Kristin Leigh Bixel

All Publications

• Sentinel Lymphadenectomy for Early-Stage Cervical Cancer - the New Standard? The New England journal of medicine Bixel, K. 2025; 393 (15): 1534-1536

  View details for DOI 10.1056/NEJMe2509846

  View details for PubMedID 41092335

• Exceptional response to trastuzumab deruxtecan in recurrent neuroendocrine cervical cancer: A case report GYNECOLOGIC ONCOLOGY REPORTS Tostrud, L., Howitt, B. E., Mills, M., Karam, A., Bixel, K. L. 2025; 60

  View details for DOI 10.1016/j.gore.2025.101798

  View details for Web of Science ID 001523391400001

• Exceptional response to trastuzumab deruxtecan in recurrent neuroendocrine cervical cancer: A case report. Gynecologic oncology reports Tostrud, L., Howitt, B. E., Mills, M., Karam, A., Bixel, K. L. 2025; 60: 101798

  Abstract

  Neuroendocrine cervical carcinomas (NECC) are a rare and aggressive cervical cancer subtype that account for 1-1.5 % of all cervical cancers. Treatment options for recurrent NECC are limited and anticipated response rates are low. Trastuzumab deruxtecan (T-DXd), an antibody drug conjugate with a topoisomerase I inhibitor payload, recently received FDA approval for previously treated patients with HER2+ (IHC3 + ) metastatic solid tumors. Data regarding use of T-DXd in NECC is very limited and it is unclear whether this histology was represented in the trial leading to approval. We sought to describe this unique case of a patient with recurrent NECC who experienced a complete and durable response to T-DXd.This is a case report and review of the literature. Written informed consent was obtained by the patient prior to submission.We describe a 44-year-old patient with recurrent, metastatic NECC who progressed following two prior lines of therapy, the most recent of which included a multi-drug regimen with topotecan (a topoisomerase I inhibitor). IHC of her tumor tissue demonstrated 3 + HER 2 expression leading to the decision to proceed with treatment with T-DXd. She experienced a partial response (64 % decrease by RECIST) at C6 and subsequent complete response which has now been maintained for > 1 year. She has tolerated therapy well with manageable toxicities and has not required treatment interruption to date.This report demonstrates the role of biomarker driven therapy for rare and aggressive cancer subtypes such as NECC and demonstrates efficacy of T-DXd after previous exposure to topoisomerase I inhibitors.

  View details for DOI 10.1016/j.gore.2025.101798

  View details for PubMedID 40678579

  View details for PubMedCentralID PMC12269842

• Atezolizumab and Stereotactic Body Radiation in Metastatic, Recurrent, or Persistent Cervical Cancer: Results from a Phase II Multi-Institutional Study. International journal of radiation oncology, biology, physics Ahmed, K. A., Quick, A. M., Chon, H. S., Chern, J. Y., Bixel, K., Kim, Y., Li, J., Montejo, M. E., Dowell, R. A., Kim, S., Fernandez, D. C., Lam, C. A., Hakam, A., Rosa, M., Shafique, M., Shahzad, M. M., Wenham, R. M. 2025

  Abstract

  Pembrolizumab is approved for PD-L1+ but not PD-L1 negative metastatic, recurrent, or persistent cervical cancer. Response rates to single agent anti-PD-1/PD-L1 therapy have been modest with no responses noted in PD-L1 negative tumors.The study is designed as a prospective, phase II multi-institutional trial of SBRT followed by atezolizumab (1200 mg intravenously q3 weeks). Key eligibility criteria included patients with metastatic, recurrent, or persistent cervical cancer with at least 2 distinct lesions. The primary objective was objective response rate measured at the unirradiated target lesion.NCTXX.A total of 21 patients were enrolled. Median follow-up is 23.6 months. The majority of patients had adenocarcinoma (n=10; 48%) and were PD-L1 negative (n=15; 71%). The best overall response was a partial response in 5 (24%) and stable disease in 12 (57%) patients. The median duration of response was 8.6 months (95% CI: 4.5-13.6 months). An objective response at the unirradiated target lesion was observed in 8 patients (38%), meeting the study defined endpoint. Responses were noted in PD-L1 negative tumors. The most common grade ≥ 2 toxicities at least possibly attributed to study therapy included lymphopenia (n=6; 29%), nausea/vomiting (n=3; 14%), and hyponatremia (n=3; 14%).In this first trial of SBRT and atezolizumab in metastatic cervical cancer unselected for PD-L1, combination therapy was well tolerated. Responses were noted in PD-L1 negative tumors. Combination therapy may allow for improved response rates to immune checkpoint inhibition in metastatic cervical cancer particularly in PD-L1 negative tumors.

  View details for DOI 10.1016/j.ijrobp.2025.05.003

  View details for PubMedID 40379142

• ROCC/GOG-3043: a randomized controlled trial of robotic versus open surgery for early-stage cervical cancer. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society Leitao, M. M., Bixel, K. L., Chase, D. M., Quick, A., McCormick, C., Black, D., Lim, P. C., Eskander, R. N., Gotlieb, W. H., LoCoco, S., Martino, M. A., Walker, J. L., Copeland, L. J., Monk, B. J., Randall, L. M. 2025: 101760

  Abstract

  The Laparoscopic Approach to Cervical Cancer trial is the only randomized trial to date addressing the role of surgical approach in cervical cancer; however, this non-inferiority trial of minimally invasive surgery vs an open approach in patients undergoing radical hysterectomy for early-stage cervical cancer did not meet its primary end point of 4.5-year disease-free survival and was terminated early because of significantly worse disease-specific survival, overall survival, and locoregional recurrence in the minimally invasive surgery cohort.Our trial compares 3-year disease-free survival after robotic-assisted or abdominal radical or simple (in select cases) hysterectomy in early-stage cervical cancer.We hypothesize that disease-free survival is non-inferior after robotic-assisted vs abdominal radical or simple hysterectomy.This multi-center, randomized non-inferiority trial conducted through the Gynecologic Oncology Group has specified surgeon qualification criteria. It requires a pelvic magnetic resonance imaging scan in all patients before enrollment and will use 1:1 randomization to assign patients to robotic-assisted or abdominal hysterectomy. All surgeons must use specified tumor-containment techniques in both arms. It does not allow trans-cervical uterine manipulators.Patients with early-stage (2018 International Federation of Gynecology and Obstetrics stages IA2-IB2) cervical cancer. Histologic types are limited to squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma. Pelvic magnetic resonance imaging must confirm a tumor that is 4 cm or less without definitive extra-cervical spread. A simple hysterectomy is allowed in select cases after trial study principal investigator review.The primary end point is the 3-year disease-free survival between robotic-assisted or abdominal hysterectomy.The trial will randomly allocate 840 patients, with planned interim analysis for futility (oncologic safety) after we have randomly allocated 370 and 640 patients.2030.ClinicalTrials.gov identifier: NCT04831580.

  View details for DOI 10.1016/j.ijgc.2025.101760

  View details for PubMedID 40188007

• Defining "enlarged" sentinel lymph nodes in the setting of endometrial cancer: What is the size cut-off? Gynecologic oncology Haight, P., Bilbe, C., Riedinger, C., Backes, F., Bixel, K., Chambers, L., Cohn, D., Copeland, L., Nagel, C., O'Malley, D., Suarez, A. A., Esnakula, A., Cosgrove, C. M. 2025; 194: 80-85

  Abstract

  Sentinel lymph node (SLN) mapping has become standard-of-care in endometrial cancer surgical staging. While removal of "enlarged" lymph nodes is recommended regardless of SLN mapping, there is no data to support definitive size criteria for intra-operative assessment. We sought to assess the size of negative and positive SLN in surgically-staged endometrial cancer patients.Surgically-staged endometrial cancer patients undergoing SLN assessment of at least one hemipelvis at a single comprehensive cancer center were retrospectively reviewed from 2017 to 2020. SLN were categorized as negative (benign) or positive (metastatic). SLN size was defined as the largest diameter (cm) of the SLN as measured in the gross description of the surgical pathology report. Size of negative and positive SLN was compared using descriptive statistics.Of 597 patients, 575 had an evaluable negative SLN, and median size was 2.0 cm [0.4-4.5 cm]. 39 patients had an evaluable positive SLN, and median size was 2.1 cm [0.5-4.9 cm]. Lymph node size ≥2 cm was 67 % sensitive and 49 % specific for detecting metastatic disease. Age < 50 and BMI ≥30 were associated with larger lymph node size (p = 0.04 and p = 0.028, respectively). For evaluable positive SLN, mismatch repair (MMR) IHC (n = 39), and p53 IHC (n = 18) did not impact size (p = 0.71 and p = 0.83, respectively).Negative and positive SLN are similar in size, thus SLN size is a poor predictor of metastasis in patients undergoing surgical staging of endometrial cancer. Intra-operative assessment of size should not serve as sole indication for targeted lymph node removal.

  View details for DOI 10.1016/j.ygyno.2025.02.007

  View details for PubMedID 39970634

• Adjuvant hormone therapy and overall survival among low-grade and apparent early-stage endometrial stromal sarcoma patients. Journal of gynecologic oncology Bixel, K. L., Meade, C. E., Brown, M., Felix, A. S. 2024

  Abstract

  Surgery is the mainstay of treatment for low-grade endometrial stromal sarcoma (LG-ESS). While adjuvant hormone therapy is recommended for patients with advanced/recurrent disease, no consensus regarding its use among early-stage patients exists. We aimed to identify correlates of adjuvant hormone therapy use and associations of adjuvant hormone therapy and overall survival (OS) in stage I LG-ESS patients.Retrospective cohort study of patients with stage I LG-ESS who underwent hysterectomy from 2004-2019 using data from the National Cancer Database. Categorical data were compared using χ² tests. Kaplan-Meier estimates and log-rank tests were used to compare OS according to adjuvant hormone use. Hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between adjuvant hormone use and OS were estimated using Cox proportional hazards regression.Of 2,386 patients included, 20.2% were treated with adjuvant hormonal therapy. Use of hormone therapy increased over time, with rates approximately doubling from 2004 to 2019 (12.6% to 24.6%). Age, tumor size, lymphovascular space invasion and adjuvant radiation were associated with adjuvant hormone therapy use. There was no association between adjuvant hormone therapy and OS (log-rank p=0.73; HR=1.05; 95% CI 0.76-1.46) for patients with LG-ESS.Use of adjuvant hormone therapy for stage I LG-ESS has increased over time though is not associated with OS in this cohort of patients. Additional evaluation is needed to understand the impact of adjuvant hormone therapy on recurrence rates, progression rates, and quality of life to fully understand its value.

  View details for DOI 10.3802/jgo.2025.36.e50

  View details for PubMedID 39727414

• Changes in anthropometry, adiposity, and inflammation in Black and White women engaged in intentional weight loss. Obesity (Silver Spring, Md.) Felix, A. S., Sinnott, J. A., Caan, B. J., Gillespie, S. L., Meade, C. E., Strafford, K. E., Cosgrove, C. M., Soma, L., Noria, S., Bixel, K. L., Salani, R., Nagel, C. I., Chambers, L. M., Cohn, D. E., Suarez, A. A., Paskett, E. D. 2024; 32 (12): 2398-2409

  Abstract

  We examined associations among changes in anthropometry, regional adiposity, and inflammatory markers in Black and White women participating in intentional weight loss.A total of 104 women with BMI ≥ 25 kg/m2 self-selected bariatric surgery (n = 66) or a diet and exercise program (n = 38). Anthropometric, dual-energy x-ray absorptiometry-quantified regional adiposity, and inflammatory markers (C-reactive protein [CRP], tumor necrosis factor α [TNF-α], soluble TNF receptor I [sTNFRI], sTNFRII, interleukin [IL]-6, and soluble IL-1 receptor antagonist) were measured at baseline and 6 months.Weight, BMI, visceral adipose tissue, and regional (android and gynoid) adiposity declined in the bariatric surgery group. Among bariatric surgery participants, Black women experienced declines of lesser magnitude in terms of weight and BMI than White women, but changes in regional adiposity and visceral adipose tissue did not differ. In the bariatric surgery group, decreases in weight and BMI were associated with decreases in CRP and IL-6 among White women, but not Black women. Decreases in weight, BMI, and android fat were associated with increases in TNF-α, sTNFRI, and sTNFRII among Black women, but not White women.Decreases in anthropometry and adiposity were observed among Black and White bariatric surgery participants; however, associations among changes in adiposity, anthropometry, and inflammation differed by race.

  View details for DOI 10.1002/oby.24151

  View details for PubMedID 39496520

  View details for PubMedCentralID PMC11589538

• Cold ischemia time and formalin fixation time in endometrial cancer: Should breast cancer guidelines for preanalytical variables be applied to hysterectomy specimens? Gynecologic oncology Haight, P. J., Lammers, S., Kistenfeger, Q., Leipold, C., Suarez, A. A., Tozbikian, G. H., Esnakula, A., Cosgrove, C., Bixel, K. L. 2024; 191: 194-200

  Abstract

  The American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) recommend cold ischemia time (cIT) be <60 min, and formalin fixation time (FFT) 6-72 h, to optimize immunohistochemistry (IHC) based on breast cancer data. We assessed whether cIT and FFT impact IHC in endometrial cancer (EC), and determined which factors affect cIT and FFT.Surgical EC cases from 2019 to 2023 were reviewed. cIT was calculated by subtracting time of tissue devascularization intra-operatively from time the specimen was placed in formalin. Demographics, clinicopathologic and peri-operative factors, and IHC for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and mismatch repair (MMR) proteins were compared between patients with cIT <60 min versus ≥60 min (prolonged), and compliant FFT (6-72 h) versus non-compliant FFT (<6 or > 72 h). Categorical variables were compared using χ2 tests.941 patients were included in the analysis. Median cIT was 33 min. Prolonged cIT occurred in 95 (10 %) cases. African American/Black race (p < 0.001), advanced stage (p < 0.001), mini-laparotomy (p < 0.001), performance of surgical procedures beyond standard EC staging (p < 0.001), longer surgical length (p < 0.001), and increased uterine weight (p < 0.001) were independently associated with prolonged cIT. There were no significant differences in ER, PR, HER2, or MMR protein expression based on cIT or FFT.Prolonged cIT was not associated with differences in biomarker expression via IHC at time of surgical staging for EC. Despite variability in cIT, which is largely due to non-modifiable factors, tumor molecular features remain consistent and can reliably be utilized for prognostic and therapeutic decision-making.

