Biomedical subjects

Aniko Szabo

Publications and source records attributed to Aniko Szabo.

14 recordsLinked to original sources

PubMed2026

MEK inhibitor-based genomically matched combinatorial targeted therapies in metastatic pancreatic adenocarcinoma with KRAS alterations.

INTRODUCTION: Pancreatic Ductal Adenocarcinoma (PDAC) is often caused by mutations in multiple genes including KRAS (activating the Ras-Raf-MEK-ERK pathway). This study evaluated the role of MEK inhibitor (MEKi)-based combinatorial targeted therapies in patients with PDAC. Methods. This is a retrospective/prospective observational, single institution study, including 29 patients with metastatic PDAC with KRAS alterations, treated with MEKi therapies between 2022-2024. RESULTS: Ten patients had KRAS G12R (34.5%), ten G12D (34.5%), and nine G12V (31%). Majority of patients received MEKi therapy as third-line and beyond (KRAS G12R/G12D/G12V 60%/50%/78%, respectively). Median overall survival from MEKi initiation for KRAS G12R/G12D/G12V was 8.2/5.1/4.7 months (P = 0.5), respectively, and median progression-free survival was 4.4/2.3/1.4 months (P = 0.11). Six (21%) patients discontinued at least one drug in the treatment combination due to toxicity. CONCLUSIONS: MEKi-based combinatorial therapies had modest disease control in patients with KRAS G12R, and minimal disease control in patients with KRAS G12D/V in the late-line setting.

KRAS↗

PubMed2006

Survival of men with clinically localized prostate cancer treated with prostatectomy, brachytherapy, or no definitive treatment: impact of age at diagnosis.

BACKGROUND: The optimal treatment for men with early stage prostate cancer remains undefined. Survival of such patients after surgery, brachytherapy, or no definitive therapy was investigated specifically to determine the impact of age at diagnosis. METHODS: In all, 60,290 men diagnosed with organ-confined, low and moderate grade prostate cancer between 1988 and 2002 were retrospectively identified from centers participating in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program. Prostate cancer-specific mortality (PCSM) and any-cause mortality (ACM) were determined. Outcomes for patients treated by brachytherapy, surgery, or receiving no definitive treatment were compared using the Wilcoxon test, stratified by T-stage and grade, and using multivariate analysis. RESULTS: The median follow-up time was 46 months (range, 0-189 months). For men under age 60 at diagnosis, PCSM at 10 years was 1.3%, 0.5%, and 3.7% for surgery, brachytherapy, and no definitive therapy, respectively. For men age 60 and older the PCSM was 3.8%, 5.3%, and 8.4%, respectively. On univariate and multivariate analysis, surgery and brachytherapy resulted in statistically equivalent PCSM and ACM, and both had a significantly lower PCSM and ACM versus no definitive therapy. CONCLUSIONS: A better survival was observed in men treated with a definitive therapy. The magnitude of the benefit on PCSM or ACM was similar for both definitive therapies irrespective of age.

Adenocarcinoma↗

PubMed2006

Progressive disease in chronic lymphocytic leukemia is correlated with the DNA methylation index.

The DNA methylation index (MI) is calculated as a percentage of methylated cytosines to cytosines. We established the DNA MI in 100 normal individuals ranging in age between 1 month and 94 years and found that the age-specific DNA MI can be calculated (4.00-0.0034 x age). We determined the DNA MI in 23 patients with CLL ranging from 47 to 90 years and compared the results with age-matched controls. Using Cox proportional hazard models for MI, adjusting for age and white blood cell count, only the DNA MI correlated with early clinical indications for systemic therapy (p=0.0038, HR=7.00, 95% CI: 1.90-26.20).

Adolescent↗

PubMed2006

The risk of secondary malignancies over 30 years after the treatment of non-Hodgkin lymphoma.

