Letters of recommendation for gynecologic oncology fellowship differ by gender and race.

INTRODUCTION: Letters of recommendation (LOR) play a significant role in applicant selection for gynecologic oncology (GO) fellowship. LORs can be agentic, associated with competence, independence and strength, or communal, associated with being accommodating, cooperative and empathetic. Agentic LORs have been shown to reflect favorably on applicants, making them more likely to be selected for interview. The primary goal of this study was to determine linguistic differences in LORs for applicants applying to GO fellowship based on applicant gender and race. METHODS: All applications to a single academic institution from the years 2018-2020 were analyzed. LORs were extracted from all applicants who self-reported their gender and race/ethnicity. Analysis was performed using Linguistic Inquiry Word Count (LIWC) in terms of agentic and communal language. All analysis was done using SAS version 9.4. RESULTS: From 2018 to 2020, there were 239 GO fellowship applications to a single academic institution. There were 186 (78.1%) applicants who identified as female and 52 (21.8%) who identified as male. Female applicants were more likely to have more research (p = 0.047) and volunteer activities (p = 0.02) than male applicants. There were no differences between female and male applicants in terms of age, geographic location of residency, USMLE scores, AOA status, number of publications or attending a Doximitiy-rated top 20 residency program. There were 139 (60.7%) applicants who identified as White, 46 (20.1%) as Asian, 16 (7.0%) as Black, 19 (8.3%) as Latinx and 9 (3.9%) as other. On multivariable analysis, LORs written for male applicants had higher agentic scores compared to females (p < 0.05), and LORs of female applicants received higher communal scores (p < 0.05). LORs for applicants who identified as Black or Latinx were found to have lower agentic scores compared to individuals who identified as White(p < 0.05 for both). CONCLUSION: There were demonstrated linguistic differences in LOR for GO fellowship based on applicant gender and race/ethnicity. LORs written for white, male applicants were more likely to have higher agentic scores compared to minority, female applicants. LORs written for female applicants were more likely to have higher communal scores. As LORs have been shown to be instrumental in GO fellowship interview selection and linguistic differences exist based on applicant gender and race/ethnicity, this study highlights the need for a more objective GO fellowship application process. DISCLOSURES: Portion of this paper was presented at the Society for Gynecologic Oncology as part of a focus plenary.

Outcomes for patients with high-risk endometrial cancer undergoing sentinel lymph node assessment versus full lymphadenectomy.

