Perspectives of gynecologic oncology fellowship training and preparedness for practice.

We aimed to examine the preparedness of recent gynecologic oncology fellowship graduates for independent practice.We conducted a web-based survey study using REDCap targeting Society of Gynecologic Oncology (SGO) members who graduated gynecologic oncology fellowship within the last six years. The survey included 52 items assessing fellowship training experiences, level of comfort in performing core gynecologic oncology surgical procedures and administering cancer-directed therapies. Questions also addressed factors driving participants' selection of fellowship programs, educational experience, research and preparedness for independent practice. A total of 296 participants were invited to complete the survey. Response rate was 42% with n = 124 completed surveys included for analysis. The highest ranked factor for fellowship selection was fit with program 36% (n = 45). Upon completing fellowship, most were uncomfortable performing ureteral conduit formation 84% (n = 103), ureteroneocystostomy 77% (n = 94), exenteration 68% (n = 83), splenectomy 67% (n = 83) and lower anterior resection 41% (n = 51). Most were comfortable managing intraoperative complications 85% (n = 104) and standard cancer staging procedures (range: 61%-99%). Majority were comfortable providing cancer directed therapies with chemotherapy 99% (n = 123), immunotherapy 84% (n = 104), and poly ADP-ribose polymerase (PARP) inhibitors 97% (n = 120). Upon completing fellowship, 77% (n = 95) report having mentorship that met their expectations during fellowship and 94% (n = 116) felt they were ready for independent practice. Majority of fellowship graduates were prepared for independent practice and felt comfortable performing routine surgical procedures and cancer directed treatment. However, most are not comfortable with ultra-radical gynecologic oncology procedures. Maximizing surgical opportunities during fellowship training and acquiring early career mentorship may help.

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.

Targeting RAS-ERK pathway alterations with MEK inhibitors to improve chemosensitivity in high grade serous ovarian cancers.

OBJECTIVE: Assess if MEK inhibitor blockade of RAS-ERK pathway adaptive response in high grade serous ovarian cancers (HGSOC) improves platinum sensitivity. METHODS: Three HGSOC cell lines and three patient derived organoid (PDOs) samples from ascites of platinum resistant HGSOC patients were collected. Cell lines and PDOs were exposed to carboplatin and MEK inhibitors cobimetinib or trametinib. Cytotoxic effects of MEK inhibitors alone or combined with carboplatin were established. Western blots demonstrated RAS-ERK pathway blockage after MEK inhibitor treatment. RNA sequencing assessed gene expression after MEK inhibitor treatment. Cell line NF1 gene knockdown was performed with corresponding chemosensitivity levels. RESULTS: High carboplatin IC50 levels indicated platinum resistance in cell lines and PDOs. Cobimetinib induced cytotoxicity in cell lines and PDOs, while trametinib was less effective. Western blot confirmed MEK-ERK pathway blockage at minimal concentrations of MEK inhibitors in cell lines and PDOs. Phosphorylated-ERK levels of untreated cells indicated higher levels of RAS-ERK pathway activation in OVSAHO and OVCAR7 compared to OVCAR3. OVSAHO harbors a NF1 mutation and had highest levels of RAS-ERK activation. Cotreatment with carboplatin and MEK inhibitors showed varying synergistic cytotoxic effects at different combinations. Synergistic effect was most prominent in the OVSAHO carboplatin and cobimetinib combination. RNA sequencing identified downregulation of c-MYC and FOXM1 gene expression after MEK inhibitor treatment. NF1 gene knockdown showed an acquired increased IC50 compared to parental cells. CONCLUSION: MEK inhibitors block RAS-ERK pathways in platinum resistant HGSOC cells and PDOs. MEK inhibitors with carboplatin have select synergistic effects which may indicate a strategy to improve platinum sensitivity.

Characterizing the regulatory Fas (CD95) epitope critical for agonist antibody targeting and CAR-T bystander function in ovarian cancer.

Receptor clustering is the most critical step to activate extrinsic apoptosis by death receptors belonging to the TNF superfamily. Although clinically unsuccessful, using agonist antibodies, the death receptors-5 remains extensively studied from a cancer therapeutics perspective. However, despite its regulatory role and elevated function in ovarian and other solid tumors, another tumor-enriched death receptor called Fas (CD95) remained undervalued in cancer immunotherapy until recently, when its role in off-target tumor killing by CAR-T therapies was imperative. By comprehensively analyzing structure studies in the context of the binding epitope of FasL and various preclinical Fas agonist antibodies, we characterize a highly significant patch of positively charged residue epitope (PPCR) in its cysteine-rich domain 2 of Fas. PPCR engagement is indispensable for superior Fas agonist signaling and CAR-T bystander function in ovarian tumor models. A single-point mutation in FasL or Fas that interferes with the PPCR engagement inhibited apoptotic signaling in tumor cells and T cells. Furthermore, considering that clinical and immunological features of the autoimmune lymphoproliferative syndrome (ALPS) are directly attributed to homozygous mutations in FasL, we reveal differential mechanistic details of FasL/Fas clustering at the PPCR interface compared to described ALPS mutations. As Fas-mediated bystander killing remains vital to the success of CAR-T therapies in tumors, our findings highlight the therapeutic analytical design for potentially effective Fas-targeting strategies using death agonism to improve cancer immunotherapy in ovarian and other solid tumors.