BACKGROUND: Survivors of non-Hodgkin lymphoma (NHL) are at increased risk for developing secondary malignancies. For the current study, the authors quantitated this risk in a group of NHL survivors over 30 years of follow-up. METHODS: Standardized incidence ratios (observed-to-expected [O/E] ratio) and absolute excess risk of secondary malignancies were assessed in 77,876 patients who were diagnosed with NHL between 1973 and 2001 from centers that participated in the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. RESULTS: There were 5638 patients who developed secondary malignancies, significantly more than the endemic rate (O/E, 1.14; P < .001). Overall, irradiated patients had a similar risk of secondary malignancies compared with unirradiated patients (relative risk, 1.04; 95% confidence interval, 0.98-1.10; P = .21). Irradiated patients had excess risk for sarcomas, breast cancers, and mesothelioma compared with unirradiated survivors (P < .05). Patients age <25 years at the time of their NHL diagnosis had the highest relative increased risk (no radiation: O/E, 2.1; P < .05; radiation: O/E, 4.51; P < .05). Overall, no statistical difference was observed for secondary cancer incidence between females and males (O/E, 1.12 vs. 1.15, respectively). Female survivors of NHL were less likely to develop breast cancer than the general population (O/E, 0.85; P < .05), but women age <25 years at the time of their NHL diagnosis were more likely to develop breast cancer (no radiation: O/E, 2.1; P < .05; radiation: O/E, 4.51; P < .05). CONCLUSIONS: The overall risk of secondary malignancies was increased for NHL survivors and varied according to age at NHL diagnosis, gender, and treatment.

Age of Onset↗

PubMed2006

Classification and risk stratification of invasive breast carcinomas using a real-time quantitative RT-PCR assay.

INTRODUCTION: Predicting the clinical course of breast cancer is often difficult because it is a diverse disease comprised of many biological subtypes. Gene expression profiling by microarray analysis has identified breast cancer signatures that are important for prognosis and treatment. In the current article, we use microarray analysis and a real-time quantitative reverse-transcription (qRT)-PCR assay to risk-stratify breast cancers based on biological 'intrinsic' subtypes and proliferation. METHODS: Gene sets were selected from microarray data to assess proliferation and to classify breast cancers into four different molecular subtypes, designated Luminal, Normal-like, HER2+/ER-, and Basal-like. One-hundred and twenty-three breast samples (117 invasive carcinomas, one fibroadenoma and five normal tissues) and three breast cancer cell lines were prospectively analyzed using a microarray (Agilent) and a qRT-PCR assay comprised of 53 genes. Biological subtypes were assigned from the microarray and qRT-PCR data by hierarchical clustering. A proliferation signature was used as a single meta-gene (log2 average of 14 genes) to predict outcome within the context of estrogen receptor status and biological 'intrinsic' subtype. RESULTS: We found that the qRT-PCR assay could determine the intrinsic subtype (93% concordance with microarray-based assignments) and that the intrinsic subtypes were predictive of outcome. The proliferation meta-gene provided additional prognostic information for patients with the Luminal subtype (P = 0.0012), and for patients with estrogen receptor-positive tumors (P = 3.4 x 10-6). High proliferation in the Luminal subtype conferred a 19-fold relative risk of relapse (confidence interval = 95%) compared with Luminal tumors with low proliferation. CONCLUSION: A real-time qRT-PCR assay can recapitulate microarray classifications of breast cancer and can risk-stratify patients using the intrinsic subtype and proliferation. The proliferation meta-gene offers an objective and quantitative measurement for grade and adds significant prognostic information to the biological subtypes.

Breast Neoplasms↗

PubMed2006

Frequency and effect of adjuvant radiation therapy among women with stage I endometrial adenocarcinoma.