  View details for DOI 10.1016/j.ygyno.2024.10.015

  View details for PubMedID 39442372

• Inhibition of Bruton's tyrosine kinase with PD-1 blockade modulates T cell activation in solid tumors. JCI insight Schwarz, E., Benner, B., Wesolowski, R., Quiroga, D., Good, L., Sun, S. H., Savardekar, H., Li, J., Jung, K. J., Duggan, M. C., Lapurga, G., Shaffer, J., Scarberry, L., Konda, B., Verschraegen, C., Kendra, K., Shah, M., Rupert, R., Monk, P., Shah, H. A., Noonan, A. M., Bixel, K., Hays, J., Wei, L., Pan, X., Behbehani, G., Hu, Y., Elemento, O., Chung, D., Xin, G., Blaser, B. W., Carson, W. E. 2024; 9 (21)

  Abstract

  BACKGROUNDInhibition of Bruton's tyrosine kinase with ibrutinib blocks the function of myeloid-derived suppressor cells (MDSC). The combination of ibrutinib and nivolumab was tested in patients with metastatic solid tumors.METHODSSixteen patients received ibrutinib 420 mg p.o. daily with nivolumab 240 mg i.v. on days 1 and 15 of a 28-day cycle. The effect of ibrutinib and nivolumab on MDSC, the immune profile, and cytokine levels were measured. Single-cell RNA-Seq and T cell receptor sequencing of immune cells was performed.RESULTSCommon adverse events were fatigue and anorexia. Four patients had partial responses and 4 had stable disease at 3 months (average 6.5 months, range 3.5-14.6). Median overall survival (OS) was 10.8 months. Seven days of Bruton's tyrosine kinase (BTK) inhibition significantly increased the proportion of monocytic-MDSC (M-MDSC) and significantly decreased chemokines associated with MDSC recruitment and accumulation (CCL2, CCL3, CCL4, CCL13). Single-cell RNA-Seq revealed ibrutinib-induced downregulation of genes associated with MDSC-suppressive function (TIMP1, CXCL8, VEGFA, HIF1A), reduced MDSC interactions with exhausted CD8+ T cells, and decreased TCR repertoire diversity. The addition of nivolumab significantly increased circulating NK and CD8+ T cells and increased CD8+ T cell proliferation. Exploratory analyses suggest that MDSC and T cell gene expression and TCR repertoire diversity were differentially affected by BTK inhibition according to patient response.CONCLUSIONIbrutinib and nivolumab were well tolerated and affected MDSC and T cell function in patients with solid metastatic tumors.TRIAL REGISTRATIONClinicalTrials.gov NCT03525925.FUNDINGNIH; National Cancer Institute Cancer; National Center for Advancing Translational Sciences; Pelotonia.

  View details for DOI 10.1172/jci.insight.169927

  View details for PubMedID 39513363

  View details for PubMedCentralID PMC11601564

• Postoperative venous thromboembolism risk in patients with vulvar carcinoma: An analysis of the National surgical Quality Improvement Program (NSQIP) database. Gynecologic oncology reports Kistenfeger, Q., Felix, A. S., Meade, C. E., Wagner, V., Bixel, K., Chambers, L. M. 2024; 54: 101411

  Abstract

  Due to low incidence of vulvar cancer (VC), incidence and predictors for development of venous thromboembolism (VTE) are poorly understood. We examined incidence and risk factors associated with VTE in patients undergoing surgery for VC.We included patients who underwent surgery for VC from the National Surgical Quality Improvement Program database. VTE within the 30-day postoperative period was captured with Current Procedural Terminology codes. Baseline demographics and clinical characteristics were compared between patients with and without VTE. Univariable and multivariable-adjusted exact logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between risk factors and VTE.We identified 1414 patients undergoing procedures for VC from the NSQIP database. Overall, 11 (0.8 %) patients developed VTE. Univariable predictors of VTE included surgery type [compared with simple vulvectomy: radical vulvectomy only (OR = 7.97, 95 % CI = 1.44, infinity) and radical vulvectomy plus unilateral IFN (OR = 15.98, 95 % CI = 2.70, infinity)], unplanned readmission (OR = 11.56, 95 % CI = 2.74, 46.38), deep surgical site infection (OR = 16.05, 95 % CI = 1.59-85.50), and preoperative thrombocytosis (OR = 6.53, 95 % CI = 0.00, 34.86). In a multivariable-adjusted model, longer operative time (≥72 min OR = 11.33, 95 % CI = 1.58-499.03) and preoperative functional status [compared with complete independence: total dependence (OR = 53.88, 95 % CI = 0.85, infinity) and partial dependence (OR = 53.88, 95 % CI = 0.85, infinity)] were associated with VTE.In this cohort of patients with VC undergoing radical vulvectomy, VTE incidence was low. Surgery type, longer operative time, dependent functional status, and wound disruption were identified as risk factors. Our findings highlight opportunities for prophylactic intervention in certain patients.

  View details for DOI 10.1016/j.gore.2024.101411

  View details for PubMedID 38803657

  View details for PubMedCentralID PMC11128827

• Does the choice of platinum doublet matter? A study to evaluate the impact of platinum doublet choice for treatment of platinum-sensitive ovarian cancer recurrence on the development of future PARP inhibitor and platinum resistance. Gynecologic oncology Levine, M. D., Wang, H., Sriram, B., Khan, A., Senter, L., McLaughlin, E. M., Bixel, K. L., Chambers, L. M., Cohn, D. E., Copeland, L. J., Cosgrove, C. M., Nagel, C. I., O'Malley, D. M., Backes, F. J. 2024; 182: 51-56

  Abstract

  The use of a platinum doublet for the treatment of platinum-sensitive epithelial ovarian cancer (EOC) recurrence is well established. The impact of the non‑platinum chemotherapy used as part of a platinum doublet on PARP inhibitor (PARPi) and platinum sensitivity it not known. We aimed to describe oncologic outcomes in cases of recurrent EOC receiving PARPi as maintenance therapy based on preceding platinum doublet.Retrospective study of patients with platinum-sensitive recurrent ovarian, fallopian tube or primary peritoneal cancer treated with platinum doublet followed by maintenance PARPi from 1/1/2015 and 1/1/2022. Comparisons were made between patients receiving carboplatin + pegylated liposomal doxorubicin (CD) versus other platinum doublets (OPDs). Descriptive statistics, Kaplan-Meier and univariate survival analyses were performed.100 patients received PARPi maintenance following a platinum doublet chemotherapy regimen for platinum-sensitive recurrence. 25/100 (25%) received CD and 75/100 (75%) received OPDs. Comparing CD and OPDs, median progression-free survival was 8 versus 7 months (p = 0.26), median time to platinum resistance was 15 versus 13 months (p = 0.54), median OS was 64 versus 90 months (p = 0.28), and median OS from starting PARPi was 25 versus 26 months (p = 0.90), respectively.Using pegylated liposomal doxorubicin as part of a platinum doublet preceding maintenance PARPi for platinum-sensitive recurrence does not seem to hasten PARPi resistance or platinum resistance compared to OPDs. Although there was a non-significant trend towards increased OS among patients who received a platinum doublet other than CD prior to PARPi, the OS from PARPi start was similar between groups. Given the retrospective nature of this study and small study population, further research is needed to evaluate if the choice of platinum doublet preceding PARPi maintenance impacts PARPi resistance, platinum resistance and survival.

  View details for DOI 10.1016/j.ygyno.2023.12.008

  View details for PubMedID 38262238

• Changes in prospectively collected patient-reported outcomes among women with incident endometrial cancer. Journal of cancer survivorship : research and practice Sinnott, J. A., Torkashvand, E., Meade, C. E., Salani, R., Vetter, M. H., Hall, B., Skolnick, R., Bixel, K. L., Cohn, D. E., Cosgrove, C. M., Copeland, L. J., Hebert, C., Felix, A. S. 2024

  Abstract

  We examined associations between patient and treatment characteristics with longitudinally collected patient-reported outcome (PRO) measures to provide a data-informed description of the experiences of women undergoing treatment for endometrial cancer.We administered National Institutes of Health Patient Reported Outcomes Measurement Information System (PROMIS) questionnaires at the preoperative visit and at 6 and 12 months after surgery. Anxiety, depression, fatigue, sleep disturbance, pain, physical function, and ability to participate in social roles were assessed. Analysis of variance (ANOVA) and linear mixed models were used to examine associations between patient characteristics and PRO measures at baseline and through time.Of 187 women enrolled, 174 (93%) and 103 (69%) completed the 6- and 12-month questionnaires, respectively. Anxiety was substantially elevated at baseline (half of one population-level standard deviation) and returned to general population mean levels at 6 and 12 months. Younger age, Medicaid/None/Self-pay insurance, prevalent diabetes, and current smoking were associated with higher symptom burden on multiple PRO measures across the three time points. Women with aggressive histology, higher disease stage, or those with adjuvant treatment had worse fatigue at 6 months, which normalized by 12 months.We observed a high symptom burden at endometrial cancer diagnosis, with most PRO measures returning to general population means by 1 year. Information on risk factor-PRO associations can be used during the clinical visit to inform supportive service referral.These findings can inform clinicians' discussions with endometrial cancer survivors regarding expected symptom trajectory following diagnosis and treatment.

  View details for DOI 10.1007/s11764-024-01536-z

  View details for PubMedID 38265703

  View details for PubMedCentralID 4946989

• Radical hysterectomy case volume and cervical cancer treatment in the era of COVID-19: A multi-site analysis of National Cancer Institute-designated Comprehensive Cancer Centers. Gynecologic oncology Wickenheisser, N. E., Dillon, M., Broadwater, G., Zacherl, K., Bixel, K., Levine, M., Newton, M., Thel, H., Tucker, K., Gehrig, P., Khetan, V. U., Brunette-Masi, L. L., Matsuo, K., Khouri, O. R., Duhon, A., Gowthaman, D., Cowan, M., Mojdehbakhsh, R., Rose, S., Olawaiye, A., Davidson, B. A., Moss, H. A., Havrilesky, L. J. 2023; 179: 70-78

  Abstract

  To compare radical hysterectomy case volume, cancer stage, and biopsy-to-treatment time of invasive cervical cancer diagnosed before and after onset of the COVID-19 pandemic.In a multi-institution retrospective cohort study conducted at 6 large, geographically diverse National Cancer Institute-designated cancer centers, patients treated for newly diagnosed invasive cervical cancer were classified into 2 temporal cohorts based on date of first gynecologic oncology encounter: (1) Pre-Pandemic: 3/1/2018-2/28/2020; (2) Pandemic & Recovery: 4/1/2020-12/31/2021. The primary outcome was total monthly radical hysterectomy case volume. Secondary outcomes were stage at diagnosis and diagnosis-to-treatment time. Statistical analyses used chi-squared and two sample t-tests.Between 3/1/2018-12/31/2021, 561 patients were diagnosed with cervical cancer. The Pre-Pandemic and Pandemic & Recovery cohorts had similar age, race, ethnicity, smoking status, and Body Mass Index (BMI). During Pandemic & Recovery, the mean monthly radical hysterectomy case volume decreased from 7[SD 2.8] to 5[SD 2.0] (p = 0.001), the proportion of patients diagnosed with Stage I disease dropped from 278/561 (49.5%) to 155/381 (40.7%), and diagnosis of stage II-IV disease increased from 281/561 (50.1%) to 224/381 (58.8%). Primary surgical management was less frequent (38.3% Pandemic & Recovery versus 46.7% Pre-Pandemic, p = 0.013) and fewer surgically-treated patients received surgery within 6 weeks of diagnosis (27.4% versus 38.9%; p = 0.025).Lower radical hysterectomy case volume, a shift to higher cervical cancer stage, and delay in surgical therapy were observed across the United States following the COVID-19 outbreak. Decreased surgical volume may result from lower detection of early-stage disease or other factors.

  View details for DOI 10.1016/j.ygyno.2023.10.010

  View details for PubMedID 37944328

• The impact of antibiotic and proton pump inhibitor use at the time of adjuvant platinum-based chemotherapy on survival in patients with endometrial cancer. Gynecologic oncology Haight, P. J., Kistenfeger, Q., Riedinger, C. J., Khadraoui, W., Backes, F. J., Bixel, K. L., Copeland, L. J., Cohn, D. E., Cosgrove, C. M., O'Malley, D. M., Nagel, C. I., Spakowicz, D. J., Chambers, L. M. 2023; 178: 14-22

  Abstract

  We sought to assess the impact of antibiotic (ABX) and proton-pump inhibitor (PPI) use on progression-free (PFS) and overall survival (OS) in patients treated with adjuvant platinum-based chemotherapy (PC) for endometrial cancer (EC).A retrospective, single-institution cohort study of EC patients treated with ≥four cycles of adjuvant PC following surgical staging from 2014 to 2020. Demographics and clinicopathologic features, including ABX and PPI use, were compared using χ2 and Fisher's exact tests. Univariate and multivariable analyses were performed, and survival outcomes were compared using the log-rank test.Of 325 patients, 95 (29%) received ABX, and 80 (24.6%) received PPI. ABX were associated with decreased 3-year PFS (49.9% vs. 66%; p = 0.0237) but not 3-year OS (68.9% vs. 79.9%; p = 0.0649). ABX targeting gram-positive bacteria were associated with decreased 3-year PFS (21.2% vs. 66.0% vs. 55.4%; p = 0.0038) and 3-year OS (36.5% vs. 79.9% vs. 75.6%; p = 0.0014) compared to no ABX and other ABX, respectively. PPI use was associated with decreased 3-year PFS (46.9% vs. 66.0%; p = 0.0001) and 3-year OS (60.7% vs. 81.9%; p = 0.0041) compared to no PPI. On multivariable regression analysis controlling for confounders including stage, histology, grade, radiation, and co-morbidities, PPI use was independently associated with worse PFS (HR 1.96, 95% CI 1.25-3.08; p = 0.0041) and OS (HR 2.06, 95% CI 1.01-4.18, p = 0.04).In this retrospective cohort study, we demonstrate that PPI use is independently associated with worse PFS and OS in patients with EC treated with PC. ABX use was associated with worse PFS on univariate analysis only. There is an unmet need to understand how PPI, ABX, and, potentially, the microbiome impact the effectiveness of chemotherapy in EC patients.

