Biomedical subjects

Masha Kocherginsky

Publications and source records attributed to Masha Kocherginsky.

15 recordsLinked to original sources

PubMed2006

Dexamethasone decreases xenograft response to Paclitaxel through inhibition of tumor cell apoptosis.

Glucocorticoid receptor (GR) activation has recently been implicated in the initiation of anti-apoptotic signaling pathways in epithelial cell lines grown in culture. However, the evidence that GR-mediated inhibition of tumor cell apoptosis is the mechanism that diminishes chemotherapy effectiveness in vivo is limited. We therefore initiated a breast cancer xenograft study to examine whether or not pretreatment with glucocorticoids (GCs) decreases tumor response to chemotherapy by inhibiting tumor cell apoptosis. Here we report a significant decrease in paclitaxel-induced apoptosis in xenografts from mice pretreated with dexamethasone (Dex). A significant difference in apoptosis in xenografts from Dex/paclitaxel versus paclitaxel treated animals was seen eight days following initiation of chemotherapy. Nine days later, mice treated with Dex/paclitaxel had significantly larger tumors compared with those that received paclitaxel alone (p = 0.032). Dex pretreatment did not significantly affect tumor cell proliferation rates. Taken together, these results demonstrate that systemic Dex administration results in significantly reduced breast cancer xenograft apoptosis in the context of chemotherapy treatment. We also found that systemic Dex treatment results in upregulation of the anti-apoptotic gene MKP-1 and downregulation of pro-apoptotic Bid and TRAIL genes in tumor cells six hours following Dex treatment. These in vivo gene expression changes correlated with significant inhibition of chemotherapy-induced apoptosis. Interestingly, the decreased chemotherapeutic response of Dex-pretreated tumors persisted for several weeks following treatment. These data suggest that GR-mediated transcriptional regulation of pro- and anti-apoptotic genes contributes to the mechanism through which GCs decrease paclitaxel-induced apoptosis.

Animals↗

PubMed2006

High survival and organ function rates after primary chemoradiotherapy for intermediate-stage squamous cell carcinoma of the head and neck treated in a multicenter phase II trial.

PURPOSE: Patients with intermediate-stage squamous cell carcinoma of the head and neck traditionally have been treated with initial surgical resection followed by radiotherapy (RT) alone or chemoradiotherapy. A previous study in this patient population reported a 91% locoregional control rate and 65% overall survival (OS) rate at 5 years, with chemoradiotherapy used as primary treatment. This study was undertaken to assess whether shortening treatment duration with hyperfractionated RT would be feasible and improve locoregional control, organ preservation, and progression-free survival. METHODS: Eligible patients with stage II or III disease received fluorouracil, hydroxyurea, and RT given twice daily on a week-on/week-off schedule. Quality-of-life scores were measured using three validated indexes. RESULTS: All 53 patients enrolled are included in the analysis, with a median follow-up of 42 months (range, 5 to 98 months). Grade 3 or 4 in-field mucositis was observed in 77% and 9%, respectively. No patients required surgical salvage at the primary tumor site (pathological complete response rate, 100%). The 3-year progression-free and OS rates are 67% and 78%, respectively. The 3-year disease-specific mortality rate is 7%. At the time of analysis, 87% of surviving patients do not require enteral feeding support. Quality-of-life and performance assessment indicated that, although acute treatment toxicities were severe, most patients returned to pretreatment function by 12 months. CONCLUSION: Concurrent chemoradiotherapy with hyperfractionated RT is feasible in this patient population and yields high local control and cure rates. Compared with our historical control using once-daily fractionation, hyperfractionation is accompanied by increased acute in-field toxicity.

Adult↗

PubMed2006

Relationship of adolescent polycystic ovary syndrome to parental metabolic syndrome.