OBJECTIVE: The objective of this study was to determine the progression free survival (PFS) and overall survival (OS) among patients with high-risk endometrial cancer (EC) who underwent sentinel lymph node (SLN) mapping and dissection compared to patients who underwent pelvic +/- para-aortic lymphadenectomy (LND). METHODS: Patients with newly diagnosed high-risk EC were identified. Inclusion criteria included patients who underwent primary surgical management from January 1, 2014 to September 1, 2020 at our institution. Patients were categorized into either the SLN or LND group based on their method of planned lymph node assessment. Patients in the SLN group had dye injected followed by successful bilateral lymph node mapping, retrieval, and processing per our institutional protocol. Clinicopathological and follow-up data were extracted from patient's medical records. The t-test or Mann-Whitney test was used to compare continuous variables and Chi-squared or Fisher's exact test were used for categorical variables. Progression-free survival (PFS) was calculated from the date of initial surgery to the date of progression, death, or last follow-up. Overall survival (OS) was calculated from the date of surgical staging to the date of death or last follow-up. Three-year PFS and OS were calculated using the Kaplan-Meier method, and the log-rank test was used to compare cohorts. Multivariable Cox regression models were used to assess the relationship between nodal assessment cohort and OS/PFS while adjusting for age, adjuvant therapy, and surgical approach. A result was considered statistically significant at the p < 0.05 level of significance and all statistical analysis was done using SAS version 9.4 (SAS Institute, Cary, NC). RESULTS: Out of 674 patients diagnosed with EC during the study period, 189 were diagnosed with high-risk EC based on our criteria. Forty-six (23.7%) patients underwent SLN assessment and 143 (73.7%) underwent LND. No difference was observed between the two groups in regards to age, histology, stage, body mass index, tumors myometrial invasion, lymphovascular space invasion, or peritoneal washing positivity. Patients in the SLN group underwent robotic-assisted procedures more frequently than those in the LND group (p < 0.0001). The three-year PFS rate was 71.1% (95% CI 51.3-84.0%) in the SLN group and 71.3% (95% CI 62.0-78.6%) in the LND group (p = 0.91). The unadjusted hazard ratio (HR) for recurrence in the SLN versus LND group was 1.11 (95% CI 0.56-2.18; p = 0.77), and after adjusting for age, adjuvant therapy, and surgical approach, the HR for recurrence was 1.04 (95% CI 0.47-2.30, p = 0.91). The three-year OS rate was 81.1% (95% CI 51.1-93.7%) in the SLN group and 95.1% (95% CI 89.4-97.8%) in the LND group (p = 0.009). Although the unadjusted HR for death was 3.74 in the SLN vs LND group (95% CI 1.39-10.09; p = 0.009), when adjusted for age, adjuvant therapy, and surgical approach, it was no longer significant with a HR of 2.90 (95% CI 0.94-8.95, p = 0.06). CONCLUSIONS: There was no difference in three-year PFS in patients diagnosed with high-risk EC who underwent SLN evaluation compared to those who underwent full LND in our cohort. The SLN group did experience shorter unadjusted OS; however, when adjusting for age, adjuvant therapy and surgical approach, there was no difference OS in patients who underwent SLN compared to LND.

Missing a chance to prevent: disparities in completion of genetic evaluation in high-risk patients with endometrial cancer.

OBJECTIVE: The primary goal of this study is to examine disparities in high-risk endometrial cancer (EC) patients in relation to rates of genetic referrals (GR), testing (GT), and counseling (GC). METHODS: This is a retrospective analysis of patients with newly diagnosed EC between January 1, 2014 and September 1, 2020 at a single institution. Patients were defined as high-risk EC patients when they were 1) diagnosed at 50 years or younger, 2) had a positive family history for cancer or 3) had evidence of loss of mismatch repair protein expression on tumor immunohistochemistry. Rates of GR, GT and GC were analyzed based on race, ethnicity, primary language and insurance status. RESULTS: During the study period, 674 patients were diagnosed with EC and 249 (36.9%) were considered high-risk EC patients. Among high-risk patients, 128 (51.2%) were referred to GT and GC. Of those referred, 103 (80.5%) underwent GT and 85 (66.4%) completed GC. Out of all high-risk patients, 20 (18.4%) were positive for LS on GT and 29 (28.2%) had VUS results. In multivariate analysis, the odds of GT and GC referral were lower among patients who identified as Hispanic (OR=0.40; 95% CI=0.19-0.87; p=0.020). Patients who identified as black were less likely to receive GC when compared to patients of other races (p=0.030). CONCLUSION: It is our hope that through this data we will increase awareness around existing disparities in genetic evaluation for patients with EC and ultimately create strategies to improve equitable access to care for all patients.

The use of Instagram by gynecologic oncology providers as a patient education tool for patients at high-risk of gynecologic cancer.