  View details for DOI 10.1016/j.ygyno.2023.09.005

  View details for PubMedID 37741201

• Prevalence of type 2 diabetes diagnoses in the perioperative and survivorship periods following surgical management of endometrial cancer: An opportunity for screening and intervention? Gynecologic oncology Morton, M., McLaughlin, E. M., Calo, C. A., Lightfoot, M., Bixel, K. L., Cohn, D. E., Cosgrove, C. M., Copeland, L. J., O'Malley, D. M., Nagel, C. I., Chambers, L. M. 2023; 177: 46-52

  Abstract

  To determine the prevalence of Type 2 diabetes mellitus (T2DM) diagnoses during the peri-operative and survivorship periods in patients following surgical management of endometrial cancer (EC).An IRB-approved, retrospective single-institution cohort study was performed in patients who underwent surgical management of EC from 2014 to 2020. The perioperative period was defined as the 30 days before and after surgery. T2DM diagnoses occurring during survivorship were recorded. T2DM diagnoses were defined by a HgbA1c ≥6.5% or a random blood glucose ≥200 mg/dL. Sequelae of peri-operative T2DM and predictors of future T2DM were examined utilizing univariate analysis.Of 519 patients meeting inclusion criteria, 37 (7.1%) were diagnosed with T2DM in the perioperative period. Patients diagnosed with T2DM in the perioperative period had significantly higher BMI (p = 0.006) compared to no T2DM, but there were no significant differences in age (p = 0.20), ethnicity/race (p > 0.05) or ECOG score (p = 0.19). The rates of intraoperative complications between groups did not significantly differ, except for vascular complications (p = 0.005), and the incidence of any postoperative complication was higher in the perioperative T2DM group (p = 0.01). With a median follow-up of 29 months [range 11.6-49.0 months], an additional 18.3% (n = 88) of the cohort met diagnostic criteria for T2DM. BMI (p < 0.001), perioperative glucose (p < 0.001), and HgbA1c (p = 0.002) demonstrate risk for a T2DM diagnosis during survivorship.In this retrospective cohort of EC patients, 25.4% were diagnosed with T2DM, with the majority diagnosed in the survivorship period. Surgical management and subsequent surveillance of EC presents an opportunity to diagnose at-risk patients with T2DM.

  View details for DOI 10.1016/j.ygyno.2023.08.009

  View details for PubMedID 37639902

• "More than a song and dance": Exploration of patient perspectives and educational quality of gynecologic cancer content on TikTok. Gynecologic oncology Morton, M., Haight, P. J., Khadraoui, W., Backes, F., Bixel, K., O'Malley, D. M., Nagel, C., Chambers, L. M. 2023; 175: 81-87

  Abstract

  To investigate themes, quality, and reliability of gynecologic cancer-related content on the social media application TikTok.TikTok was systematically searched for the 100 most popular posts for ovarian cancer (OC), endometrial cancer (EC), cervical cancer (CC), vulvar cancer (VC), and gestational trophoblastic disease (GTD) in August 2022. Data was collected for demographics, tone, and themes. Educational videos were rated for quality and reliability utilizing the modified DISCERN scale. Relationships between content demographics, disease sites, and themes were assessed.As of August 2022, the top five hashtags for each gynecologic cancer on TikTok had 466.7 million views. 430 of the top 500 posts were eligible for inclusion (OC: n = 86, CC: n = 93, EC: n = 98, GTD: n = 63, VC: n = 90). The majority of creators (n = 323, 75.1%) were White, 33 (7.7%) were Black, 20 (4.6%) were Asian/Pacific Islander (API), 10 (2.3%) were South Asian, 20 (4.7%) were Hispanic/Latino/a, 24 (5.5%) were unable to determine. Eleven central themes were identified, with significant differences when analyzed by disease site and race. The median DISCERN score for all posts was 1.0, indicating poor educational quality and reliability. When compared by race, South Asian/API posters received the highest scores (3, IQR 2.5) versus Black (2: IQR 3), Hispanic/Latino/a (2: IQR 0), and White posters (1, IQR 2) (p = 0.0013).Gynecologic cancer-related content on TikTok is of poor educational quality, and racial disparities in gynecologic cancer extend to social media. Opportunities exist to create more diverse content to support racial and cultural experiences in gynecologic cancer treatment.

  View details for DOI 10.1016/j.ygyno.2023.06.004

  View details for PubMedID 37329872

• Glassy cell carcinoma of the cervix: Findings from a combined National Cancer Database analysis and single institution review of treatment patterns and outcomes. Gynecologic oncology Levine, M. D., Barrington, D. A., Meade, C. E., Lammers, S. M., McLaughlin, E. M., Suarez, A. A., Backes, F. J., Copeland, L. J., O'Malley, D. M., Cosgrove, C. M., Cohn, D. E., Nagel, C. I., Felix, A. S., Bixel, K. L. 2023; 173: 15-21

  Abstract

  To describe stage, treatment patterns, and survival for glassy cell carcinoma of the cervix (GCCC), a poorly understood rare tumor.Clinical data and survival were compared between GCCC and more common histologic types using the National Cancer Database (NCDB) from 2004 to 2017. A retrospective review of GCCC cases at our institution from 2012 to 2020 was simultaneously performed with staging updated according to 2018 FIGO staging. Descriptive statistics and survival analyses were performed, and outcomes compared to historical references.143/89,001 (0.16%) NCDB cervical cancer cases were GCCC. Compared to other histologies, GCCC cases were younger, with 74.8% diagnosed before age 50. Stage distribution was similar. Stage I cases were less commonly treated with surgery alone (19/69, 27%). 79.4% of locally advanced (stage II-IVA) cases were treated with definitive chemoradiation. GCCC demonstrated worse OS for early-stage and locally-advanced disease. No survival differences were observed for patients with stage IVB disease. Our institutional review identified 14 GCCC cases. Median age at diagnosis was 34 years. All nine early-stage cases underwent radical hysterectomy. Adjuvant radiation was given for cases meeting Sedlis criteria (4/9, 44%). All five advanced stage cases were stage IIIC and received definitive chemoradiation. Recurrence rate was 0% (0/9) for early-stage and 60% (3/5) for advanced-stage cases. 3-year PFS was 100% for early-stage and 40% for advanced-stage. 3-year OS was 100% for early-stage and 60% for advanced-stage GCCC.GCCC presents at earlier ages than other cervical cancer histologic types. Although NCDB showed worse OS, our more contemporary institutional review, which incorporates updated staging and newer treatment modalities found outcomes more similar to historical references of more common histologic subtypes.

  View details for DOI 10.1016/j.ygyno.2023.03.023

  View details for PubMedID 37037083

• Postoperative venous thromboembolism risk stratification in patients with uterine cancer. American journal of obstetrics and gynecology Wagner, V. M., Piver, R. N., Levine, M. D., Backes, F. J., Chambers, L. J., Cohn, D. E., Copeland, L. J., Cosgrove, C. M., Nagel, C. I., O'Malley, D. M., Bixel, K. L. 2023; 228 (5): 555.e1-555.e8

  Abstract

  Uterine cancers are associated with a high risk for venous thromboembolisms. The American Society of Clinical Oncology practice guidelines recommend that all patients undergoing pelvic surgery for cancer should receive extended pharmacologic thromboprophylaxis with the duration being dependent on risk. However, risk stratification for patients with uterine cancer is not clearly defined. The Caprini score is the most widely used risk assessment model but it has been found to have limited use in the gynecologic oncology population. A modified Caprini score has been explored in other populations. The Khorana score is an additional risk assessment model that has not been studied in this context.Our objective was to evaluate the ability of a modified Caprini model and the Khorana score to risk stratify patients with uterine cancer for postoperative venous thromboembolisms within 90 days of surgery.Following institutional review board approval, a retrospective cohort study was performed, and all patients with uterine cancer who underwent a hysterectomy over a 4-year period were included. The Caprini and Khorana scores were calculated for each patient. The Caprini score cutoff for highest risk was evaluated at ≥7, ≥8, and ≥9 (modified Caprini) and the Khorana score cutoff was evaluated at ≥2 and ≥3. To determine the prognostic use of each score and other clinico-pathologic criteria related to the development of a venous thromboembolism, univariate analyses were performed using independent t tests, chi-square tests, or Fisher's exact tests; a multivariate analysis was performed using logistic regression.A total of 954 patients were included. The rate of venous thromboembolism development was 1.7% (16/954). A minimally invasive surgical approach was used in 90.5% (863/954) of patients. The mean Caprini score for patients with a venous thromboembolism was 10.3 compared with 8.1 for patients without a venous thromboembolism (95% confidence interval, 1.17-3.33; P<.0001). The mean Khorana score for the venous thromboembolism group was 2.4 vs 1.9 for those without (95% confidence interval, 0.04-0.82; P=.03). Both the Caprini and Khorana scores were found to be associated with venous thromboembolisms, but only a Caprini score with a cutoff of ≥8 or ≥9 was statistically significant (risk ratio, 31.25; 95% confidence interval, 1.88-519.49; risk ratio, 4.59; 95% confidence interval, 1.49-14.13, respectively), with high accuracy based on the area under the curve (0.75 and 0.68, respectively). Of the minimally invasive subgroup, 11.7% (101/863) of patients had same-day discharge with no postoperative thromboprophylaxis; none of these patients developed venous thromboembolisms. Despite extended prophylaxis among the laparotomy patients (30 days), the rate of venous thromboembolisms was more than 3 times that of the minimally invasive group (5.49% vs 1.7%). Advanced tumor stage and leukocytosis were noted to be independent risk factors for venous thromboembolisms.Our study suggests that using a modified Caprini score could help to identify the highest-risk patients who would benefit from prolonged thromboprophylaxis, could reduce the incidence of postoperative venous thromboembolisms, and could minimize the cost and harm of overtreatment. These findings need to be validated in a prospective manner, and further research is needed to determine the optimal duration of therapy.

  View details for DOI 10.1016/j.ajog.2022.12.310

  View details for PubMedID 36574873

• The modified 5-item frailty index is a predictor of post-operative complications in vulvar cancer: a National Surgical Quality Improvement Program (NSQIP) analysis. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society Levine, M. D., Felix, A. S., Meade, C. E., Bixel, K. L., Chambers, L. M. 2023; 33 (4): 465-472

  Abstract

  To determine whether frailty is associated with post-operative complications following surgery for vulvar cancer.This retrospective study used a multi-institutional dataset from the National Surgical Quality Improvement Program (NSQIP) database (2014-2020) to analyze the relationship between frailty, procedure type, and post-operative complications. Frailty was determined using the modified frailty index-5 (mFI-5). Univariate and multivariable-adjusted logistic regression analyses were performed.Of 886 women, 49.9% underwent radical vulvectomy alone, and 19.5% and 30.6% underwent concurrent unilateral or bilateral inguinofemoral lymphadenectomy, respectively; 24.5% had mFI ≥2 and were considered frail. Compared with non-frail women, those with an mFI ≥2 were more likely to have an unplanned readmission (12.9% vs 7.8%, p=0.02), wound disruption (8.3% vs 4.2%, p=0.02), and deep surgical site infection (3.7% vs 1.4%, p=0.04). On multivariable-adjusted models, frailty was a significant predictor for minor (OR 1.58, 95% CI 1.09 to 2.30) and any complications (OR 1.46, 95% CI 1.02 to 2.08). Specifically, for radical vulvectomy with bilateral inguinofemoral lymphadenectomy, frailty was significantly associated with major (OR 2.13, 95% CI 1.03 to 4.40) and any complications (OR 2.10, 95% CI 1.14 to 3.87).In this analysis of the NSQIP database, nearly 25% of women undergoing radical vulvectomy were considered frail. Frailty was associated with increased post-operative complications, especially in women concurrently undergoing bilateral inguinofemoral lymphadenectomy. Frailty screening prior to radical vulvectomy may assist in patient counseling and improve post-operative outcomes.

  View details for DOI 10.1136/ijgc-2022-004175

  View details for PubMedID 36898698

• Use of the Khorana score to predict venous thromboembolism in patients undergoing chemotherapy for uterine cancer. Gynecologic oncology reports Piver, R. N., Wagner, V. M., Levine, M. D., Backes, F. J., Chambers, L. J., Cohn, D. E., Copeland, L. J., Cosgrove, C. M., Nagel, C. I., O'Malley, D. M., Bixel, K. L. 2023; 46: 101156

  Abstract

  Gynecologic cancers are associated with a high risk of venous thromboembolism (VTE). The Khorana score is a validated tool to assess risk of VTE in cancer patients. The purpose of this study is to determine if the Khorana score can be used as a risk stratification tool for VTE in patients with uterine cancer undergoing chemotherapy.A retrospective cohort study of patients with newly diagnosed uterine cancer receiving chemotherapy over a 4-year period was conducted. The patients were stratified based on their Khorana score as well as their chemotherapy sequence, neoadjuvant or definitive versus adjuvant.A total of 276 patients were included: 40 received neoadjuvant or definitive, 236 adjuvant chemotherapy. Most patients had advanced stage disease (64.5%). 18 (6.5%) patients developed VTE within 180 days of initiating chemotherapy. High Khorana score was associated with a non-significant increase in VTE (K ≥ 2 OR 1.17, CI 0.40-3.39, K ≥ 3 OR 1.69, CI 0.61-4.69) but had poor predictive accuracy based on area under the curve (K ≥ 2 0.51, K ≥ 3 0.55). The VTE rate was higher in the neoadjuvant/definitive chemotherapy group to adjuvant (12.5% vs 5.5%, p = 0.11). While the former group had a higher average Khorana score (2.35 vs 1.93, p = 0.0048), this was not predictive of VTE.While validated in other cancer types, the Khorana score was found to be a poor predictor of VTE in patients with uterine cancer. The use of the Khorana score to guide routine thromboprophylaxis in these patients should be used with caution and further investigation is warranted.