CONTEXT: We determined the relationship of metabolic syndrome (MBS) to polycystic ovary syndrome (PCOS). OBJECTIVE: We tested the hypothesis that parental MBS is related to the PCOS phenotype in their offspring. DESIGN/SETTING: We phenotyped for MBS and PCOS in our General Clinical Research Center. PATIENTS: Girls with PCOS, 12-19 yr old (n = 36, including one pair of siblings), and their parents (35 mothers, 19 fathers) were recruited from the Pediatric Endocrinology Clinic. Healthy girls, 12-19 yr old (n = 21), were recruited as a reference population. INTERVENTIONS: We measured anthropometrics, blood pressure, fasting lipids and androgens, oral glucose tolerance, and ultrasonographically determined polycystic ovary status. MAIN OUTCOME MEASURES: MBS in parents, and PCOS features in mothers, were related to the presence of PCOS features in probands. RESULTS: Fathers had strikingly high prevalence of excess adiposity (94% were obese or overweight) and MBS (79%). Premenopausal mothers more commonly had MBS (36%) than features of PCOS (< or =22%). Polycystic ovaries in proband offspring of premenopausal mothers were associated with maternal polycystic ovaries only in a minority of cases. Proband polycystic ovary status was completely concordant to fathers' MBS status (P = 0.008), but not their own or their mothers' MBS status, in families whose premenopausal mothers lacked polycystic ovaries. Proband prevalence of MBS was 27.8%, 3-fold greater than expected for obesity status. CONCLUSION: Familial factors related to paternal MBS seem to be fundamental to the pathogenesis of PCOS.

Adolescent↗

PubMed2006

Gene expression profiles in acute myeloid leukemia with common translocations using SAGE.

Identification of the specific cytogenetic abnormality is one of the critical steps for classification of acute myeloblastic leukemia (AML) which influences the selection of appropriate therapy and provides information about disease prognosis. However at present, the genetic complexity of AML is only partially understood. To obtain a comprehensive, unbiased, quantitative measure, we performed serial analysis of gene expression (SAGE) on CD15(+) myeloid progenitor cells from 22 AML patients who had four of the most common translocations, namely t(8;21), t(15;17), t(9;11), and inv(16). The quantitative data provide clear evidence that the major change in all these translocation-carrying leukemias is a decrease in expression of the majority of transcripts compared with normal CD15(+) cells. From a total of 1,247,535 SAGE tags, we identified 2,604 transcripts whose expression was significantly altered in these leukemias compared with normal myeloid progenitor cells. The gene ontology of the 1,110 transcripts that matched known genes revealed that each translocation had a uniquely altered profile in various functional categories including regulation of transcription, cell cycle, protein synthesis, and apoptosis. Our global analysis of gene expression of common translocations in AML can focus attention on the function of the genes with altered expression for future biological studies as well as highlight genes/pathways for more specifically targeted therapy.

Apoptosis↗

PubMed2006

Performance status and comorbidity predict transplant-related mortality after allogeneic hematopoietic cell transplantation.

Comorbidity measurements have recently been used to improve estimation of tolerance to allogeneic hematopoietic cell transplantation (HCT). We sought to determine the independent effect of comorbidity and performance status on HCT outcome and to devise a simple risk classification system for transplant-related mortality. We analyzed 105 consecutively enrolled patients who underwent HCT and received reduced intensity conditioning with fludarabine, melphalan, and alemtuzumab. Comorbid conditions were tabulated using 2 scales, the Charlson Comorbidity Index (CCI) and the Kaplan-Feinstein Scale (KFS). Comorbid conditions were found in 47% of patients by the KFS and in 27% by the CCI (P < .001). Using the Eastern Cooperative Oncology Group Performance Status (PS) scale, 34% had a PS score >0 (range, 0-2). A simple scale combining the KFS and PS enabled separation of high- from low-risk patients, with 6-month cumulative incidences 50% and 15%, respectively for transplant-related mortality (P = .001) and enhanced prognostic power over the CCI alone (P = .018). Prospective studies evaluating more comprehensive functional and comorbidity measurements are warranted.

Adult↗

PubMed2006

Order of patient entry influences outcome for metastatic renal cell cancer after non-myeloablative allogeneic stem cell transplantation.

Allogeneic transplantation for renal cell carcinoma has shown encouraging preliminary results. We reviewed the published literature to evaluate the impact of patient selection. Most studies did not include information on prognostic factors. We used patient entry rank within individual studies as a novel surrogate for patient selection, motivated by our own experience of an apparent impact of entry rank. One hundred patients were identified from nine studies. Twenty-six per cent of patients demonstrated either a partial or complete response. Median overall survival was 12.3 months. Grade 2-4 acute graft-versus-host disease correlated with an increased likelihood of response (odds ratio: 5.4, 95% confidence interval: 1.6-18.1, P = 0.006) but not survival. Earlier patient entry rank on each trial was associated with a higher probability of response (P = 0.004) and superior survival (P = 0.004). Patient entry rank served as a powerful prognostic factor, suggesting bias in patient selection that evolved over the course of the study. Further studies are warranted to determine the influence of order of patient entry in other early clinical trial settings.

Acute Disease↗

PubMed2006

Variability in mesothelioma tumor response classification.