CONTEXT: The benefit of adjuvant radiation therapy (RT) in stage I endometrial adenocarcinoma remains controversial despite several phase 3 trials. OBJECTIVE: To evaluate the frequency and effect of adjuvant RT on overall and relative survival within a large US population database. DESIGN, SETTING, AND POPULATION: A retrospective analysis that used data from the Surveillance, Epidemiology, and End Results program of the US National Cancer Institute from January 1, 1988, to December 31, 2001. A total of 21,249 patients with American Joint Committee on Cancer stage IA-C node-negative endometrial adenocarcinoma comprised the study population. MAIN OUTCOME MEASURES: Overall survival curves were constructed using Kaplan-Meier method and compared via stratified log-rank test within T stage/grade combinations, adjusted for age. Relative survival was performed to assess the effects of age, race, stage, grade, whether nodes were examined, and whether adjuvant RT was administered. RESULTS: Of 21,249 women, 4080 received adjuvant RT (19.2%) and 17,169 did not receive adjuvant RT (80.8%). The mean age at diagnosis was 63.2 years (range, 14-99 years). Adjuvant RT significantly improved overall survival for patients with stage IC/grade 1 (P<.001) and stage IC/grades 3 and 4 (P<.001). Cox proportional hazards regression analysis revealed a statistically detectable association of adjuvant RT with improved relative survival in patients with stage IC/grade 1 and stage IC/grades 3 and 4 (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.31-0.63; P<.001; and HR, 0.72; 95% CI, 0.57-0.92; P = .009; respectively). A separate analysis of those patients with a surgical lymph node examination at the time of total abdominal hysterectomy and bilateral salpingo-oophorectomy revealed similar estimates (HR, 0.59; 95% CI, 0.39-0.90; P = .01; and HR, 0.73; 95% CI, 0.55-0.96; P = .02; respectively). CONCLUSIONS: As the largest reported population analysis to date of adjuvant RT in early stage endometrial adenocarcinoma, our study reveals a statistically significant association between improved overall and relative survival and adjuvant RT in stage IC disease (grades 1 and 3-4). Future work is needed to continue to delineate clinical and biological factors, which can guide treatment decisions and account for disparities in outcome between varied subsets of patients.

Adenocarcinoma↗

PubMed2006

Video capsule endoscopy compared with standard endoscopy for the evaluation of small-bowel polyps in persons with familial adenomatous polyposis (with video).

BACKGROUND: Video capsule endoscopy (VCE) may be useful for surveillance of small-bowel polyps in patients with familial adenomatous polyposis (FAP). OBJECTIVE: To compare VCE to standard endoscopy for diagnosing small-bowel polyps in a defined segment of small bowel (proximal to a tattoo) and the entire examined small bowel. DESIGN: Prospective. SETTING: Single tertiary referral center. PATIENTS: Participants with FAP (n = 32). The majority were selected for their high number of proximal small-bowel polyps and prior endoscopic tattoo placement in the proximal small bowel. INTERVENTIONS: VCE (interpreted by 2 readers), push enteroscopy (PE), and lower endoscopy (LE) to count and measure small-bowel polyps. RESULTS: In the defined segment, VCE detected a median of 10.0 (interquartile range [IQR], 5.0-19.0) and 9.0 (IQR, 6.0-16.0) polyps for each reader compared with a median of 41.0 (IQR, 19.0-64.0) polyps on PE (P = .002). Agreement between the 2 methods was fair (kappa = 0.34, 0.36). Agreement between VCE and PE was poor to fair (kappa = 0.10, 0.22) for estimating the size of the largest polyp and poor (kappa = -0.20, -0.27) for detecting large polyps (> or =1 cm). In the entire examined small bowel, VCE diagnosed a median of 38.0 (IQR, 10.5-71.5) and 54.0 (IQR, 13.0-100.0) polyps for each reader compared with a median of 123.0 (IQR, 38.5-183.0) for combination endoscopy (PE and LE) (P < .001). Agreement between the 2 methods was fair to moderate (kappa = 0.21, 0.56). LIMITATIONS: Participants selected for high polyp burden, and results may not be applicable to all patients with FAP. CONCLUSIONS: VCE underestimates the number of small-bowel polyps in persons with FAP and does not reliably detect large polyps.

Adenomatous Polyposis Coli↗

PubMed2005

A conscious mouse model of gastric ileus using clinically relevant endpoints.