Social media outlets have increased in popularity within the last decade and are influencing the ways in which patients interact with the healthcare system. The objective of this study is to examine the presence of gynecologic oncology divisions on Instagram and to analyze the content of their posts. Secondary objectives included examining and analyzing the use of Instagram as a tool for patient education among people at increased genetic risk of gynecologic cancers. Seventy-one NCI-Designated Cancer Centers, their gynecologic oncology divisions and hereditary gynecologic cancer related posts were searched on Instagram. Content was reviewed and authorship was analyzed. Of the 71 NCI-designated Cancer Centers, 29 (40.8 %) had Instagram accounts, whereas, four (6 %) gynecologic oncology divisions had Instagram accounts. The search of the seven most common gynecologic oncology genetic terms yielded 126,750 posts with the majority under BRCA1(n = 56,900) and BRCA2 (n = 45,000) followed by Lynch syndrome (n = 14,700) and hereditary breast and ovarian cancer (n = 8,900). In terms of authorship, 93 (66 %) of all top 140 posts were written by patients, 20 (14.2 %) were written by health care providers and 27 (19.3 %) were written by "other." This study highlights the lack of presence of divisions of gynecologic oncology at NCI-designated Cancer Centers on Instagram but does demonstrate the existence of active discussion on hereditary gynecologic cancers on Instagram by patients.

SMAC Mimetics Synergistically Cooperate with HDAC Inhibitors Enhancing TNF-α Autocrine Signaling.

The overexpression of inhibitor of apoptosis (IAP) proteins is strongly related to poor survival of women with ovarian cancer. Recurrent ovarian cancers resist apoptosis due to the dysregulation of IAP proteins. Mechanistically, Second Mitochondrial Activator of Caspases (SMAC) mimetics suppress the functions of IAP proteins to restore apoptotic pathways resulting in tumor death. We previously conducted a phase 2 clinical trial of the single-agent SMAC mimetic birinapant and observed minimal drug response in women with recurrent ovarian cancer despite demonstrating on-target activity. Accordingly, we performed a high-throughput screening matrix to identify synergistic drug combinations with birinapant. SMAC mimetics in combination with an HDAC inhibitor showed remarkable synergy and was, therefore, selected for further evaluation. We show here that this synergy observed both in vitro and in vivo results from multiple convergent pathways to include increased caspase activation, HDAC inhibitor-mediated TNF-α upregulation, and alternative NF-kB signaling. These findings provide a rationale for the integration of SMAC mimetics and HDAC inhibitors in clinical trials for recurrent ovarian cancer where treatment options are still limited.

COVID-19 and Gynecologic Oncology: What Have We Learned?

OPINION STATEMENT: COVID-19 has transformed the care we provide to gynecologic oncology patients. In addition to directly impacting the diagnosis and treatment of women with gynecologic cancer, it has affected our patient's ability to undergo recommended surveillance and has made an impact on every caregiver providing care during this time. Herein we review the current literature on the impact of COVID-19 on gynecologic oncology and highlight new approaches and innovations that have resulted in gynecologic cancer care as a result of the pandemic. The impact of COVID-19 on the field of gynecologic oncology has been profound. In addition to directly impacting the diagnosis and treatment of women with cancer, it has also challenged the very ethics with which we practice medicine. The equitable distribution of resources is paramount to upholding the Hippocratic Oath which we all invoke. The COVID-19 pandemic has stripped this oath down to its very core, forcing all medical practitioners to scrutinize who gets what resources and when. As the pandemic continues to unfold, the question remains - in the setting of a strained and overburdened healthcare system, how do we maximize beneficence to one group of patients, while maintaining non-maleficence to others? As gynecologic oncologists, we are responsible for advocating for our patients to ensure that the quality of their cancer care is not compromised, while also not overutilizing resources that are sorely needed for the care of COVID-19 victims, and not making them more likely to succumb to COVID-19 by the very nature of the treatment we provide. The effects of the pandemic are far-reaching and broad, and many of these are yet to be determined. Future studies are needed to analyze how the above-utilized strategies in GYN cancer care during the pandemic will impact the long-term outcomes of our patients.