  View details for DOI 10.1016/j.gore.2023.101156

  View details for PubMedID 36910448

  View details for PubMedCentralID PMC9995928

• Recurrence rate in early-stage epithelial ovarian cancer: Is there a role for upfront maintenance with PARP inhibitors in stages I and II? Gynecologic oncology reports Levine, M. D., O'Malley, D. M., Haight, P. J., Senter, L., Wagner, V., Bixel, K. L., Cohn, D. E., Copeland, L. J., Cosgrove, C. M., McLaughlin, E. M., Backes, F. J. 2023; 46: 101173

  Abstract

  To determine the recurrence rate and survival among early-stage epithelial ovarian cancer cases considering homologous recombination deficiency (HRD) status.Single institution retrospective study of stage I/II EOC patients from 2017 to 2020. HRD was defined as evidence of germline or somatic BRCA mutation, or loss of heterozygosity (LOH)/genomic instability (GIS) as determined by companion diagnostic tests. Kaplan-Meier analyses were performed.89 stage I/II cases were included. 4/89 (4.5%) had a germline BRCA1/2 mutation, 8 (9%) were germline negative but had a somatic BRCA mutation, and 8 (9%) were BRCA wild-type but had evidence of LOH/GIS on somatic testing; these 20/89 (22%) cases comprised the HRD group. The remaining tumors were confirmed homologous recombination proficient (HRP, 35/89, 39%) or homologous recombination unknown (HRU, 34/89, 38%). The overall recurrence rate was 33/89 (37%). There were more recurrences among HRD cases (14/20, 70%) compared to HRP/HRU cases (19/69, 27.5%, p = 0.0012). Median Recurrence-Free Survival (RFS) was 35 months for HRD cases and 225 months for HRP/HRU cases (p = 0.001). At 2 years, there were 60% HRD cases and 88% HRP/HRU cases recurrence-free. At 5 years there were 29% HRD and 69% HRP/HRU cases recurrence-free (p = 0.001).Despite a high rate of complete surgical staging and six cycles of adjuvant chemotherapy, recurrence rate was high in this early-stage cohort. Higher recurrence rates were seen in the HRD group, however these data are likely biased by the clinical practice of tumor testing primarily at the time of recurrence rather than the upfront setting. RFS was significantly lower for HRD cases.

  View details for DOI 10.1016/j.gore.2023.101173

  View details for PubMedID 37082521

  View details for PubMedCentralID PMC10111944

• Lifestyle intervention in ovarian cancer enhanced survival (LIVES) study (NRG/GOG0225): Recruitment, retention and baseline characteristics of a randomized trial of diet and physical activity in ovarian cancer survivors. Gynecologic oncology Thomson, C. A., Crane, T. E., Miller, A., Gold, M. A., Powell, M., Bixel, K., Van Le, L., DiSilvestro, P., Ratner, E., Lele, S., Guntupalli, S., Huh, W., Robertson, S. E., Modesitt, S., Casey, A. C., Basen-Engquist, K., Skiba, M., Walker, J., Kachnic, L., Alberts, D. S. 2023; 170: 11-18

  Abstract

  The Lifestyle Intervention for oVarian cancer Enhanced Survival (LIVES) is a national study of a combined diet and physical activity intervention for stage II-IV ovarian cancer survival, an under-represented cancer in lifestyle behavioral intervention research. Here, we present the data on recruitment, retention, and baseline demographic, clinical and lifestyle behavior characteristics of the LIVES study participants.The LIVES study (NRG Oncology/GOG 0225) is a Phase III diet plus physical activity intervention trial testing the hypothesis that ovarian cancer survivors in the lifestyle intervention will demonstrate better progression-free survival than those in the control condition. Study interventions were delivered via centralized telephone-based health coaching. Baseline descriptive statistics were computed for demographic, clinical, and lifestyle behavior characteristics.The LIVES study exceeded its recruitment goals, enrolling 1205 ovarian cancer survivors from 195 NRG/NCORP-affiliated oncology practices across 49 states from 2012 to 2018. The mean age of enrollees was 59.6 years; the majority (69.4%) with stage III disease; 89% White, 5.5% Hispanic; 64% overweight/obese. Baseline self-reported diet showed a mean daily intake of 6.6 servings of fruit and vegetables, 62.7 fat grams, and 21.7 g of fiber. Physical activity averaged 13.0 MET-hours/week of moderate to vigorous physical activity; 50.9 h/week of sedentary time. Retention rates exceeded 88%.The LIVES study demonstrates efficiency in recruiting and retaining ovarian cancer survivors in a 24-month study of diet and physical activity intervention with a primary endpoint of progression free survival that will be reported.ClinicalTrials.govNCT00719303.

  View details for DOI 10.1016/j.ygyno.2022.12.017

  View details for PubMedID 36608382

  View details for PubMedCentralID PMC10023359

• Safety and feasibility of same-day discharge following minimally invasive hysterectomy in the morbidly obese patient population. Gynecologic oncology Haight, P. J., Barrington, D. A., Graves, S. M., Piver, R. N., Baek, J., Ardizzone, M., Akinduro, J. A., Busho, A. C., Fadoju, D., Pandit, R., Stephens, R., Strowder, L. M., Tadepalli, S., VanNoy, B., Sriram, B., McLaughlin, E. M., Lightfoot, M. D., Bixel, K. L., Cohn, D. E., Cosgrove, C. M., O'Malley, D., Salani, R., Nagel, C. I., Backes, F. J. 2023; 170: 203-209

  Abstract

  To determine whether morbid obesity should serve as an independent factor in the decision for same day discharge following minimally invasive hysterectomy.Retrospective review was performed of patients with BMI ≥ 40 who underwent minimally invasive hysterectomy within a single comprehensive cancer center between January 2018 - August 2020. Demographics, perioperative factors, post-operative monitoring, complications, and readmissions were compared between patients who underwent same day discharge and overnight observation using Fisher's exact tests and Wilcoxon rank-sum tests.374 patients with BMI ≥ 40 were included. Eighty-three (22.2%) patients underwent same day discharge, and 291 (77.8%) patients underwent overnight observation. Factors associated with increased likelihood of same day discharge included younger age (median age 53 vs 58; p = 0.001), lower BMI (median BMI 45 vs 47; p = 0.005), and fewer medical co-morbidities (Charlson Co-Morbidity Index 2 vs 3; p < 0.001). On multivariate regression analysis, frailty (OR 2.16 [1.14-4.11], p = 0.019) and surgical completion time after 12 PM (OR 3.67 [2.16-6.24], p < 0.001) were associated with increased risk of overnight observation. Few patients admitted for routine overnight observation required medical intervention (n = 14, 4.8%); most of these patients were frail (64.3%). The overall hospital readmission rate within 30 days of discharge was 3.2% (n = 12), with no patients discharged on the day of surgery being readmitted.Morbid obesity alone should not serve as a contraindication to same day discharge following minimally invasive hysterectomy. Admission for observation was associated with low rates of clinically meaningful intervention, and patients who underwent same day discharge were not at increased risk of adverse outcome.

  View details for DOI 10.1016/j.ygyno.2023.01.013

  View details for PubMedID 36709661

• Less is more: clinical utility of postoperative laboratory testing following minimally invasive hysterectomy for endometrial cancer. American journal of obstetrics and gynecology Lightfoot, M. D., Felix, A. S., Calo, C. A., Hosmer-Quint, J. T., Taylor, K. L., Brown, M. B., Salani, R., Copeland, L. J., O'Malley, D. M., Bixel, K. L., Cohn, D. E., Fowler, J. M., Backes, F. J., Cosgrove, C. M. 2023; 228 (1): 59.e1-59.e13

  Abstract

  With the increasing rates of same-day discharge following minimally invasive surgery for endometrial cancer, the need for and value of routine postoperative testing is unclear.This study aimed to determine whether routine postoperative laboratory testing following minimally invasive hysterectomy for endometrial cancer leads to clinically significant changes in postoperative care.This was a single-institution retrospective cohort study of patients undergoing minimally invasive hysterectomy for endometrial cancer by a gynecologic oncologist between June 2014 and June 2017. Patient demographics, preoperative comorbidities, operative and postoperative data, and pathologic findings were manually extracted from the patients' medical records. The financial burden of laboratory testing was computed using hospital-level cost data.Of the 649 women included in the analysis, most (91.4%) were White, with a mean age of 61 years, and mean body mass index of 38.0 kg/m2. The most common comorbidities were diabetes mellitus (31.9%, n=207), chronic pulmonary disease (7.9%, n=51), and congestive heart failure (3.2%, n=21). Median operative time was 151 minutes (range, 61-278), and median estimated blood loss was 100 mL (range, 10-1500). Most patients (68.6%, n=445) underwent lymphadenectomy. All patients had postoperative laboratory tests ordered: 100% complete blood count, 99.7% chemistry, 62.9% magnesium, 46.8% phosphate, 37.4% calcium, and 1.2% liver function tests. Twenty-six patients (4.0%) had a change in management owing to postoperative laboratory test results. Of these 26 women, 88% experienced a change in clinical status that would have otherwise prompted testing. Only 3 (0.5% of entire cohort) were asymptomatic: 1 received a blood transfusion for asymptomatic anemia, and the other 2, who did not carry a diagnosis of diabetes mellitus, had interventions for hyperglycemia. On univariable analysis, peripheral and cerebrovascular disease, diabetes mellitus with end-organ damage, and a Charlson Comorbidity Index of ≥3 were associated with increased odds of change in management; these were not significant on multivariable analysis. Routine postoperative laboratory evaluation in this cohort increased hospital costs by $292,000.Routine postoperative laboratory tests are unlikely to lead to significant changes in management for women undergoing minimally invasive hysterectomy for endometrial cancer, and may increase cost without providing a discernible clinical benefit. In the setting of strict postoperative guidelines, laboratory tests should be ordered when clinically indicated rather than as part of routine postoperative management for women undergoing minimally invasive hysterectomy for endometrial cancer.

  View details for DOI 10.1016/j.ajog.2022.07.056

  View details for PubMedID 35931127

• Help wanted: low provider density is associated with advanced stage cervical cancer. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society Calo, C., Barrington, D. A., Mclaughlin, E. M., Bixel, K. 2022; 32 (11): 1370-1376

  Abstract

  Patients in rural areas have a higher incidence of cervical cancer with increased rates of metastatic disease than their urban counterparts.To evaluate whether medical provider density, acting as a surrogate for screening availability, is associated with the incidence of cervical cancer or proportion diagnosed with advanced stage disease.Cervical cancer cases by county from 2015 were retrieved from the SEER database. The numbers of primary obstetric-gynecologists (OB-GYN), family practice, and internal medicine providers were obtained from the Area Health Resource File, and population estimates for each county were used to calculate provider to resident ratios. Spearman rank correlations were used to compare the number of providers per 100 000 residents with the overall incidence of cervical cancer as well as the proportion diagnosed at an advanced stage. Multivariable logistic regression was performed to assess factors independently associated with advanced stage disease, accounting for county of residence. Mortality was compared across different OB-GYN provider density categories.A total of 3505 cases of cervical cancer from 405 counties were included. Spearman correlation demonstrated a significant inverse association between the number of OB-GYN providers per 100 000 residents and the incidence of cervical cancer (p<0.0001) as well as the proportion diagnosed at an advanced stage (p=0.003). Compared with those living in counties with ≤5 OB-GYN providers per 100 000 residents, those living in counties with >10 providers had a 29% reduction in the odds of presenting with advanced stage disease (OR=0.71; 95% CI 0.55 to 0.91). An inverse association between cervical cancer-related mortality and OB-GYN provider density was also noted.A significant inverse correlation between provider density and incidence of cervical cancer, proportion with advanced stage disease, and cervical cancer-related mortality was observed. Increasing provider density in these underserved, high-risk areas may improve timely cancer detection.

  View details for DOI 10.1136/ijgc-2022-003779

  View details for PubMedID 36170995

• The contemporary presentation and diagnosis of endometrial cancer recurrence: When, where, and how? Gynecologic oncology Riedinger, C. J., Patterson, J. M., Backes, F. J., O'Malley, D., Bixel, K. L., Copeland, L. J., Cohn, D. E., Goodfellow, P. J., Cosgrove, C. M. 2022; 167 (2): 174-180

  Abstract

  To examine patients with confirmed endometrial cancer recurrence; evaluate patterns, presentation, and mode of diagnosis.A retrospective review of women with endometrial cancer diagnosis between 2014 and 2020. Disease recurrences were evaluated. Medical records were reviewed focusing on presentation at time of recurrence. Relationships were assessed using χ2, Fisher's exact test, t-test, and Wilcoxon test. The Kaplan-Meier product limit was used to estimate survival. Multiple logistic regression analysis was used to assess the impact of covariates.Endometrial cancer recurrence was identified in 201 (11.7%) patients. Sixty percent (120/201) of patients presented with symptoms. Pain was the most common presenting symptom (23.4%, 47/201) and bleeding was reported in <14% (28/201). Patients with symptomatic presentation were less likely to be able to receive treatment for their recurrent disease (76.7% vs 91.3%, p = 0.005). Asymptomatic pelvic exam diagnosed recurrence in 13.4% (27/201) and was more common in patients initially diagnosed with early-stage disease (66.7% vs 34.5% p = 0.001) of endometrioid histology (66.7% vs 36.8%, p = 0.003) without prior adjuvant therapy (48.2% vs 17.9%, p = 0.001). More than1/3 of diagnoses were made by providers outside of the oncologic care team.The majority of women with recurrent endometrial cancer were symptomatic and pain is a common complaint associated with disease recurrence. Patients with symptomatic presentation of disease recurrence were less likely to receive treatment for recurrent disease but this did not result in an overall survival (OS) difference. Given the rising mortality rate of endometrial cancer further work is needed to develop multidisciplinary surveillance strategies that will enable meaningful treatment of disease recurrence.

