Biomedical subjects

Sean C Dowdy

Publications and source records attributed to Sean C Dowdy.

At least 19 recordsLinked to original sources

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

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

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↗

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

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↗

PubMed2005

Overexpression of the TGF-beta antagonist Smad7 in endometrial cancer.

OBJECTIVE: We have shown that HER2/Neu may activate the Smad7 promoter in endometrial, ovarian, and breast cancer cell lines. Elevated Smad7 levels could then antagonize the TGF-beta pathway, leading to a reduction in tumor surveillance and potential cancer formation. Our aim was to determine if Smad7 was in fact overexpressed in endometrial cancers and whether Smad7 RNA levels correlated with tumor grade or clinical endpoints. METHODS: Snap-frozen endometrial cancer specimens from 16 patients with grade 1 disease and 23 patients with grade 3 disease were obtained. Additionally, the endometrium from 18 patients who underwent hysterectomy for benign indications was collected as a control. RNA was extracted and subjected to quantitative real-time PCR to determine the degree of Smad7 RNA expression. Clinical outcomes including time to recurrence were recorded through retrospective chart review. RESULTS: Smad7 transcripts in the tumors were over 11-fold elevated on average than in controls (P < 0.001). There was no significant difference in Smad7 RNA between grades 1 and 3 tumors. For the 19 patients who recurred, median time to recurrence was 56.3 months for those with low Smad7 expression versus 30 months for those with high Smad7 expression (P < 0.004). CONCLUSION: Smad7 appears to be upregulated in endometrial cancers compared to normal endometrium. Furthermore, high Smad7 gene expression was associated with a shorter time to recurrence. Given that many endometrial cancers have been shown to be TGF-beta-unresponsive, Smad7 should be investigated as a potential target to restore TGF-beta responsiveness and limit tumor growth.

Cytoskeletal Proteins↗

PubMed2005

Salvage whole-abdominal radiation therapy after second-look laparotomy or secondary debulking surgery in patients with ovarian cancer.

OBJECTIVES: Our aim was to determine the outcomes associated with use of whole-abdominal radiation therapy (WART) in women with ovarian cancer, to identify predictors of response, and to assess associated toxicity. METHODS: From 1981 through 2000, 171 women received WART at our institution after ovarian cancer surgery. Relevant clinical information was extracted through retrospective chart review. RESULTS: One hundred nine patients received WART after positive second-look laparotomy (SLL), and 62 were treated after secondary debulking (SD) for recurrent disease. The median dose to the whole abdomen was 25.5 Gy (range, 1.0-30.5 Gy). Therapy included a pelvic boost in 120 patients (70%) and a para-aortic boost in 21 patients (12%). The planned radiation course was completed in 123 patients (72%). In the SLL group, 5-year survival was 29% with a median follow-up of 98.4 months. The 5-year progression-free survival (PFS) was 41% in those with microscopic disease. There was one treatment-related death (1%). For the SD group, median PFS was 11 months and associated with treatment-related mortality in 5%. Overall, treatment-related small bowel obstruction occurred in 26 patients (15%). CONCLUSIONS: In patients with a positive SLL, WART should be considered only for those with microscopic residual disease. Treatment-related small bowel obstruction can be expected in 15% of these patients. Use of WART for recurrent disease appears to be related to serious bowel toxicity in 5% with an associated short disease-free interval; the therapeutic index of WART may not be acceptable in patients with recurrent disease regardless of the degree of cytoreduction.

Combined Modality Therapy↗

PubMed2005

Up-regulation of DNA methyltransferase 3B expression in endometrial cancers.