Adapting and avoiding coping strategies for women with ovarian cancer during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has resulted in unprecedented challenges for people living with cancer, impacting not only physical health but psychological well-being. The psychological response affects the individual as well as the community and can persist long after the outbreak. We aim to assess coping strategies employed by women with ovarian cancer during the COVID-19 pandemic. METHODS: Women with a current or prior diagnosis of ovarian cancer completed an online survey which included a query about coping strategies during the COVID-19 pandemic. The survey was distributed from March 30th through April 13, 2020 through survivor networks and social media. RESULTS: Six hundred and three women visited the survey website during the study period and 555 (92.0%) completed the survey. Four hundred and eight (73.5%) provided information on coping strategies utilized during COVID-19. Among those who responded, the median age was 58 years (range 20-85) and 150 participants (40.8%) were undergoing active cancer treatment. Commonly utilized adaptive coping strategies included emotional support (159, 39.0%), self care (148, 36.3%), hobbies (139, 34.1%), planning (87, 21.3%), positive reframing (54, 13.2%), religion (50, 12.3%) and instrumental support (38, 9.3%). Many participants also relied on avoidance coping strategies including self distraction (111, 27.2%) and substance use (19, 4.7%). CONCLUSIONS: Most ovarian cancer survivors are using adaptive, problem-focused coping strategies during the COVID-19 pandemic, however many are practicing avoidance strategies as well. As coping mechanisms profoundly impact quality of life, oncology providers must assist patients in identifying coping strategies that optimize physical and psychological well-being.

Matrix Drug Screen Identifies Synergistic Drug Combinations to Augment SMAC Mimetic Activity in Ovarian Cancer.

Inhibitor of apoptosis (IAP) proteins are frequently upregulated in ovarian cancer, resulting in the evasion of apoptosis and enhanced cellular survival. Birinapant, a synthetic second mitochondrial activator of caspases (SMAC) mimetic, suppresses the functions of IAP proteins in order to enhance apoptotic pathways and facilitate tumor death. Despite on-target activity, however, pre-clinical trials of single-agent birinapant have exhibited minimal activity in the recurrent ovarian cancer setting. To augment the therapeutic potential of birinapant, we utilized a high-throughput screening matrix to identify synergistic drug combinations. Of those combinations identified, birinapant plus docetaxel was selected for further evaluation, given its remarkable synergy both in vitro and in vivo. We showed that this synergy results from multiple convergent pathways to include increased caspase activation, docetaxel-mediated TNF-α upregulation, alternative NF-kB signaling, and birinapant-induced microtubule stabilization. These findings provide a rationale for the integration of birinapant and docetaxel in a phase 2 clinical trial for recurrent ovarian cancer where treatment options are often limited and minimally effective.

Evaluation of the Anti-Tumor Activity of the Humanized Monoclonal Antibody NEO-201 in Preclinical Models of Ovarian Cancer.

Purpose: Despite high initial response rates with cytoreductive surgery, conventional chemotherapy and the incorporation of biologic agents, ovarian cancer patients often relapse and die from their disease. New approaches are needed to improve patient outcomes. This study was designed to evaluate the antitumor activity of NEO-201 monoclonal antibody (mAb) in preclinical models of ovarian cancer where the NEO-201 target is highly expressed. Experimental Design: Functional analysis of NEO-201 against tumor cell lines was performed by antibody-dependent cellular cytotoxicity (ADCC) assays. Binding of NEO-201 to tumor tissues and cell lines were determined by immunohistochemistry (IHC) and flow cytometry, respectively. Further characterization of the antigen recognized by NEO-201 was performed by mass spectrometry. Ovarian cancer models were used to evaluate the anti-tumor activity of NEO-201 in vivo. NEO-201 at a concentration of 250 g/mouse was injected intraperitoneally (IP) on days 1, 4, and 8. Human PBMCs were injected IP simultaneously as effector cells. Results: Both IHC and flow cytometry revealed that NEO-201 binds prominently to the colon, pancreatic, and mucinous ovarian cancer tissues and cell lines. Immunoprecipitation of the antigen recognized by NEO-201 was performed in human ovarian, colon, and pancreatic cancer cell lines. From these screening, carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and CEACAM6 were identified as the most likely targets of NEO-201. Our results confirmed that NEO-201 binds different types of cancers; the binding is highly selective for the tumor cells without cross reactivity with the surrounding healthy tissue. Functional analysis revealed that NEO-201 mediates ADCC killing against human ovarian and colorectal carcinoma cell lines in vitro. In addition, NEO-201 inhibited tumor growth in the presence of activated human PBMCs in orthotopic mouse models of both primary and metastatic ovarian cancer. Importantly, NEO-201 prolonged survival of tumor-bearing mice. Conclusions: These data suggested that NEO-201 has an antitumor activity against tumor cells expressing its antigen. Targeting an antigen expressed in tumors, but not in normal tissues, allows patient selection for optimal treatment. These findings strongly indicate that NEO-201 warrants clinical testing as both a novel therapeutic and diagnostic agent for treatment of ovarian carcinomas. A first in human clinical trial evaluating NEO-201 in adults with chemo-resistant solid tumors is ongoing at the NIH clinical Center.

