Documentation of Infertility Risk Discussion in Cancer Patients Receiving Cancer-Directed Therapy: The UC Davis Cancer Center Experience.

Purpose: A complication of cancer-directed therapy that often goes undiscussed is infertility. Although guidelines recommend addressing the possibility of infertility and fertility preservation approaches before initiating treatment, an internal review at our institution showed only 49% of female patients had infertility risk counseling documented. As a result, a fertility assessment communication was added into all oncology treatment plans to improve rates of fertility discussion and documentation. Methods: This retrospective observational study included newly diagnosed patients of childbearing potential who initiated cancer-directed therapy between January 1, 2020, and October 31, 2021. Patients who were no longer of childbearing potential due to age or surgery were excluded. Patients were divided into pre- and post-implementation groups to assess the impact of the fertility assessment communication implemented on November 1, 2020. Results: A total of 152 patients met inclusion criteria, with 80 patients in the pre-implementation group and 72 patients in the post-implementation group. The primary outcome of documentation of infertility risk discussion was 47.5% in the pre-implementation group and 86.1% in the post-implementation group (p < 0.0001). Discussion of fertility preservation options was documented in 28.7% of the pre-implementation group and 43.1% in the post-implementation group (p = 0.13). In the pre-implementation group, 5% underwent fertility preservation versus 27.8% in the post-implementation group (p = 0.0001). Of the 27 patients who received fertility preservation, 13 received hormonal therapy, 11 sperm banking, and 3 egg harvesting. Conclusion: This intervention significantly increased rates of infertility risk discussion and fertility preservation approaches received. There are opportunities to help patients receive fertility preservation, especially sperm banking and egg harvesting.

Multiple Components of Protein Homeostasis Pathway Can Be Targeted to Produce Drug Synergies with VCP Inhibitors in Ovarian Cancer.

Protein quality control mechanisms play an important role in cancer progression by providing adaptive responses and morphologic stability against genome-wide copy number alterations, aneuploidy, and conformation-altering somatic mutations. This dependency on protein quality control mechanisms creates a vulnerability that may be exploited for therapeutic benefits by targeting components of the protein quality control mechanism. Recently, valosin-containing protein (VCP), also known at p97 AAA-ATPase, has emerged as a druggable target in cancer cells to affect their dependency on protein quality control. Here, we show that VCP inhibitors induce cytotoxicity in several ovarian cancer cell lines and these compounds act synergistically with mifepristone, a drug previously shown to induce an atypical unfolded protein response. Although mifepristone at a clinically achievable dose induces a weak unfolded protein response, it enhances the cytotoxic effects of VCP inhibitor CB-5083. Mechanistically, mifepristone blocks the cytoprotective effect of ATF6 in response to endoplasmic reticulum (ER) stress while activating the cytotoxic effects of ATF4 and CHOP through the HRI (EIF2AK1)-mediated signal transduction pathway. In contrast, CB-5083 activates ATF4 and CHOP through the PERK (EIF2AK3)-mediated signaling pathway. This combination activates ATF4 and CHOP while blocking the adaptive response provided by ATF6, resulting in increased cytotoxic effects and synergistic drug interaction.

Tetraspanins are unevenly distributed across single extracellular vesicles and bias sensitivity to multiplexed cancer biomarkers.

BACKGROUND: Tetraspanin expression of extracellular vesicles (EVs) is often used as a surrogate for their detection and classification, a practice that typically assumes their consistent expression across EV sources. RESULTS: Here we demonstrate that there are distinct patterns in colocalization of tetraspanin expression of EVs enriched from a variety of in vitro and in vivo sources. We report an optimized method for the use of single particle antibody-capture and fluorescence detection to identify subpopulations according to tetraspanin expression and compare our findings with nanoscale flow cytometry. We found that tetraspanin profile is consistent from a given EV source regardless of isolation method, but that tetraspanin profiles are distinct across various sources. Tetraspanin profiles measured by flow cytometry do not totally agree, suggesting that limitations in subpopulation detection significantly impact apparent protein expression. We further analyzed tetraspanin expression of single EVs captured non-specifically, revealing that tetraspanin capture can bias the apparent multiplexed tetraspanin profile. Finally, we demonstrate that this bias can have significant impact on diagnostic sensitivity for tumor-associated EV surface markers. CONCLUSION: Our findings may reveal key insights into protein expression heterogeneity of EVs that better inform EV capture and detection platforms for diagnostic or other downstream use.

