investigating a novel neoadjuvant regimen involving gemcitabine, cisplatin, and weekly docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) in patients with mediastinoscopically confirmed N2 disease.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

[Analysis of telomeric length in epithelial carcinoma of the ovary].

BACKGROUND: As a consequence of the high cell division rate, telomeric repeat reduction in human tumor cells, giving rise to genetic instability, has recently been described. The aim of this study was to analyze by Southern blot telomeric length alterations in a retrospective group of patients with ovarian epithelial carcinoma. PATIENTS AND METHODS: Tumor and corresponding normal DNA were isolated from paraffin-embedded tissue of 16 patients with ovarian epithelial carcinoma. Telomeric Restriction Fragments (TRF) were studied by Southern blot and densitometric analysis. RESULTS: No telomere alterations were detected in 37.5% of patients (6/16). Of the remaining ten, 5 were found to have telomere reduction and five telomere elongation. No significant correlation was found between clinicopathological variables, response to chemotherapy, survival rate or time to progression, and telomere length alterations. CONCLUSIONS: In ovarian epithelial carcinoma telomere elongation may be a marker of the presence of immortal cells within the tumor, but telomere or the absence of telomeric alterations do not rule out the presence of these cells. Although TRF analysis can be performed in paraffin-embedded tissues, it is not the best indicator of telomerase activity and thus of tumor aggressiveness in early stages of this carcinoma.

Blotting, Southern↗
PubMed1998

Allelic loss on chromosome 18q as a prognostic marker in stage II colorectal cancer.

BACKGROUND & AIMS: Loss of heterozygosity (LOH) on chromosome 18q is frequent in colorectal cancer (CRC) and has been associated with poor prognosis in stage II tumors. This study investigated the frequency of LOH in sporadic CRC and its effect on patient prognosis. METHODS: One hundred forty-four patients were screened for LOH at 18q by polymerase chain reaction using three polymorphic microsatellite markers. RESULTS: Nineteen patients were excluded because their tumors showed microsatellite instability in at least one marker. Of the remaining 125 patients, 121 were informative in at least one marker; 45% (54 of 121) showed 18q LOH. Five-year survival was 42% in those with 18q LOH and 73% in those without 18q LOH (P = 0.008). Multivariate analysis showed that tumor side (P = 0.0001) and 18q LOH (P = 0.01) were the only independent prognostic factors. Examining markers individually showed that only the lost of D18S474 had a significant influence on survival in patients with stage II CRC (P = 0.016). CONCLUSIONS: 18q LOH indicates an unfavorable outcome in patients with stage II CRC. Our results emphasize the importance of the 18q21.1 region, where several tumor-suppressor genes have been mapped. Microsatellite analysis may be useful in identifying high-risk patients who might benefit from adjuvant therapy.

Adult↗
PubMed1998

Phase II trial assessing the combination of gemcitabine and cisplatin in advanced non-small cell lung cancer (NSCLC).

BACKGROUND: There is need for more active and better tolerated combinations in non-small cell lung cancer (NSCLC). The Spanish Lung Cancer Group (SLCG) therefore conducted this phase II study to define the efficacy and toxicity profile of the combination of higher doses than usual of gemcitabine along with cisplatin in patients with advanced NSCLC. PATIENTS AND METHODS: Forty patients with pathologically documented advanced NSCLC were included in this trial (34 men, six women; aged 34-74 years; mean 64 years). Twenty-two patients had unresectable stage IIIB disease and 18 had stage IV disease. Karnofsky performance status was > or =70%. In five patients, surgery had previously been performed and four patients had received radiotherapy. Gemcitabine at a dose of 1200 mg/m2 was administered weekly (days 1, 8 and 15) and cisplatin 100 mg/m2 on day 15 of each 28-day cycle. RESULTS: Responses were scored according to standard World Health Organization criteria. Of 40 assessable patients, 19 had a partial response for an overall response rate of 47.5% (95% confidence interval (CI) 32-64%). To date, median survival for the whole group is 10.4 months (95% CI 6.2-11.7 months), with a 1-year survival rate of 35%. Toxicity was mainly haematological. Seven patients (18%) had grade 4 neutropenia (one episode of febrile neutropenia). Thrombocytopenia (12.8% grade 3 and 2.6% grade 4) was not associated with clinical bleeding. One patient had a grade 4 transient rise in transaminase. There was no grade 3 or 4 renal toxicity. There was no grade 4 symptomatic toxicity. The most common grade 3 toxicities were nausea and vomiting (28.2%) and alopecia (10.3%) both related to cisplatin. CONCLUSIONS: Gemcitabine can be safely administered at a dose of 1200 mg/m2 in combination with cisplatin. Thrombocytopenia seems to be less than in schedules with cisplatin given on day 1. The results of this studyshow promising activity (47.5% response rate) with modest toxicity. As this combination of gemcitabine and cisplatin deserves further evaluation in prospective randomized trials, the SLCG is comparing gemcitabine-cisplatin with etoposide-cisplatin in a phase III randomized study.