  View details for DOI 10.1016/j.ygyno.2022.09.014

  View details for PubMedID 36154763

• Beyond mismatch repair deficiency? Pre-treatment neutrophil-to-lymphocyte ratio is associated with improved overall survival in patients with recurrent endometrial cancer treated with immunotherapy. Gynecologic oncology Barrington, D. A., Calo, C., Baek, J., Brown, M., Wagner, V., Gonzalez, L., Huffman, A., Benedict, J., Bixel, K. 2022; 166 (3): 522-529

  Abstract

  To determine the association of pre-treatment neutrophil-to-lymphocyte ratio (NLR) with progression-free survival (PFS) and overall survival (OS) for patients with recurrent endometrial cancer (EC) treated with immunotherapy.Recurrent EC patients treated with immunotherapy alone or in combination from 2016 to 2021 were included. Demographics, pre-treatment laboratory results, pathologic data, response at first radiographic assessment, and cancer outcomes were obtained from the medical record. Kaplan-Meier curves were generated to compare PFS and OS stratified by NLR.The 106 patients included in the study were stratified by NLR <6 (n = 77, 72.6%) or NLR ≥6 (n = 29, 27.3%). Most had endometrioid pathology (59%), widely metastatic disease, and 36.8% had received ≥2 treatment lines before initiating immunotherapy. Mismatch repair deficiency (dMMR) was noted in 52 (49.1%) tumors. Most dMMR patients (94.3%) were treated with single-agent pembrolizumab, and most MMR proficient patients (78.7%) were treated with lenvatinb plus pembrolizumab. In the overall cohort, 40.2% (partial response (PR) 29.9%, complete response (CR) 10.4%) of patients with a NLR <6 responded at first radiographic assessment, compared to 31% (PR 27.5%, CR 3.4%) of patients with NLR ≥6 (p 0.691). Kaplan-Meier curves stratified by NLR <6 vs. ≥6 showed no difference in PFS. However, NLR <6 was associated with improved OS (p < 0.05). In the NLR < 6 group, the probability of survival at one year was 69% (95% CI: 58%, 82%), compared to 41% (95% CI: 26%, 67%) for the NLR > 6 group.Pre-treatment NLR <6 was associated with improved OS for recurrent EC patients treated with immunotherapy. NLR holds promise as a predictive biomarker for survival after immunotherapy treatment for patients with recurrent EC.

  View details for DOI 10.1016/j.ygyno.2022.07.010

  View details for PubMedID 35907683

• High pre-treatment neutrophil-to-lymphocyte ratio as a prognostic marker for worse survival in patients with recurrent/metastatic cervical cancer treated with immune checkpoint inhibitors. Gynecologic oncology reports Calo, C. A., Barrington, D. A., Brown, M., Gonzalez, L., Baek, J., Huffman, A., Benedict, J., Backes, F., Chambers, L., Cohn, D., Copeland, L., Cosgrove, C., Nagel, C., O'Malley, D., Bixel, K. 2022; 42: 101040

  Abstract

  To evaluate the association between pre-treatment neutrophil-to-lymphocyte ratio (NLR) and survival outcomes among patients with recurrent/metastatic cervical cancer treated with PD-1/PD-L1 inhibitors.A retrospective analysis of patients with recurrent/metastatic cervical cancer treated with PD-1/PD-L1 inhibitors from 2016 to 2021 was conducted. Progression free survival (PFS) and overall survival (OS) outcomes were assessed for patients stratified by NLR (<8 vs ≥ 8) utilizing Kaplan-Meier method. Univariable analysis was performed to compare baseline characteristics between the two groups.A total of 49 patients were included in analysis. A majority of patients had squamous cell histology (57%), were PD-L1 positive (55%), received ≤ 1 prior lines of systemic therapy (57%), and had distant metastatic disease at the time of treatment (69%). The groups were well-balanced with respect to age, race, histology, smoking status, PD-L1 positivity, prior lines of treatment (≤1 vs > 1), prior radiation therapy, ECOG performance status, and disease distribution for patients with a NLR < 8 (n = 35) compared to those with a NLR ≥ 8 (n = 14). A pre-treatment NLR of < 8 was associated with improved survival (p < 0.01), with 57% (95% CI: 41%, 78%) probability of survival at one year compared to 26% (95% CI: 10%, 66%) for those with NLR ≥ 8. No statistically significant differences in probability of PFS at 1 year were seen between NLR < 8 compared to those with NLR ≥ 8 (p = 0.70).Pre-treatment NLR may hold prognostic value for patients with metastatic/recurrent cervical cancer treated with PD-1/PD-L1 inhibitors, with NLR < 8 associated with improved survival.

  View details for DOI 10.1016/j.gore.2022.101040

  View details for PubMedID 35855965

  View details for PubMedCentralID PMC9287632

• Effect of risk-reducing salpingo-oophorectomy on sex steroid hormone serum levels among postmenopausal women: an NRG Oncology/Gynecologic Oncology Group study. American journal of obstetrics and gynecology Mai, P. L., Miller, A., Black, A., Falk, R. T., Boggess, J. F., Tucker, K., Stuckey, A. R., Rodriguez, G. C., Wong, C., Amatruda, T. T., Wilkinson, K. J., Modesitt, S. C., Yamada, S. D., Bixel, K. L., Glaser, G. E., Rose, P. G., Greene, M. H., Sherman, M. E. 2022; 227 (1): 61.e1-61.e18

  Abstract

  Risk-reducing salpingo-oophorectomy is an effective ovarian cancer risk reduction strategy. However, bilateral oophorectomy has also been associated with increased long-term nonneoplastic sequelae, effects suggested to be mediated through reductions in systemic sex steroid hormone levels. Currently, it is unclear whether the postmenopausal ovary contributes to the systemic hormonal milieu or whether postmenopausal ovarian volume or other factors, such as body mass index and age, affect systemic hormone levels.We examined the impact of oophorectomy on sex steroid hormone levels in postmenopausal women. Furthermore, we explored how well ovarian volume measured by transvaginal ultrasound correlated with direct ovarian measures obtained during surgical pathology evaluation and investigated the association between hormone levels and ovarian volumes.Postmenopausal women who underwent risk-reducing salpingo-oophorectomy (180 cases) or ovarian cancer screening (38 controls) enrolled in an international, prospective study of risk-reducing salpingo-oophorectomy and risk of ovarian cancer algorithm-based screening among women at increased risk of ovarian cancer (Gynecologic Oncology Group-0199) were included in this analysis. Controls were frequency matched to the cases on age at menopause, age at study entry, and time interval between blood draws. Ovarian volume was calculated using measurements obtained from transvaginal ultrasound in both cases and controls and measurements recorded in surgical pathology reports from cases. Serum hormone levels of testosterone, androstenedione, androstenediol, dihydrotestosterone, androsterone, dehydroepiandrosterone, estrone, estradiol, and sex hormone-binding globulin were measured at baseline and follow-up. Spearman correlation coefficients were used to compare ovarian volumes as measured on transvaginal ultrasound and pathology examinations. Correlations between ovarian volumes by transvaginal ultrasound and measured hormone levels were examined using linear regression models. All models were adjusted for age. Paired t tests were performed to evaluate individual differences in hormone levels before and after risk-reducing salpingo-oophorectomy.Ovarian volumes measured by transvaginal ultrasound were only moderately correlated with those reported on pathology reports (Spearman rho [ρ]=0.42). The median time interval between risk-reducing salpingo-oophorectomy and follow-up for the cases was 13.3 months (range, 6.0-19.3), and the median time interval between baseline and follow-up for the controls was 12.7 months (range, 8.7-13.4). Sex steroid levels decreased with age but were not correlated with transvaginal ultrasound ovarian volume, body mass index, or time since menopause. Estradiol levels were significantly lower after risk-reducing salpingo-oophorectomy (percentage change, -61.9 post-risk-reducing salpingo-oophorectomy vs +15.2 in controls; P=.02), but no significant differences were seen for the other hormones.Ovarian volumes measured by transvaginal ultrasound were moderately correlated with volumes directly measured on pathology specimens and were not correlated with sex steroid hormone levels in postmenopausal women. Estradiol was the only hormone that declined significantly after risk-reducing salpingo-oophorectomy. Thus, it remains unclear whether the limited post-risk-reducing salpingo-oophorectomy changes in sex steroid hormones among postmenopausal women impact long-term adverse outcomes.

  View details for DOI 10.1016/j.ajog.2022.02.022

  View details for PubMedID 35216968

  View details for PubMedCentralID PMC9253062

• An investigation into human papillomavirus (HPV) vaccination for patients undergoing surgery for high-grade cervical or vulvar dysplasia. Gynecologic oncology reports Boyles, G. P., Baek, J., Pandit, R., Cosgrove, C. M., Bixel, K. L. 2022; 41: 101001

  Abstract

  Eligibility for the human papillomavirus (HPV) vaccine now includes adults 27 through 45 years. It has not been reported how providers are addressing HPV vaccination in patients with existing preinvasive disease. Our objectives were to determine the rates at which vaccination is offered to and received by patients undergoing surgery for high-grade cervical or vulvar dysplasia.This was a single-institution retrospective cohort study including patients ages 18 through 45 years undergoing surgery for high-grade cervical or vulvar dysplasia from 10/2018 to 2/2020. Our primary outcome was the rate at which HPV vaccination was discussed at the pre- and/or post-operative visits. The secondary outcome was the rate of vaccine uptake in these individuals. Characteristics of those offered HPV vaccination were compared to those not offered vaccination.Of the 115 patients included, 36 (31.3%) had HPV vaccination addressed in the perioperative setting. Thirty-two of these patients had never been vaccinated, and 21 of these (65.6%) went on to receive partial or complete HPV vaccination. Those in whom HPV vaccination was addressed were more likely to be under 27 years (RR 3.2; 95% CI 2.1-4.8) and less likely to be smokers (RR 0.5; 95% CI 0.2-0.9) or have prior excisional procedures (RR 0.3; 95% CI 0.1-0.9). The absolute rate of discussing HPV vaccination with patients improved from 26.0% within six months of vaccine age eligibility expansion, to 35.4% after six months (P = 0.32).Providers did not consistently address HPV vaccination among patients being treated for high-grade cervical or vulvar dysplasia despite the potential benefits. However, a high proportion of these patients are amenable to vaccination. Quality improvement initiatives are warranted to increase the rate of HPV vaccine counseling in this context.

  View details for DOI 10.1016/j.gore.2022.101001

  View details for PubMedID 35603128

  View details for PubMedCentralID PMC9120215

• Who will be readmitted? Evaluation of the laparoscopic hysterectomy readmission score in a gynecologic oncology population undergoing robotic-assisted hysterectomy. Gynecologic oncology Lightfoot, M. D., Felix, A. S., Bishop, E. E., Henderson, A. P., Vetter, M. H., Salani, R., O'Mallley, D. M., Bixel, K. L., Cohn, D. E., Fowler, J. M., Backes, F. J. 2022; 164 (3): 628-638

  Abstract

  The laparoscopic hysterectomy readmission score (LHRS) was created to identify patients for whom same day discharge (SDD) after minimally invasive hysterectomy (MIH) may not be advisable and includes diabetes, chronic obstructive pulmonary disease, disseminated cancer, chronic steroid use, bleeding disorder, length of surgery, and any postoperative complication prior to discharge. We evaluated the performance of the score at predicting readmission in a gynecologic oncology population, and additionally sought to determine if any factors known prior to surgery could replace those that are not known until the time of surgery (operative time and postoperative complication).This was a single-institution retrospective cohort study of women undergoing robotic hysterectomy by a gynecologic oncologist in 2018. Associations between pre-operative, operative and post-operative factors and 30-day readmission, SDD and postoperative complications were assessed using logistic regression.The 30-day readmission rate among the 423 women in the cohort was 4.5% and 1.9% in those undergoing SDD. Readmission rates by LHRS were: score 1 (4.9%), score 2 (7.8%), score 3 (13.6%), score 4 (16.7%). Patients with a LHRS of ≥3 had higher odds of readmission compared to those with a lower score (OR 4.20, p = 0.02). Infectious morbidity accounted for the majority of postoperative complications, emergency room visits and readmissions. We did not identify preoperative factors to replace the intra- and post-operative factors used in the score.The readmission rate following MIH is low, and a LHRS of ≥3 is associated with increased risk of readmission. Our findings support the applicability of the LHRS to a gynecologic oncology population; addressing risk factors for postoperative infection or closer follow up for patients with a LHRS ≥3 could reduce postoperative readmissions.