OBJECTIVE: The objective of our study was to evaluate observer variability in the measurement of temporal change in mesothelioma tumor thickness and in the resulting tumor response classification from CT scans. In addition, the performance of a semiautomated measurement method was evaluated. MATERIALS AND METHODS: Four observers individually used an interface that displayed two serial CT scans from the same patient to measure mesothelioma tumor thickness on the follow-up CT scans of 22 patients based on baseline scan measurements. During one session, observers acquired measurements on the follow-up scans based on written reports of baseline scan measurements; in another session, baseline scan measurements were superimposed on the baseline scan for direct visual comparison. Follow-up scan measurements also were obtained from a semiautomated method. Measurement variability and tumor response classification concordance were evaluated for manual measurements acquired in both modes and for semiautomated measurements. RESULTS: Although only a small increase in tumor response classification concordance rate was obtained with the visual approach (84.8%) relative to the more standard written-report approach (82.6%), the actual measurements acquired by observers were statistically significantly different between the two approaches (p = 0.03). Both the semiautomated measurements and the resulting tumor response classifications were consistent with manual measurements. CONCLUSION: The presentation of baseline scan tumor measurements affects measurements acquired on follow-up scans and could influence tumor response classification. The potential utility of semiautomated tumor thickness measurements was shown in the context of measuring tumor response.

Adult↗

PubMed2005

Suppression of metastatic colonization by the context-dependent activation of the c-Jun NH2-terminal kinase kinases JNKK1/MKK4 and MKK7.

Advances in clinical, translational, and basic studies of metastasis have identified molecular changes associated with specific facets of the metastatic process. Studies of metastasis suppressor gene function are providing a critical mechanistic link between signaling cascades and biological outcomes. We have previously identified c-Jun NH2-terminal kinase (JNK) kinase 1/mitogen-activated protein kinase (MAPK) kinase 4 (JNKK1/MKK4) as a prostate cancer metastasis suppressor gene. The JNKK1/MKK4 protein is a dual-specificity kinase that has been shown to phosphorylate and activate the JNK and p38 MAPKs in response to a variety of extracellular stimuli. In this current study, we show that the kinase activity of JNKK1/MKK4 is required for suppression of overt metastases and is sufficient to prolong animal survival in the AT6.1 model of spontaneous metastasis. Ectopic expression of the JNK-specific kinase MKK7 suppresses the formation of overt metastases, whereas the p38-specific kinase MKK6 has no effect. In vivo studies show that both JNKK1/MKK4 and MKK7 suppress the formation of overt metastases by inhibiting the ability of disseminated cells to colonize the lung (secondary site). Finally, we show that JNKK1/MKK4 and MKK7 from disseminated tumor cells are active in the lung but not in the primary tumor, providing a biochemical explanation for why their expression specifically suppressed metastasis while exerting no effect on the primary tumor. Taken together, these studies contribute to a mechanistic understanding of the context-dependent function of metastasis regulatory proteins.

Animals↗

PubMed2005

Coordinate expression of the PI3-kinase downstream effectors serum and glucocorticoid-induced kinase (SGK-1) and Akt-1 in human breast cancer.

The phosphatidylinositol 3-kinase (PI3-K) signalling pathway has been implicated in breast cancer development and resistance to therapy. Akt-1 and serum and glucocorticoid-induced kinase-1 (SGK-1) are homologous kinases which are important downstream effectors of PI3-K signalling. We sought to determine the individual expression patterns of these two kinases in order to better understand their respective roles in PI3-K signalling in breast cancer. To this end, we examined the expression of both p-Akt-1 and SGK-1 in 40 breast cancers. p-Akt-1 expression was seen in 58% of tumour samples, while SGK-1 overexpression was detected in 48%. Interestingly, a highly significant association was found between the expression of p-Akt-1 and SGK-1 (P=0.002), suggesting complementary physiological functions in PI3-K signalling. This finding is consistent with recent genetic data from Caenorhabditis elegans suggesting that both SGK-1 and Akt-1 are required for signalling downstream of insulin receptor activation.

Adult↗

PubMed2005

Progression of Barrett's metaplasia to adenocarcinoma is associated with the suppression of the transcriptional programs of epidermal differentiation.

