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ABSTRACT: We planned to determine the relationship between angiogenesis and p53 mutational status in advanced-stage epithelial ovarian cancer. Using 190 tumor samples from patients with Stage III and IV ovarian cancer we performed p53 sequencing, immunohistochemistry, and CD31 microvessel density (MVD) determination. MVD was elevated in tumors with p53 null mutations compared to p53 missense mutation or no mutation. Disease recurrence was increased with higher MVD in both unadjusted and adjusted analyses. In adjusted analysis, p53 null mutation was associated with increased recurrence and worse overall survival.Worse overall survival and increased recurrence risk were also associated with the combination of CD31 MVD values > 25 vessels/HPF and any p53 mutation. P53 mutation status and MVD may have prognostic significance in patients with advanced-stage ovarian cancer. Tumors with p53 null mutations are likely to be more vascular, contributing to decreased survival and increased recurrence probability.
Cancer letters 12/2012; · 4.86 Impact Factor
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Andrew Schrepf,
Lauren Clevenger,
Desire Christensen,
Koen Degeest,
David Bender,
Amina Ahmed, Michael J Goodheart,
Laila Dahmoush,
Frank Penedo,
Joseph A Lucci,
Parvin Ganjei-Azar,
Luis Mendez,
Kristian Markon,
David M Lubaroff,
Premal H Thaker,
George M Slavich,
Anil K Sood,
Susan K Lutgendorf
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ABSTRACT: Elevations in the pro-inflammatory cytokine interleukin-6 (IL-6) and alterations in the anti-inflammatory hormone cortisol have been reported in a variety of cancers. IL-6 has prognostic significance in ovarian cancer and cortisol has been associated with fatigue, disability, and vegetative depression in ovarian cancer patients prior to surgery. Ovarian cancer patients undergoing primary treatment completed psychological self-report measures and collected salivary cortisol and plasma IL-6 prior to surgery, at 6months, and at 1year. Patients included in this study had completed chemotherapy and had no evidence of disease recurrence. At 6months, patients showed significant reductions in nocturnal cortisol secretion, plasma IL-6, and a more normalized diurnal cortisol rhythm, changes that were maintained at 1year. The reductions in IL-6 and nocturnal cortisol were associated with declines in self-reported fatigue, vegetative depression, and disability. These findings suggest that primary treatment for ovarian cancer reduces the inflammatory response. Moreover, patients who have not developed recurrent disease by 1year appear to maintain more normalized levels of cortisol and IL-6. Improvement in fatigue and vegetative depression is associated with the normalization of IL-6 and cortisol, a pattern which may be relevant for improvements in overall quality of life for ovarian cancer patients.
Brain Behavior and Immunity 08/2012; · 4.72 Impact Factor
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Susan K Lutgendorf,
Koen De Geest,
David Bender,
Amina Ahmed, Michael J Goodheart,
Laila Dahmoush,
M Bridget Zimmerman,
Frank J Penedo,
Joseph A Lucci,
Parvin Ganjei-Azar,
Premal H Thaker,
Luis Mendez,
David M Lubaroff,
George M Slavich,
Steven W Cole,
Anil K Sood
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ABSTRACT: Previous research has demonstrated relationships of social support with disease-related biomarkers in patients with ovarian cancer. However, the clinical relevance of these findings to patient outcomes has not been established. This prospective study examined how social support relates to long-term survival among consecutive patients with ovarian cancer. We focused on two types of social support: social attachment, a type of emotional social support reflecting connections with others, and instrumental social support reflecting the availability of tangible assistance.
Patients were prospectively recruited during a presurgical clinic visit and completed surveys before surgery. One hundred sixty-eight patients with histologically confirmed epithelial ovarian cancer were observed from the date of surgery until death or December 2010. Clinical information was obtained from medical records.
In a Cox regression model, adjusting for disease stage, grade, histology, residual disease, and age, greater social attachment was associated with a lower likelihood of death (hazard ratio [HR], 0.87; 95% CI, 0.77 to 0.98; P = .018). The median survival time for patients with low social attachment categorized on a median split of 15 was 3.35 years (95% CI, 2.56 to 4.15 years). In contrast, by study completion, 59% of patients with high social attachment were still alive after 4.70 years. No significant association was found between instrumental social support and survival, even after adjustment for covariates.