Short-term organoid culture for drug sensitivity testing of high-grade serous carcinoma.

OBJECTIVE: Cancer patient-derived organoids (PDOs) grow as three dimensional (3D) structures in the presence of extracellular matrix and have been found to represent the original tumor's genetic complexity. In addition, PDOs can be grown and subjected to drug sensitivity testing in a shorter time course and with lesser expense than patient-derived xenograft models. Many patients with recurrent ovarian cancer develop malignant effusions that become refractory to chemotherapy. Since these same patients often present for palliative aspiration of ascites or pleural effusions, there is a potential opportunity to obtain tumor specimens in the form of multicellular spheroids (MCS) present in malignant effusion fluids. Our objective was to develop a short duration culture of MCS from ovarian cancer malignant effusions in conditions selected to support organoid growth and use them as a platform for empirical drug sensitivity testing. METHODS: In this study, malignant effusion specimens were collected from patients with high-grade serous ovarian carcinoma (HGSOC). MCS were recovered and subjected to culture conditions designed to support organoid growth. In a subset of specimens, RNA-sequencing was performed at two time points during the short-term culture to determine changes in transcriptome in response to culture conditions. Organoid induction was also characterized in these specimens using Ki67 staining and histologic analysis. Drug sensitivity testing was performed on all specimens. RESULTS: Our model describes organoids formed within days of primary culture, which can recapitulate the histological features of malignant ascites fluid and can be expanded for at least 6 days. RNA-seq analysis of four patient specimens showed that within 6 days of culture, there was significant up-regulation of genes related to cellular proliferation, epithelial-mesenchymal transition, and KRAS signaling pathways. Drug sensitivity testing identified several agents with therapeutic potential. CONCLUSIONS: Short duration organoid culture of MCS from HGSOC malignant effusions can be used as a platform for empiric drug sensitivity testing. These ex vivo models may be helpful in screening new or existing therapeutic agents prior to individualized treatment options.

Multiple Reaction Monitoring for the Quantitation of Serum Protein Glycosylation Profiles: Application to Ovarian Cancer.

Protein glycosylation fingerprints are widely recognized as potential markers for disease states, and indeed differential glycosylation has been identified in multiple types of autoimmune diseases and several types of cancer. However, releasing the glycans leave the glycoproteins unknown; therefore, there exists a need for high-throughput methods that allow quantification of site- and protein-specific glycosylation patterns from complex biological mixtures. In this study, a targeted multiple reaction monitoring (MRM)-based method for the protein- and site-specific quantitation involving serum proteins immunoglobulins A, G and M, alpha-1-antitrypsin, transferrin, alpha-2-macroglobulin, haptoglobin, alpha-1-acid glycoprotein and complement C3 was developed. The method is based on tryptic digestion of serum glycoproteins, followed by immediate reverse phase UPLC-QQQ-MS analysis of glycopeptides. To quantitate protein glycosylation independent of the protein serum concentration, a nonglycosylated peptide was also monitored. Using this strategy, 178 glycopeptides and 18 peptides from serum glycoproteins are analyzed with good repeatability (interday CVs of 3.65-21-92%) in a single 17 min run. To assess the potential of the method, protein glycosylation was analyzed in serum samples from ovarian cancer patients and controls. A training set consisting of 40 cases and 40 controls was analyzed, and differential analyses were performed to identify aberrant glycopeptide levels. All findings were validated in an independent test set (n = 44 cases and n = 44 controls). In addition to the differential glycosylation on the immunoglobulins, which was reported previously, aberrant glycosylation was also observed on each of the glycoproteins, which could be corroborated in the test set. This report shows the development of a method for targeted protein- and site-specific glycosylation analysis and the potential of such methods in biomarker development.

The Use of Endometrial Cancer Patient-Derived Organoid Culture for Drug Sensitivity Testing Is Feasible.