Adult↗
PubMed1998

Detection of chromosome 3p alterations in serum DNA of non-small-cell lung cancer patients.

BACKGROUND: The generally dismal outcome of non-small-cell lung cancer (NSCLC) is believed to be associated with the systemic nature of this disease. In current practice, the decision to begin adjuvant chemotherapy in completely resected early stages is based on empirical criteria and has not yet been influenced by the presence of individual risk factors. Nonetheless, recent studies indicate that soluble tumor DNA is found in the serum and plasma of cancer patients, and microsatellite alterations have been identified in small-cell lung cancer and in head and neck neoplasms. PATIENTS AND METHODS: We have investigated serum DNA from 22 completely resected stage I-IIIA NSCLC patients using a polymerase chain reaction microsatellite analysis with four microsatellite markers at chromosome 3p (D3S1038, D3S1611, D3S1067 and D3S1284). RESULTS: Our analyses showed serum tumor DNA in 6 of 22 (28%) cases, with microsatellite alterations, either as a shift (changes in the size of the microsatellite sequence in the autoradiograph) or as a loss of heterozygosity (LOH). LOH in both tumor and serum DNA at one or more microsatellite markers was found in four patients. Although it is still premature to look for prognostic implications, one patient with stage I serum DNA was identified prior to the development of distant metastases. CONCLUSIONS: The findings suggest that detection of free circulating DNA in sera of NSCLC patients is incidentally linked to the systemic nature of lung cancer even at the earliest stage. These observations provide the first hint that serum tumor DNA is present in NSCLC patients. The detection of DNA from cancer cells in the sera of NSCLC patients could be useful for monitoring relapse in a relatively non-invasive way, and the potential sensitivity of this test may help in selecting candidates for adjuvant chemotherapy.

Adult↗
PubMed1998

The integration of newer agents into neoadjuvant therapy.

The overall prognosis for N2 non-small cell lung cancer treated by surgical resection alone is dismal. At this stage, the disease is systemic, and the presence of occult micrometastases leads to relapse in the majority of cases. Progress against the disease therefore requires a multimodality approach involving chemotherapy, radiotherapy, and surgery. At least two randomized trials have demonstrated that cisplatin-based induction chemotherapy before surgery substantially improves median and 5-year survival compared with surgery alone. Induction chemotherapy has an equally impressive effect when it precedes definitive thoracic radiotherapy. In both settings, cisplatin-based combinations can achieve cure in certain stage IIIA patients. Attaining complete resection and downstaging N2 disease are useful surrogates for long-term survival. One focus for future research is the earlier stages of disease, in which induction chemotherapy also may have a role. Another challenge is to integrate new active agents, such as docetaxel, into the neoadjuvant setting, and trials of either a cisplatin or a carboplatin plus docetaxel regimen are under way. A further aim is to use molecular biological markers of malignancy to identify patients at highest risk of metastatic relapse and, hence, those in greatest need of chemotherapy.

Carcinoma, Non-Small-Cell Lung↗
PubMed1998

An update on European randomized studies in non-small cell lung cancer.

Less than 25% of non-small cell lung cancer (NSCLC) patients present with surgically resectable stage I and II disease, and the majority of patients will eventually die of disseminated disease. Cisplatin-based chemotherapy has been shown to prolong survival and improve quality of life in patients with stage III and IV disease. In recent years, new chemotherapeutic agents (eg, gemcitabine, paclitaxel, docetaxel, vinorelbine, and irinotecan) have shown definite activity in advanced NSCLC. The activity of these agents has led to phase II studies combining them with cisplatin, producing response rates that are generally in excess of 35%. Randomized trials suggest that survival is improved when combinations of gemcitabine/cisplatin, vinorelbine/cisplatin, and paclitaxel/cisplatin are compared with cisplatin alone or cisplatin/etoposide. The following report reviews the ongoing trials in NSCLC.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

The activity of gemcitabine plus cisplatin in randomized trials in untreated patients with advanced non-small cell lung cancer.