Impact of the coronavirus disease 2019 pandemic on the quality of life for women with ovarian cancer.

BACKGROUND: The coronavirus disease 2019 pandemic has resulted in unprecedented challenges for the oncology community. For people living with cancer, treatments are interrupted, surgeries cancelled, and regular oncology evaluations rescheduled. People with cancer and their physicians must balance plausible fears of coronavirus disease 2019 and cancer treatment with the consequences of delaying cancer care. OBJECTIVE: We aim to evaluate the experience of women with ovarian cancer during the coronavirus disease 2019 pandemic. STUDY DESIGN: Women with a current or previous diagnosis of ovarian cancer completed an online survey focusing on treatment interruptions and quality of life. The quality of life was measured with the Cancer Worry Scale and Hospital Anxiety and Depression Scale. The survey was distributed through survivor networks and social media. Univariate and multivariable linear regression analysis were used to evaluate the effect of participant characteristics on quality of life survey scores. RESULTS: A total of 603 women, from 41 states, visited the survey website between March 30, 2020, and April 13, 2020, and 555 (92.0%) completed the survey. The median age was 58 years (range, 20-85). At the time of survey completion, 217 participants (43.3%) were in active treatment. A total of 175 participants (33%) experienced a delay in some component of their cancer care. Ten (26.3%) of the 38 participants scheduled for surgery experienced a delay, as did 18 (8.3%) of the 217 participants scheduled for nonsurgical cancer treatment. A total of 133 participants (24.0%) had a delayed physician appointment, 84 (15.1%) laboratory tests, and 53 (9.6%) cancer-related imaging. Among the cohort, 88.6% (489) reported significant cancer worry, 51.4% (285) borderline or abnormal anxiety, and 26.5% (147) borderline or abnormal depression. On univariate analysis, age less than 65 years, being scheduled for cancer treatment or cancer surgery, delay in oncology care, being self-described as immunocompromised, and use of telemedicine were all associated with higher levels of cancer worry. Higher anxiety scores were associated with age less than 65 years and being self-described as immunocompromised. Higher depression scores were associated with age less than 65 years, being scheduled for cancer surgery, delay in oncology care, being self-described as immunocompromised, and use of telemedicine. On multivariable linear regression analysis, age less than 65 and being self-described as immunocompromised were independently predictive of greater cancer worry, anxiety, and depression, and delay in cancer care was predictive of anxiety and depression. CONCLUSION: The coronavirus disease 2019 crisis is affecting care of patients with ovarian cancer; surgeries, treatments, scheduled physician appointments, laboratory tests, and imaging are cancelled or delayed. Younger age, presumed immunocompromise, and delay in cancer care were associated with significantly higher levels of cancer worry, anxiety, and depression. Providers must work with patients to balance competing risks of coronavirus disease 2019 and cancer, recognizing that communication is a critical clinical tool to improve quality of life in these times.