OBJECTIVE: Patient-derived organoids (PDOs), used in multiple tumor types, have allowed evaluation of tumor characteristics from individual patients. This study aimed to assess the feasibility of applying PDO in vitro culture for endocrine-based and drug sensitivity testing in endometrial cancer. METHODS: Endometrial cancer cells were enzymatically dissociated from tumors retrieved from fresh hysterectomy specimens and cultured within basement membrane extract in serum-free medium. An organoid growth assay was developed to assess the inhibitory effects of a variety of drugs including endocrine treatments. Organoid cultures were also prepared for histological and immunohistochemical comparison to the tumors of origin. RESULTS: Fifteen endometrial cancer specimens were successfully cultured as PDOs. Small spherical structures formed within 24 hours, and many continued to grow to larger, denser organoids, providing the basis for an organoid growth assay. The STAT3 transcription factor inhibitor, BBI608 (Napabucasin), strongly inhibited growth in almost all PDO cultures, suggesting that stemness programing is involved in organoid formation and/or growth. Inhibition by different growth factor receptor tyrosine kinase inhibitors was observed in several PDO specimens. Four cultures were inhibited by fulvestrant, implying the importance of estrogen-receptor signaling in some PDO cultures. Organoids closely resembled their tumors of origin in both histomorphology and immunohistochemical expression. CONCLUSIONS: The use of endometrial cancer PDO cultures for development of drug sensitivity testing for individual patient tumors is feasible. The potential value of the PDO model for clinical decision making will require clinical trial evaluation.

Optimal perioperative anesthesia management for gynecologic interstitial brachytherapy.

PURPOSE: To propose an optimal perioperative pain management clinical care pathway for interstitial brachytherapy for gynecologic cancer based on our interdepartmental experience. MATERIAL AND METHODS: We conducted a retrospective review of 23 women who underwent 32 interstitial brachytherapy procedures for gynecological cancers, analyzing patient demographics, type of anesthetic, medications, postoperative pain scores, adverse events, and delays in discharge. We measured the association of postoperative nausea and/or vomiting (PONV) with hydromorphone use, and postoperative pain scores and total narcotic administration with type of anesthesia. RESULTS: In 91% of patients postoperative pain was managed with an epidural infusion plus, as needed (PRN), IV or patient controlled analgesia (PCA) narcotics. The most common postoperative adverse event was PONV (53%), followed by delirium (22%). Hospital discharge was delayed, at least by one night, in 26% of patients. Use of a basal rate on the PCA was associated with all cases of delayed discharge from over-sedation and PONV. The use of 5 mg or more of intravenous (IV) hydromorphone during the first 24-hours postoperatively was associated with PONV (p = 0.01). Use of a basal PCA was associated with delirium (p = 0.03). Postoperative pain scores were not significantly associated with the type of anesthesia. CONCLUSIONS: Interstitial gynecologic brachytherapy requires a multidisciplinary effort for optimal perioperative management. Our study outlines the appropriate preoperative, intraoperative, and postoperative anesthesia clinical care pathway. Decreased narcotic use during hospitalization and utilization of a patient-directed infusion may decrease side effects and allow for a more efficient hospital discharge.

Multispectral Optical Tweezers for Biochemical Fingerprinting of CD9-Positive Exosome Subpopulations.

Extracellular vesicles (EVs), including exosomes, are circulating nanoscale particles heavily implicated in cell signaling and can be isolated in vast numbers from human biofluids. Study of their molecular profiling and materials properties is currently underway for purposes of describing a variety of biological functions and diseases. However, the large, and as yet largely unquantified, variety of EV subpopulations differing in composition, size, and likely function necessitates characterization schemes capable of measuring single vesicles. Here we describe the first application of multispectral optical tweezers (MS-OTs) to single vesicles for molecular fingerprinting of EV subpopulations. This versatile imaging platform allows for sensitive measurement of Raman chemical composition (e.g., variation in protein, lipid, cholesterol, nucleic acids), coupled with discrimination by fluorescence markers. For exosomes isolated by ultracentrifugation, we use MS-OTs to interrogate the CD9-positive subpopulations via antibody fluorescence labeling and Raman spectra measurement. We report that the CD9-positive exosome subset exhibits reduced component concentration per vesicle and reduced chemical heterogeneity compared to the total purified EV population. We observed that specific vesicle subpopulations are present across exosomes isolated from cell culture supernatant of several clonal varieties of mesenchymal stromal cells and also from plasma and ascites isolated from human ovarian cancer patients.