Social attachment is associated with a survival advantage for patients with ovarian cancer. Clinical implications include the importance of screening for deficits in the social environment and consideration of support activities during adjuvant treatment.
Journal of Clinical Oncology 07/2012; 30(23):2885-90. · 18.37 Impact Factor
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ABSTRACT: Despite the questions and barriers, the incorporation of molecular therapy into treatment regimens in endometrial cancer is an exciting area of investigation with the potential to improve outcomes. Outside of the development of a reliable screening test for endometrial cancer, converting the disease to a chronic state and improving progression-free survival is our best hope to reverse the concerning trend of decreasing 5-year survival for this disease.
Obstetrics and Gynecology Clinics of North America 06/2012; 39(2):255-68. · 1.70 Impact Factor
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Lauren Clevenger,
Andrew Schrepf,
Desire Christensen,
Koen Degeest,
David Bender,
Amina Ahmed, Michael J Goodheart,
Frank Penedo,
David M Lubaroff,
Anil K Sood,
Susan K Lutgendorf
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ABSTRACT: Pro-inflammatory cytokines, such as interleukin-6 (IL-6), have been implicated in the underlying processes contributing to sleep regulation and fatigue. Despite evidence for sleep difficulties, fatigue, and elevations in IL-6 among women with ovarian cancer, the association between these symptoms and IL-6 has not been investigated. To address this knowledge gap, we examined relationships between sleep disturbance, fatigue, and plasma IL-6 in 136 women with ovarian cancer prior to surgery. These relationships were also examined in 63 of these women who were disease-free and not receiving chemotherapy one year post-diagnosis. At both time-points, higher levels of IL-6 were significantly associated with sleep disturbances (p<0.05), controlling for potentially confounding biological and psychosocial covariates. Higher IL-6 was significantly associated with fatigue prior to surgery (p<0.05); however, when sleep disturbance was included in the model, the relationship was no longer significant. IL-6 was not significantly associated with fatigue at one year. Changes in sleep over time were significantly associated with percent change in IL-6 from pre-surgery to one year, adjusting for covariates (p<0.05). These findings support a direct association of IL-6 with sleep disturbances in this population, whereas the relationship between IL-6 and fatigue prior to surgery may be mediated by poor sleep. As this study is the first to examine cytokine contributions to sleep and fatigue in ovarian cancer, further research is warranted to clarify the role of biological correlates of sleep and fatigue in this population.
Brain Behavior and Immunity 04/2012; 26(7):1037-44. · 4.72 Impact Factor
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ABSTRACT: Uterine carcinosarcoma (UCS) is a rare but very aggressive cancer of the female reproductive tract with an extremely poor prognosis. With the goal of understanding the role of microRNA (miRNA) dysregulation in these tumors, we profiled the expression of 667 human miRNAs in a panel of eight UCS patients and five benign control primary tissue samples. These expression profiles revealed two important characteristics of UCS. First, compared with the two most common uterine cancers, endometrial endometrioid adenocarcinoma and endometrial serous adenocarcinoma, UCS samples display a virtually unique pattern of miRNA dysregulation with an overlap of only 5% among the three tumor types. In addition, nearly one-third of the miRNAs significantly dysregulated in UCS tissues compared with benign endometrium (32 of 114) lie in a single small (250-kb) imprinted region of chromosome 14q32. These data suggest that the presence of such a global, region-specific disruption substantially contributes to the unique histology and poor outcome of this type of cancer.
Experimental and therapeutic medicine 04/2012; 3(4):677-682.
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ABSTRACT: A simple meta-analysis of the eight surveys of microRNA (miRNA) expression in endometrial cancers reveals a panel of sixteen miRNAs that are significantly over-expressed (n = 15) or under-expressed (n = 1) in at least three surveys. Examination of these miRNAs indicates that they target mRNAs involved in a number of basic cellular processes including the crucial epithelial to mesenchymal transition (EMT) and hypoxia response. The central role played by these miRNAs is reinforced by the demonstration that they are all members of some of the most ancient of all animal miRNA families. This suggests that they may be part of a core set of miRNAs dysregulated as part of the carcinogenic cellular reprogramming process.
