Biomedical subjects

Melania Pintilie

Publications and source records attributed to Melania Pintilie.

13 recordsLinked to original sources

PubMed2003

Factors associated with failure to publish large randomized trials presented at an oncology meeting.

CONTEXT: Large clinical trials are the criterion standard for making treatment decisions, and nonpublication of the results of such trials can lead to bias in the literature and contribute to inappropriate medical decisions. OBJECTIVES: To determine the rate of full publication of large randomized trials presented at annual meetings of the American Society of Clinical Oncology (ASCO), quantify bias against publishing nonsignificant results, and identify factors associated with time to publication. DESIGN: Survey of 510 abstracts from large (sample size, > or =200), phase 3, randomized controlled trials presented at ASCO meetings between 1989 and 1998. Trial results were classified as significant (P< or =.05 for the primary outcome measure) or nonsignificant (P>.05 or not reported), and the type of presentation and sponsorship were identified. Subsequent full publication was identified using a search of MEDLINE and EMBASE, completed November 1, 2001; the search was updated in November 2002, using the Cochrane Register of Controlled Trials. Authors were contacted if the searches did not find evidence of publication. MAIN OUTCOME MEASURES: Publication rate at 5 years; time from presentation to full publication. RESULTS: Of 510 randomized trials, 26% were not published in full within 5 years after presentation at the meeting. Eighty-one percent of the studies with significant results had been published by this time compared with 68% of the studies with nonsignificant results (P<.001). Studies with oral or plenary presentation were published sooner than those not presented (P =.002), and studies with pharmaceutical sponsorship were published sooner than studies with cooperative group sponsorship or studies for which sponsorship was not specified (P =.02). These factors remained significant in a multivariable model. The most frequent reason cited by authors for not publishing was lack of time, funds, or other resources. CONCLUSIONS: A substantial number of large phase 3 trials presented at an international oncology meeting remain unpublished 5 years after presentation. Bias against publishing nonsignificant results is a problem even for large randomized trials. Nonpublication breaks the contract that investigators make with trial participants, funding agencies, and ethics boards.

Bias↗

PubMed2003

Costimulation through the inducible costimulator ligand is essential for both T helper and B cell functions in T cell-dependent B cell responses.

Costimulation through the inducible costimulator (ICOS) and its ligand (ICOSL) is essential for T cell-dependent B cell responses, but the cellular and temporal dynamics underlying its in vivo effects are poorly defined. Here we have shown that Icosl(-/-) and Icos(-/-) mice had similar phenotypes and that ICOS-ICOSL costimulation modulated the early but not late phases of IgG1 affinity maturation. Exploiting the adoptive transfer of T or B cells from primed Icosl(-/-) mice, we provided genetic evidence that costimulation through ICOSL was essential for primary but not secondary helper T cell responses and for the control of both T and B cell activities, resulting in T cell-dependent IgG1 production.

Animals↗

PubMed2003

Estimating hypoxic status in human tumors: a simulation using Eppendorf oxygen probe data in cervical cancer patients.

PURPOSE: To define the minimal number of pO(2) measurements, with 90% sensitivity and 90% specificity, needed to categorize cervical tumors as either hypoxic or oxic. METHODS AND MATERIALS: Using Eppendorf oxygen probe data from our ongoing prospective trial, we simulated the measurement of tumor oxygenation with a smaller number of data points in 135 patients with cervical cancer. The hypoxic proportion, defined as the percentage of pO(2) values <5 mm Hg (HP5), was calculated for each tumor. Hypoxic tumors were defined as those with a median HP5 >50%, and tumors with normal oxygen levels as those with a median HP5 < or =50%. A small number of pO(2) measurements were randomly selected from the Eppendorf measurements in each tumor, or per Eppendorf track, and used to define the tumor as hypoxic or oxic. The sensitivity and specificity were calculated, considering the classification as given by the complete set of Eppendorf measurements as the reference standard. RESULTS: The probability of falsely classifying the tumor decreased as the selected number of pO(2) measurements per tumor increased, and at 16 measurements was approximately 10%. Adding additional measurements per tumor beyond 24 improved the ability to classify the tumor accurately only slightly. The probability of falsely classifying the tumor decreased as the pO(2) measurements per track increased. At five measurements per track, the probability of falsely classifying the tumor was approximately 9%. CONCLUSION: Approximately 20 measurements per tumor, or five measurements per track, using the Eppendorf pO(2) histograph, are sufficient to categorize cervical tumors as hypoxic or oxic. The results of this study will serve as a guide for research clinicians in the use of this and other systems in the assessment of tumor oxygenation in humans.

