Karl Podratz - Academia.edu (original) (raw)

Papers by Karl Podratz

Research paper thumbnail of Abstract 3477: Discovery and validation of methylation markers for early detection of endometrial cancer

Research paper thumbnail of Activity of lapatinib a novel HER2 and EGFR dual kinase inhibitor in human endometrial cancer cells

British journal of cancer, Jan 25, 2008

In this study, we explore the therapeutic potential of lapatinib a selective inhibitor of both th... more In this study, we explore the therapeutic potential of lapatinib a selective inhibitor of both the EGFR and HER2 tyrosine kinases for the treatment of endometrial cancer. The effect of lapatinib on tumour cell growth and receptor activation was studied in a panel of human endometrial cancer cell lines. Candidate molecular markers predicting sensitivity were assessed by baseline gene expression profiling, ELISA, and western blot analyses. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions between chemotherapeutic drugs and lapatinib. Concentration-dependent anti-proliferative effects of lapatinib were seen in all endometrial cancer cell lines tested, but varied significantly between individual cell lines (IC(50) range: 0.052-10.9 micromol). HER2 overexpression or increased expression of EGFR was significantly associated with in vitro sensitivity (P=0.024 or 0.011, respectively). Lapatinib exerts growth inhibition in a PTEN-independent ...

Research paper thumbnail of Microarray analysis on gene regulation by estrogen, progesterone and tamoxifen in human endometrial stromal cells

International journal of molecular sciences, 2015

Epithelial stromal cells represent a major cellular component of human uterine endometrium that i... more Epithelial stromal cells represent a major cellular component of human uterine endometrium that is subject to tight hormonal regulation. Through cell-cell contacts and/or paracrine mechanisms, stromal cells play a significant role in the malignant transformation of epithelial cells. We isolated stromal cells from normal human endometrium and investigated the morphological and transcriptional changes induced by estrogen, progesterone and tamoxifen. We demonstrated that stromal cells express appreciable levels of estrogen and progesterone receptors and undergo different morphological changes upon hormonal stimulation. Microarray analysis indicated that both estrogen and progesterone induced dramatic alterations in a variety of genes associated with cell structure, transcription, cell cycle, and signaling. However, divergent patterns of changes, and in some genes opposite effects, were observed for the two hormones. A large number of genes are identified as novel targets for hormonal r...

Research paper thumbnail of HER2 gene amplification and EGFR expression in a large cohort of surgically staged patients with nonendometrioid (type II) endometrial cancer

British journal of cancer, Jan 13, 2009

Type II endometrial cancers (uterine serous papillary and clear cell histologies) represent rare ... more Type II endometrial cancers (uterine serous papillary and clear cell histologies) represent rare but highly aggressive variants of endometrial cancer (EC). HER2 and EGFR may be differentially expressed in type II EC. Here, we evaluate the clinical role of HER2 and EGFR in a large cohort of surgically staged patients with type II (nonendometrioid) EC and compare the findings with those seen in a representative cohort of type I (endometrioid) EC. In this study HER2 gene amplification was studied by fluorescence in situ hybridisation (FISH) and EGFR expression by immunohistochemistry. Tissue microarrays were constructed from 279 patients with EC (145 patients with type I and 134 patients with type II EC). All patients were completely surgically staged and long-term clinical follow up was available for 258 patients. The rate of HER2 gene amplification was significantly higher in type II EC compared with type I EC (17 vs 1%, P<0.001). HER2 gene amplification was detected in 17 and 16%...

Research paper thumbnail of Pathophysiology and palliation of inoperable bowel obstruction in patients with ovarian cancer

The journal of supportive oncology

Malignant bowel obstruction is the cause of death in the majority of women who die of ovarian can... more Malignant bowel obstruction is the cause of death in the majority of women who die of ovarian cancer. Some patients are considered acceptable surgical candidates for relief of the obstruction. For many patients, however, lack of such surgical options has spawned a broad range of medical interventions, including palliative strategies to target pain and nausea and vomiting. This review discusses the general approach to patients with ovarian cancer and inoperable malignant bowel obstruction, with an emphasis on such palliative strategies.