Proceedings in Obstetrics and Gynecology. 08/2011; 2.
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ABSTRACT: microRNAs (miRNAs) control a multitude of pathways in human cancers. Differential expression of miRNAs among different histological types of tumors within the same type of tissue offers insight into the mechanism of pathogenesis and may help to direct treatment to improve prognosis. We assessed expression of 667 miRNAs in endometrial endometrioid and serous adenocarcinomas using RNA extracted from benign endometrium as well as from primary endometrial tumors. Quantitative miRNA profiling of endometrial adenocarcinomas revealed four overlapping groups of significantly overexpressed and underexpressed miRNAs. The first group was composed of 20 miRNAs significantly dysregulated in both adenocarcinoma types compared with benign endometrium, two groups were composed of miRNAs significantly dysregulated in either endometrioid adenocarcinomas or in serous adenocarcinomas compared with benign endometrium, and the fourth group was composed of 17 miRNAs that significantly distinguished between endometrioid adenocarcinomas and serous adenocarcinomas themselves. Validation of the expression levels of the selected miRNAs was carried out in a second panel composed of ten endometrioid and five serous tumors. Experimentally validated mRNA targets of these dysregulated miRNAs were identified using published sources, whereas TargetScan was used to predict targets of miRNAs in the first and fourth profile groups. These validated and potential miRNA target lists were filtered using published lists of genes displaying significant overexpression or underexpression in endometrial cancers compared to benign endometrium. Our results revealed a number of dysregulated miRNAs that are commonly found in endometrial (and other) cancers as well as several dysregulated miRNAs not previously identified in endometrial cancers. Understanding these differences may permit the development of both prognostic and diagnostic biomarkers.
Oncology Reports 07/2011; 26(4):995-1002. · 1.84 Impact Factor
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ABSTRACT: The aim of this study was to identify prognostic factors and markers that influence clinical outcomes in patients with primary fallopian tube carcinoma at a single tertiary health care center. These prognostic factors may be of clinical importance and can subsequently be included in future clinical trials.
A retrospective review of our Tumor Registry and Gynecologic Oncology database was conducted to include any patients with a diagnosis of fallopian tube carcinoma between the years 1994 and 2005. We identified clinicopathological data to evaluate factors important in recurrence, disease-specific and overall survival. Kaplan-Meier curves were generated, and log-rank tests were used to evaluate survival differences.
Thirty-six patients had a diagnosis with primary fallopian tube carcinoma at a median age of 69 years. Patients most frequently presented with abdominal pain (19%) and a palpable mass (14%). The most common histological subtype was papillary serous adenocarcinoma in 56% of cases. Stage III disease (39%) and poorly differentiated tumors (81%) were most common. The median follow-up was 39.6 months. The 5-year cancer-specific survival was 42%, and the overall survival rate was 34%. Factors important in disease-free survival were International Federation of Gynecology and Obstetrics stage, tumor laterality, and serum CA-125, whereas International Federation of Gynecology and Obstetrics stage, serum CA-125, and residual disease were prognostic factors for overall survival. The most common locations of recurrence were pelvis and abdomen (63%) as opposed to distant sites. Factors associated with recurrence were stage, tumor laterality, and serum CA-125.
Fallopian tube malignancies are rare. We have identified factors associated with recurrence, disease specific survival, and overall survival that could be further examined and included in larger clinical trials involving this uncommon malignancy.