NCCN Guidelines® Insights: Ovarian Cancer, Version 3.2022.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years following diagnosis. The NCCN Guidelines for Ovarian Cancer provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with ovarian, fallopian tube, and primary peritoneal cancers. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised guidance on alternative chemotherapy regimens for patients with advanced age and/or comorbidities, a new algorithm for recurrent low-grade serous carcinoma based on developing research and novel therapeutic agents, and updated language regarding tumor molecular analysis applications in ovarian cancer.

Time to completion of radiation treatment in locally advanced squamous cell carcinoma of the vulva and the impact on survival.

OBJECTIVE: To assess whether radiation completion within a planned timeframe in locally advanced squamous cell vulvar cancer impacts overall survival (OS). METHODS: The National Cancer Database from 2004 to 2017 was used to identify women ≥18 years old with stage II-IVA squamous cell vulvar cancer. We included women who received radiation alone (RT) or concurrent chemoradiation (CRT) for initial vulvar cancer treatment. Primary outcome was overall survival associated with time of delay in radiation completion. RESULTS: There were 2378 women identified (n = 856 RT and n = 1522 CRT). Median age was 67 (IQR 56-78), majority (88.35%) were white with advanced stage III or IVA (72.29%) disease. Median radiation dose was 5720 c-Gray (IQR 5040-6300). Radiation completion with delay ≥7 days resulted in reduction in survival compared to delay of <7 days (unadjusted HR 1.183 [95%CI: 1.066-1.313], p = 0.0016). When delays extended to ≥14 days compared to <14 days there was increased hazard of death (unadjusted HR: 1.263 [95%CI:1.126-1.416], p < 0.0001). Survival improved for patients with <7 versus ≥7 days delay whether treatment was with RT (median OS: 34.9 months versus 21.6 months, p < 0.01) or CRT (Median OS:58 months versus 41.3 months, p < 0.01). Stage IVA disease was associated with the greatest increase in hazard of death (HR 1.759 [95%CI 1.517-2.039], p < 0.0001) compared to stage II. CONCLUSION: Radiation completion with <7 days delay is associated with improved overall survival, independent of concurrent chemotherapy. This suggest that strategies to minimize delays in radiation are crucial in locally advanced vulvar cancer.

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.

Protein-Specific Differential Glycosylation of Immunoglobulins in Serum of Ovarian Cancer Patients.

Previous studies indicated that glycans in serum may serve as biomarkers for diagnosis of ovarian cancer; however, it was unclear to which proteins these glycans belong. We hypothesize that protein-specific glycosylation profiles of the glycans may be more informative of ovarian cancer and can provide insight into biological mechanisms underlying glycan aberration in serum of diseased individuals. Serum samples from women diagnosed with epithelial ovarian cancer (EOC, n = 84) and matched healthy controls (n = 84) were obtained from the Gynecologic Oncology Group. Immunoglobulin (IgG, IgA, and IgM) concentrations and glycosylation profiles were quantified using multiple reaction monitoring mass spectrometry. Differential and classification analyses were performed to identify aberrant protein-specific glycopeptides using a training set. All findings were validated in an independent test set. Multiple glycopeptides from immunoglubins IgA, IgG, and IgM were found to be differentially expressed in serum of EOC patients compared with controls. The protein-specific glycosylation profiles showed their potential in the diagnosis of EOC. In particular, IgG-specific glycosylation profiles are the most powerful in discriminating between EOC case and controls. Additional studies of protein- and site-specific glycosylation profiles of immunoglobulins and other proteins will allow further elaboration on the characteristics of biological functionality and causality of the differential glycosylation in ovarian cancer and thus ultimately lead to increased sensitivity and specificity of diagnosis.

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.

The impact of a vaginal brachytherapy boost to pelvic radiation in stage III endometrial cancer.

PURPOSE: We investigate the use and impact of a vaginal brachytherapy boost (VBB) after pelvic radiotherapy for stage III endometrial adenocarcinoma on vaginal and pelvic control. MATERIAL AND METHODS: One hundred patients treated from 1998-2011 with surgery and adjuvant therapy with or without a VBB were included. Variables examined were grade, stage, lymphovascular space invasion (LVSI), vaginal involvement (VI), cervical stromal involvement (CSI), myometrial invasion (MI), and a VBB. Failure was scored as vaginal, or pelvic. Fisher's exact test assessed association between variables with vaginal and pelvic control. RESULTS: With a median follow up of 43 months, 31% were stage IIIA, 6% stage IIIB, and 63% stage IIIC. Thirty-eight (38%) received pelvic radiotherapy alone, and 62% received adjuvant chemotherapy. Of the 100 patients, 82 were treated with a VBB, 10 were not treated with a VBB, and 8 were not treated with RT. Of the 82 patients who received a VBB, 5 failed in the vagina with vaginal and pelvic control rates of 94% and 92%. The impact of VB reached borderline significance with its impact on pelvic control, 92% vs. 70% (p = 0.056), and did not affect vaginal control, 94% and 90% (p = 0.50). Neither tumor grade, LVSI, CSI, stage, nor LVSI (p > 0.05) statistically significantly impacted vaginal control. CONCLUSIONS: There are no clinical guidelines for the use of a VBB in stage III endometrial cancer. The majority of our patients were treated with a VBB and experienced excellent pelvic and vaginal control. The presence of traditional adverse features did not negatively impact control in our patient cohort. However, the role of a VBB needs further investigation to understand the incremental benefit beyond pelvic RT.