Biomedical subjects

Karl C Podratz

Publications and source records attributed to Karl C Podratz.

At least 19 recordsLinked to original sources

PubMed2006

Analysis of factors impacting operability in stage IV ovarian cancer: rationale use of a triage system.

OBJECTIVES: Determine impact of tumor distribution and surgery on prognosis in patients with stage IV epithelial ovarian cancer (EOC). METHODS: Retrospective analysis of stage IV EOC patients undergoing primary surgery between 1994 and 1998. Simple statistics, univariate and multivariable analysis were performed. RESULTS: Forty-nine patients met the inclusion criteria and entered the study. Five-year overall survival (OS) was 18.2%. Residual disease (RD) and radical surgical procedures (RSP) independently predicted survival (p<0.001). Optimal debulking rate (RD <1 cm) was 49% and median survival for optimal patients was 3.2 years. A very high risk group of patients based on extent of peritoneal disease, parenchymal liver metastases and ASA could be identified in whom the rate of optimal debulking was less than 25% (median survival 1.4 years). No patients with multiple liver metastases were optimally cytoreduced and the median survival was 1 year. CONCLUSIONS: Based on patient factors and extent of disease, a high risk group of patients can be identified with a poor prognosis and low probability of optimal debulking. It appears justified in these patients to first exclude those with unresectable pleural disease and then perform laparoscopic assessment to determine extent of disease to triage patients to alternative strategies such as neoadjuvant chemotherapy.

Adult↗

PubMed2006

Is it justified to classify patients to Stage IIIC epithelial ovarian cancer based on nodal involvement only?

BACKGROUND: Stage IIIC epithelial ovarian cancer is generally associated with upper abdominal tumor implants of greater than 2 cm and carries a grave prognosis. A subset of patients is upstaged to Stage IIIC because of lymph node metastases, in which prognosis is not well defined. We undertook this study to describe the clinical behavior of occult Stage IIIC. METHODS: All consecutive patients found to have Stage IIIC epithelial ovarian cancer during a 9-year period (1994-2002) were analyzed for surgical procedures, pathology, and disease-free (DFS) and overall survival (OS). RESULTS: Thirty-six patients were upstaged to Stage IIIC by virtue of positive nodes. Nine had small volume upper abdominal disease (IIIA/B before upstaging), 15 had disease limited to the pelvis and 12 had disease confined to the ovaries. 32/36 patients had no gross residual disease at the conclusion of surgery. The 5-year DFS and OS survivals were 52% and 76% respectively, for all patients. We observed no significant difference in outcomes between patients upstaged from IIIA/B versus I-II stage disease. The outcomes were superior to a control group of patients cytoreduced to either no gross RD or RD<1 cm, who had large volume upper abdominal disease at beginning of surgery (p<0.001). CONCLUSIONS: Patients upstaged to Stage IIIC epithelial ovarian cancer for node involvement have an excellent 5-year OS relative to all patients with Stage IIIC disease. These data demonstrate the necessity for stratifying patients classified as having Stage IIIC disease based solely on nodal disease when comparing outcomes. This information is particularly valuable when counseling patients regarding prognosis.

Adult↗

PubMed2006

Is time to chemotherapy a determinant of prognosis in advanced-stage ovarian cancer?

OBJECTIVES: Clinicians often question when to start chemotherapy after patients undergo surgery for ovarian cancer. A major unproven concern is whether a long postoperative delay reduces the benefits of an extensive procedure and leads to disease progression. Our objectives were to evaluate the correlation between clinical and pathologic variables and to evaluate the effect of the "time to chemotherapy" (TTC) interval on survival. METHODS: We retrospectively studied data from 218 patients with International Federation of Gynecology and Obstetrics stage IIIC or IV ovarian cancer (TNM stage T3c or T4) who were consecutively treated between January 1, 1994, and December 31, 1998. RESULTS: Mean age at diagnosis was 64 years (range, 24-87 years; median, 65 years), and 206 patients received postoperative platinum-based chemotherapy. Mean TTC interval was 26 days (range, 7-79 days; median, 25 days). No correlation was found between operative time and TTC interval length (P=0.99). Age and performance of rectosigmoidectomy were correlated with longer TTC interval (P=0.009 and P=0.005, respectively), but TTC was not a predictor of overall survival (odds ratio, 1.00; 95% confidence interval, 0.98-1.01; P=0.85). Differences in TTC interval length (< or =17 days, 18-26 days, 27-33 days, or > or =34 days) did not affect survival (P=0.93). Even after categorizing patients by residual disease (<1 cm or > or =1 cm), no statistically significant effect of TTC on prognosis was identified. CONCLUSIONS: Concerns about the TTC interval should not be used to justify spending less time in the operative arena or using a more conservative approach for patients with advanced ovarian cancer.