  View details for DOI 10.1016/j.ygyno.2021.12.010

  View details for PubMedID 34969534

• Prognostic significance of ethnicity and age in advanced stage epithelial ovarian cancer: An NRG oncology/gynecologic oncology group study. Gynecologic oncology duPont, N. C., Enserro, D., Brady, M. F., Moxley, K., Walker, J. L., Cosgrove, C., Bixel, K., Tewari, K. S., Thaker, P., Wahner Hendrickson, A. E., Rubin, S., Fujiwara, K., Casey, A. C., Soper, J., Burger, R. A., Monk, B. J. 2022; 164 (2): 398-405

  Abstract

  Age and ethnicity are among several factors that influence overall survival (OS) in ovarian cancer. The study objective was to determine whether ethnicity and age were of prognostic significance in women enrolled in a clinical trial evaluating the addition of bevacizumab to front-line therapy.Women with advanced stage ovarian, primary peritoneal, or fallopian tube cancer were enrolled in a phase III clinical trial. All women had surgical staging and received adjuvant chemotherapy with one of three regimens. Cox proportional hazards models were used to evaluate the relationship between OS with age and race/ethnicity among the study participants.One-thousand-eight-hundred-seventy-three women were enrolled in the study. There were 280 minority women and 328 women over the age of 70. Women age 70 and older had a 34% increase risk for death when compared to women under 60 (HR = 1.34; 95% CI 1.16-1.54). Non-Hispanic Black women had a 54% decreased risk of death with the addition of maintenance bevacizumab (HR = 0.46, 95% CI:0.26-0.83). Women of Asian descent had more hematologic grade 3 or greater adverse events and a 27% decrease risk of death when compared to non-Hispanic Whites (HR = 0.73; 95% CI: 0.59-0.90).Non-Hispanic Black women showed a decreased risk of death with the addition of bevacizumab and patients of Asian ancestry had a lower death rate than all other minority groups, but despite these clinically meaningful improvements there was no statistically significant difference in OS among the groups.

  View details for DOI 10.1016/j.ygyno.2021.11.013

  View details for PubMedID 34857397

  View details for PubMedCentralID PMC9400113

• Determinants of Surgical Approach and Survival Among Women with Endometrial Carcinoma. Journal of minimally invasive gynecology Bixel, K., Barrington, D. A., Vetter, M. H., Suarez, A. A., Felix, A. S. 2022; 29 (2): 219-230

  Abstract

  To investigate determinants of surgical approach among women with endometrial carcinoma (EC) and associations between surgical approach and overall survival (OS).Retrospective cohort.The National Cancer Database, 2010 to 2015.A total of 140 470 patients with histologically confirmed EC who underwent hysterectomy.Patients were grouped according to surgical approach.A total of 140 470 patients with EC were included. Robotic-assisted laparoscopy (RAL) was the most common surgical approach (48.8%), followed by laparotomy (33.6%) and traditional laparoscopy (17.6%). Use of RAL increased over the study period, and the percentages of cases managed by laparotomy decreased. Older women, those with insurance, residing in ZIP codes with lower proportions of individuals who did not graduate from high school, and those treated at noncommunity cancer programs were less likely to undergo laparotomy than RAL, and non-white women, those diagnosed with high-grade histology, and those with advanced-stage EC were more likely to undergo laparotomy than RAL. Compared with RAL, all other surgical approaches were associated with worse OS (laparotomy: hazard ratio 1.21; 95% confidence interval, 1.18-1.25; traditional laparoscopy: hazard ratio 1.06; 95% confidence interval, 1.02-1.09). Significant effect modification of the surgical approach and OS relationship according to age, race, histology, stage, and adjuvant treatment was observed.RAL increased in frequency over the study period and was associated with improved OS, supporting the continued use of RAL for EC management.

  View details for DOI 10.1016/j.jmig.2021.07.018

  View details for PubMedID 34348183

  View details for PubMedCentralID PMC8803987

• Endometrial Cancer: Who Lives, Who Dies, Can We Improve Their Story? The oncologist Cosgrove, C. M., Backes, F. J., O'Malley, D., Bixel, K. L., Suarez, A. A., Fowler, J. M., Copeland, L. J., Goodfellow, P. J., Cohn, D. E. 2021; 26 (12): 1044-1051

  Abstract

  Endometrial cancer (EC) is the most common gynecologic cancer in the U.S. The objective of this cohort study was to characterize the clinical and pathologic features that are associated with endometrial cancer-specific death for women cared for at a single National Cancer Institute-designated comprehensive cancer center.This is a retrospective cohort from 2014 to 2017 including all women who had a hysterectomy for EC. Charts were reviewed for clinical and pathologic data, focusing on survival outcomes.Seven hundred seventy-one patients with EC underwent hysterectomy with 760 informative for outcomes. Seventy-six (10%) deaths were related to their EC; 62 women died from recurrent EC. Nonendometrioid histology and advanced stage were predictors of recurrence and EC death. Among patients with endometrioid ECs, mismatch repair status was significantly associated with EC-specific survival (relative risk = 4.8; 95% confidence interval, 2.3-10.3; p < .0001). Most patients with EC who recurred died of their disease 62/83 (74.7%). Nearly half of the patients that recurred (27/62) had no additional therapy at the time of recurrence. Overall survival was significantly longer for those women who had additional treatment at the time of recurrence; however, the improvement in overall survival with therapy at recurrence was largely attributable to effects in those women who were adjuvant therapy naïve.Although there is benefit of treatment at the time of recurrence for treatment-naïve women; only approximately half of patients were able to receive therapy. There is an urgent need for continued efforts for more effective EC therapy in both the front-line and recurrent setting as well as early identification of cancer diagnosis and recurrence.Approximately 10% of patients died of their endometrial cancer. Most deaths were from recurrent disease; however, almost 20% of endometrial cancer deaths were within 120 days of surgery. Although treatment at the time of recurrence improves overall survival, only approximately half of patients will receive therapy at the time of recurrence. Traditional prognostic features like histology and stage remain important to predict risk of recurrence, and newer biomarkers, such as mismatch repair status, may improve risk stratification and targeted therapy. There remains an urgent need for improved therapy and early detection of diagnosis and recurrence.

  View details for DOI 10.1002/onco.13934

  View details for PubMedID 34402130

  View details for PubMedCentralID PMC8649025

• Wound complications following vulvar excision for nonmalignant lesions. AJOG global reports Boyles, G. P., Weaver, A. M., Cohn, D. E., Backes, F. J., Copeland, L. J., Bixel, K. L., Fowler, J. M., O'Malley, D. M., Cosgrove, C. M. 2021; 1 (4): 100022

  Abstract

  There is a paucity of literature regarding the outcomes following vulvar excision for nonmalignant lesions. This is a common procedure among gynecologists and gynecologic oncologists, and a body of evidence is warranted to guide clinical care and future research.This study aimed to estimate the rate of wound complications following simple vulvar excision and to identify the risk factors for these outcomes. Our secondary objectives were to determine the rates of (1) positive margins and (2) occult carcinoma in the cases of vulvar dysplasia.We conducted a single-institution, retrospective cohort study of the patients who underwent simple vulvar excision procedures for suspected premalignant or benign lesions between June 2016 and February 2020. Our primary outcome was the rate of composite wound complications, including wound separation or breakdown, infection, or hematoma. Our secondary outcomes were the incidence of (1) margins positive for residual dysplasia and (2) occult minimally invasive carcinoma. The Fisher exact tests and chi-squared tests were used to compare the categorical variables and logistic regression models and independent student t tests were used for continuous variables, as appropriate. Multivariate stepwise selection and multiple logistic regression was performed to evaluate the risk factors for complications and generate the odds ratios.Of the 338 patients included in the study, 143 (42.3%) experienced wound complication. Most of these complications were wound separation or breakdown (n=134, 39.6%), followed by infection (n=22, 6.5%), and hematoma (n=4, 1.2%). On multivariate analysis, the presence of high-grade vulvar dysplasia (adjusted odds ratio, 1.83; 95% confidence interval, 1.06-3.15), longer specimen diameter (adjusted odds ratio, 1.03; 95% confidence interval, 1.01-1.05), and lesion location on the perineum (adjusted odds ratio, 2.25; 95% confidence interval, 1.38-3.66) were independent risk factors. With high-grade vulvar dysplasia, the rate of positive margins was 50.2% (114/227) and that of occult microinvasive carcinoma was 17.2% (39/227). Notably, the primary and secondary outcomes were similar among gynecologic oncologists and gynecologists.Wound complications following vulvar excision for nonmalignant lesions are common. Select groups may benefit from anticipatory counseling and future interventional studies to prevent complication. The incidence of positive surgical margins and occult minimally invasive carcinoma is also high, reflecting the challenging nature of treating vulvar disease.

  View details for DOI 10.1016/j.xagr.2021.100022

  View details for PubMedID 36277453

  View details for PubMedCentralID PMC9563940

• Lenvatinib plus pembrolizumab in advanced recurrent endometrial cancer: A cost-effectiveness analysis. Gynecologic oncology Barrington, D. A., Haight, P. J., Calhoun, C., Tubbs, C., Cohn, D. E., Bixel, K. L. 2021; 162 (3): 626-630

  Abstract

  To determine the cost-effectiveness of lenvatinib plus pembrolizumab (LP) in patients with microsatellite stable (MSS), recurrent, pretreated endometrial cancer (EC).A decision analysis model was created to evaluate the cost-effectiveness of LP relative to doxorubicin, pegylated liposomal doxorubicin (PLD), and bevacizumab in patients with recurrent pretreated MSS EC. Published data was used to estimate quality adjusted life years (QALYs) and drug cost estimates were obtained using average wholesale prices. A health state utility (HSU) penalty of -0.10 was applied to the LP group to account for treatment toxicity. Incremental cost-effectiveness ratios (ICERs) were calculated to determine cost/QALY. The willingness to pay threshold (WTP) was set at $100,000 per QALY saved. Sensitivity analyses were performed on cost, effectiveness, and HSU penalty for LP.Costs of treatment with doxorubicin, PLD, and bevacizumab are $23.7 million (M), $56.9 M, and $250.8 M respectively. Cost of treatment with LP is $1.8 billion. Relative to doxorubicin, the ICERs for PLD, bevacizumab, and LP are $56,808, $345,824, and $1.6 M respectively. A sensitivity analysis varying the cost of LP shows that if the combined drug cost decreases from over $58,000 to less than $11,000 per cycle, this strategy would be cost-effective. Eliminating the HSU penalty for LP decreased the ICER $1.0 M while increasing the penalty to -0.20 increased the ICER to $3.7 M.LP is not cost-effective in patients with recurrent pretreated, MSS EC. A dramatic reduction in cost of LP is required for this novel strategy to be cost-effective.

  View details for DOI 10.1016/j.ygyno.2021.06.014

  View details for PubMedID 34148720

• Phase I evaluation of lenvatinib and weekly paclitaxel in patients with recurrent endometrial, ovarian, fallopian tube, or primary peritoneal Cancer. Gynecologic oncology Backes, F. J., Wei, L., Chen, M., Hill, K., Dzwigalski, K., Poi, M., Phelps, M., Salani, R., Copeland, L. J., Fowler, J. M., Cohn, D. E., Bixel, K., Cosgrove, C., Hays, J., O'Malley, D. 2021; 162 (3): 619-625

  Abstract

  To estimate the maximally tolerated dose (MTD) and describe toxicities associated with lenvatinib and weekly paclitaxel in patients with recurrent endometrial and platinum resistant epithelial ovarian cancer.Using a 3 + 3 design patients were given weekly paclitaxel 80 mg/m2 IV day 1, 8, 15 and oral levantinib daily on a 28-day cycle. Lenvatinib dose levels were 8 mg, 12 mg, 16 mg, 20 mg. Toxicities were recorded using CTCAE v4.03 and response was determined with imaging after cycle 2, then every 3rd cycle, using RECIST 1.1 criteria.26 patients were enrolled; 19 with ovarian cancer (14 high grade serous, 1 low grade serous, 2 clear cell, 1 endometrioid, and 1 carcinosarcoma), and 7 with endometrial cancer (3 serous, and 4 endometrioid). The MTD was established at lenvatinib 16 mg and weekly paclitaxel 80 mg/m2. Toxicities (all grades) occurring in ≥25% of patients included anemia, neutropenia, lymphopenia, mucositis, nausea, diarrhea, anorexia, hypertension, fatigue, proteinuria, epistaxis, hoarseness. Twenty-three patients were evaluable for response and PFS; 15 (65%) had a partial response, 7 (30%) stable, 1 (4%) progressive disease with an objective response rate of 65%; 71% in ovarian and 50% in endometrial cancer. Median progression free survival (PFS) is 12.4 months; 14.0 months in endometrial cancer, 7.2 months in ovarian cancer; 54% had a PFS > 6 months. The median duration of response for PR patients (n = 15) was 10.9 months.The regimen was tolerable with manageable side effects. Encouraging activity was observed in endometrial and ovarian cancer, and warrants further development.

  View details for DOI 10.1016/j.ygyno.2021.06.032

  View details for PubMedID 34272090

• Pathologic and clinical tumor size discordance in early-stage cervical cancer: Does it matter? Gynecologic oncology Vetter, M. H., Smrz, S., Gehrig, P. A., Peng, K., Matsuo, K., Davidson, B. A., Cisa, M. P., Lees, B. F., Brunette, L. L., Tucker, K., Stuart Staley, A., Gotlieb, W. H., Holloway, R. W., Essel, K. G., Holman, L. L., Goldfeld, E., Olawaiye, A., Rose, S., Uppal, S., Bixel, K. 2020; 159 (2): 354-358

  Abstract

  The objective of this study was to assess the rate of discordance between clinical and pathologic tumor size for women with stage IB1 cervical cancer (FIGO 2009 criteria), assess risk factors for discordance, and determine the impact of discordance on oncologic outcomes.This was a secondary analysis of a prior multi-institutional retrospective review of patients diagnosed with stage IB1 (FIGO 2009 staging) cervical cancer undergoing radical hysterectomy between 2010 and 2017. Demographic, clinicopathologic, and oncologic data were collected. Pathologic upstaging was defined as having a preoperative diagnosis of stage IB1 cervical cancer with pathology demonstrating a tumor size >4 cm. Demographic and clinicopathologic data was compared using chi-square, fisher exact or 2-sided t-test. Survival was estimated using the Kaplan-Meier method.Of the 630 patients, 77 (12%) were upstaged. Patients who were upstaged had lower rates of preoperative conization (p < .001) or preoperative tumor sizes ≤2 cm (p < .001). Upstaged patients had increased odds of deep stromal invasion, lymphovascular space invasion, positive margins and positive lymph nodes. Almost 88% of upstaged patients received adjuvant therapy compared to 29% of patients with tumors ≤4 cm (odds 18.49, 95% CI 8.99-37.94). Finally, pathologic upstaging was associated with an increased hazard of recurrence (hazard ratio [HR] 1.95, 95% CI 1.03-3.67) and all-cause death (HR 2.31, 95% CI 1.04-5.11).Pathologic upstaging in stage IB1 cervical cancer is relatively common. Upstaging is associated with an 18-fold increased risk of receipt of adjuvant therapy. Patients undergoing preoperative conization and those with tumors <2 cm had lower risks of upstaging. Improvement in preoperative assessment of tumor size may better inform primary treatment decisions.