International Journal of Gynecological Cancer 06/2011; 21(7):1232-40. · 1.65 Impact Factor
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Susan K Lutgendorf,
Elizabeth Mullen-Houser,
Daniel Russell,
Koen Degeest,
Geraldine Jacobson,
Laura Hart,
David Bender,
Barrie Anderson,
Thomas E Buekers, Michael J Goodheart,
Michael H Antoni,
Anil K Sood,
David M Lubaroff
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ABSTRACT: Patients receiving chemoradiation for cervical cancer are at risk for distress, chemoradiation-related side-effects, and immunosuppression. This prospective randomized clinical trial examined effects of a complementary therapy, Healing Touch (HT), versus relaxation training (RT) and usual care (UC) for (1) supporting cellular immunity, (2) improving mood and quality of life (QOL), and (3) reducing treatment-associated toxicities and treatment delay in cervical cancer patients receiving chemoradiation. Sixty women with stages IB1 to IVA cervical cancer were randomly assigned to receive UC or 4 ×/weekly individual sessions of either HT or RT immediately following radiation during their 6-week chemoradiation treatment. Patients completed psychosocial assessments and blood sampling before chemoradiation at baseline, weeks 4 and 6. Multilevel regression analyses using orthogonal contrasts tested for differences between treatment conditions over time. HT patients had a minimal decrease in natural killer cell cytotoxicity (NKCC) over the course of treatment whereas NKCC of RT and UC patients declined sharply during chemoradiation (group by time interaction: p = 0.018). HT patients showed greater decreases in two different indicators of depressed mood (CES-D depressed mood subscale and POMS depression scale) compared to RT and UC (group by time interactions: p<0.05). No between group differences were observed in QOL, treatment delay, or clinically-rated toxicities. HT may benefit cervical cancer patients by moderating effects of chemoradiation on depressed mood and cellular immunity. Effects of HT on toxicities, treatment delay, QOL, and fatigue were not observed. Long-term clinical implications of findings are not known.
Brain Behavior and Immunity 11/2010; 24(8):1231-40. · 4.72 Impact Factor
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ABSTRACT: Intestinal lymphangiectasia is an obstruction of the lymphatic system. We report on a patient with mesenteric adenopathy and an elevated CA125 level, which were suspicious for peritoneal carcinoma. Further evaluation and bowel resection identified intestinal lymphangiectasia. This disease should be considered in patients with mesenteric adenopathy and a small bowel mass.
American journal of obstetrics and gynecology 10/2010; 203(4):e9-e11. · 3.28 Impact Factor
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ABSTRACT: The purpose of this study was to determine whether thromboembolic events (TE) in cervical cancer patients are associated with survival by comparing the survival of patients with and without thromboembolic events over a seven year period.
Utilizing a retrospective chart review we identified patients with any diagnosis of a TE, associated risk factors for TE development and overall survival. We also collected clinico-pathological data including stage, histology, height, weight, smoking history, radiation and chemotherapy treatment data and the temporal relationship of the development of TE to the time of cancer diagnosis. Data sources included the University of Iowa Hospitals and Clinics (UIHC) Tumor Registry and the UIHC Gynecologic Oncology Tumor Data Base as well as a search of UIHC medical record data bases using ICD-9 codes to initially identify all patients diagnosed with cervical carcinoma.
In this study, the incidence of TE in cervical cancer patients was 11.7%. There was a clear and significant difference in survival between patients with and without TE. We identified an association between TE and stage, chemotherapy, brachytherapy, and radiation therapy.
The major findings of our study are a significant incidence of thromboembolism in patients with cervical cancer, and a significant decrease in survival in patients who experience thromboembolism at presentation or during treatment. Deaths in these patients were overwhelmingly related to progressive cancer rather than the TE itself, suggesting that this adverse prognostic event may be related to aggressive tumor biology.
Gynecologic Oncology 03/2009; 113(2):240-4. · 3.89 Impact Factor
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ABSTRACT: Multiple angiogenic factors may influence tumor progression and metastasis. Several are modified by the p53 gene. We sought to identify molecular markers for high-risk stage I epithelial ovarian cancers.
Seventy-seven consecutive stage I epithelial ovarian cancers were evaluated for p53, CD31 microvessel density, thrombospondin-1, vascular endothelial growth factor (VEGF), p21 immunohistochemical staining, and p53 gene mutations. Molecular marker impact upon disease-specific survival, disease recurrence, and distant recurrence was evaluated with Cox regression.