Adult↗

PubMed2006

Role of rectosigmoidectomy and stripping of pelvic peritoneum in outcomes of patients with advanced ovarian cancer.

BACKGROUND: The peritoneum of the cul-de-sac is frequently affected in advanced ovarian cancer patients. Stripping of the pelvic peritoneum (SoP) combined with rectosigmoidectomy (RS) in patients with confluent tumor are safe techniques that can eradicate macroscopic disease. We evaluated the therapeutic value of this maximal surgical effort in advanced ovarian cancer. STUDY DESIGN: Data from all consecutive patients with stages IIIC and IV epithelial ovarian cancer, primarily operated on from 1994 through 1998, were collected and analyzed using the chi-square test, Cox regression analysis, and Kaplan-Meier curves including log-rank test. RESULTS: Two hundred forty-four eligible patients were identified; 209 patients had tumor involving the peritoneum of the cul-de-sac. For this subgroup, those who were managed with stripping of the peritoneum (SoP, n=77) or rectosigmoidectomy (RS, N=57) had improved 5-year overall survivals relative to those who were not (n=75). (SoP=37% versus RS=39% versus neither=6%; p < 0.0001). In the subgroup of patients with cul-de-sac involvement optimally cytoreduced, we noted a survival benefit for those who were managed with a maximal pelvic surgical effort (5-year overall survival, 38% [SoP] versus 38% [RS] versus 15% [neither]; p=0.02). When evaluating patients with no macroscopic residual disease, a survival advantage for patients managed with RS compared with SoP was observed (5-year overall survival, 89% (RS) versus 50% (RS); p=0.04). CONCLUSIONS: Surgical resection of cul-de-sac disease by SoP and RS is associated with improved survival in ovarian cancer patients. Tumor resection with en bloc RS may be preferable to allowing microscopic or infiltrative residual tumor.

Adult↗

PubMed2006

hMLH1 promoter methylation and silencing in primary endometrial cancers are associated with specific alterations in MBDs occupancy and histone modifications.

OBJECTIVE: To investigate the relationship between hMLH1 promoter methylation and changes in chromatin composition. To study how the occupancy of methyl CpG binding domain proteins (MBDs) and histone acetylation/methylation in hMLH1 promoter may participate in hMLH1 silencing. METHODS: 64 endometrial cancer samples were screened for hMLH1 mRNA expression. hMLH1 promoter methylation status was confirmed by methylation-specific PCR in cancers with high and low levels of hMLH1 expression. Chromatin immunoprecipitation was performed to compare the MBD occupancy and histone modifications between the methylated/silenced and unmethylated/active hMLH1 genes in multiple primary endometrial cancers. RESULTS: We demonstrated that MeCP2, MBD1 and MBD2, but not MBD3 and MBD4, specifically bind to methylated hMLH1 promoters. Hyperacetylated histones H3 and H4 were found to be associated with the unmethylated and transcriptionally active hMLH1 promoters. While H3 lysine-4 methylation was present in unmethylated hMLH1 promoters, H3 lysine-9 methylation was found exclusively in methylated promoters. Western blot analysis showed that similar global levels of MBDs and histones were present in the two cancer groups with high and low hMLH1 expression. CONCLUSIONS: A distinct combination of MBDs and histone modification is associated with the silencing of the hMLH1 gene. The changes in hMLH1 chromatin composition are closely related to methylation status of hMLH1 promoters. These changes are not accounted by the global expression levels of MBDs and histones in endometrial cancers.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Splenectomy as part of cytoreductive surgery in ovarian cancer.