  View details for DOI 10.1016/j.ygyno.2020.08.004

  View details for PubMedID 32888724

• Pathologic chemotherapy response score in epithelial ovarian cancer: Surgical, genetic, and survival considerations. Surgical oncology Barrington, D. A., Felix, A. S., Owda, R., Suarez, A. A., Cohen, D. W., Senter, L., Copeland, L. J., Fowler, J. M., Backes, F. J., Cohn, D. E., Bixel, K. L., O'Malley, D. M., Salani, R., Cosgrove, C. M. 2020; 34: 40-45

  Abstract

  A pathologic chemotherapy response score (CRS) is used to grade ovarian cancer response to neoadjuvant chemotherapy (NACT). We evaluated the prognostic significance of the CRS in a single institution cohort.A retrospective review of all consecutive epithelial ovarian cancer patients undergoing interval debulking surgery (IDS) after NACT from 2016 to 2017 were included. Clinical, pathologic, surgical, outcomes, and genetic data were abstracted from medical records. CRS was assigned by pathology based on a section of omentum as follows: 1 = minimal response, 2 = moderate response, and 3 = near complete response.Among the 50 subjects, 14 (28%) were classified as CRS1, 29 (58%) as CRS2, and 7 (14%) as CRS3. The majority of patients were diagnosed with high grade serous histology (94%). Most women in this cohort underwent either an optimal or complete cytoreduction to no gross residual disease (96%). Women in the CRS2 group were most likely to have a pathogenic variant (51.7%) while those in the CRS1 were least likely (7.1%). Most women recurred regardless of CRS. CRS was not associated with progression-free survival (log-rank p = 0.82) or overall survival (log-rank p = 0.30).Though previous data support the use of CRS as a prognostic indicator, we failed to show a correlation between CRS and survival in our continuous single institution cohort. The high rate of optimal debulking across all CRS groups in this study may mitigate the prognostic significance of the scoring system. Nevertheless, tumors that respond poorly to traditional chemotherapy should remain of avid interest for potential novel therapies.

  View details for DOI 10.1016/j.suronc.2020.03.001

  View details for PubMedID 32891351

• Recurrence Rates in Patients With Cervical Cancer Treated With Abdominal Versus Minimally Invasive Radical Hysterectomy: A Multi-Institutional Retrospective Review Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Uppal, S., Gehrig, P. A., Peng, K., Bixel, K. L., Matsuo, K., Vetter, M. H., Davidson, B. A., Cisa, M. P., Lees, B. F., Brunette, L. L., Tucker, K., Stuart Staley, A., Gotlieb, W. H., Holloway, R. W., Essel, K. G., Holman, L. L., Goldfeld, E., Olawaiye, A., Rose, S. L. 2020; 38 (10): 1030-1040

  Abstract

  To compare the disease-free survival (DFS) between open and minimally invasive radical hysterectomies (RH) performed in academic medical institutions.Retrospective multi-institutional review of patients undergoing RH for stage IA1 (with lymphovascular invasion), IA2, and IB1 squamous, adenocarcinoma, or adenosquamous carcinoma between January 1, 2010 and December 31, 2017.Of 815 patients, open RH was performed in 255 cases (29.1%) and minimally invasive RH in 560 cases (70.9%). There were 19 (7.5%) recurrences in the open RH and 51 (9.1%) recurrences in the minimally invasive group (P = .43). Risk-adjusted analysis revealed that minimally invasive RH was independently associated with an increased hazard of recurrence (aHR, 1.88; 95% CI, 1.04 to 3.25). Other factors independently associated with an increased hazard of recurrence included tumor size, grade, and adjuvant radiation. Conization before surgery was associated with lower recurrence risk (aHR, 0.4; 95% CI, 0.23 to 0.71). There was no difference in OS in the unadjusted analysis (HR, 1.14; 95% CI, 0.61 to 2.11) or after risk adjustment (aHR, 1.01; 95% CI, 0.5 to 2.2). Of 264 patients with tumors ≤ 2 cm on final pathology (excluding those with no residual tumor on final pathology), 2/82 (2.4%) recurred in the open RH group and 16/182 (8.8%) in the minimally invasive RH group (P = .058). In propensity score matching analysis, 7/159 (4.4%) recurrences were noted in the open RH group and 18/156 (11.5%) in the minimally invasive RH group (P = .019). Survival analysis revealed an increased risk of recurrence in the minimally invasive group in propensity-matched cohort (HR, 2.83; 95% CI, 1.1 to 7.18).In this retrospective series, patients undergoing minimally invasive radical hysterectomy, including those with tumor size ≤ 2 cm on final pathology, had inferior DFS but not overall survival in the entire cohort.

  View details for DOI 10.1200/JCO.19.03012

  View details for PubMedID 32031867

• Intraperitoneal chemotherapy following neoadjuvant chemotherapy and optimal interval tumor reductive surgery for advanced ovarian cancer. Gynecologic oncology Bixel, K., Vetter, M., Davidson, B., Berchuck, A., Cohn, D., Copeland, L., Fowler, J. M., Havrilesky, L., Lee, P. S., O'Malley, D. M., Salani, R., Valea, F., Alvarez Secord, A., Backes, F. 2020; 156 (3): 530-534

  Abstract

  Intraperitoneal (IP) chemotherapy following neoadjuvant chemotherapy (NACT) and interval tumor reductive surgery (TRS) for advanced ovarian cancer is feasible, however, the impact on disease outcomes remains unclear. We compare outcomes of patients treated with IP chemotherapy versus intravenous (IV) chemotherapy following NACT and interval TRS.In this retrospective review, patients with advanced ovarian cancer were included if they received NACT followed by optimal interval TRS between 1/2004 and 4/2017. Patients were excluded if they had an ECOG PS >1, received >6 cycles of NACT or postoperative chemotherapy, and/or received bevacizumab during primary therapy. Primary outcomes were progression free survival (PFS) and overall survival (OS).There were 134 patients included in this study, 37 (28%) received IP and 97 (72%) received IV chemotherapy postoperatively. Patients in the IV group were older (median 66.3 vs 59.7 years, p = 0.0039) though there were no differences in BMI, race, BRCA status, stage, or histology. Median PFS was 3 months longer in the IP group (14.5 versus 11.5 months, p = 0.028) however there was no significant difference in OS. On univariate analysis, increasing number of NACT cycles (HR 1.914, 95% CI 1.024-3.497) and residual disease at completion of TRS (HR 1.541, 95% CI 1.042-2.248) were associated with decreased PFS; IP chemotherapy was associated with increased PFS (HR 0.633, 95% CI 0.414-0.944). These associations remained on multivariate analysis. Toxicity was comparable between the groups.IP after NACT and optimal interval TRS was associated with in improved PFS compared to IV chemotherapy without significant differences in toxicity.

  View details for DOI 10.1016/j.ygyno.2019.12.016

  View details for PubMedID 31937450

• Preoperative predictors of endometrial cancer at time of hysterectomy for endometrial intraepithelial neoplasia or complex atypical hyperplasia. American journal of obstetrics and gynecology Vetter, M. H., Smith, B., Benedict, J., Hade, E. M., Bixel, K., Copeland, L. J., Cohn, D. E., Fowler, J. M., O'Malley, D., Salani, R., Backes, F. J. 2020; 222 (1): 60.e1-60.e7

  Abstract

  Endometrial intraepithelial neoplasia, also known as complex atypical hyperplasia, is a precancerous lesion of the endometrium associated with a 40% risk of concurrent endometrial cancer at the time of hysterectomy. Although a majority of endometrial cancers diagnosed at the time of hysterectomy for endometrial intraepithelial neoplasia are low risk and low stage, approximately 10% of patients ultimately diagnosed with endometrial cancers will have high-risk disease that would warrant lymph node assessment to guide adjuvant therapy decisions. Given these risks, some physicians choose to refer patients to a gynecologic oncologist for definitive management. Currently, few data exist regarding preoperative factors that can predict the presence of concurrent endometrial cancer in patients with endometrial intraepithelial neoplasia. Identification of these factors may assist in the preoperative triaging of patients to general gynecology or gynecologic oncology.To determine whether preoperative factors can predict the presence of concurrent endometrial cancer at the time of hysterectomy in patients with endometrial intraepithelial neoplasia; and to describe the ability of preoperative characteristics to predict which patients may be at a higher risk for lymph node involvement requiring lymph node assessment at the time of hysterectomy.We conducted a retrospective cohort study of women undergoing hysterectomy for pathologically confirmed endometrial intraepithelial neoplasia from January 2004 to December 2015. Patient demographics, imaging, pathology, and outcomes were recorded. The "Mayo criteria" were used to determine patients requiring lymphadenectomy. Unadjusted associations between covariates and progression to endometrial cancer were estimated by 2-sample t-tests for continuous covariates and by logistic regression for categorical covariates. A multivariable model for endometrial cancer at the time of hysterectomy was developed using logistic regression with 5-fold cross-validation.Of the 1055 charts reviewed, 169 patients were eligible and included. Of these patients, 87 (51.5%) had a final diagnosis of endometrial intraepithelial neoplasia/other benign disease, whereas 82 (48.5%) were ultimately diagnosed with endometrial cancer. No medical comorbidities were found to be strongly associated with concurrent endometrial cancer. Patients with endometrial cancer had a thicker average endometrial stripe compared to the patients with no endometrial cancer at the time of hysterectomy (15.7 mm; standard deviation, 9.5) versus 12.5 mm; standard deviation, 6.4; P = .01). An endometrial stripe of ≥2 cm was associated with 4.0 times the odds of concurrent endometrial cancer (95% confidence interval, 1.5-10.0), controlling for age. In all, 87% of endometrial cancer cases were stage T1a (Nx or N0). Approximately 44% of patients diagnosed with endometrial cancer and an endometrial stripe of ≥2 cm met the "Mayo criteria" for indicated lymphadenectomy compared to 22% of endometrial cancer patients with an endometrial stripe of <2 cm.Endometrial stripe thickness and age were the strongest predictors of concurrent endometrial cancer at time of hysterectomy for endometrial intraepithelial neoplasia. Referral to a gynecologic oncologist may be especially warranted in endometrial intraepithelial neoplasia patients with an endometrial stripe of ≥2 cm given the increased rate of concurrent cancer and potential need for lymph node assessment.

  View details for DOI 10.1016/j.ajog.2019.08.002

  View details for PubMedID 31401259

  View details for PubMedCentralID PMC7201377

• Surgical complexity score and role of laparoscopy in women with advanced ovarian cancer treated with neoadjuvant chemotherapy. Gynecologic oncology Davidson, B. A., Broadwater, G., Crim, A., Boccacio, R., Bixel, K., Backes, F., Previs, R. A., Salinaro, J., Salani, R., Moore, K., Secord, A. A. 2019; 152 (3): 554-559

  Abstract

  To evaluate surgical complexity scores (SCS) and minimally invasive surgery (MIS) at interval debulking surgery (IDS) in advanced epithelial ovarian cancer (EOC) patients receiving neoadjuvant chemotherapy (NACT).A multi-institutional study of NACT with IDS for advanced EOC was conducted. Demographic data were abstracted and SCS assigned based on IDS findings. Disease-specific overall survival (DSS) was defined as the time from completion of adjuvant chemotherapy to death due to disease. Cox proportional hazards regression models were used for univariate and multivariate survival analyses.282 patients were identified; 80.5% had high-grade serous histology and 54.6% were <75 (median 63.9; range 34.1-84.8). Approximately 84% were optimally cytoreduced (61% R0; 23% <1 cm). In multivariate analyses, age 75+ (p ≤ 0.001), residual disease (>1 cm; p = 0.03), and SCS ≥ 3 (p = 0.04) were significantly predictive of worse DSS when morbidity and ASA score were also in the model. When optimally debulked was defined as R0, only age 75+ (<0.001) was significantly associated with decreased DSS. In the R0 cohort, SCS did not significantly predict DSS. However, subset analysis defining optimal ≤1 cm, revealed higher SCS was associated with a 1.6-fold increased risk of death (p = 0.02). Fifty-one patients underwent laparoscopic IDS. Twenty-four (47%) were converted to laparotomy to achieve optimal debulking in 21 patients (87.5%); while 25 had laparoscopic optimal cytoreduction (19/25 [76%] R0).In women with advanced EOC treated with NACT, older age, SCS ≥ 3, and residual disease >1 cm at IDS were predictors of worse survival. MIS appears safe and feasible with acceptable optimal cytoreduction rates.