OBJECTIVE: To understand the role of epigenetic regulation in the pathogenesis of endometrial cancer, we have characterized DNA methyltransferase 3B (DNMT3B) gene expression in normal, Grade I and Grade III endometrioid cancers, and examined DNMT3B promoter activities in endometrial cancer cell lines. METHODS: DNMT3B expression was measured in normal, Grade I, and Grade III endometrioid cancer samples. Real-time PCR and Western blot analysis were performed to compare DNMT3B mRNA and protein levels. DNMT3B levels were also compared among endometrial cell lines including those for Ishikawa, KLE, AN3, RL-95, HEC-1A, and HEC-1B. DNMT3B promoter reporter plasmids were constructed. Promoter activities in well and poorly differentiated cell lines were compared by in vitro reporter gene transfection. RESULTS: DNMT3B was significantly up-regulated in both Grade I and Grade III cancers as compared to normal controls. Western blot analysis confirmed the increased DNMT3B protein expression in cancer tissues. It was also found that the well-differentiated endometrial cell line, Ishikawa, expressed lower levels of DNMT3B than the poorly differentiated KLE cells, the expression patterns similar to those observed in tumor specimens. CONCLUSION: The results suggest that DNMT3B overexpression may play a significant role in endometrial cancer development. In addition, the transfection experiments indicated that DNMT3B promoters are more active in the poorly differentiated endometrial cancer cell lines, suggesting that the in vitro assay provides a useful model for studying the DNMT3B transactivation mechanism related to tumor transformation.

Carcinoma, Endometrioid↗

PubMed2005

Opposite alterations of DNA methyltransferase gene expression in endometrioid and serous endometrial cancers.

OBJECTIVE: To examine the DNA methyltransferase (DNMT) mRNA and protein levels in endometrioid and serous cancers and to study the relationship between DNA methyltransferase expression and endometrial cancer development. METHODS: Normal endometrium, Grade I and Grade III endometrioid carcinoma tissues and cell lines, as well as serous cancer tissues, were analyzed for DNMT expression. Real-time PCR and Western blot techniques were employed to measure the mRNA and protein levels of the four DNA methyltransferases, DNMT1, DNMT2, DNMT3A, and DNMT3B. Immunohistochemistry was performed to detect alterations in DNMT nuclear localization and spatial organization patterns. RESULTS: While DNMT2 and DNMT3A expression appear to be normal, two- to fourfold increase in DNMT1 and DNMT3B were found in both Grade I and Grade III endometrioid cancers. In addition, the poorly differentiated cell lines expressed relatively higher DNMT levels than well-differentiated cells. In contrast to endometrioid carcinomas, serous cancers expressed substantially lower levels of DNMT1 and DNMT3B than normal controls, with four- and twofold reduction observed in DNMT1 and DNMT3B mRNA levels, respectively. Western blot analysis confirmed opposite expression patterns of DNMT1 and DNMT3B protein in endometrioid and serous cancers. Immunohistochemistry showed normal nuclear localization of DNMT1 and DNMT3B in Type I and Type II cancer specimens as well as cell cultures. CONCLUSION: Two opposite DNMT expression patterns were identified in endometrioid and serous cancers. The concerted upregulation in maintenance and de novo DNA methyltransferases in endometrioid carcinomas is consistent with a tendency for gene-specific hypermethylation observed in this histologic subtype, and may be implicated in tumor suppressor silencing. In contrast, the downregulation of maintenance and de novo DNA methyltransferases in serous cancers suggests that these tumors may contain hypomethylated genomic DNA, which has been associated with a higher mutation rate and is consistent with the known pathogenesis of serous-specific phenotypes. Taken together, the data suggest that divergent DNA methylation pathways may be implicated in the development of Type I and Type II endometrial cancers.

Carcinoma, Endometrioid↗

PubMed2005

Predictors of vaginal relapse in stage I endometrial cancer.