Adenocarcinoma↗

PubMed2003

Dysregulated PTEN-PKB and negative receptor status in human breast cancer.

Recent studies demonstrate that abnormalities in PTEN may be one of the most frequent genetic events observed in human cancers. PTEN dysfunction leads to tumorigenesis through unopposed survival signals mediated via activated protein kinase B (PKB), which may also be associated with hormone-independence. We therefore investigated the relationship between PTEN-PKB and receptor status in human breast cancer. Several molecular variables, including immunohistochemical staining for PTEN, PKB (phosphorylated on ser473), p53 and p21 were evaluated. The p53 gene was sequenced from exons 2-11. Seventy-eight participants in a randomised breast cancer trial served as the cohort for our study. Twenty-eight of 77 (36%) patients' tumours demonstrated absent or reduced PTEN expression; 17 of 78 (22%) tumours over-expressed P-PKB. A significant inverse relationship was observed between reduced PTEN and increased P-PKB expression. Reduced PTEN also correlated with reduced ER or PR expression. None of the molecular variables correlated with survival. ER and PR negative tumours, however, experienced a significantly inferior disease-free survival than other ER/PR status tumours. Immunohistochemical analyses of ER expression in mammary carcinomas arising in PTEN heterozygous knockout mice did not demonstrate a reduction in ER immunoreactivity, in comparison to wild-type mice. Our data demonstrate that the PTEN-PKB pathway is abnormal in approximately 1/3 of lymph node negative breast cancer. Dysregulated PTEN-PKB was also associated with reduced ER/PR expression, but this does not appear to be a simple direct causal relationship. These observations support the contention that dysregulation in PTEN-PKB contributes to disease progression and hormone resistance of human breast cancer.

Aged↗

PubMed2003

Limitation of conventional two dimensional radiation therapy planning in nasopharyngeal carcinoma.

PURPOSE: To assess the adequacy of coverage of gross tumor volume (GTV) with traditional two dimensional (2D) radiation therapy (RT) planning in patients with nasopharyngeal cancer (NPC). MATERIALS AND METHODS: The study comprised 94 of 179 patients treated with definitive RT between 1993 and 1997. The inclusion requirement was the availability of a digitally archived pretreatment magnetic resonance imaging. The digital images were used to record the precise location of the GTV in the sagittal plane. As a separate procedure, sagittal dose distributions for each treatment phase were created by digitizing the simulation field parameters into treatment planning software without knowledge of the GTV. The location of the GTV and dose distribution in the sagittal plane were superimposed on each other and GTV coverage by the 50, 90 and 95% isodose lines determined for each phase of treatment. RESULTS: The 1997 tumour node metastasis (TNM) stage distribution was: 7 (8%) stage I, 16 (16%) stage II, 30 (32%) stage III and 41 (44%) stage IV. Median follow-up was 4.4 years. Median primary dose was 66 Gy. The actuarial 5-year overall survival, disease free survival and local relapse free rates were 88, 54 and 66%, respectively. The GTV was covered by the 50, 90 and 95% isodose lines for all phases of the multiphase plan in only 53, 20 and 9% of patients, respectively. The GTV was more likely to be undercovered in the latter phases of the plan particularly in those patients with advanced T category. CONCLUSION: 2D RT planning has significant limitations in achieving adequate GTV coverage in NPC. We strongly recommend 3D planning using either conformal techniques of dose delivery or intensity modulated radiation therapy for the treatment of these patients.

Adolescent↗

PubMed2003

Loss of p16 expression has prognostic significance in human nasopharyngeal carcinoma.