OBJECTIVE: Epithelial ovarian carcinoma with extensive upper abdominal disease may require splenectomy for optimal tumor cytoreduction. We describe patients who required splenectomy during tumor reduction procedures for primary or recurrent epithelial ovarian carcinoma. METHODS: Data were abstracted from records of 112 patients who underwent splenectomy as part of primary or secondary cytoreductive surgery. RESULTS: Of 112 patients, 66 had primary and 46 had secondary cytoreduction. Some patients also required bowel resection (50%), formal lymphadenectomy (31%), or urinary tract resection (5%). The most common indications for splenectomy were direct metastatic involvement (46%), facilitation of an en bloc resection of perisplenic disease (41%), and intraoperative trauma (13%). Histologically, 65% had hilar involvement; 52%, capsular involvement; and 16%, parenchymal metastases. Short-term complications included wound infections (7), pneumonias (5), thromboembolic events (9), and sepsis (5). Sepsis was associated with an anastomotic bowel leak in 1 patient, with fungal infections in 2 patients (1 pneumonia and 1 pelvic abscess), and with no identifiable infectious source in 2. Two patients required reoperation for bleeding: 1 for diffuse intraabdominal bleeding, including the splenic bed, and 1 for pelvic sidewall bleeding. The perioperative mortality rate at splenectomy was 5%: 3 from sepsis (1 anastomotic leak, 2 pneumonias), 2 from pulmonary embolism, and 1 for which the precise cause of death was not ascertainable. The primary cytoreduction group had a median survival of 1.8 years, with an estimated 2-year survival rate of 46%. The median survival in the secondary debulking group was 1.7 years, with an estimated 2-year survival of 42%. CONCLUSIONS: In patients with clinically significant upper abdominal disease, splenectomy as part of primary or secondary cytoreductive surgery is associated with modest morbidity and mortality. The risk-benefit ratio of aggressive surgical cytoreduction must be considered.

Adult↗

PubMed2006

Efficacy of systematic lymphadenectomy and adjuvant radiotherapy in node-positive endometrial cancer patients.

OBJECTIVE: To assess the efficacy of systematic lymphadenectomy and adjuvant radiotherapy in minimizing pelvic sidewall and para-aortic failures. METHODS: Between January 1984 and December 2001, a total of 146 patients with stage III and IV endometrial cancer and lymph node metastases were treated at our institution. Adequate pelvic lymphadenectomy was defined as the removal of more than 10 pelvic lymph nodes, and adequate para-aortic lymphadenectomy was defined as removal of 5 or more para-aortic lymph nodes. The 24 patients who received adjuvant chemotherapy were excluded. We assessed the ability of adequate pelvic and para-aortic lymphadenectomy, together with radiotherapy, to prevent pelvic and para-aortic recurrences. RESULTS: Of the 122 patients studied, 94 (77%) had adequate pelvic lymphadenectomy and 47 (39%) had adequate para-aortic lymphadenectomy. Pelvic radiotherapy was administered to 78% and para-aortic radiotherapy to 29% of patients. Median follow-up of censored patients was 56 months. Twenty-five percent of patients had pelvic sidewall failure at 5 years. Pelvic sidewall failures at 5 years occurred in 57% of patients who had inadequate node dissection and/or no radiotherapy, compared with 10% for those having both adequate lymphadenectomy and radiotherapy (P < 0.001). After risk factor assessment in a regression model, only treatment with adequate lymphadenectomy and radiotherapy was a significant independent predictor of pelvic control (P = 0.03). The performance of definitive pelvic lymphadenectomy may have increased treatment-related morbidity in the subgroup of patients who had postoperative radiotherapy. For the 41 patients with positive para-aortic lymph nodes, the 5-year para-aortic failure rate was 34% after adequate lymphadenectomy but without adjuvant para-aortic radiotherapy. Likewise, 69% failed in the para-aortic area when adjuvant para-aortic radiotherapy was administered to patients not having adequate para-aortic lymphadenectomy; however, none of the 11 patients failed in the para-aortic area after adequate lymphadenectomy and para-aortic radiotherapy (P = 0.08). CONCLUSIONS: Adequate (pelvic and para-aortic) lymphadenectomy and adjuvant radiotherapy appear complementary in reducing failures in both the pelvis and para-aortic areas in patients with node-positive endometrial cancer.