OBJECTIVE: To identify factors predictive of vaginal relapse in stage I endometrial cancer, thereby potentially facilitating the selection of patients who may benefit from vaginal brachytherapy. METHODS: The study population included 632 patients with stage I endometrial cancer managed with hysterectomy at our institution between 1984 and 1996. Median follow-up was 73 months; 122 patients (19%) received adjuvant radiotherapy. RESULTS: Overall, 2.9% of the stage I cohort developed vaginal relapse at 5 years. Vaginal relapse was observed in 1.7% of patients who received radiotherapy and in 3.0% of those whose treatment did not include radiotherapy (P = 0.36). Cox regression analysis (including radiotherapy) identified only grade 3 differentiation (hazard ratio = 3.83, P = 0.007) as an independent predictor of vaginal relapse. Patients with a low-grade tumor had a 5-year vaginal relapse rate of 2%, compared with 7% for those with a grade 3 tumor. When only patients who did not receive adjuvant radiotherapy were considered, both grade 3 tumor and lymphovascular invasion were significant predictors of vaginal relapse (P < 0.05). When neither variable was present, 2% of patients experienced vaginal relapse at 5 years, compared with 11% when either 1 was present (P < 0.001). Depth of myometrial invasion was not a significant predictor of vaginal recurrence. CONCLUSION: Histologic grade 3 tumor and lymphovascular invasion were the cogent predictors of vaginal relapse in our population. The cost and morbidity of vaginal brachytherapy should be balanced against the potential risk of vaginal relapse in this group of patients.

Cohort Studies↗

PubMed2005

Epigenetic-mediated upregulation of progesterone receptor B gene in endometrial cancer cell lines.

OBJECTIVES: To determine if epigenetic interference can restore progesterone receptor-B (PR-B) expression in PR-B negative endometrial adenocarcinoma cell lines, and to characterize the kinetics of PR-B induction mediated by DNA methyltransferase and histone deacetylase inhibitors. METHODS: The PR-B negative endometrioid cancer cell lines KLE and HEC-1B were used as study models. PR-B mRNA and protein expression levels were measured using real-time PCR and Western blot analysis, respectively. DNA methylation levels of the PR-B promoter were determined by methylation-specific PCR. Dose-response correlations and the duration of response to aza-deoxycytidine (ADC) and trichostatin A (TSA) were characterized. Cell responses to prolonged and repeated drug treatment were also examined. RESULTS: Relatively low concentrations of ADC and TSA over a 24-h period induced PR-B expression. Furthermore, ADC and TSA acted synergistically to reactivate PR-B expression. Depending on the cell line used, PR-B mRNA was induced 10-110 fold. This elevated PR-B expression continued for 48 h after drug withdrawal. Sustained upregulation of PR-B mRNA and protein was observed during prolonged and repeated drug treatment. CONCLUSION: The epigenetically silenced PR-B gene remains sensitive to changes in DNA demethylation and histone acetylation in uterine adenocarcinoma cell lines. Treatment with ADC and/or TSA results in a robust and sustainable PR-B upregulation. These small molecule epigenetic modifying agents may be used to sensitize poorly differentiated, PR-B negative endometrial cancers to progestational therapy.

Adenocarcinoma↗

PubMed2005

Biallelic methylation and silencing of paternally expressed gene 3 (PEG3) in gynecologic cancer cell lines.

OBJECTIVE: To measure mRNA expression levels of paternally expressed gene 3 (PEG3) in gynecologic cancer cell lines and to determine if DNA methylation is involved in the control of PEG3 expression. METHODS: PEG3 mRNA levels were measured with real-time PCR from 28 gynecologic cancer cell lines and compared to normal tissues. PEG3 mRNA expression was correlated to promoter methylation levels measured by real-time methylation-specific PCR. Polymorphism-specific restriction digestion was employed to analyze PEG3 allele distribution. RESULTS: While expressed in normal gynecologic tissues, PEG3 is silenced in all endometrial and cervical cancer cell lines studied. In the eight ovarian cancer cell lines, five were found to be PEG3 negative, the remaining three express low levels of PEG3 mRNA. In contrast, loss of maternal imprinting and relatively high PEG3 expression levels were detected in all four choriocarcinomas cell lines studied. No cell line confirmed to contain two copies of PEG3 expressed PEG3 mRNA, suggesting that PEG3 downregulation is not due to genetic deletion. PEG3 mRNA expression was, however, quantitatively correlated to its promoter methylation status. Treatment of PEG3 negative cells with DNA methyltransferase inhibitor 5'-aza-deoxycytidine led to partial promoter demethylation and biallelic reactivation of PEG3 transcription, confirming the methylation-mediated mechanism for PEG3 silencing. CONCLUSION: PEG3 silencing is associated with DNA hypermethylation but not gene deletion in cell lines tested. These results suggest that loss of PEG3 expression may be a frequent event in gynecologic cancers. Given the known role of PEG3 in p53-mediated apoptosis, it is possible that PEG3 functions as a tumor suppressor.