Factors Predicting Use of Neoadjuvant Chemotherapy Compared With Primary Debulking Surgery in Advanced Stage Ovarian Cancer-A National Cancer Database Study.

OBJECTIVES: We performed a patterns-of-care study to characterize the types of patients with epithelial ovarian cancer (EOC) who received neoadjuvant chemotherapy (NACT) versus primary debulking surgery (PDS) using the National Cancer Database (NCDB). METHODS: We identified patients with stages IIIC and IV EOC in the NCDB diagnosed from 2003 to 2011. Patients who received chemotherapy (CT) prior to surgery were classified as receiving NACT; if surgery preceded CT, then it was classified as PDS. Data collected from the NCDB included demographics, medical comorbidity index, cancer characteristics and treatment, and hospital characteristics. Univariate and multivariable analyses were performed using χ test, logistic regression, log-rank test, and Cox proportional hazards modeling as indicated. Statistical significance was set at P < 0.05. RESULTS: A total of 62,727 patients with stages IIIC and IV EOC were identified. The sequence of surgery and CT was identified, of which 6922 (11%) had NACT and 31,280 (50%) had PDS. Neoadjuvant CT was more frequently done in stage IV than stage IIIC (13% vs 9%), and its use markedly increased over time. Variables associated with increased likelihood of NACT use were as follows: age older than 50 years and those with higher comorbidities, stage IV, and higher-grade EOC. Neoadjuvant CT use was also associated with hospitals that were adherent to the National Comprehensive Cancer Network guidelines, high-volume facilities, those in the Midwest and West, and academic centers. CONCLUSIONS: Evidence suggests that patients with greater adverse risk factors are more likely to receive NACT instead of PDS. Use of NACT has significantly increased over the study period, especially in patients with stage IV ovarian cancer.

Glycoproteomic Analysis of Malignant Ovarian Cancer Ascites Fluid Identifies Unusual Glycopeptides.

Ovarian cancer is a major cause of cancer mortality among women, largely due to late diagnosis of advanced metastatic disease. More extensive molecular analysis of metastatic ovarian cancer is needed to identify post-translational modifications of proteins, especially glycosylation that is particularly associated with metastatic disease to better understand the metastatic process and identify potential therapeutic targets. Glycoproteins in ascites fluid were enriched by affinity binding to lectins (ConA or WGA) and other affinity matrices. Separate glycomic, proteomic, and glycopeptide analyses were performed. Relative abundances of different N-glycan groups and proteins were identified from ascites fluids and a serum control. Levels of biomarkers CA125, MUC1, and fibronectin were also monitored in OC ascites samples by Western blot analysis. N-Glycan analysis of ascites fluids showed the presence of large, highly fucosylated and sialylated complex and hybrid glycans, some of which were not observed in normal serum. OC ascites glycoproteins, haptoglobin, fibronectin, lumican, fibulin, hemopexin, ceruloplasmin, alpha-1-antitrypsin, and alpha-1-antichymotrypsin were more abundant in OC ascites or not present in serum control samples. Further glycopeptide analysis of OC ascites identified N- and O-glycans in clusterin, hemopexin, and fibulin glycopeptides, some of which are unusual and may be important in OC metastasis.

Refusal of Recommended Chemotherapy for Ovarian Cancer: Risk Factors and Outcomes; a National Cancer Data Base Study.