Aged↗

PubMed2006

Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells.

Lapatinib (GW572016) is a selective inhibitor of both epidermal growth factor receptor (EGFR) and HER-2 tyrosine kinases. Here, we explore the therapeutic potential of lapatinib by testing its effect on tumor cell growth in a panel of 31 characterized human breast cancer cell lines, including trastuzumab-conditioned HER-2-positive cell lines. We further characterize its activity in combination with trastuzumab and analyze whether EGFR and HER-2 expression or changes induced in the activation of EGFR, HER-2, Raf, AKT, or extracellular signal-regulated kinase (ERK) are markers of drug activity. We report that concentration-dependent antiproliferative effects of lapatinib were seen in all breast cancer cell lines tested but varied significantly between individual cell lines with up to 1,000-fold difference in the IC(50)s (range, 0.010-18.6 micromol/L). Response to lapatinib was significantly correlated with HER-2 expression and its ability to inhibit HER-2, Raf, AKT, and ERK phosphorylation. Long-term in vivo lapatinib studies were conducted with human breast cancer xenografts in athymic mice. Treatment over 77 days resulted in a sustained and significant reduction in xenograft volume compared with untreated controls. For the combination of lapatinib plus trastuzumab, synergistic drug interactions were observed in four different HER-2-overexpressing cell lines. Moreover, lapatinib retained significant in vitro activity against cell lines selected for long-term outgrowth (>9 months) in trastuzumab-containing (100 microg/mL) culture medium. These observations provide a clear biological rationale to test lapatinib as a single agent or in combination with trastuzumab in HER-2-overexpressing breast cancer and in patients with clinical resistance to trastuzumab.

Animals↗

PubMed2006

Role of lymphadenectomy in the management of grossly apparent advanced stage epithelial ovarian cancer.

OBJECTIVE: The purpose of this study was to determine the factors that are related to the performance of lymph node assessment and its impact on prognosis in ovarian cancer. STUDY DESIGN: This was a retrospective analysis of stage IIIC/IV epithelial ovarian cancer in patients who had undergone primary surgery between 1994 and 1998. Simple statistics and univariate and multivariable analysis were performed. RESULTS: Two hundred nineteen patients met the inclusion criteria; lymph node assessment was performed for 93 of these patients (41%). Sixty-one patients (65.5%) underwent complete pelvic and para-aortic lymphadenectomy, and 32 patients (34.5%) underwent a more limited lymph node sampling. In patients with residual disease >1 cm, lymph node assessment was an independent predictor of outcome. In this same subgroup, lymphadenectomy appeared to be superior to lymph node sampling (5-year overall survival, 50% (lymphadenectomy) vs 33% (lymph node sampling) vs 29% (no lymph node assessment); P = .01). Considering survival of the subgroup who underwent lymph node assessment, we observed a significantly worse outcome for those with lymphatic involvement (5-year overall survival, 31.5% [positive for nodal metastases] vs 54% [negative for nodal metastases]; P = .003). Although multiple factors were correlated with the decision to perform lymph node assessment in univariate analysis, only the surgeon (P < .001), low residual disease (P = .004), American Society of Anesthesiology 1 or 2 (P = .004), and the absence of carcinomatosis (P = .0002) were independent factors in the multivariable analysis. Further, if lymph node assessment was performed, the decision to do lymphadenectomy versus lymph node sampling was associated independently with the surgeon (P < .001), low residual disease (P < .001), and patient age of <65 years (P < .001). CONCLUSION: Removal of obviously involved lymph nodes in patients with residual disease near 1 cm and lymphadenectomy for patients with complete or near complete resection of abdominal disease appears to be justified. A lack of standard recommendation in advanced ovarian cancer results in wide variations that are based on individual preference in addition to logical factors.

Adult↗

PubMed2006

Quality improvement in gynecologic surgery: the new frontier.