Three separate phase III randomized studies were conducted to compare the efficacy of a gemcitabine plus cisplatin combination (GC) with other chemotherapy regimens in the treatment of European and North American patients with inoperable (stage IIIB or IV) non-small cell lung cancer (NSCLC). The Spanish Lung Cancer Group (SLCG) compared the GC regimen with an etoposide plus cisplatin combination (EP), the Hoosier Oncology Group (HOG) compared it with single-agent cisplatin, and the Italian Lung Cancer Project (ILCP) compared it with a mitomycin plus ifosfamide plus cisplatin combination (MIC). The three studies each had a different primary objective (response rate, survival, or quality of life, respectively). From July 1995 to February 1997, 751 patients were enrolled into the three studies. In the SLCG study, 69 were entered in the GC arm and 64 in the EP arm; in the HOG study, 155 were entered in the GC arm and 154 in the cisplatin-alone arm; and in the ILCP study, 154 were entered in the GC arm and 152 in the MIC arm. In the SLCG study, gemcitabine 1,250 mg/m2 was given by 30-minute infusion on days 1 and 8 of each 21-day cycle. In the HOG and ILCP studies, gemcitabine 1,000 mg/m2 was given on days 1, 8, and 15 of each 28-day cycle. Cisplatin 100 mg/m2 was given on day 1 in the SLCG and HOG studies and on day 2 in the ILCP study. In the EP arm, etoposide 100 mg/m2 was given on days 1, 2, and 3 of each 21-day cycle. In the MIC arm, mitomycin 6 mg/m2 and ifosfamide 3 g/m2 were given on day 1 of each 28-day cycle. In the SLCG study, 28 patients (40.6%) in the GC arm and 14 patients (21.2%) in the EP arm achieved an objective response (P = .01). In the HOG study, 48 patients (31%) in the GC arm and 14 patients (9.1%) in the cisplatin-alone arm attained on objective response (P < .001). In the ILCP study, 61 patients (40%) in the GC arm and 42 patients (28%) in the MIC arm achieved an objective response (P = .03). Progression-free time was significantly longer for the GC arm (6.8 months) than for the cisplatin-alone arm (4.2 months) (P < .001). The median survival time was remarkably identical for the GC arms in the three studies (8.7 months), whereas it was 7.2 months for the EP arm, 7.6 months for the cisplatin-alone arm, and 9.5 months for the MIC arm. The main toxicities were myelosuppression and vomiting. The assessment of quality of life in the ILCP study is ongoing. Both 21- and 28-day cycles of GC were effective in the treatment of NSCLC, and this combination can be considered as a current "standard" therapy for advanced NSCLC patients.

Adult↗
PubMed1998

Superiority of sequential versus concurrent administration of paclitaxel with etoposide in advanced non-small cell lung cancer: comparison of two Phase II trials.

Paclitaxel and etoposide are two chemotherapy agents with broad cytotoxic activity and different mechanisms of action and resistance. Preclinical studies of their combined cytotoxicity have yielded conflicting results. We performed two sequential Phase II trials using different sequence schedules of paclitaxel and etoposide as first-line treatment in advanced non-small cell lung cancer (NSCLC). Forty-four patients with stage IIIB or IV NSCLC were included between July 1995 and September 1996. All patients received etoposide at 100 mg/m2, given as an i.v. infusion on days 1, 2, and 3. The first 20 patients (part A) also received paclitaxel at 175 mg/m2 as a 3-h infusion on day 1, immediately prior to etoposide. The subsequent 24 patients (part B) were given the same paclitaxel dose, but on day 4. Grade 3-4 granulocytopenia was seen in 70% of the patients in part A and in 37% of those in part B (P = 0.04). Twenty-five % of the courses in part A and 4% of the courses in part B were associated with granulocyte nadir < or =500/microl (P = 0.00006). No responses were observed in part A, although disease was stabilized in 14 patients (70%). In part B, there were two complete responses and seven partial responses, for an overall response rate of 37.5% (95% confidence interval, 21-58%). In conclusion, toxicity and antitumor activity of the paclitaxel/etoposide combination may be sequence dependent. Our findings suggest that etoposide followed by paclitaxel is well tolerated and has greater activity in NSCLC than concurrent administration.

Adult↗
PubMed1998

[Evaluation of the prognostic significance of P53 mutation in patients with non-small cell lung cancer].