Sixteen year-old with leiomyosarcoma in a prior benign myomectomy site.

Uterine leiomyosarcoma in a prior myomectomy site is a rare phenomenon. We report an unusual case of a leiomyosarcoma arising six months post myomectomy in a 16-year old female.

Molecular Pathways: The Balance between Cancer and the Immune System Challenges the Therapeutic Specificity of Targeting Nuclear Factor-κB Signaling for Cancer Treatment.

The NF-κB signaling pathway is a complex network linking extracellular stimuli to cell survival and proliferation. Cytoplasmic signaling to activate NF-κB can occur as part of the DNA damage response or in response to a large variety of activators, including viruses, inflammation, and cell death. NF-κB transcription factors play a fundamental role in tumorigenesis and are implicated in the origination and propagation of both hematologic and solid tumor types, including melanoma, breast, prostate, ovarian, pancreatic, colon, lung, and thyroid cancers. On the other hand, NF-κB signaling is key to immune function and is likely necessary for antitumor immunity. This presents a dilemma when designing therapeutic approaches to target NF-κB. There is growing interest in identifying novel modulators to inhibit NF-κB activity as impeding different steps of the NF-κB pathway has potential to slow tumor growth, progression, and resistance to chemotherapy. Despite significant advances in our understanding of this pathway, our ability to effectively clinically block key targets for cancer therapy remains limited due to on-target effects in normal tissues. Tumor specificity is critical to developing therapeutic strategies targeting this antiapoptotic signaling pathway to maintain antitumor immune surveillance when applying such therapy to patients. Clin Cancer Res; 22(17); 4302-8. ©2016 AACR.

A clinicopathologic study of vaginal intraepithelial neoplasia.

OBJECTIVE: To evaluate the natural history of vaginal intraepithelial neoplasia (VAIN) and to identify risk factors for invasive vaginal carcinoma. METHODS: The records of all women with VAIN diagnosed at military treatment facilities over a 10-year period with minimum follow-up of 12 months were reviewed. Patient demographics and clinical information related to the diagnosis and treatment of VAIN were recorded. RESULTS: One hundred twenty-seven women with VAIN met inclusion criteria. The mean age was 47.4 years, and median surveillance was 34 months (range 12-169 months). Seventy-five patients had low-grade vaginal dysplasia as their initial diagnosis, and 15 (20%) of these patients underwent treatment. Fifty-two patients had high-grade vaginal dysplasia, of which 38 (73%) underwent treatment. Overall, 113 patients (89%) demonstrated normalization of disease, 11 patients (9%) demonstrated persistence of disease, and three patients (2%) experienced recurrence of disease. No patients experienced development of invasive vaginal carcinoma. However, median time to normalization was 6 months longer in patients with low-grade dysplasia compared with those with high-grade dysplasia (15.9 months compared with 10.0 months; hazard ratio 1.5; 95% confidence interval 1.004-2.1; P=.045). Patients with high-grade dysplasia had more biopsies performed during their surveillance than patients with low-grade dysplasia (3.3 compared with 2.5; P=.045). CONCLUSION: Overall, 89% of patients demonstrated normalization of VAIN, and none had progression to invasive cancer. Normalization, persistence, and recurrence rates did not significantly differ by grade of dysplasia or treatment status. Based on our findings regarding the time to normalization, annual surveillance with combined cytology and colposcopy is likely adequate. Because 11% of patients with VAIN either will experience recurrence or will have persistent disease, lifetime surveillance is recommended. LEVEL OF EVIDENCE: : III.

Takotsubo cardiomyopathy following laparoscopic port placement in a patient with ovarian cancer.

► Gynecologic oncology patients can be exposed to both chronic and acute physical and emotional stress. ► Gynecologic oncology patients appear to represent an at-risk population for the development of Takotsubo's cardiomyopathy.