The continual and disproportionate increase in health care costs without showing improvement has regulatory organizations and purchasers of surgical care demanding comparative documentation of surgical quality and outcomes. Support for implementing performance standards is derived from 2 risk-adjusted national surgical quality improvement programs which documented substantial decreases in perioperative morbidity and mortality. These dramatic improvements in patient outcomes and corresponding decreases in health care costs are transitioning to "pay-for-performance" for surgical disciplines. With the requisite budget-neutral environment, quality incentive payments will be offset by reduced reimbursement for substandard performances. For specialties that have not developed specific performance metrics, the implications are substantial. Therefore, the gynecologic surgical community has an exigent need to develop standards and methods to assess quality within our discipline that are specialty specific, equitable and risk adjusted.

Female↗

PubMed2006

The granulin-epithelin precursor is a steroid-regulated growth factor in endometrial cancer.

OBJECTIVES: The majority of endometrial cancers arise as a result of estrogen stimulation, the molecular targets of which remain incompletely defined. We hypothesize that the granulin-epithelin precursor (GEP) may be one such target. In this study, we examined the frequency of GEP and estrogen receptor (ER) co-expression in human endometrial cancers. Once we established the co-expression of GEP with the estrogen receptor we examined the potential estrogen regulation of GEP expression, as well as the functional significance of GEP expression in vitro. METHODS: Double immunofluorescence and confocal microscopy were used to compare GEP and ER expression among 41 endometrial cancers. The effects of estradiol and tamoxifen treatment on GEP expression in two endometrial cancer cell lines, KLE and HEC-1-A, were assessed through reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis. The antiproliferative effect of GEP silencing by short hairpin (sh)RNA, was evaluated in HEC-1-A cells using an MTT assay. RESULTS: GEP co-expression with ER was observed in 63% of the cancers examined. A two- to fivefold increase in GEP expression with estradiol and/or tamoxifen treatment was observed in KLE cells. Silencing of GEP in HEC-1-A cells using shRNA resulted in a decrease in proliferation among transfected cells. CONCLUSIONS: Co-expression of GEP and ER in endometrial cancer cells, and the regulation of GEP by estrogen, suggests a role for GEP in steroid-mediated endometrial cancer cell growth. Further characterization of GEP as a steroid-mediated growth factor in these cells may broaden our understanding of endometrial cancer biology and also provide guidance in the development of novel therapeutic targets.

Adult↗

PubMed2006

Radical pelvic resection and intraoperative radiation therapy for recurrent endometrial cancer: technique and analysis of outcomes.

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. METHODS: From 1986 to 2002, 25 patients received treatment including radical resection and IOERT for recurrent endometrioid, endometrial cancer. Relevant clinical information was extracted through retrospective chart review. RESULTS: Treatment prior to referral included radiation in 56% and either a secondary surgery or chemotherapy in 48%. External radiation (EBRT) was administered in addition to IOERT in 84%. Radical procedures performed at the time of IOERT included resection of the pelvic sidewall en bloc with the obturator nerve, external iliac vein, psoas, iliacus, or obturator internus muscles, ureter, or boney ileum. Seven patients required exenteration in combination with resection of the pelvic sidewall. The median IOERT dose was 1500 cGy (range 1000-2500 cGy). Overall five-year survival was 47% vs. 71% for those with a gross total resection but close margins. Two patients with recurrences limited to the para-aortic area are alive without evidence of disease at 54 and 71 months. Proportional hazards modeling showed concurrent EBRT, tumor size after resection, grade, and age to be associated with improved survival. The most common complications were peripheral neuropathy, functional ureteral obstruction, and fistula formation. CONCLUSIONS: With an aggressive treatment approach including radical resection combined with IOERT, long-term survival is possible in a significant number of patients with localized recurrent endometrial cancer. Preoperative radiation paired with complete surgical resection utilizing extended procedures is paramount to achieving optimal outcomes.

Adult↗

PubMed2006

Aggressive surgical effort and improved survival in advanced-stage ovarian cancer.