  View details for DOI 10.1016/j.ygyno.2018.12.011

  View details for PubMedID 30558972

• Outpatient desensitization of patients with moderate (high-risk) to severe platinum hypersensitivity reactions. Gynecologic oncology Vetter, M. H., Khan, A., Backes, F. J., Bixel, K., Cohn, D. E., Copeland, L. J., Fowler, J. M., Salani, R., Li, Q., O'Malley, D. M. 2019; 152 (2): 316-321

  Abstract

  Platinum hypersensitivity reactions (HSR) affect approximately 5% of the general oncologic population. Here we report the efficacy and safety of outpatient platinum desensitization protocol (PD) in gynecologic oncology patients with moderate (high-risk) to severe platinum HSR.This is a retrospective report of patients with gynecologic malignancies undergoing an outpatient PD for moderate (high-risk) to severe platinum HSR from 2011 to 2017. Patient demographics, chemotherapy histories, and PD outcomes were collected. Descriptive statistics were performed given the exploratory nature of the study.Forty-eight patients meeting inclusion criteria were identified. Most patients were being treated for ovarian cancer (56.3%) and were receiving carboplatin during their initial platinum HSR (75.0%). Patients received a mean of 10.3 platinum doses prior to their initial HSR. Transient hypertension was the most common sign of moderate (high-risk) HSR while persistent tachycardia was the most common sign of severe HSR. A total of 295 PD cycles were attempted with a successful completion rate of 96.6%. The mean number of PD cycles received by patients was 5.1. Almost 65% of patients experienced breakthrough reactions but over 58% of these breakthrough reactions were isolated to the first PD cycle. Only 8.3% of patients had severe breakthrough reactions, all of whom initially underwent shortened desensitization. Of these 4 patients, 2 successfully underwent desensitization with a prolonged protocol.Outpatient PD is safe and effective in patients with gynecologic malignancies. This may present a feasible option for institutions with multi-disciplinary teams experienced with the management of platinum HSR.

  View details for DOI 10.1016/j.ygyno.2018.10.037

  View details for PubMedID 30503265

• STAT3/PIAS3 Levels Serve as "Early Signature" Genes in the Development of High-Grade Serous Carcinoma from the Fallopian Tube. Cancer research Saini, U., Suarez, A. A., Naidu, S., Wallbillich, J. J., Bixel, K., Wanner, R. A., Bice, J., Kladney, R. D., Lester, J., Karlan, B. Y., Goodfellow, P. J., Cohn, D. E., Selvendiran, K. 2018; 78 (7): 1739-1750

  Abstract

  The initial molecular events that lead to malignant transformation of the fimbria of the fallopian tube (FT) through high-grade serous ovarian carcinoma (HGSC) remain poorly understood. In this study, we report that increased expression of signal transducer and activator of transcription 3 (pSTAT3 Tyr705) and suppression or loss of protein inhibitor of activated STAT3 (PIAS3) in FT likely drive HGSC. We evaluated human tissues-benign normal FT, tubal-peritoneal junction (TPJ), p53 signature FT tissue, tubal intraepithelial lesion in transition (TILT), serous tubal intraepithelial carcinoma (STIC) without ovarian cancer, and HGSC for expression of STAT3/PIAS3 (compared with their known TP53 signature) and their target proliferation genes. We observed constitutive activation of STAT3 and low levels or loss of PIAS3 in the TPJ, p53 signature, TILT, and STIC through advanced stage IV (HGSC) tissues. Elevated expression of pSTAT3 Tyr705 and decreased levels of PIAS3 appeared as early as TPJ and the trend continued until very advanced stage HGSC (compared with high PIAS3 and low pSTAT3 expression in normal benign FT). Exogenous expression of STAT3 in FT cells mediated translocation of pSTAT3 and c-Myc into the nucleus. In vivo experiments demonstrated that overexpression of STAT3 in FT secretory epithelial cells promoted tumor progression and metastasis, mimicking the clinical disease observed in patients with HGSC. Thus, we conclude that the STAT3 pathway plays a role in the development and progression of HGSC from its earliest premalignant states.Significance: Concomitant gain of pSTAT3 Tyr705 and loss of PIAS3 appear critical for initiation and development of high-grade serous carcinoma. Cancer Res; 78(7); 1739-50. ©2018 AACR.

  View details for DOI 10.1158/0008-5472.CAN-17-1671

  View details for PubMedID 29339537

  View details for PubMedCentralID PMC5907493

• Targeting STAT3 by HO3867 induces apoptosis in ovarian clear cell carcinoma. International journal of cancer Bixel, K., Saini, U., Kumar Bid, H., Fowler, J., Riley, M., Wanner, R., Deepa Priya Dorayappan, K., Rajendran, S., Konishi, I., Matsumura, N., Cohn, D. E., Selvendiran, K. 2017; 141 (9): 1856-1866

  Abstract

  Advanced ovarian clear cell carcinoma (OCCC) carries a very poor prognosis in large part secondary to the extremely high rate of resistance to standard platinum and taxane chemotherapy. Signal transducer and activator of transcription 3(STAT3) expression and activation has been shown to regulate tumor progression in various human cancers, though has not been well studied in OCCC. Preliminary work in our lab has demonstrated constitutive activation of STAT3 (pSTAT3Tyr705 or pSTAT3727) in OCCC cell lines as well as human OCCC tumor tissue samples. Significantly, pSTAT3 is expressed in the absence of other forms of activated STAT (pSTAT1, 2, 6). Therefore, this work was planned to investigate the role of STAT3 and examine the efficacy of a novel anti-cancer compound -HO-3867, which is an inhibitor of STAT3, using known OCCC cell lines. Results demonstrate that treatment with HO-3867 decreased expression of pSTAT3 Tyr705 as well pSTAT3 Ser727, while total STAT3 remained constant. STAT3 overexpression increased the migration capability in OVTOKO cells in vitro and led to an increased tumor size when injected in vivo. The inhibitory effect of HO-3867 on cell proliferation and cell survival was accompanied by increased apoptosis, within 24 h post treatment. Treatment with HO-3867 resulted in a decrease in Bcl-2 and increase of cleavage of caspase 3, caspase 7, and PARP, confirming induction of apoptosis after treatment with HO-3867. In addition, HO-3867 significantly inhibited formation of human umbilical vein endothelial cells capillary-like structures and invasion at both 5 and 10 µM concentrations. STAT3 expression plays an important role in the spread of OCCC in vitro as well as in vivo. Thus, we can exploit the STAT3 pathway for targeted drug therapy. Inhibition of pSTAT3 using HO-3867in OCCC cell lines appears to be a promising therapy. This is of utmost importance given the poor response of OCCC to standard chemotherapy regimens.

  View details for DOI 10.1002/ijc.30847

  View details for PubMedID 28646535

  View details for PubMedCentralID PMC5812255

• Elevated STAT3 expression in ovarian cancer ascites promotes invasion and metastasis: a potential therapeutic target. Oncogene Saini, U., Naidu, S., ElNaggar, A. C., Bid, H. K., Wallbillich, J. J., Bixel, K., Bolyard, C., Suarez, A. A., Kaur, B., Kuppusamy, P., Hays, J., Goodfellow, P. J., Cohn, D. E., Selvendiran, K. 2017; 36 (2): 168-181

  Abstract

  Although activation of the STAT3 pathway has been associated with tumor progression in a wide variety of cancer types (including ovarian cancer), the precise mechanism of invasion and metastasis due to STAT3 are not fully delineated in ovarian cancer. We found that pSTAT3 Tyr705 is constitutively activated in patient ascites and ascites-derived ovarian cancer cells (ADOCCs), and the range of STAT3 expression could be very high to low. In vivo transplantation of ADOCCs with high pSTAT3 expression into the ovarian bursa of mice resulted in a large primary tumor and widespread peritoneal metastases. In contrast, ADOCCs with low STAT3 expression or ADOCCs with STAT3 expression knockdown, led to reduced tumor growth and an absence of metastases in vivo. Cytokines derived from the ADOCC culture medium activate the interleukin (IL)-6/STAT pathway in the STAT3 knockout (KO) cells, compensating for the absence of inherent STAT3 in the cells. Treatment with HO-3867 (a novel STAT3 inhibitor at 100 p.p.m. in an orthotopic murine model) significantly suppressed ovarian tumor growth, angiogenesis and metastasis by targeting STAT3 and its downstream proteins. HO-3867 was found to have cytotoxic effects in ex vivo cultures of freshly collected human ovarian cancers, including those resistant to platinum-based chemotherapy. Our results show that STAT3 is necessary for ovarian tumor progression/metastasis and highlight the potential for targeting STAT3 by HO-3867 as a therapeutic strategy for ovarian cancer.

  View details for DOI 10.1038/onc.2016.197

  View details for PubMedID 27292260

  View details for PubMedCentralID PMC5338638

• Use and Effectiveness of Neoadjuvant Chemotherapy for Treatment of Ovarian Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Meyer, L. A., Cronin, A. M., Sun, C. C., Bixel, K., Bookman, M. A., Cristea, M. C., Griggs, J. J., Levenback, C. F., Burger, R. A., Mantia-Smaldone, G., Matulonis, U. A., Niland, J. C., O'Malley, D. M., Wright, A. A. 2016; 34 (32): 3854-3863

  Abstract

  Purpose In 2010, a randomized clinical trial demonstrated noninferior survival for patients with advanced ovarian cancer who were treated with neoadjuvant chemotherapy (NACT) compared with primary cytoreductive surgery (PCS). We examined the use and effectiveness of NACT in clinical practice. Patients and Methods A multi-institutional observational study of 1,538 women with stages IIIC to IV ovarian cancer who were treated at six National Cancer Institute-designated cancer centers. We examined NACT use in patients who were diagnosed between 2003 and 2012 (N = 1,538) and compared overall survival (OS), morbidity, and postoperative residual disease in a propensity-score matched sample of patients (N = 594). Results NACT use increased from 16% during 2003 to 2010 to 34% during 2011 to 2012 in stage IIIC disease ( Ptrend < .001), and from 41% to 62% in stage IV disease ( Ptrend < .001). Adoption of NACT varied by institution, from 8% to 30% for stage IIIC disease (P < .001) and from 27% to 61% ( P = .007) for stage IV disease during this time period. In the matched sample, NACT was associated with shorter OS in stage IIIC disease (median OS: 33 v 43 months; hazard ratio [HR], 1.40; 95% CI, 1.11 to 1.77) compared with PCS, but not stage IV disease (median OS: 31 v 36 months; HR, 1.16; 95% CI, 0.89 to 1.52). Patients with stages IIIC and IV disease who received NACT were less likely to have ≥ 1 cm postoperative residual disease, an intensive care unit admission, or a rehospitalization (all P ≤ .04) compared with those who received PCS treatment. However, among women with stage IIIC disease who achieved microscopic or ≤ 1 cm postoperative residual disease, NACT was associated with decreased OS (HR, 1.49; 95% CI, 1.01 to 2.18; P = .04). Conclusion Use of NACT increased significantly between 2003 and 2012. In this observational study, PCS was associated with increased survival in stage IIIC, but not stage IV disease. Future studies should prospectively consider the efficacy of NACT by extent of residual disease in unselected patients.

  View details for DOI 10.1200/JCO.2016.68.1239

  View details for PubMedID 27601552

  View details for PubMedCentralID PMC5477982

• Use of CA-125 Tests and Computed Tomographic Scans for Surveillance in Ovarian Cancer. JAMA oncology Esselen, K. M., Cronin, A. M., Bixel, K., Bookman, M. A., Burger, R. A., Cohn, D. E., Cristea, M., Griggs, J. J., Levenback, C. F., Mantia-Smaldone, G., Meyer, L. A., Matulonis, U. A., Niland, J. C., Sun, C., O'Malley, D. M., Wright, A. A. 2016; 2 (11): 1427-1433

  Abstract

  A 2009 randomized clinical trial demonstrated that using cancer antigen 125 (CA-125) tests for routine surveillance in ovarian cancer increases the use of chemotherapy and decreases patients' quality of life without improving survival, compared with clinical observation. The Society of Gynecologic Oncology guidelines categorize CA-125 testing as optional and discourage the use of radiographic imaging for routine surveillance. To date, few studies have examined the use of CA-125 tests in clinical practice.To examine the use of CA-125 tests and computed tomographic (CT) scans in clinical practice before and after the 2009 randomized clinical trial and to estimate the economic effect of surveillance testing.A prospective cohort of 1241 women with ovarian cancer in clinical remission after completion of primary cytoreductive surgery and chemotherapy at 6 National Cancer Institute-designated cancer centers between January 1, 2004, and December 31, 2011, was followed up through December 31, 2012, to study the use of CA-125 tests and CT scans before and after 2009. Data analysis was conducted from April 9, 2014, to March 28, 2016.The use of CA-125 tests and CT scans before and after 2009. Secondary outcomes included the time from CA-125 markers doubling to retreatment among women who experienced a rise in CA-125 markers before and after 2009, and the costs associated with surveillance testing using 2015 Medicare reimbursement rates.Among 1241 women (mean [SD] age 59 [12] years; 1112 white [89.6%]), the use of CA-125 testing and CT scans was similar during the study period. During 12 months of surveillance, the cumulative incidence of patients undergoing 3 or more CA-125 tests was 86% in 2004-2009 vs 91% in 2010-2012 (P = .95), and the cumulative incidence of patients undergoing more than 1 CT scan was 81% in 2004-2009 vs 78% in 2010-2012 (P = .50). Among women whose CA-125 markers doubled (n = 511), there was no significant difference in the time to retreatment with chemotherapy before and after 2009 (median, 2.8 vs 3.5 months; P = .40). During a 12-month period, there was a mean of 4.6 CA-125 tests and 1.7 CT scans performed per patient, resulting in a US population surveillance cost estimate of $1 999 029 per year for CA-125 tests alone and $16 194 647 per year with CT scans added.CA-125 tests and CT scans are still routinely used for surveillance testing in patients with ovarian cancer, although their benefit has not been proven and their use may have significant implications for patients' quality of life as well as costs.

  View details for DOI 10.1001/jamaoncol.2016.1842

  View details for PubMedID 27442965

  View details for PubMedCentralID PMC5106306