Research paper thumbnail of Radical pelvic resection and intraoperative radiation therapy for recurrent endometrial cancer: Technique and analysis of outcomes

Gynecologic Oncology, 2006

Objective.To describe the technique and assess outcomes and morbidity following radical resection... more Objective.To describe the technique and assess outcomes and morbidity following radical resection combined with intraoperative electron radiation therapy (IOERT) in patients with recurrent endometrial cancer.

Research paper thumbnail of Diaphragm resection for ovarian cancer: technique and short-term complications

Gynecologic Oncology, 2004

Objective.Diaphragm resection (DR) is occasionally necessary to achieve optimal cytoreductive sur... more Objective.Diaphragm resection (DR) is occasionally necessary to achieve optimal cytoreductive surgery in ovarian carcinoma (OC). In a recent survey of the SGO membership, bulky diaphragm disease was one of the most common justifications for suboptimal debulking (Gynecol. Oncol. 82 (2001) 489). The aim of this study was to assess postoperative complications of DR in OC.

Research paper thumbnail of Pancreaticoduodenectomy in optimal primary cytoreduction of epithelial ovarian cancer: A case report and review of the literature

Gynecologic Oncology Reports, 2014

•Aggressive multi-organ resection of epithelial ovarian cancer (EOC) at the time of primary cytor... more •Aggressive multi-organ resection of epithelial ovarian cancer (EOC) at the time of primary cytoreduction improves patient survival.•We describe pancreaticoduodenectomy (Whipple procedure) as an efficacious tool for optimal cytoreduction in bulky upper abdominal EOC.

Research paper thumbnail of Long-term follow-up of women with ovarian cancer after positive second-look laparotomy

Gynecologic Oncology, 2003

ObjectivePrevious reports indicate that cytoreduction and salvage therapy with P32 or whole abdom... more ObjectivePrevious reports indicate that cytoreduction and salvage therapy with P32 or whole abdominal radiation may improve survival in patients with positive findings at second-look laparotomy (SLL). The aim of this investigation was to determine whether these findings held true with extended follow-up and a larger patient cohort.

Research paper thumbnail of Human Epithelial Ovarian Cancer Allelotype

To determine which chromosomesand chromosomalregions contain putativetumor suppressorgenes import... more To determine which chromosomesand chromosomalregions contain putativetumor suppressorgenes importantfor humanepithelialovarian cancer,we performedloss of heterozygosity(LOH)studies on 37 primary epithelial ovarian tumors. Using 70 polymorphicmarkers, we examined all chromosomearms (excludingacrocentricarms) on all specimens. Our findingsshow a high frequencyof LOHfor the followingchromo some arms: 5q (43%); 6p (62%); 6q (57%); 7p (36%); 8p (40%); 9q (54%); 13q (56%); 14q (47%); 15q (36%); 17p

Research paper thumbnail of Detection of Endometrial Cancer via Molecular Analysis of DNA Collected with Vaginal Tampons

Gynecologic Oncology, 2015

We demonstrate the feasibility of detecting EC by combining minimally-invasive specimen collectio... more We demonstrate the feasibility of detecting EC by combining minimally-invasive specimen collection techniques with sensitive molecular testing. Prior to hysterectomy for EC or benign indications, women collected vaginal pool samples with intravaginal tampons and underwent endometrial brushing. Specimens underwent pyrosequencing for DNA methylation of genes reported to be hypermethylated in gynecologic cancers and recently identified markers discovered by profiling over 200 ECs. Methylation was evaluated individually across CpGs and averaged across genes. Differences between EC and benign endometrium (BE) were assessed using two-sample t-tests and area under the curve (AUC). Thirty-eight ECs and 28 BEs were included. We evaluated 97 CpGs within 12 genes, including previously reported markers (RASSF1, HSP2A, HOXA9, CDH13, HAAO, and GTF2A1) and those identified in discovery work (ASCL2, HTR1B, NPY, HS3ST2, MME, ADCYAP1, and additional CDH13 CpG sites). Mean methylation was higher in tampon specimens from EC v. BE for 9 of 12 genes (ADCYAP1, ASCL2, CDH13, HS3ST2, HTR1B, MME, HAAO, HOXA9, and RASSF1) (all p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). Among these genes, relative hypermethylation was observed in EC v. BE across CpGs. Endometrial brush and tampon results were similar. Within tampon specimens, AUC was highest for HTR1B (0.82), RASSF1 (0.75), and HOXA9 (0.74). This is the first report of HOXA9 hypermethylation in EC. DNA hypermethylation in EC tissues can also be identified in vaginal pool DNA collected via intravaginal tampon. Identification of additional EC biomarkers and refined collection methods are needed to develop an early detection tool for EC.