Alleles↗

PubMed2004

The utility of computed tomography scans in predicting suboptimal cytoreductive surgery in women with advanced ovarian carcinoma.

BACKGROUND: Computed tomography (CT) scans of the abdomen and pelvis may predict which patients with ovarian carcinoma can undergo optimal cytoreduction at primary surgery. Previous studies have demonstrated that patients with ovarian carcinoma had optimal cytoreduction rates ranging from 50-60%. The authors sought to determine whether these findings applied to a surgical practice with a higher rate of optimal debulking. A predictive model using CT scanning and CA 125 values would allow the authors to determine which patients would be more appropriately treated with neoadjuvant chemotherapy. METHODS: Preoperative CT scans for patients with Stage III/IV ovarian carcinoma (according to the staging system of the International Federation of Gynecology and Obstetrics) who were treated between 1996 and 2001 were evaluated retrospectively by 2 radiologists for 17 criteria evaluating the extent of disease. Clinical data were extracted from medical records. Residual tumors measuring > or = 1 cm were considered suboptimal. Logistic regression was used to evaluate which criteria correlated with optimal cytoreduction. RESULTS: Eighty-seven patients were identified retrospectively who met entry criteria and had preoperative CT scans of sufficient diagnostic quality. Sixty-two patients (71%) received optimal cytoreductive surgery and 45 (52%) required aggressive surgical procedures. In a multivariate model, only diffuse peritoneal thickening (DPT) independently predicted suboptimal surgical resection (P = 0.016). However, a model using both DPT and ascites on most CT scans had a positive predictive value of 68% and a sensitivity of 52% for predicting suboptimal cytoreduction. CONCLUSIONS: The presence of DPT and large-volume ascites was associated with a very low rate of optimal cytoreduction (32%) in a surgical practice. These patients may be more appropriately treated with neoadjuvant chemotherapy followed by surgical cytoreduction.

Ascites↗

PubMed2004

Surgical risk reduction: prophylactic salpingo-oophorectomy and prophylactic mastectomy.

Investigators have used retrospective and prospective study designs to provide much needed data on the extent of risk reduction after prophylactic oophorectomy and mastectomy in women at increased risk for breast and ovarian cancer. In this publication we identify those women who may wish to consider prophylactic surgery, review data demonstrating the efficacy of prophylactic surgery, and discuss potential surgical complications. We also present data about the frequency of use and psychosocial impact of prophylactic surgery in this typically young group of women. Finally, we provide general treatment guidelines for the practicing clinician.

Breast Neoplasms↗

PubMed2004

High-risk endometrial cancer subgroups: candidates for target-based adjuvant therapy.