We did expressional profiling on 24 paired samples of normal esophageal epithelium, Barrett's metaplasia, and esophageal adenocarcinomas. Matching tissue samples representing the three different histologic types were obtained from each patient undergoing esophagectomy for adenocarcinoma. Our analysis compared the molecular changes accompanying the transformation of normal squamous epithelium with Barrett's esophagus and adenocarcinoma in individual patients rather than in a random cohort. We tested the hypothesis that expressional profiling may reveal gene sets that can be used as molecular markers of progression from normal esophageal epithelium to Barrett's esophagus and adenocarcinoma. Expressional profiling was done using U133A GeneChip (Affymetrix), which represent approximately two thirds of the human genome. The final selection of 214 genes permitted the discrimination of differential gene expression of normal esophageal squamous epithelium, Barrett's esophagus, and adenocarcinoma using two-dimensional hierarchical clustering of selected genes. These data indicate that transformation of Barrett's esophagus to adenocarcinoma is associated with suppression of the genes involved in epidermal differentiation, including genes in 1q21 loci and corresponding to the epidermal differentiation complex. Correlation analysis of genes concordantly expressed in Barrett's esophagus and adenocarcinoma revealed 21 genes that represent potential genetic markers of disease progression and pharmacologic targets for treatment intervention. PCR analysis of genes selected based on DNA array experiments revealed that estimation of the ratios of GATA6 to SPRR3 allows discrimination among normal esophageal epithelium, Barrett's dysplasia, and adenocarcinoma.

Adenocarcinoma↗

PubMed2005

Evaluation of semiautomated measurements of mesothelioma tumor thickness on CT scans.

RATIONALE AND OBJECTIVES: To evaluate the clinical acceptability of semiautomated methods for the measurement of mesothelioma tumor thickness in computed tomography (CT) scans. MATERIALS AND METHODS: A computer interface was developed to allow the acquisition of semiautomated mesothelioma tumor thickness measurements, which require the manual selection of a point along the outer margin of the tumor in a CT section. After application of an automated lung segmentation method, the computer automatically identifies a corresponding point along the inner margin of the tumor (as represented by the lung boundary), constructs a line segment between the manually selected outer tumor margin point and the computer-determined inner tumor margin point, and computes tumor thickness as the length of this line segment. Three radiologists and oncologists independently reviewed line segments representing the semiautomated measurements generated by three different algorithms at 134 measurement sites in the CT scans of 22 mesothelioma patients. The observers either accepted a measurement line segment or modified it through the interface. Differences between the initial semiautomated measurements and the measurements as modified by the observers were analyzed. RESULTS: The frequency with which observers accepted the semiautomated measurements without modification was as high as 86%. Of all measurements across all observers and methods (1,206 measurements), 89% were changed by 2 mm or less. CONCLUSION: We have developed semiautomated methods to measure mesothelioma tumor thickness. The potential of these methods has been demonstrated through an observer study. We expect these methods to become important tools for the efficient quantification of tumor extent.

Adult↗

PubMed2005

Abnormal placentation: twenty-year analysis.

OBJECTIVE: This study was undertaken to determine whether the rate of abnormal placentation is increasing in conjunction with the cesarean rate and to evaluate incidence, risk factors, and outcomes. STUDY DESIGN: Cases from 1982-2002 were identified by histopathologic or strong clinical criteria. Risk factors were assessed in a matched case-control study, and analyzed using conditional logistic regression models. RESULTS: There were 64,359 deliveries, with cesarean rates increasing from 12.5% (1982) to 23.5% (2002). The overall incidence of placenta accreta was 1 in 533. Significant risk factors for placenta accreta in our final analysis included advancing maternal age (odds ratio [OR] 1.13, 95% CI 1.089-1.194, P < .0001), 2 or more cesarean deliveries (OR 8.6, 95% CI 3.536-21.078, P < .0001), and previa (OR 51.4, 95% CI: 10.646-248.390, P < .0001). CONCLUSION: The rate of placenta accreta increased in conjunction with cesarean deliveries; the most important risk factors were previous cesarean delivery, previa, and advanced maternal age.

Case-Control Studies↗

PubMed2004

Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan.