Research paper thumbnail of Proliferating cell nuclear antigen in epithelial ovarian cancer: Relation to results at second-look laparotomy and survival

Gynecologic Oncology, 1992

We determined the proliferative index (PI) of 92 previously untreated advanced epithelial ovarian... more We determined the proliferative index (PI) of 92 previously untreated advanced epithelial ovarian cancers using PCNA/cyclin immunostaining and image analysis quantitation. In this retrospective study, there was a relationship between tumor PI and 5-year survival. For patients with a tumor PI greater than the median, the estimated S-year survival was 44%; for patients with a tumor PI below the median, the estimated 5-year survival was 15% (P = 0.003). This may partly reflect sensitivity to chemotherapy, as those patients with more rapidly proliferating tumors were more likely to achieve a pathologic complete response to platinum-based therapy. o IWZ Academic PMS, 1~.

Research paper thumbnail of Prognostic and therapeutic relevance of molecular subtypes in high-grade serous ovarian cancer

Downloaded from P = .002; de novo: P = .002). Three patients who had both age and stage data miss... more Downloaded from P = .002; de novo: P = .002). Three patients who had both age and stage data missing and two who had a missing de novo score were excluded. CI = confidence interval; HR = hazard ratio, SE = standard error.

Research paper thumbnail of Evaluation of treatment and survival after positive second-look laparotomy

Gynecologic Oncology, 1988

During the 9-year interval 1977 through 1985, of 250 patients undergoing second-look laparotomy, ... more During the 9-year interval 1977 through 1985, of 250 patients undergoing second-look laparotomy, 116 (46%) were found to have clinically occult ovarian carcinoma. Salvage therapy consisted of external irradiation in 37, intraperitoneal 32P in 12, chemotherapy in 63, and no therapy in 3 or other therapy in 1. Eligible follow-up time ranged from 1 to 9 years. The Kaplan-Meier projected median time-to-progression and survival were 15 and 22.5 months, respectively, with 4-year progression-free and overall survival rates being 21 and 27%, respectively. Survival was independent of the original stage of disease but was significantly influenced by histologic grade and microscopic (55%) versus macroscopic (19%) residual tumor after the laparotomy. Projected 4-year salvage rates in patients with microscopic or residual disease less than or equal to 5 mm was 72, 39, and 19% for intraperitoneal 32P, external irradiation (33/37, whole abdominopelvic), and chemotherapy, respectively. However, multivariable analysis demonstrated that histologic grade and isotope therapy retained independent influence on survival, but no therapeutic advantage for external irradiation over chemotherapy was demonstrable. Furthermore, use of regimens that were identical to, partially altered from, or different from the first-trial agents did not affect chemotherapy salvage rates.

Research paper thumbnail of Soluble Epidermal Growth Factor Receptor: A Biomarker of Epithelial Ovarian Cancer

Cancer Treatment and Research, 2009

The stark difference in clinical outcome for patients with ovarian cancer diagnosed at early stag... more The stark difference in clinical outcome for patients with ovarian cancer diagnosed at early stages (95% survival at 5 years) versus late stages (27.6% survival at 5 years) has driven a decades-long quest for effective biomarkers that will enable earlier detection of ovarian cancer. Yet despite intense efforts, including the application of modern high throughput technologies including transcriptomics and proteomics, there has been little improvement in performance compared to the gold standard of quantifying serum CA125 immunoreactivity paired with transvaginal ultrasound. This review describes the strategies that have been used for identification of ovarian cancer biomarkers, including the recent introduction of novel bioinformatic approaches. Results obtained using high throughput-based vs. biologically rational approaches for the discovery of diagnostic early detection biomarkers are compared and analyzed for functional enrichment.