BACKGROUND: Gastric ileus is an unsolved clinical problem and current treatment is limited to supportive measures. Models of ileus using anesthetized animals, muscle strips or isolated smooth muscle cells do not adequately reproduce the clinical situation. Thus, previous studies using these techniques have not led to a clear understanding of the pathophysiology of ileus. The feasibility of using food intake and fecal output as simple, clinically relevant endpoints for monitoring ileus in a conscious mouse model was evaluated by assessing the severity and time course of various insults known to cause ileus. METHODS: Delayed food intake and fecal output associated with ileus was monitored after intraperitoneal injection of endotoxin, laparotomy with bowel manipulation, thermal injury or cerulein induced acute pancreatitis. The correlation of decreased food intake after endotoxin injection with gastric ileus was validated by measuring gastric emptying. The effect of endotoxin on general activity level and feeding behavior was also determined. Small bowel transit was measured using a phenol red marker. RESULTS: Each insult resulted in a transient and comparable decrease in food intake and fecal output consistent with the clinical picture of ileus. The endpoints were highly sensitive to small changes in low doses of endotoxin, the extent of bowel manipulation, and cerulein dose. The delay in food intake directly correlated with delayed gastric emptying. Changes in general activity and feeding behavior were insufficient to explain decreased food intake. Intestinal transit remained unchanged at the times measured. CONCLUSION: Food intake and fecal output are sensitive markers of gastric dysfunction in four experimental models of ileus. In the mouse, delayed gastric emptying appears to be the major cause of the anorexic effect associated with ileus. Gastric dysfunction is more important than small bowel dysfunction in this model. Recovery of stomach function appears to be simultaneous to colonic recovery.

Animals↗

PubMed2004

Discriminate gene lists derived from cDNA microarray profiles of limited samples permit distinguishing mesenchymal neoplasia ex vivo.

BACKGROUND: Mesenchymal neoplasia comprises a heterogeneous group of tumors with over 200 benign neoplasms and 100 sarcomas. Currently, tumors are classified using histologic and immunocytologic characteristics, with diagnostic error rates reported as high as 40% of cases. As a feasibility study, our goal was to generate a preliminary discriminatory gene list for selected mesenchymal tumors, including sarcomas. This technique may enable an eventual molecular classification schema based on expression profiles that can complement current clinical and pathologic diagnostic procedures in mesenchymal tumors. METHODS: cDNA microarray analyses were preformed on connective tissue tumors obtained at time of surgical resection or biopsy. Messenger RNA (mRNA) from four general tumor classes was competitively hybridized against a human dermal fibroblast cell line comparator and the resulting gene expression profiles processed by ANOVA and linear discriminate analysis. RESULTS: The tissue classification involved 18 patients with malignant peripheral nerve sheath tumors, giant cell containing tumors, benign spindle cell lesions, or Ewing's family of tumors. Lymph nodes from two patients served comparative purposes. Twenty-five differentially regulated genes considered most variable among the five tissue classes were identified. The tissues were segregated into five classes by linear discriminate analysis. CONCLUSIONS: Linear discriminate analysis of cDNA gene expression profiles partitioned mesenchymal tumor classes, even when constrained by limited sample sizes.

Analysis of Variance↗

PubMed2004

Statistical modeling for selecting housekeeper genes.

There is a need for statistical methods to identify genes that have minimal variation in expression across a variety of experimental conditions. These 'housekeeper' genes are widely employed as controls for quantification of test genes using gel analysis and real-time RT-PCR. Using real-time quantitative RT-PCR, we analyzed 80 primary breast tumors for variation in expression of six putative housekeeper genes (MRPL19 (mitochondrial ribosomal protein L19), PSMC4 (proteasome (prosome, macropain) 26S subunit, ATPase, 4), SF3A1 (splicing factor 3a, subunit 1, 120 kDa), PUM1 (pumilio homolog 1 (Drosophila)), ACTB (actin, beta) and GAPD (glyceraldehyde-3-phosphate dehydrogenase)). We present appropriate models for selecting the best housekeepers to normalize quantitative data within a given tissue type (for example, breast cancer) and across different types of tissue samples.

ATPases Associated with Diverse Cellular Activitie↗

PubMed2004

Correlation of transdermal iontophoretic phenylalanine and mannitol transport: test of the internal standard concept under DC iontophoresis and constant resistance AC iontophoresis conditions.