OBJECTIVE: To identify risk factors associated with refusal of recommended chemotherapy and its impact on patients with epithelial ovarian cancer (EOC). METHODS: We identified patients in the National Cancer Data Base diagnosed with EOC from January 1998 to December 2011. Patients who refused chemotherapy were identified and compared with those who received recommended, multiagent chemotherapy. Univariate and multivariable analyses were performed using chi-square test with Bonferroni correction, binary logistic regression, log-rank test, and Cox proportional hazards modeling. The threshold for statistical significance was set at a P value of less than 0.05. RESULTS: From a cohort of 147,713 eligible patients, 2,707 refused chemotherapy. These patients were compared with 92,212 patients who received recommended multiagent chemotherapy. Older age, more medical comorbidities, not having insurance, and later year of diagnosis were directly and significantly associated with chemotherapy refusal when analyzed using multivariable logistic regression. In addition, lower-than-expected facility adherence to NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Ovarian Cancer, treatment at low-volume center, lower grade, and higher stage were all significantly and independently associated with chemotherapy refusal. Median overall survival of patients who received multiagent chemotherapy was significantly longer than that of those who refused chemotherapy (43 vs 4.8 months; P<.0005). After controlling for known patient, facility, and disease prognostic factors, chemotherapy refusal is significantly associated with increased risk of death. CONCLUSIONS: Refusal of recommended chemotherapy carries significant risk of early death from ovarian cancer. Our data demonstrate that the decision to refuse chemotherapy is multifactorial and, in addition to unalterable factors (eg, stage/grade, age), involves factors that can be changed, including facility type and payor. Efforts at addressing these discrepancies in care can improve compliance with chemotherapy recommendations in the NCCN Guidelines for Ovarian Cancer and outcomes.

Characteristics of Long-Term Survivors of Epithelial Ovarian Cancer.

OBJECTIVE: To identify characteristics associated with long-term survival for patients with epithelial ovarian cancer using the California Cancer Registry. METHODS: A descriptive analysis of survival of all California residents diagnosed with epithelial ovarian cancer between 1994 and 2001 was conducted using patients identified through the cancer registry with follow-up through 2011. Characteristics of the patients who survived more than 10 years (long-term survivors) were compared with three other cohorts: patients who survived less than 2 years, those who survived at least 2 but no more than 5 years, and those who survived at least 5 but no more than 10 years. RESULTS: A total of 3,582 out of 11,541 (31%, confidence interval 30.2-31.8%) of the patients survived more than 10 years. Younger age, early stage, low-grade, and nonserous histology were significant predictors of long-term survival, but long-term survivors also included women with high-risk cancer. CONCLUSION: Long-term survival is not unusual in patients with epithelial ovarian cancer, even in those with high-risk disease. Many of the prognostic factors are well known, but it remains to be determined why some patients with advanced-stage high-grade cancers survive longer than others with the same histology. These findings are important for patient counseling. LEVEL OF EVIDENCE: III.

Evaluation of glycomic profiling as a diagnostic biomarker for epithelial ovarian cancer.

BACKGROUND: Prior studies suggested that glycans were differentially expressed in patients with ovarian cancer and controls. We hypothesized that glycan-based biomarkers might serve as a diagnostic test for ovarian cancer and evaluated the ability of glycans to distinguish ovarian cancer cases from matched controls. METHODS: Serum samples were obtained from the tissue-banking repository of the Gynecologic Oncology Group, and included healthy female controls (n = 100), women diagnosed with low malignant potential (LMP) tumors (n = 52), and epithelial ovarian cancers (EOC) cases (n = 147). Cases and controls were matched on age at enrollment within ±5 years. Serum samples were analyzed by glycomics analysis to detect abundance differences in glycan expression levels. A two-stage procedure was carried out for biomarker discovery and validation. Candidate classifiers of glycans that separated cases from controls were developed using a training set in the discovery phase and the classification performance of the candidate classifiers was assessed using independent test samples that were not used in discovery. RESULTS: The patterns of glycans showed discriminatory power for distinguishing EOC and LMP cases from controls. Candidate glycan-based biomarkers developed on a training set (sensitivity, 86% and specificity, 95.8% for distinguishing EOC from controls through leave-one-out cross-validation) confirmed their potential use as a detection test using an independent test set (sensitivity, 70% and specificity, 86.5%). CONCLUSION: Formal investigations of glycan biomarkers that distinguish cases and controls show great promise for an ovarian cancer diagnostic test. Further validation of a glycan-based test for detection of ovarian cancer is warranted. IMPACT: An emerging diagnostic test based on the knowledge gained from understanding the glycobiology should lead to an assay that improves sensitivity and specificity and allows for early detection of ovarian cancer.