Research paper thumbnail of Modified Radical Hysterectomy: Morbidity and Mortality

Gynecologic Oncology, 1995

Among 375 patients who underwent a modified radical hysterectomy at the Mayo Clinic, the complica... more Among 375 patients who underwent a modified radical hysterectomy at the Mayo Clinic, the complication rate was 24%, and the operative mortality was 0.5%. When compared with radical hysterectomy, this procedure is associated with a lower overall incidence of complications, particularly those related to the urinary tract.

Research paper thumbnail of Staging and Therapeutic Value of Lymphadenectomy in Endometrial Cancer

Gynecologic Oncology, 1998

During 1998, an estimated 36,100 new cases and 6300 deaths will be attributed to endometrial canc... more During 1998, an estimated 36,100 new cases and 6300 deaths will be attributed to endometrial cancer . Of major concern is the realization that while the incidence of endometrial carcinoma has remained stable over the past decade, the number of deaths annually from this disease has more than doubled since 1987 (2900 deaths). Presumably the cause of these sobering statistics are multifactorial, but it obligates us to reassess more objectively and critically the screening, diagnostic, staging, and treatment processes that guide the overall management of this neoplasm. Exemplary of the vulnerability of management is the variability in the staging and treatment algorithms that are generally predicated on institutional and/or individual physician philosophies. Perhaps the most controversial management issues relate to the staging and therapeutic values (or lack thereof) of lymphadenectomy at the time of hysterectomy.

Research paper thumbnail of Histone deacetylase inhibitors and paclitaxel cause synergistic effects on apoptosis and microtubule stabilization in papillary serous endometrial cancer cells

Molecular Cancer Therapeutics, 2006

The use of histone deacetylase (HDAC) inhibitors has shown promise for a variety of malignancies.... more The use of histone deacetylase (HDAC) inhibitors has shown promise for a variety of malignancies. In this investigation, we define the activity of this class of inhibitors in combination with traditional cytotoxic chemotherapy in endometrial cancer cells. Significant reductions in growth were observed in Ark2 and KLE endometrial cancer cells following treatment with paclitaxel, doxorubicin, carboplatin, or the HDAC inhibitor trichostatin A (TSA). However, only combined treatment with TSA/paclitaxel caused synergistic inhibition of cell growth. This combination also resulted in significant changes in cell morphology. Using cell cycle analysis, nuclear staining, and Western blot analysis for poly(ADP-ribose) polymerase and caspase-9 degradation products, TSA/paclitaxel showed the most dramatic activation of the apoptotic cascade. These effects were also observed when the HDAC inhibitors HDAC inhibitor-1 or oxamflatin were substituted for TSA. The anticancer properties of paclitaxel are known to result in part from inhibition of microtubule depolymerization, which results in apoptosis. We show that TSA administration also stabilizes microtubules via alpha-tubulin acetylation. Furthermore, using Western blot and immunohistochemical analysis, treatment with TSA/paclitaxel led to a significant increase in acetylated tubulin and microtubule stabilization. These effects were confirmed in a mouse xenograft model. Moreover, TSA/paclitaxel resulted in a 50% reduction in tumor weight compared with either agent alone. This study provides in vivo evidence of nonhistone protein acetylation as one possible mechanism by which HDAC inhibitors reduce cancer growth. The TSA/paclitaxel combination seems to hold promise for the treatment of serous endometrial carcinoma and other malignancies with limited sensitivity to paclitaxel.

Research paper thumbnail of Lymphadenectomy in endometrial cancer

Research paper thumbnail of Quality Improvement in the Surgical Approach to Advanced Ovarian Cancer: The Mayo Clinic Experience

Journal of the American College of Surgeons, 2009

BACKGROUND: After observing disparate rates of cytoreduction, we initiated efforts to improve out... more BACKGROUND: After observing disparate rates of cytoreduction, we initiated efforts to improve outcomes through feedback and education, and we reassessed outcomes. STUDY DESIGN: Outcomes from group A (2006 and 2007, n ϭ 105) were compared with those from the cohort predating quality-improvement efforts (group B, 2000 to 2003, n ϭ 132). All stage IIIC ovarian cancer patients at our institution were evaluated for tumor dissemination, age, performance status, surgical complexity, residual disease (RD), morbidity, and mortality. A surgical complexity score previously described was used to categorize extent of operation.