PURPOSE: Severe toxicity is commonly observed in cancer patients receiving irinotecan. UDP-glucuronosyltransferase 1A1 (UGT1A1) catalyzes the glucuronidation of the active metabolite SN-38. This study prospectively evaluated the association between the prevalence of severe toxicity and UGT1A1 genetic variation. PATIENTS AND METHODS: Sixty-six cancer patients with advanced disease refractory to other treatments received irinotecan 350 mg/m(2) every 3 weeks. Toxicity and pharmacokinetic data were measured during cycle 1. UGT1A1 variants (-3279G>T, -3156G>A, promoter TA indel, 211G>A, 686C>A) were genotyped. RESULTS: The prevalence of grade 4 neutropenia was 9.5%. Grade 4 neutropenia was much more common in patients with the TA indel 7/7 genotype (3 of 6 patients; 50%) compared with 6/7 (3 of 24 patients; 12.5%) and 6/6 (0 of 29 patients; 0%) (P =.001). The TA indel genotype was significantly associated with the absolute neutrophil count nadir (7/7 < 6/7 < 6/6, P =.02). The relative risk of grade 4 neutropenia was 9.3 (95% CI, 2.4 to 36.4) for the 7/7 patients versus the rest of the patients. Pretreatment total bilirubin levels (mean +/- standard deviation) were significantly higher in patients with grade 4 neutropenia (0.83 +/- 0.08 mg/dL) compared to those without grade 4 neutropenia (0.47 +/- 0.03 mg/dL; P <.001). The -3156G>A variant seemed to distinguish different phenotypes of total bilirubin within the TA indel genotypes. The -3156 genotype and the SN-38 area under the concentration versus time curve were significant predictors of ln(absolute neutrophil count nadir; r(2) = 0.51). CONCLUSION: UGT1A1 genotype and total bilirubin levels are strongly associated with severe neutropenia, and could be used to identify cancer patients predisposed to the severe toxicity of irinotecan. The hypothesis that the -3156G>A variant is a better predictor of UGT1A1 status than the previously reported TA indel requires further testing.

Antineoplastic Agents, Phytogenic↗

PubMed2004

Measurement of mesothelioma on thoracic CT scans: a comparison of manual and computer-assisted techniques.

Our purpose in this study was to evaluate the variability of manual mesothelioma tumor thickness measurements in computed tomography (CT) scans and to assess the relative performance of six computerized measurement algorithms. The CT scans of 22 patients with malignant pleural mesothelioma were collected. In each scan, an initial observer identified up to three sites in each of three CT sections at which tumor thickness measurements were to be made. At each site, five observers manually measured tumor thickness through a computer interface. Three observers repeated these measurements during three separate sessions. Inter- and intra-observer variability in the manual measurement of tumor thickness was assessed. Six automated measurement algorithms were developed based on the geometric relationship between a specified measurement site and the automatically extracted lung regions. Computer-generated measurements were compared with manual measurements. The tumor thickness measurements of different observers were highly correlated (r > or = 0.99); however, the 95% limits of agreement for relative inter-observer difference spanned a range of 30%. Tumor thickness measurements generated by the computer algorithms also correlated highly with the average of observer measurements (r > or = 0.93). We have developed computerized techniques for the measurement of mesothelioma tumor thickness in CT scans. These techniques achieved varying levels of agreement with measurements made by human observers.

Adult↗

PubMed2004

Analysis of prostate-specific antigen rebound interval in patients with prostate cancer receiving hormonal therapy and external-beam radiation therapy.

The goal of this investigation is to characterize the clinical significance of the rebound interval (RI) after neoadjuvant short-course hormonal therapy (HT) and external-beam radiation therapy (RT), during which the prostate-specific antigen (PSA) may rise because of hormone withdrawal prior to full RT efficacy. The charts of 257 consecutive patients with localized prostate cancer who received short-course neoadjuvant HT and RT were reviewed. A piecewise-linear log PSA versus time curve was generated for each patient and averaged over the population to facilitate identification of the RI start and end dates. Existing definitions of biochemical failure--American Society for Therapeutic Radiology and Oncology (ASTRO), Vancouver and Houston--were applied, as were these same definitions modified to exclude failures during the RI. Sensitivity and specificity were analyzed, using no evidence (by digital rectal examination or radiology) of disease failure as the gold standard. The 5-year biochemical survival with different failure definitions were ASTRO versus ASTRO-modified: 81.6% versus 86.7%; Houston versus Houston-modified: 71.4% versus 76.7%; and Vancouver versus Vancouver-modified: 83.5% versus 85.6%. The sensitivity and specificity comparisons were ASTRO versus ASTRO-modified 58.3% versus 33.3%; 91.4% versus 94.3%, Vancouver versus Vancouver-modified: 50% versus 50%; 92.7% versus 95.5%, Houston versus Houston-modified: 100% versus 66.7%; 90.6% versus 92.2%. The RI after HT and RT is likely not merely an artifact of hormone withdrawal but is correlated with ultimate clinical outcome. Excluding RI failures can marginally improve specificity but may possibly have an unacceptable risk of lowering sensitivity. Further work is needed to design and validate definitions of failure, which account for the RI.

Aged↗