There were 12 deaths from disease. Twelve of the 77 tumors contained p53 mutations-10 missense and 3 null (one tumor had two mutations). Fesddration Internationale des Gynaecologistes et Obstetristes substage (IA/IB versus IC; P < 0.001) and VEGF staining (P = 0.02) were significant in bivariate models with relationship to disease-specific survival. Stage (P = 0.0004), grade (P = 0.008), histology (P = 0.0025), p53 dysfunction (positive stain and/or mutation; P = 0.048), and microvessel density (P = 0.04) were significant in bivariate models with relationship to time to recurrence. In multivariate analyses among stage IC patients, failure to receive chemotherapy and microvessel density were associated with disease-specific survival, time to recurrence, and time to distant recurrence with hazard ratios of 4.8 to 44.1.
The p53-dependent molecular markers of angiogenesis are of limited utility in developing a clinical strategy for postoperative management of stage I ovarian carcinoma. Microvessel density impacts survival and metastasis for high-risk stage IC disease. Adjuvant chemotherapy is necessary, but not sufficient, for cure of high-risk stage I epithelial ovarian cancers.
Clinical Cancer Research 05/2005; 11(10):3733-42. · 7.74 Impact Factor
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ABSTRACT: Determine the incidence of and risk factors for thromboembolic events (TE) in patients treated with definitive chemoradiation for cervical cancer at our institution.
A retrospective chart review was performed of all patients with a diagnosis of invasive carcinoma of the cervix (FIGO Stage IB-IVA) treated with definitive chemoradiation at University of Iowa Hospitals and Clinics (UIHC) from July 2002 to December 2003. Forty-eight patients met these criteria. All but one patient received 45 Gy to the pelvis followed by brachytherapy, IMRT, or conformal boost. One patient received 39.6 Gy to the pelvis. Cisplatin chemotherapy, 40 mg/m squared, was given weekly for 6 weeks. Data were collected for FIGO stage, age, body mass index (BMI), and smoking history. TE were confirmed by Doppler ultrasound or pulmonary imaging. Log-rank tests were used to examine the association between time to TE and the variables FIGO stage and smoking status. The association between time to TE and the continuous variables age and BMI was examined with Cox proportional hazards regression. All tests were two-sided and carried out to the 5% level of significance using the SAS statistical software package.
Minimum follow-up was 8 months. Eight patients (16.7%) developed a TE. The associations were not statistically significant for stage (P = 0.72), smoking status (P = 0.72), age (P = 0.63) or BMI (P = 0.86). Risk factors were similar in both groups. Data review suggests that the entire group had risk factors for TE.
We noted a high incidence of TE (16.7%) in patients treated at UIHC with chemoradiation for invasive cervical cancer. We did not find a statistical association between age, stage, smoking history, or BMI and risk of TE in this group. Patients with and without TE had multiple risk factors for TE.
Gynecologic Oncology 03/2005; 96(2):470-4. · 3.89 Impact Factor
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ABSTRACT: hMLH1, the human MutL homologue, has been linked to microsatellite instability (MSI) in gastrointestinal tumors. However, to the authors' knowledge, the role of hMLH1, the other mismatch repair genes (MMR), and MSI in ovarian carcinoma has not been well defined. The purpose of the current study was to determine the relation between MSI of ovarian carcinoma and MMR gene expression, hMLH1 and hMSH2 hypermethylation, and hMLH1 and hMSH2 null mutations.
hMLH1 mRNA was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) and amplification of cDNA using a housekeeping gene (glycerol 3-phosphate dehydrogenase) as a control for mRNA quality and quantity. Methylation-specific PCR (MS-PCR) was used to correlate methylation of the hMLH1 and hMSH2 CpG islands with mRNA expression status. Similar techniques were used to evaluate the concomitant expression of five other MMR: hMSH2, hMSH3, hMSH6, PMS1, and PMS2. Microsatellite instability was studied using the National Cancer Institute consensus markers (D2S123, D5S346, D17S250, BAT25, and BAT26) and NM23 as described previously.