Accounting for undetected compounds in statistical analyses of mass spectrometry 'omic studies.

Mass spectrometry is an important high-throughput technique for profiling small molecular compounds in biological samples and is widely used to identify potential diagnostic and prognostic compounds associated with disease. Commonly, this data generated by mass spectrometry has many missing values resulting when a compound is absent from a sample or is present but at a concentration below the detection limit. Several strategies are available for statistically analyzing data with missing values. The accelerated failure time (AFT) model assumes all missing values result from censoring below a detection limit. Under a mixture model, missing values can result from a combination of censoring and the absence of a compound. We compare power and estimation of a mixture model to an AFT model. Based on simulated data, we found the AFT model to have greater power to detect differences in means and point mass proportions between groups. However, the AFT model yielded biased estimates with the bias increasing as the proportion of observations in the point mass increased while estimates were unbiased with the mixture model except if all missing observations came from censoring. These findings suggest using the AFT model for hypothesis testing and mixture model for estimation. We demonstrated this approach through application to glycomics data of serum samples from women with ovarian cancer and matched controls.

Chip-based nLC-TOF-MS is a highly stable technology for large-scale high-throughput analyses.

Many studies focused on the discovery of novel biomarkers for the diagnosis and treatment of disease states are facilitated by mass spectrometry-based technology. HPLC coupled to mass spectrometry is widely used; miniaturization of this technique using nano-liquid chromatography (LC)-mass spectrometry (MS) usually results in better sensitivity, but is associated with limited repeatability. The recent introduction of chip-based technology has significantly improved the stability of nano-LC-MS, but no substantial studies to verify this have been performed. To evaluate the temporal repeatability of chip-based nano-LC-MS analyses, N-glycans released from a serum sample were repeatedly analyzed using nLC-PGC-chip-TOF-MS on three non-consecutive days. With an average inter-day coefficient of variation of 4 %, determined on log10-transformed integrals, the repeatability of the system is very high. Overall, chip-based nano-LC-MS appears to be a highly stable technology, which is suitable for the profiling of large numbers of clinical samples for biomarker discovery.

Isomer-specific chromatographic profiling yields highly sensitive and specific potential N-glycan biomarkers for epithelial ovarian cancer.

Aberrant glycosylation has been observed for decades in essentially all types of cancer, and is now well established as an indicator of carcinogenesis. Mining the glycome for biomarkers, however, requires analytical methods that can rapidly separate, identify, and quantify isomeric glycans. We have developed a rapid-throughput method for chromatographic glycan profiling using microfluidic chip-based nanoflow liquid chromatography (nano-LC)/mass spectrometry. To demonstrate the utility of this method, we analyzed and compared serum samples from epithelial ovarian cancer cases (n=46) and healthy control individuals (n=48). Over 250 N-linked glycan compound peaks with over 100 distinct N-linked glycan compositions were identified. Statistical testing identified 26 potential glycan biomarkers based on both compositional and structure-specific analyses. Using these results, an optimized model was created incorporating the combined abundances of seven potential glycan biomarkers. The receiver operating characteristic (ROC) curve of this optimized model had an area under the curve (AUC) of 0.96, indicating robust discrimination between cancer cases and healthy controls. Rapid-throughput chromatographic glycan profiling was found to be an effective platform for structure-specific biomarker discovery.

The glycolyzer: automated glycan annotation software for high performance mass spectrometry and its application to ovarian cancer glycan biomarker discovery.