Research paper thumbnail of Abstract 3477: Discovery and validation of methylation markers for early detection of endometrial cancer

Research paper thumbnail of Activity of lapatinib a novel HER2 and EGFR dual kinase inhibitor in human endometrial cancer cells

British journal of cancer, Jan 25, 2008

In this study, we explore the therapeutic potential of lapatinib a selective inhibitor of both th... more In this study, we explore the therapeutic potential of lapatinib a selective inhibitor of both the EGFR and HER2 tyrosine kinases for the treatment of endometrial cancer. The effect of lapatinib on tumour cell growth and receptor activation was studied in a panel of human endometrial cancer cell lines. Candidate molecular markers predicting sensitivity were assessed by baseline gene expression profiling, ELISA, and western blot analyses. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions between chemotherapeutic drugs and lapatinib. Concentration-dependent anti-proliferative effects of lapatinib were seen in all endometrial cancer cell lines tested, but varied significantly between individual cell lines (IC(50) range: 0.052-10.9 micromol). HER2 overexpression or increased expression of EGFR was significantly associated with in vitro sensitivity (P=0.024 or 0.011, respectively). Lapatinib exerts growth inhibition in a PTEN-independent ...

Research paper thumbnail of Microarray analysis on gene regulation by estrogen, progesterone and tamoxifen in human endometrial stromal cells

International journal of molecular sciences, 2015

Epithelial stromal cells represent a major cellular component of human uterine endometrium that i... more Epithelial stromal cells represent a major cellular component of human uterine endometrium that is subject to tight hormonal regulation. Through cell-cell contacts and/or paracrine mechanisms, stromal cells play a significant role in the malignant transformation of epithelial cells. We isolated stromal cells from normal human endometrium and investigated the morphological and transcriptional changes induced by estrogen, progesterone and tamoxifen. We demonstrated that stromal cells express appreciable levels of estrogen and progesterone receptors and undergo different morphological changes upon hormonal stimulation. Microarray analysis indicated that both estrogen and progesterone induced dramatic alterations in a variety of genes associated with cell structure, transcription, cell cycle, and signaling. However, divergent patterns of changes, and in some genes opposite effects, were observed for the two hormones. A large number of genes are identified as novel targets for hormonal r...

Research paper thumbnail of HER2 gene amplification and EGFR expression in a large cohort of surgically staged patients with nonendometrioid (type II) endometrial cancer

British journal of cancer, Jan 13, 2009

Type II endometrial cancers (uterine serous papillary and clear cell histologies) represent rare ... more Type II endometrial cancers (uterine serous papillary and clear cell histologies) represent rare but highly aggressive variants of endometrial cancer (EC). HER2 and EGFR may be differentially expressed in type II EC. Here, we evaluate the clinical role of HER2 and EGFR in a large cohort of surgically staged patients with type II (nonendometrioid) EC and compare the findings with those seen in a representative cohort of type I (endometrioid) EC. In this study HER2 gene amplification was studied by fluorescence in situ hybridisation (FISH) and EGFR expression by immunohistochemistry. Tissue microarrays were constructed from 279 patients with EC (145 patients with type I and 134 patients with type II EC). All patients were completely surgically staged and long-term clinical follow up was available for 258 patients. The rate of HER2 gene amplification was significantly higher in type II EC compared with type I EC (17 vs 1%, P<0.001). HER2 gene amplification was detected in 17 and 16%...

Research paper thumbnail of Pathophysiology and palliation of inoperable bowel obstruction in patients with ovarian cancer

The journal of supportive oncology

Malignant bowel obstruction is the cause of death in the majority of women who die of ovarian can... more Malignant bowel obstruction is the cause of death in the majority of women who die of ovarian cancer. Some patients are considered acceptable surgical candidates for relief of the obstruction. For many patients, however, lack of such surgical options has spawned a broad range of medical interventions, including palliative strategies to target pain and nausea and vomiting. This review discusses the general approach to patients with ovarian cancer and inoperable malignant bowel obstruction, with an emphasis on such palliative strategies.