One hundred twenty-five primary tumors were analyzed. High-frequency MSI (MSI-H) was found in 21 tumors (16.8%). hMLH1 mRNA was absent in 10 of these 21 tumors (47.6%). In each case, coordinated hypermethylation of both regions A and C of the promoter was identified. Microsatellite stable and low-frequency MSI tumors all were found to express not only hMLH1 but the other MMR genes as well (P < 0.001). Absence of expression of hMSH2 and the four other MMRs occurred in tumors with absent hMLH1 mRNA expression because of CpG island hypermethylation. No absence of expression of hMSH2, hMSH3, hMSH6, PMS1, or PMS2 was found to occur in tumors expressing hMLH1. None of the 11 MSI-H tumors without promoter hypermethylation demonstrated a null mutation in hMLH1 or hMSH2.
A molecular mechanism to explain > 50% of the MSI-H phenotype in ovarian carcinoma cases was demonstrated. MSI-H may occur because of MMR defects, especially hMLH1 promoter hypermethylation. Additional mechanisms are required to explain the balance between the cases of MSI-H as well as the phenomenon of MSI-L tumors.
Cancer 11/2003; 98(10):2199-206. · 4.77 Impact Factor
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ABSTRACT: Although survival with a p53 missense mutation is highly variable, p53-null mutation is an independent adverse prognostic factor for advanced stage ovarian cancer. By evaluating ovarian cancer survival based upon a structure function analysis of the p53 protein, we tested the hypothesis that not all missense mutations are equivalent.
The p53 gene was sequenced from 267 consecutive ovarian cancers. The effect of individual missense mutations on p53 structure was analyzed using the International Agency for Research on Cancer p53 Mutational Database, which specifies the effects of p53 mutations on p53 core domain structure. Mutations in the p53 core domain were classified as either explained or not explained in structural or functional terms by their predicted effects on protein folding, protein-DNA contacts, or mutation in highly conserved residues. Null mutations were classified by their mechanism of origin.
Mutations were sequenced from 125 tumors. Effects of 62 of the 82 missense mutations (76%) could be explained by alterations in the p53 protein. Twenty-three (28%) of the explained mutations occurred in highly conserved regions of the p53 core protein. Twenty-two nonsense point mutations and 21 frameshift null mutations were sequenced. Survival was independent of missense mutation type and mechanism of null mutation.
The hypothesis that not all missense mutations are equivalent is, therefore, rejected. Furthermore, p53 core domain structural alteration secondary to missense point mutation is not functionally equivalent to a p53-null mutation. The poor prognosis associated with p53-null mutation is independent of the mutation mechanism.
Clinical Cancer Research 10/2003; 9(11):4139-44. · 7.74 Impact Factor
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ABSTRACT: Tumor microvessel density, measured by CD31 immunohistochemistry, correlates with survival in patients with ovarian cancer. CA 125 is secreted by most ovarian cancers, and we have previously shown that the rate of decline of CA 125 is also predictive of ovarian cancer survival. Because increased tumor vascularity may allow metastases on one hand, while facilitating the delivery of chemotherapy on the other, we investigated the relationship of tumor microvessel density to preoperative CA 125, residual disease, and the initial response to treatment.
FIGO stage, grade, age, residual disease, and CD31 microvessel density count were correlated with consecutive patients (n = 202) diagnosed with epithelial ovarian cancer who met entry criteria. The relationship of CD31 staining to preoperative CA 125, and the rate of decline in CA 125 (slope) as a measure of initial response to therapy, was also evaluated based on complete CA 125 data. Spearman correlation and the Wilcoxon rank sum test were used for bivariate analyses. Linear and logistic regression was used for multivariate analysis.