Human serum glycomics is a promising method for finding cancer biomarkers but often lacks the tools for streamlined data analysis. The Glycolyzer software incorporates a suite of analytic tools capable of identifying informative glycan peaks out of raw mass spectrometry data. As a demonstration of its utility, the program was used to identify putative biomarkers for epithelial ovarian cancer from a human serum sample set. A randomized, blocked, and blinded experimental design was used on a discovery set consisting of 46 cases and 48 controls. Retrosynthetic glycan libraries were used for data analysis and several significant candidate glycan biomarkers were discovered via hypothesis testing. The significant glycans were attributed to a glycan family based on glycan composition relationships and incorporated into a linear classifier motif test. The motif test was then applied to the discovery set to evaluate the disease state discrimination performance. The test provided strongly predictive results based on receiver operator characteristic curve analysis. The area under the receiver operator characteristic curve was 0.93. Using the Glycolyzer software, we were able to identify a set of glycan biomarkers that highly discriminate between cases and controls, and are ready to be formally validated in subsequent studies.

Venous thromboembolism in uterine cancer.

OBJECTIVES: To determine the incidence, time course, and risk factors associated with the development of venous thromboembolism (VTE) and the effect of VTE on survival in women with uterine cancer. METHODS: Using the California Cancer Registry, the date, stage, and histology of all incident uterine cancer cases during 1993-1999 were identified. These cases were linked with the state's hospital discharge database, allowing identification of incident VTE events, after excluding cases with a previous history of VTE. Proportional hazards modeling was used to analyze the association of baseline risk factors with the development of VTE (<1 year), using major surgery as a time-dependent covariate. In a similar model for death (<2 years), VTE was included as a time-dependent covariate. RESULTS: Among 18,440 cases with uterine cancer, the 2-year cumulative incidence of VTE was 2.7%. The cumulative incidence varied from 1.5% among women with local stage disease to 10.5% among women with advanced disease. Among cases diagnosed with local disease, risk factors for the development of VTE within 1 year in localized disease included major surgery (hazard ratio [HR]=2.1, P<0.01), presence of long-term comorbidities (HR=2.9 for ≥3 comorbidities, P<0.0001), black race (HR=2.0, P<0.006), and sarcoma histology (HR=1.7, P<0.04). Among cases with regional disease, presence of comorbidities, black race, and sarcomas or nonendometrioid carcinomas were all associated with significantly higher risk of VTE. In advanced disease, the presence of any comorbidities and black race were the strongest predictors (HR=2.4 and 1.9, respectively). Women (aged<45 years) with advanced disease had a notably high 2-year incidence of 18%. Age did not predict VTE in localized and regional diseases. For all stages of cancer, development of VTE within 2 years was a significant predictor of decreased survival, and the magnitude of the risk was greatest among the cases diagnosed with localized disease (HR=6.1; confidence interval, 4.6-8.1). CONCLUSIONS: The incidence of VTE in women with uterine cancer was high, particularly in younger women with metastatic disease. The strong association between development of VTE and death suggests a close coupling between the biological aggressiveness of the cancer and the activation of thrombosis.

Surgical staging of early stage epithelial ovarian cancer: results from the CDC-NPCR ovarian patterns of care study.

OBJECTIVES: The objectives of this study were to determine the adequacy of surgical staging performed on surgically treated epithelial ovarian cancer (EOC) patients with apparent early stage disease and to determine if receipt of surgical staging had an influence on survival. METHODS: Detailed surgical staging information was collected from medical records for 721 patients diagnosed between 1998 and 2000 with EOC. Patients resided in California or New York and were identified through population-based cancer registries. RESULTS: Nearly 90% of patients had removal of the omentum and evaluation of bowel serosa and mesentery but only 72% had assessment of retroperitoneal lymph nodes and the majority of patients did not receive biopsies of other peritoneal locations. Only lymph node assessment (as well as node assessment combined with washings and omentectomy) had a statistically significant association with improved survival. The 5-year survival for women with node sampling was 84.2% versus 69.6% for those without this surgical procedure, and patients who did not have lymph node assessment had nearly twice the risk of death as those who did. When patients were stratified by receipt of chemotherapy, lack of node sampling had an effect only on patients who also had no chemotherapy (adjusted HR=2.2, CI=1.0-4.5). CONCLUSIONS: The results of this population-based study confirm the prognostic importance of surgical staging for women with EOC, and the important role of gynecologic oncologists in treating these patients. Adjuvant chemotherapy does not appear to further improve survival for those women who receive adequate surgical staging.