OBJECTIVE: To identify patients with endometrial cancer at risk for hematogenous, lymphatic, or peritoneal recurrence (or combinations of them) who might potentially benefit from target-based therapies. METHODS: During a 13-year period, 915 patients had endometrial cancer managed with hysterectomy and standard adjuvant therapy. On the basis of our previous regression analyses, depth of myometrial invasion predicted the risk for hematogenous recurrence; positive lymph nodes and cervical stromal invasion predicted lymphatic recurrence; stage IV disease or combination of nonendometrioid histology, cervical stromal invasion, positive lymph nodes, and positive peritoneal cytology was predictive of peritoneal recurrence. Median follow-up was 66 months. RESULTS: Applying the above criteria to the population of 915 patients, 24% were considered at risk for hematogenous recurrence, 18% for lymphatic recurrence, and 16% for peritoneal recurrence. The respective relapse rates at 5 years were 28% for patients who were at risk for hematogenous recurrence, 31% for lymphatic recurrence, and 42% for peritoneal recurrence. This contrasted with less than a 5% recurrence rate in the corresponding subgroups not at risk for relapse (P < 0.001). Collectively, of the 915 patients, 324 (35%) were considered at risk for recurrence in one or more of the above three sites. Overall, 89% of all recurrences were identified in this at-risk group. Importantly, 46% of the patients considered at risk subsequently had recurrence in one or more of the three sites, compared with only 2% of patients not at risk for relapse (P < 0.001). CONCLUSION: Patients at risk for relapse had a 46% probability of experiencing recurrence within 5 years despite management with standard therapy. New target-based algorithms for the 35% of endometrial cancer patients deemed at risk should be incorporated in the development of future prospective multimodality clinical trials predicated on site(s) of recurrence.

Adult↗

PubMed2003

HER2/Neu- and TAK1-mediated up-regulation of the transforming growth factor beta inhibitor Smad7 via the ETS protein ER81.

The cytokine transforming growth factor beta (TGF-beta) plays an important role in preventing tumor formation by blocking cell cycle progression. Accordingly, many cancers demonstrate mutations in TGF-beta signaling components or enhanced expression of inhibitors of the TGF-beta pathway such as Smad7. In this report we show that the oncoprotein HER2/Neu is able to collaborate with the ETS transcription factor ER81 to activate Smad7 transcription in breast, endometrial, and ovarian cancer cell lines. ER81 binds to two ETS sites within the Smad7 promoter, and mutation of one of these ETS sites greatly decreases Smad7 induction by HER2/Neu and ER81. Furthermore, we show that Smad7 activation involves the processing of signals from HER2/Neu to ER81 via the ERK mitogen-activated protein kinase pathway. Thus, we have uncovered a novel mechanism by which oncogenic HER2/Neu, in collaboration with ER81, can induce carcinogenesis through Smad7 up-regulation. Moreover, we show that TAK1, a TGF-beta-activated protein kinase, stimulates ER81 via the p38 mitogen-activated protein kinase pathway and thereby induces the Smad7 promoter. This suggests that attenuation of TGF-beta signaling by activating Smad7 transcription may proceed not only through TGF-beta receptor-regulated Smad proteins but also through an independent pathway involving ER81 and TAK1.

Binding Sites↗

PubMed2003

Long-term follow-up of women with ovarian cancer after positive second-look laparotomy.

OBJECTIVE: Previous 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. METHODS: From 1977 (the year platinum-based chemotherapy was introduced to our institution) to 1989, 150 patients had persistent disease at SLL. Relevant clinical information was extracted through retrospective chart review. RESULTS: One hundred forty-five patients were followed until death, with a median follow-up of 15.4 years for the 5 living patients. Median actuarial survival from the time of SLL was 18 months. Tumor grade (P = 0.003) and pre- and post-SLL tumor size (P < 0.0001) were significant determinants of survival by univariate analysis. Patients with microscopic disease or those with < or =1 cm disease rendered microscopic at SLL had improved survival relative to those with < or =1 cm and macroscopic disease following SLL (P = 0.03) (median survivals of 3.3, 2.5, and 1.4 years, respectively). In contrast, median survival of those with >1 cm disease cytoreduced to microscopic disease was no different than those with macroscopic residual, even if < or =1 cm (1.3 and 1.0 years, respectively). After adjusting for tumor size, salvage treatment was not a significant predictor of survival. CONCLUSION: With long-term follow-up there was no suggestion that the type of salvage therapy (e.g., P32 or WART) influenced survival. Rather, low-grade disease and low tumor burdens following cytoreduction were associated with improved survival on multivariate analysis.

Aged↗