Research paper thumbnail of Radical pelvic resection and intraoperative radiation therapy for recurrent endometrial cancer: Technique and analysis of outcomes

Gynecologic Oncology, 2006

Objective.To describe the technique and assess outcomes and morbidity following radical resection... more Objective.To describe the technique and assess outcomes and morbidity following radical resection combined with intraoperative electron radiation therapy (IOERT) in patients with recurrent endometrial cancer.

Research paper thumbnail of Diaphragm resection for ovarian cancer: technique and short-term complications

Gynecologic Oncology, 2004

Objective.Diaphragm resection (DR) is occasionally necessary to achieve optimal cytoreductive sur... more Objective.Diaphragm resection (DR) is occasionally necessary to achieve optimal cytoreductive surgery in ovarian carcinoma (OC). In a recent survey of the SGO membership, bulky diaphragm disease was one of the most common justifications for suboptimal debulking (Gynecol. Oncol. 82 (2001) 489). The aim of this study was to assess postoperative complications of DR in OC.

Research paper thumbnail of Pancreaticoduodenectomy in optimal primary cytoreduction of epithelial ovarian cancer: A case report and review of the literature

Gynecologic Oncology Reports, 2014

•Aggressive multi-organ resection of epithelial ovarian cancer (EOC) at the time of primary cytor... more •Aggressive multi-organ resection of epithelial ovarian cancer (EOC) at the time of primary cytoreduction improves patient survival.•We describe pancreaticoduodenectomy (Whipple procedure) as an efficacious tool for optimal cytoreduction in bulky upper abdominal EOC.

Research paper thumbnail of Long-term follow-up of women with ovarian cancer after positive second-look laparotomy

Gynecologic Oncology, 2003

ObjectivePrevious reports indicate that cytoreduction and salvage therapy with P32 or whole abdom... more ObjectivePrevious reports indicate that cytoreduction and salvage therapy with P32 or whole abdominal radiation may improve survival in patients with positive findings at second-look laparotomy (SLL). The aim of this investigation was to determine whether these findings held true with extended follow-up and a larger patient cohort.

Research paper thumbnail of Human Epithelial Ovarian Cancer Allelotype

To determine which chromosomesand chromosomalregions contain putativetumor suppressorgenes import... more To determine which chromosomesand chromosomalregions contain putativetumor suppressorgenes importantfor humanepithelialovarian cancer,we performedloss of heterozygosity(LOH)studies on 37 primary epithelial ovarian tumors. Using 70 polymorphicmarkers, we examined all chromosomearms (excludingacrocentricarms) on all specimens. Our findingsshow a high frequencyof LOHfor the followingchromo some arms: 5q (43%); 6p (62%); 6q (57%); 7p (36%); 8p (40%); 9q (54%); 13q (56%); 14q (47%); 15q (36%); 17p

Research paper thumbnail of Detection of Endometrial Cancer via Molecular Analysis of DNA Collected with Vaginal Tampons

Gynecologic Oncology, 2015

We demonstrate the feasibility of detecting EC by combining minimally-invasive specimen collectio... more We demonstrate the feasibility of detecting EC by combining minimally-invasive specimen collection techniques with sensitive molecular testing. Prior to hysterectomy for EC or benign indications, women collected vaginal pool samples with intravaginal tampons and underwent endometrial brushing. Specimens underwent pyrosequencing for DNA methylation of genes reported to be hypermethylated in gynecologic cancers and recently identified markers discovered by profiling over 200 ECs. Methylation was evaluated individually across CpGs and averaged across genes. Differences between EC and benign endometrium (BE) were assessed using two-sample t-tests and area under the curve (AUC). Thirty-eight ECs and 28 BEs were included. We evaluated 97 CpGs within 12 genes, including previously reported markers (RASSF1, HSP2A, HOXA9, CDH13, HAAO, and GTF2A1) and those identified in discovery work (ASCL2, HTR1B, NPY, HS3ST2, MME, ADCYAP1, and additional CDH13 CpG sites). Mean methylation was higher in tampon specimens from EC v. BE for 9 of 12 genes (ADCYAP1, ASCL2, CDH13, HS3ST2, HTR1B, MME, HAAO, HOXA9, and RASSF1) (all p&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). Among these genes, relative hypermethylation was observed in EC v. BE across CpGs. Endometrial brush and tampon results were similar. Within tampon specimens, AUC was highest for HTR1B (0.82), RASSF1 (0.75), and HOXA9 (0.74). This is the first report of HOXA9 hypermethylation in EC. DNA hypermethylation in EC tissues can also be identified in vaginal pool DNA collected via intravaginal tampon. Identification of additional EC biomarkers and refined collection methods are needed to develop an early detection tool for EC.