PURPOSE: p16 is an important inhibitor of cell cycle progression; absence of p16 can thus result in increased cellular proliferation. In nasopharyngeal carcinoma (NPC), absence of p16 has been reported in association with presence of the EBV and pRb. We therefore examined p16, pRb, and EBV-encoded RNA (EBER) expression in biopsy specimens from 84 patients with newly diagnosed NPC, who were treated primarily with curative radiation therapy. Our objective was to determine whether there was a correlation between these parameters and clinical outcome in NPC. EXPERIMENTAL DESIGN: Sections were cut from archival formalin-fixed, paraffin-embedded tumor blocks from NPC patients. p16 and pRb expression were determined using polyclonal and monoclonal antibodies, respectively. The presence of EBV was determined by in situ hybridization for EBER. The percentage of positively staining tumor nuclei was scored for p16 or pRb immunoreactivity. Relative intensity and proportion of cells with EBER signals were also documented. RESULTS: p16 expression was reduced (</=5% positive immunoexpression) in 59 of 84 (70%) NPC samples; in contrast, pRb was observed in all (100%) tumors. EBER signals were detected in 67 of 83 (81%) NPC specimens. There was a weak correlation between EBER presence and loss of p16 (P = 0.1). Using a Cox regression model controlling for known prognostic parameters, such as age, weight loss, and tumor stage, complete absence of p16 expression (0%, i.e., no immunostaining identified throughout the specimen) was associated with an inferior overall survival rate (P = 0.022). In addition, EBER-positive NPC was strongly associated with improved overall survival (P = 0.005) as reported previously (Shi et al., Cancer, 94: 1997, 2002). CONCLUSION: These results provide the first evidence suggesting that inactivation of p16 appears to be a significant predictor for poor overall survival in NPC. Given that reduced p16 expression is observed in the majority of patients with NPC, this indicates that therapeutic strategies targeting the p16 pathway may be a biologically rational approach for NPC. The favorable prognostic value of EBER suggests that future clinical trials with NPC should consider stratifying for EBER status.

Adult↗

PubMed2003

Expression and prognostic significance of kit, protein kinase B, and mitogen-activated protein kinase in patients with small cell lung cancer.

PURPOSE: The Kit receptor has been proposed as a key molecular target for the treatment of small cell lung cancer (SCLC). Protein kinase B (PKB/Akt) and mitogen-activated protein kinase (MAPK) are intracellular kinases that regulate cell survival and proliferation and may play a role in Kit signal transduction. This study was designed to examine the expression and importance of Kit, PKB/Akt, and MAPK relative to standard clinical prognostic factors in SCLC. EXPERIMENTAL DESIGN: Kit, PKB/Akt, and MAPK expression was assessed by immunohistochemistry in SCLC biopsies. Clinical data were collected on tumor stage, weight loss, hematology, biochemistry, response to treatment, and survival. Univariate and multivariate analyses were performed to evaluate prognostic significance. RESULTS: Biopsies from 42 patients were evaluable, and significant Kit expression (>/=35% cells) was detected in 51% of the tumors, phosphorylated PKB/Akt was detected in 62% of the tumors, and phosphorylated MAPK was detected in 48% of the tumors. Neither Kit nor PKB/Akt expression predicted for survival. Only increased expression of cytoplasmic MAPK was prognostic for survival (median, 1 year for negative staining versus 1.8 years for positive staining; P = 0.0054). CONCLUSIONS: Kit, PKB/Akt, and MAPK are expressed in a high percentage of SCLCs, and our data suggest that MAPK is an independent positive predictive factor in this malignancy.

Adult↗

PubMed2002

Dealing with competing risks: testing covariates and calculating sample size.

It is universally agreed that Kaplan-Meier estimates overestimate the probability of the event of interest in the presence of competing risks. Kalbfleisch and Prentice recommend using the cumulative incidence as an estimate of the probability of an event of interest. However, there is no consensus on how to test the effect of a covariate in the presence of competing risks. Using simulations, this paper illustrates that the Cox proportional hazards model gives valid results when employed in testing the effect of a covariate on the hazard rate and when estimating the hazard ratio. A method to calculate the sample size for testing the effect of a covariate on outcome in the presence of competing risks is also provided.