OBJECTIVE: Residual disease after initial surgery for ovarian cancer is the strongest prognostic factor for survival. However, the extent of surgical resection required to achieve optimal cytoreduction is controversial. Our goal was to estimate the effect of aggressive surgical resection on ovarian cancer patient survival. METHODS: A retrospective cohort study of consecutive patients with International Federation of Gynecology and Obstetrics stage IIIC ovarian cancer undergoing primary surgery was conducted between January 1, 1994, and December 31, 1998. The main outcome measures were residual disease after cytoreduction, frequency of radical surgical resection, and 5-year disease-specific survival. RESULTS: The study comprised 194 patients, including 144 with carcinomatosis. The mean patient age and follow-up time were 64.4 and 3.5 years, respectively. After surgery, 131 (67.5%) of the 194 patients had less than 1 cm of residual disease (definition of optimal cytoreduction). Considering all patients, residual disease was the only independent predictor of survival; the need to perform radical procedures to achieve optimal cytoreduction was not associated with a decrease in survival. For the subgroup of patients with carcinomatosis, residual disease and the performance of radical surgical procedures were the only independent predictors. Disease-specific survival was markedly improved for patients with carcinomatosis operated on by surgeons who most frequently used radical procedures compared with those least likely to use radical procedures (44% versus 17%, P < .001). CONCLUSION: Overall, residual disease was the only independent predictor of survival. Minimizing residual disease through aggressive surgical resection was beneficial, especially in patients with carcinomatosis. LEVEL OF EVIDENCE: II-2.

Adult↗

PubMed2006

Histone deacetylase inhibitors and paclitaxel cause synergistic effects on apoptosis and microtubule stabilization in papillary serous endometrial cancer cells.

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.

Animals↗

PubMed2005

Phase III comparison of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) vs. doxorubicin and cisplatin (AC) in women with advanced primary or recurrent metastatic carcinoma of the uterine endometrium.

OBJECTIVES: The North Central Cancer Treatment Group Phase III trial compared efficacy of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) with doxorubicin plus cisplatin (AC) for patients with advanced endometrial cancer. METHODS: Twenty-eight patients were randomly assigned to treatment with doxorubicin 30 mg/m2 + cisplatin 70 mg/m2 IV q 4 weeks vs. methotrexate 30 mg/m2 IV days 1, 15, and 22, vinblastine 3 mg/m2 IV days 2, 15, and 22, doxorubicin 30 mg/m2 IV day 2, and cisplatin 70 mg/m2 day 2 of a 4-week cycle. The trial was terminated prematurely due to slow accrual. RESULTS: Prior to early closure of the protocol, there were 15 patients entered on the AC regimen and 13 to the MVAC regimen. There were 3 PR (20%) for AC and 3 CR (23%) and 3 PR (23%) for MVAC. Median PFS was 4.0 months for AC and 6.9 months for MVAC. Median survival was 13.2 months for AC and 16.8 months for MVAC. Toxicity was substantial for MVAC vs. AC with severe leukopenia seen in 69% vs. 33% of patients and severe thrombocytopenia 23% vs. 0%. No treatment-related deaths were seen. DISCUSSION: MVAC and AC are active regimens in the treatment of advanced/recurrent or metastatic endometrial cancer. The premature closure of the protocol resulted in small patient numbers that left the protocol underpowered to address the primary objective of demonstrating improved CR rate for MVAC over AC. MVAC has substantial toxicity compared to AC and is not substantially superior to AC. MVAC cannot be considered as a standard for treatment in this patient population.

Adult↗

PubMed2005

Surgical treatment of diaphragm disease correlates with improved survival in optimally debulked advanced stage ovarian cancer.