Research paper thumbnail of Proliferating cell nuclear antigen in epithelial ovarian cancer: Relation to results at second-look laparotomy and survival

Gynecologic Oncology, 1992

We determined the proliferative index (PI) of 92 previously untreated advanced epithelial ovarian... more We determined the proliferative index (PI) of 92 previously untreated advanced epithelial ovarian cancers using PCNA/cyclin immunostaining and image analysis quantitation. In this retrospective study, there was a relationship between tumor PI and 5-year survival. For patients with a tumor PI greater than the median, the estimated S-year survival was 44%; for patients with a tumor PI below the median, the estimated 5-year survival was 15% (P = 0.003). This may partly reflect sensitivity to chemotherapy, as those patients with more rapidly proliferating tumors were more likely to achieve a pathologic complete response to platinum-based therapy. o IWZ Academic PMS, 1~.

Research paper thumbnail of Prognostic and therapeutic relevance of molecular subtypes in high-grade serous ovarian cancer

Downloaded from P = .002; de novo: P = .002). Three patients who had both age and stage data miss... more Downloaded from P = .002; de novo: P = .002). Three patients who had both age and stage data missing and two who had a missing de novo score were excluded. CI = confidence interval; HR = hazard ratio, SE = standard error.

Research paper thumbnail of Evaluation of treatment and survival after positive second-look laparotomy

Gynecologic Oncology, 1988

During the 9-year interval 1977 through 1985, of 250 patients undergoing second-look laparotomy, ... more During the 9-year interval 1977 through 1985, of 250 patients undergoing second-look laparotomy, 116 (46%) were found to have clinically occult ovarian carcinoma. Salvage therapy consisted of external irradiation in 37, intraperitoneal 32P in 12, chemotherapy in 63, and no therapy in 3 or other therapy in 1. Eligible follow-up time ranged from 1 to 9 years. The Kaplan-Meier projected median time-to-progression and survival were 15 and 22.5 months, respectively, with 4-year progression-free and overall survival rates being 21 and 27%, respectively. Survival was independent of the original stage of disease but was significantly influenced by histologic grade and microscopic (55%) versus macroscopic (19%) residual tumor after the laparotomy. Projected 4-year salvage rates in patients with microscopic or residual disease less than or equal to 5 mm was 72, 39, and 19% for intraperitoneal 32P, external irradiation (33/37, whole abdominopelvic), and chemotherapy, respectively. However, multivariable analysis demonstrated that histologic grade and isotope therapy retained independent influence on survival, but no therapeutic advantage for external irradiation over chemotherapy was demonstrable. Furthermore, use of regimens that were identical to, partially altered from, or different from the first-trial agents did not affect chemotherapy salvage rates.

Research paper thumbnail of Soluble Epidermal Growth Factor Receptor: A Biomarker of Epithelial Ovarian Cancer

Cancer Treatment and Research, 2009

The stark difference in clinical outcome for patients with ovarian cancer diagnosed at early stag... more The stark difference in clinical outcome for patients with ovarian cancer diagnosed at early stages (95% survival at 5 years) versus late stages (27.6% survival at 5 years) has driven a decades-long quest for effective biomarkers that will enable earlier detection of ovarian cancer. Yet despite intense efforts, including the application of modern high throughput technologies including transcriptomics and proteomics, there has been little improvement in performance compared to the gold standard of quantifying serum CA125 immunoreactivity paired with transvaginal ultrasound. This review describes the strategies that have been used for identification of ovarian cancer biomarkers, including the recent introduction of novel bioinformatic approaches. Results obtained using high throughput-based vs. biologically rational approaches for the discovery of diagnostic early detection biomarkers are compared and analyzed for functional enrichment.