The purpose of this study was to test the feasibility of using an internal standard approach to predict the transdermal flux of phenylalanine (Phe) across human epidermal membrane (HEM) in vitro during iontophoresis of constant direct current (DC), constant skin resistance alternating current (AC) with DC offset (AC-plus-DC), symmetric constant resistance AC (AC-only), and constant current DC with the application of a polyelectrolyte. Under the constant current DC and AC-plus-DC conditions, a linear relationship between the permeation of Phe and that of mannitol was observed with a slope close to unity. The ratios of the Phe permeability coefficients to those of mannitol during iontophoresis with different HEM samples were essentially constant with significantly smaller inter-sample and intra-sample variabilities than those of the raw Phe permeability coefficient data. This demonstrates that mannitol is a good internal standard for predicting the transdermal iontophoretic flux of Phe under these two conditions. On the other hand, the correlations of the permeability coefficients of Phe and mannitol under the AC-only iontophoresis and iontophoresis with the polyelectrolyte are poorer than those observed during DC and AC-plus-DC iontophoresis. The poor correlations are believed to be related to Phe being a zwitterion and its anionic form in HEM. Previously, iontophoretic transport of glucose has been demonstrated to be essentially the same as that of mannitol. The good correlations between Phe and mannitol transport across HEM during DC and AC-plus-DC iontophoresis in the present study therefore suggest that glucose and its extraction can be used as the internal standard for iontophoretic Phe monitoring.

Administration, Cutaneous↗

PubMed2003

Multivariate exploratory tools for microarray data analysis.

The ultimate success of microarray technology in basic and applied biological sciences depends critically on the development of statistical methods for gene expression data analysis. The most widely used tests for differential expression of genes are essentially univariate. Such tests disregard the multidimensional structure of microarray data. Multivariate methods are needed to utilize the information hidden in gene interactions and hence to provide more powerful and biologically meaningful methods for finding subsets of differentially expressed genes. The objective of this paper is to develop methods of multidimensional search for biologically significant genes, considering expression signals as mutually dependent random variables. To attain these ends, we consider the utility of a pertinent distance between random vectors and its empirical counterpart constructed from gene expression data. The distance furnishes exploratory procedures aimed at finding a target subset of differentially expressed genes. To determine the size of the target subset, we resort to successive elimination of smaller subsets resulting from each step of a random search algorithm based on maximization of the proposed distance. Different stopping rules associated with this procedure are evaluated. The usefulness of the proposed approach is illustrated with an application to the analysis of two sets of gene expression data.

Algorithms↗

PubMed2002

Estimating an oncogenetic tree when false negatives and positives are present.

Human solid tumors are believed to be caused by a sequence of genetic abnormalities arising in the tumor cells. The understanding of these sequences is extremely important for improving cancer treatment. Models for the occurrence of the abnormalities include linear structure and a recently proposed tree-based structure. In this paper we extend the pure oncogenetic tree model by introducing false positive and false negative observations. We state conditions sufficient for the reconstruction of the generating tree. As an example we analyze a comparative genomic hybridization data set and show that addition of the error model significantly improves the ability of the model to describe the data.

Adenocarcinoma, Clear Cell↗

PubMed2002

Identification of gene expression profiles that segregate patients with childhood leukemia.

To identify genes whose expression correlated with biological features of childhood leukemia, we prospectively analyzed the expression profiles of 4608 genes using cDNA microarrays in 51 freshly processed bone marrow samples from children with acute leukemia, over a 24-month period, at a single institution. Two supervised methods of analysis were used to identify the 20 best discriminating genes between the following cohorts: acute myelogenous leukemia (AML) versus acute lymphoblastic leukemia (ALL); B-lineage versus T-lineage ALL; newly diagnosed B-lineage standard-risk versus high-risk ALL; and B-lineage leukemia harboring the TEL-AML 1 fusion versus patients without a molecularly characterized translocation. These methods identified overlapping sets of genes that segregated patients within described subgroups. Cross-validation demonstrated that the majority of patients could be correctly classified based on these genes alone, and hierarchical clustering grouped patients with similar clinical and biological disease features. The potential for select genes to discriminate patients was validated using real-time PCR in samples that were analyzed by microarray profiling and in other uniformly processed leukemic marrow samples. As expected, microarray technology can successfully segregate patients defined by traditional measures such as immunophenotype and cytogenetic alterations. However, among specific subgroups, this preliminary analysis also suggests that microarrays can identify unanticipated similarities and diversity in individual patients and thus may be useful in augmenting risk-group stratification in the future.

Child↗