BACKGROUND: Diaphragm involvement by ovarian cancer is often considered to be a major obstacle to successful cytoreductive surgery. Lack of evidence of survival benefit, concerns over safety and lack of experience are common justifications for this belief. In this study, we sought to evaluate the therapeutic value of diaphragmatic surgery in advanced ovarian cancer. METHODS: Relevant data from all consecutive patients with stage IIIC and IV epithelial ovarian cancer, primarily operated at Mayo Clinic from 1994 through 1998, were collected and analyzed. Statistical analyses were performed using chi(2) test, Cox regression model and Kaplan-Meier curves including log rank test. For comparison of trends in performing procedures, an additional 91 consecutive patients undergoing surgery from August 1, 2002 and August 31, 2004 were analyzed. RESULTS: 244 eligible patients were identified. Mean age was 64 years (range: 24-87), and 5-year overall survival (OS) was 31.5%. For the entire cohort, residual disease (RD) was the only independent prognostic factor in multivariate analysis (P < 0.0001) when considering other factors including demographic, intraoperative findings and procedures performed. For the subgroup of patients with tumor involving the diaphragm (N = 181), patients who underwent diaphragm surgery (stripping of the diaphragmatic peritoneum, full or partial thickness diaphragm resection, excision of nodules or CUSA) had improved 5-year OS relative to those that did not (53% vs. 15%; P < 0.0001). Furthermore, in multivariate analysis of patients with diaphragm disease, both RD and performance of diaphragm surgery were independent predictors of outcome (P < 0.001). Considering the subgroup of patients with RD < 1 cm, we noted a strong survival advantage for those patients who underwent diaphragm surgical procedures (5-year survival: 55% vs. 28%; P = 0.0005). Over time, we noted a statistically significant increase in the rate of diaphragm procedures for patients with diaphragm involvement from 1994-98 relative to 2002-3 (22.5% vs. 40%: P = 0.022). CONCLUSIONS: Surgical procedures to treat diaphragm disease increase the rate of complete and optimal debulking and correlate with improved survival even compared to patients optimally debulked without diaphragm surgery performed.

Adult↗

PubMed2005

Ovarian cancer surgical resectability: relative impact of disease, patient status, and surgeon.

OBJECTIVES: Currently, we are unable to predict which patients are most likely to undergo successful debulking of ovarian cancer. We investigated the impact of clinical and surgical-pathologic factors at the time of initial exploration on the ability to achieve optimal cytoreduction. METHODS: All consecutive patients with IIIC epithelial ovarian cancer operated at Mayo Clinic between 1994 and 1998 were included. The following pre- and intraoperative factors were included as dichotomous variables: age, ASA, CA125, ascites volume, carcinomatosis, diaphragm and mesentery involvement, and tendency of the operating surgeon (defined by the performance of radical procedures in more vs. less than 50% of patients operated). Pearson chi(2) test and logistic regression analysis were used for statistical analysis. RESULTS: ASA, ascites, carcinomatosis, diaphragmatic tumor, mesentery involvement, and surgeon tendency all significantly correlated with residual disease (RD) in univariate analysis. However, only ASA, carcinomatosis and surgeon were independently associated with optimal RD. The subset of patients having ASA 3 or 4 and carcinomatosis comprised a high-risk group with just 46% achieving optimal RD overall. Even within this high-risk group, the rate of optimal cytoreduction ranged from 67% to 42% dependent upon surgeon tendency to employ radical procedures. CONCLUSIONS: High-risk factors such as patient condition and extent of disease impact the ability to achieve optimal RD. However, this is greatly influenced by surgical effort. Models to predict optimal surgical outcomes based only on tumor and patient characteristics will be highly practice-dependent: thus, their utility in selecting patient for non-traditional primary approach to ovarian cancer must be looked at cautiously.

Adult↗

PubMed2005

Histone deacetylase inhibitors decrease DNA methyltransferase-3B messenger RNA stability and down-regulate de novo DNA methyltransferase activity in human endometrial cells.

It is well known that the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) acts synergistically with the DNA methyltransferase (DNMT) inhibitor 5-aza-2'-deoxycytidine (ADC) to reactivate DNA methylation-silenced genes. Moreover, in several studies, TSA was capable of inducing DNA demethylation even in the absence of ADC. Here we describe a mechanism by which HDAC inhibitors affect DNA methylation through their regulation on DNMT3B, a methyltransferase responsible for de novo DNA methylation. Using quantitative real-time PCR and Western blot analysis, we show that TSA down-regulates DNMT3B mRNA and protein expression in human endometrial cancer cells. This decrease in DNMT3B mRNA results in a significant reduction in de novo methylation activities. Further experiments indicated that TSA decreases DNMT3B mRNA stability and reduces its half-life from approximately 4 to 2.5 hours. We established that protein synthesis is required for posttranscriptional regulation, suggesting the involvement of an RNase and/or key mRNA stabilization factor(s) controlling the DNMT3B mRNA stability. Therefore, TSA may not only modify histone acetylation, but also potentially alter DNA methylation. Since the HDAC inhibitors are frequently used in epigenetic studies and are considered to be promising anticancer drugs, these new findings will have implications in both laboratory and clinical settings.

Azacitidine↗