Research paper thumbnail of Modified Radical Hysterectomy: Morbidity and Mortality

Gynecologic Oncology, 1995

Among 375 patients who underwent a modified radical hysterectomy at the Mayo Clinic, the complica... more Among 375 patients who underwent a modified radical hysterectomy at the Mayo Clinic, the complication rate was 24%, and the operative mortality was 0.5%. When compared with radical hysterectomy, this procedure is associated with a lower overall incidence of complications, particularly those related to the urinary tract.

Research paper thumbnail of Staging and Therapeutic Value of Lymphadenectomy in Endometrial Cancer

Gynecologic Oncology, 1998

During 1998, an estimated 36,100 new cases and 6300 deaths will be attributed to endometrial canc... more During 1998, an estimated 36,100 new cases and 6300 deaths will be attributed to endometrial cancer . Of major concern is the realization that while the incidence of endometrial carcinoma has remained stable over the past decade, the number of deaths annually from this disease has more than doubled since 1987 (2900 deaths). Presumably the cause of these sobering statistics are multifactorial, but it obligates us to reassess more objectively and critically the screening, diagnostic, staging, and treatment processes that guide the overall management of this neoplasm. Exemplary of the vulnerability of management is the variability in the staging and treatment algorithms that are generally predicated on institutional and/or individual physician philosophies. Perhaps the most controversial management issues relate to the staging and therapeutic values (or lack thereof) of lymphadenectomy at the time of hysterectomy.

Research paper thumbnail of Histone deacetylase inhibitors and paclitaxel cause synergistic effects on apoptosis and microtubule stabilization in papillary serous endometrial cancer cells

Molecular Cancer Therapeutics, 2006

The use of histone deacetylase (HDAC) inhibitors has shown promise for a variety of malignancies.... more The use of histone deacetylase (HDAC) inhibitors has shown promise for a variety of malignancies. In this investigation, we define the activity of this class of inhibitors in combination with traditional cytotoxic chemotherapy in endometrial cancer cells. Significant reductions in growth were observed in Ark2 and KLE endometrial cancer cells following treatment with paclitaxel, doxorubicin, carboplatin, or the HDAC inhibitor trichostatin A (TSA). However, only combined treatment with TSA/paclitaxel caused synergistic inhibition of cell growth. This combination also resulted in significant changes in cell morphology. Using cell cycle analysis, nuclear staining, and Western blot analysis for poly(ADP-ribose) polymerase and caspase-9 degradation products, TSA/paclitaxel showed the most dramatic activation of the apoptotic cascade. These effects were also observed when the HDAC inhibitors HDAC inhibitor-1 or oxamflatin were substituted for TSA. The anticancer properties of paclitaxel are known to result in part from inhibition of microtubule depolymerization, which results in apoptosis. We show that TSA administration also stabilizes microtubules via alpha-tubulin acetylation. Furthermore, using Western blot and immunohistochemical analysis, treatment with TSA/paclitaxel led to a significant increase in acetylated tubulin and microtubule stabilization. These effects were confirmed in a mouse xenograft model. Moreover, TSA/paclitaxel resulted in a 50% reduction in tumor weight compared with either agent alone. This study provides in vivo evidence of nonhistone protein acetylation as one possible mechanism by which HDAC inhibitors reduce cancer growth. The TSA/paclitaxel combination seems to hold promise for the treatment of serous endometrial carcinoma and other malignancies with limited sensitivity to paclitaxel.

Research paper thumbnail of Lymphadenectomy in endometrial cancer

Research paper thumbnail of Quality Improvement in the Surgical Approach to Advanced Ovarian Cancer: The Mayo Clinic Experience

Journal of the American College of Surgeons, 2009

BACKGROUND: After observing disparate rates of cytoreduction, we initiated efforts to improve out... more BACKGROUND: After observing disparate rates of cytoreduction, we initiated efforts to improve outcomes through feedback and education, and we reassessed outcomes. STUDY DESIGN: Outcomes from group A (2006 and 2007, n ϭ 105) were compared with those from the cohort predating quality-improvement efforts (group B, 2000 to 2003, n ϭ 132). All stage IIIC ovarian cancer patients at our institution were evaluated for tumor dissemination, age, performance status, surgical complexity, residual disease (RD), morbidity, and mortality. A surgical complexity score previously described was used to categorize extent of operation.