Prognostic value of p53 gene mutation was determined in 95 radically operated non small cell lung cancer patients (78 males and 17 females, mean age 57.8 years). Study group included 62 cases of squamous cell carcinoma, 30--adenocarcinoma and 3--large cell carcinoma. There were 52 patients in stage I disease, 16--in stage II, 26--in stage IIIa and one--in stage IIIb. Paraffin-embedded samples of resected tumors were assayed for p53 mutations with the use of PCR/SSCP analysis. p53 mutation were present in 22 cases (23%). The median survival in patients with and without p53 mutations were 49 and 75 months (p = 0.46), respectively, and the five-year survival rate 53% and 50%, respectively. In stage I disease the median survival for patients with p53 mutation was 53 months and for those without mutations the median survival could not be determined as more then a half of them were alive. Median survival in stage II patients with and without mutations was 35 months and 44 months (p = 0.62), and in stage IIIA--9.5 months and 17 months, respectively (p = 0.37). The results of this study indicate that p53 gene mutation is not correlated with prognosis in non-small cell lung cancer patients.

Adult↗
PubMed1997

TP53 mutational pattern in Spanish and Polish non-small cell lung cancer patients: null mutations are associated with poor prognosis.

Inactivation of TP53 tumor suppressor gene is the most frequent molecular alteration in NSCLC, involving up to 60% of cases. Furthermore, TP53 mutational spectrum is related to the type of mutagen exposure, as well as racial and/or diet differences. Nearly 95% of TP53 perturbations affect codons included within exons 5-8 which encode for almost the entire DNA-binding domain. In this study we addressed the possible prognostic value of the molecular alterations identified in exons 5-8 of the TP53 gene in DNAs from 151 paraffin-embedded NSCLC sections corresponding to 59 Spanish and 92 Polish stage I-IIIA resected patients. PCR/single-strand conformation polymorphism (SSCP) analysis revealed that the occurrence of TP53 exon 5-8 mutations was 17/59 (29%) in the Spanish cohort and 17/92 (18%) in the Polish group. However, when DNA sequencing analysis was performed, these frequencies were reduced because of the presence of SSCP-false positive, intronic and silent mutations and polymorphisms. Fifteen of the 59 Spanish NSCLC tumors (25%) harbored TP53 mutations affecting exons 5-8 coding sequences, whereas only 12 of 92 Polish neoplasms (13%) contained alterations in the central hydrophobic region of p53. Our results indicate that the occurrence of TP53 mutations affecting exon 5-8 coding sequences in some European NSCLC populations may be lower than previously reported, and that the TP53 mutational patterns of these cohorts differ somewhat. The Spanish NSCLC patients contained missense mutations (9/59, 15%) and a relatively high percentage of null mutations (5/59, 8%) while the Polish patients mostly harbored missense mutations (9/92, 10%) and only one tumor contained a null type (1/92, 1%). Moreover, most TP53 missense mutations in the Spanish group were located outside the conserved regions, whereas the same mutations in the Polish group affected conserved amino acids. Furthermore, the Polish patients harbored a high percentage of G-->A transitions (most of them at non-CpG sites), while G-->T transversions were predominant in the Spanish group. Our findings suggest that there may be different racial or exogenous factors in these two populations which may help to explain both the distinct TP53 mutational pattern and the lower frequency obtained in the Polish group. The presence of missense mutations did not confer a worse clinical outcome in these subsets of NSCLC patients. However, patients whose tumors contained null TP53 gene mutations had a 5 month median disease-free survival time in contrast with 42 months in those patients without mutations (P=0.008). These findings suggest that loss of p53 function may enhance tumor progression in NSCLC patients independently of whether dominant negative TP53 missense mutations are present.

Aged↗
PubMed1997

[Positron emission tomography detection of residual disease in a case of lung cancer].

To date, computed tomography is considered the best procedure to detect either relapse or residual disease in non-small cell lung cancer. However, in recent years several studies have stressed the value of F-18 fluorodeoxyglucose positron emission tomography (FDG PET) which takes advantage of the enhanced glucose uptake observed in neoplastic cells. We present the case of a patient with a locally advanced non-small cell lung cancer who received trimodal treatment with induction chemotherapy followed by surgical resection and postoperative irradiation and lately developed brain metastases which were treated with chemoradiotherapy plus radiosurgery. However a small residual lesion remained in the brain magnetic resonance. Such abnormality was evaluated by means of FDG PET which did not show any increase on FDG uptake. The present case prompt us to review the role of FDG PET as a procedure that enable to detect subclinical disease and its potential usefulness taking into account the improvement in management strategies that has been attained in non-small cell lung cancer.

Adult↗