Breast Neoplasms↗

PubMed2002

Expression of hypoxia-inducible factor-1alpha in cervical carcinomas: correlation with tumor oxygenation.

PURPOSE: To investigate the relations between hypoxia-inducible factor-1 (HIF-1), tumor oxygenation, and clinical correlates in patients with locally advanced carcinoma of the uterine cervix. METHODS AND MATERIALS: Biopsies from 42 patients with invasive cervical carcinoma and previous polarographic O2 measurements were assessed for the expression of HIF-1alpha using digitized microscopic imaging and analysis. RESULTS: The HIF-1alpha expression levels ranged from <0.1% to 10.7% of the total tumor area; the positive staining was localized exclusively to the nuclei. Three distinct arrangement patterns of HIF-1alpha-positive cells in relation to blood vessels were identified using spatial image mapping: (1) most HIF-1alpha-positive cells were located within the typical oxygen diffusion distance in tissue (< or =150 microm to the nearest blood vessel); (2) most HIF-1alpha-positive cells were located in the vicinity (< or =60 microm) of the blood vessels; and (3) no apparent spatial relationship was found between HIF-1alpha-positive cells and blood vessels. A statistically significant association was found between HIF-1alpha expression and tumor oxygenation (Spearman correlation coefficient = 0.4, p <0.01), as determined with the Eppendorf pO2 histograph. No correlation was found between the level of HIF-1alpha expression and patient outcome, using disease-free survival as the end point. CONCLUSION: Our results suggest that HIF-1alpha expression may represent a useful biologic marker for hypoxia in uterine cervical cancer.

Aged↗

PubMed2002

Molecular profiling of non-small cell lung cancer and correlation with disease-free survival.

Recent studies have suggested that information from gene expression profiles could be used to develop molecular classifications of cancer. We hypothesized that expression levels of specific genes in operative specimens could be correlated to recurrence risk in non-small cell lung cancer (NSCLC). We performed expression profiling using 19.2 K cDNA microarrays on tumor specimens from a total of 39 NSCLC patients with known clinical follow-up information. Statistical analysis and clustering approaches were used to determine patterns of gene expression segregating with clinical outcome. The results provide evidence that molecular subtyping of NSCLC can identify distinct profiles of gene expression correlating with disease-free survival.

Adult↗

PubMed2002

Assessment of coronary heart disease morbidity and mortality after radiation therapy for early breast cancer.

PURPOSE: To assess the risk of fatal and nonfatal myocardial infarction (MI) after breast-conserving surgery (BCS) and radiation therapy (RT) for left-sided breast cancer. PATIENTS AND METHODS: A hospital-based retrospective cohort linkage study of all breast cancer patients registered at the Princess Margaret Hospital (PMH), Toronto, Canada, between 1982 and 1988 who were treated with postlumpectomy RT was performed. Available identifiers for the study cohort were linked to two province-wide health files: the Canadian Institute for Health Information Hospitalization File and the Ontario Mortality Database. Admissions to hospital for MI and deaths attributable to MI were identified. The relevant original health records were abstracted to verify the diagnosis of MI according to diagnostic criteria used in the World Health Organization multinational monitoring of trends and determinants in cardiovascular disease (MONICA) project. We compared incidence of MI in the study cohort with the general population and incidence of MI after therapy for left- versus right-sided breast cancer. RESULTS: A cohort of 2,128 patients was identified. The median length of follow-up was 10.2 years. The incidence of MI in the study cohort was comparable to that in an age-matched general population of women in Ontario. There were 70 coronary events among 56 patients after breast irradiation. According to MONICA criteria, 53 and six events were characterized as definite and possible MIs, respectively. Eleven events did not satisfy MONICA criteria for MI. Twenty-six patients treated for left-sided and 23 patients treated for right-sided breast cancer experienced at least one definite or possible MI (log-rank test, P =.66). There were eight fatal MIs among the left-sided group and six among the right-sided group. There was no excess of other cardiac diseases among patients who received left-sided radiotherapy compared to the right-sided group. CONCLUSION: We have found no evidence for excess morbidity and mortality from coronary artery disease among women treated with RT to the left breast after BCS at 10.2 years of follow-up. Longer follow-up is required to confirm that excess cardiac disease has been completely avoided.