There were 21 stage I, 14 stage II, 125 stage III, and 42 stage IV patients diagnosed with epithelial ovarian cancer included in the study. More than half (N = 126) of the patients were optimally cytoreduced. Elevated microvessel density was associated with advanced stage of disease (P = 0.0453), grade (P = 0.0002), and an increased amount of residual disease (P = 0.0144). CA 125 values were higher in patients with residual disease versus patients without residual disease (P = 0.0357), and the decline in the CA 125 (slope) was less steep in patients without residual disease versus patients with residual disease (P = 0.0003). However, the initial response to chemotherapy was unrelated to the microvessel density count as measured by CD31 antibody staining (P = 0.7911). In multivariate analyses, CD31 counts remained significant in relationship to grade. Nonideal slopes, indicating decreased response, were associated with increasing age (P = 0.0008) and residual disease (P = 0.0035).
Elevated ovarian cancer microvessel density count is related to advanced stage and grade of disease, and compromised potential for cytoreduction. Residual disease is associated with higher CA 125 levels and faster CA 125 decline rates. The rate of decline of CA 125 during the initial response to treatment cannot be predicted based on CD31 counts, confirming a complex relationship between tumor vascularity, metastasis, and response to treatment.
Gynecologic Oncology 10/2003; 90(3):566-71. · 3.89 Impact Factor
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ABSTRACT: p21 is a direct p53 response gene. Although several studies have correlated p21 and p53 expression, only one has evaluated p21 expression as a function of sequenced p53 gene mutation. We hypothesize that such an analysis may be useful in prognosticating outcome for individuals diagnosed with epithelial ovarian cancer.
DNA from the primary ovarian cancers of 267 patients was studied. p53 mutations were directly sequenced. Two percent or greater nuclear staining with WAF1/CIP1 monoclonal antibody was determined by a hazard ratio analysis to constitute positive p21 expression.
Positive p21 nuclear staining occurred more frequently in p53 wild-type ovarian tumors than tumors found to have a p53 mutation (P = 0.001). Positive p21 staining conferred an overall survival advantage (P = 0.02). p21 expression in cancers with p53 missense mutations was not prognostic but did show a strong trend toward significance in the wild-type p53 subset (P = 0.056). Surprisingly, positive p21 staining reflected compromised survival for individuals with p53-null ovarian cancers (P = 0.005). The mean expression level for p21-positive stains in the wild-type group was greater than in null p53 cancers (23 versus 11%; P = 0.001). A Cox multivariable analysis revealed p21 to be a strong independent prognostic factor in p53-null ovarian cancer (P = 0.02).
p21 expression is closely related to sequenced p53 mutations. This is the first study of positive p21 staining as an independent poor prognostic factor in p53-null ovarian cancer. A dual role for p21 activity, dependent on levels of expression, appears to explain these paradoxical results and is consistent with a complex model for regulation of p21.
Clinical Cancer Research 04/2003; 9(3):1028-32. · 7.74 Impact Factor
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ABSTRACT: The objective of this study was to investigate the relationship between microvessel density, as measured by CD31 staining, and histopathologic factors as well as p53 tumor suppressor gene mutation in ovarian cancer.
Ovarian cancers (n = 77) were analyzed for p53 gene mutations and CD31 immunohistochemical expression. Histopathologic and mutational data were related to CD31 staining utilizing the Mantel correlation statistic. The microvessel density was scored by averaging counts from three high-power (200x) fields. Survival was based upon maximizing the hazard ratio.
The mean microvessel density counts based on CD31 staining (vessels/HPF) for each FIGO stage and mutation type are as follows: Stage I (10.2), Stage II (10.7), Stage III (13.8), Stage IV (22.0), wild-type p53 (9.3), missense p53 mutation (14.4), and null p53 mutation (23.1). There was a significant correlation between microvessel density count and FIGO stage (P = 0.026), grade (P = 0.04), and p53 mutation type (P = 0.02). Median survival was more than doubled (6.4 vs 2.9 years; P = 0.009) for tumors with microvessel density counts less than or equal to 14 vessels/HPF.
These data are consistent with the hypothesis that ovarian cancer p53 mutation functions to directly influence angiogenesis, which in turn compromises disease-specific survival. It also suggests validity to targeting p53 alterations with gene replacement as well as the use of antiangiogenesis agents as novel molecular-based therapeutics for ovarian cancer.
Gynecologic Oncology 08/2002; 86(1):85-90. · 3.89 Impact Factor