Adult↗

PubMed2002

Factors influencing risk of acute urinary retention after TRUS-guided permanent prostate seed implantation.

PURPOSE: To look for factors predictive of acute urinary retention (AUR) after permanent seed prostate brachytherapy. METHODS AND MATERIALS: From March 1999 to February 2001, 150 permanent seed prostate implants were performed at Princess Margaret Hospital (Stage T1c, n = 113; T2a, n = 37; mean prostate-specific antigen level 5.9 ng/mL, prescription dose 145 Gy per Task Group No. 43). alpha-Blockers were used routinely after implantation. Dosimetry was based on the 1-month postimplant CT scan. The International Prostate Symptom Score (IPSS) and catheterization were recorded at 1 month and 3 months and then every 3 months. The following variables were examined: age, baseline IPSS, prior androgen ablation, prostate transrectal ultrasound volume, number of seeds, D(90), V(100), V(200), and urethral dose. RESULTS: Twenty patients (13%) experienced AUR. No difference was seen in the mean D(90) (149 Gy vs. 152 Gy, p = 0.6), V(100) (90% vs. 91%, p = 0.6), V(200) (23% vs. 25% p = 0.4), IPSS (6.4 vs. 5.9, p = 0.8), or maximal urethral dose (204 Gy vs. 210 Gy, p = 0.5). The prostate volume was significantly larger in men with AUR (39.8 cm(3) vs. 34.3 cm(3), p = 0.003), and the mean number of seeds was higher (112 vs. 103, p = 0.006). Of the 20 patients experiencing AUR, 11 (55%) had received prior antiandrogen therapy to downsize their prostates vs. 35 (27%) of the 130 who did not have AUR (p = 0.02). Multivariate analysis showed prostate volume and prior hormone use to be independent predictors of AUR. CONCLUSIONS: Implant quality as determined by D(90), V(100), V(200), and urethral dose did not predict AUR. Prostate size was the major determinant of AUR. For any given prostate size, prior androgen ablation increased the risk of AUR. Men with larger prostates should be aware of the increased risk when contemplating brachytherapy.

Aged↗

PubMed2002

Radiotherapy alone in patients with advanced nasopharyngeal cancer: comparison with an intergroup study. Is combined modality treatment really necessary?

PURPOSE: To examine the outcome of radiotherapy (RT) alone in patients with advanced nasopharyngeal cancer (NPC) and to compare the results with those reported by the Intergroup study 0099 (IGS) comparing RT to combined modality therapy (CMT). MATERIALS AND METHODS: During the period 1985-1992, 198 NPC patients presenting without distant metastatic disease were treated for cure. Of these, 172 had stage III/IV (UICC 1987, 1992). Planned RT was 2 Gy/day fraction to 60-66 Gy to the primary tumor, with 50 and 60 Gy to the node negative and to palpable nodes, respectively. Outcomes included overall survival (OS) and disease-free survival (DFS), defined from the time of registration at our institution. RESULTS: The TNM categories and other prognostic factors were similar to the IGS, though 80% had stage IV compared to 91% in IGS. The 5 year OS and DFS for the 172 patients with stage III/IV disease were 62 and 48%, respectively, as compared to the IGS results of OS 37% and DFS 29% for RT alone, and OS 67% and DFS 58% for the CMT arm of IGS. When the distribution of adverse prognostic factors was balanced between both studies the comparative results were unchanged. CONCLUSIONS: The early results for RT alone of this single institution experience are superior to those of the IGS control arm (RT), while somewhat inferior to those reported in the chemo-radiotherapy arm. The surprisingly poor outcome of the IGS/RT control arm may have resulted by chance, suggesting the need for a confirmatory randomized trial to fully establish the role of combined chemotherapy and radiation, as used in the IGS.

Adolescent↗