Kristen Starbuck - Academia.edu (original) (raw)
Papers by Kristen Starbuck
Gynecologic Oncology, Jun 1, 2019
Objective: Molecular determinants of ovarian cancer (OC) racial disparity have been under investi... more Objective: Molecular determinants of ovarian cancer (OC) racial disparity have been under investigation in order to find avenues for improved targeted therapeutics. Our objective was to evaluate and compare the immunologic landscape of primary ovarian cancer stratified by race. Method: Self-reported black and white patients with OC were matched for age, stage, and survival. A full genome RNAseq library was constructed and sequenced on an Illumina HiSeq instrument with differentially expressed genes inferred using DESeq2 software. Candidate gene sets of significantly regulated genes were used for functional and pathway enrichment analyses. Using a global 700-gene panel for immuneoncology, a validated tumor inflammation signature (TIS) algorithm was used to determine the presence of a pre-existing adaptive immune response of "hot" versus "cold" tumors. Results: OC tissue samples from 94 patients with primary advanced-stage OC were identified and matched by survival and platinum sensitivity. Self-reported patients were 55% white (n = 52) and 45% (n = 42) black. Groups were similar in age, BMI, histology, and grade. A total of 4,392 genes demonstrated significant differential expression when races were compared. Subsequent pathway analyses revealed significant upregulation of five genes associated with indoleamine 2.3-dioxygenase (IDO) pathway in black patients (WARS, IDO1, IDO2, AFMID, GCDH, p b 0.01). When compared to IDO low , progression-free survival (PFS) was shown to be worse in IDO high cancers, 18 versus 12 months (P = 0.03). Global immune-oncology gene signature panel showed IDO high cancers exhibited escape from immune control via adaptive resistance by overexpression of T cells and IFN-gamma and enhanced resistance to apoptosis. IDO high cancers served as a surrogate marker for global immune escape with significant correlation to elevated TIS (P = 0.008). Conclusion: In a well-matched cohort, OC from black patients demonstrated higher proportion IDO pathway expression that correlated to worse survivals. Genetic mapping revealed a global immune escape by an adaptive resistance mediated by T-cell secretion of IFN-gamma. These findings support an opportunity to selectively utilize immunotherapy for "hot" tumors preferentially found in black patients and offers the potential to close the disparity gap.
Gynecologic Oncology, Jun 1, 2018
Gynecologic Oncology, Jun 1, 2018
Gynecologic Oncology, Jul 1, 2017
Objective-The presence of miliary disease during initial ovarian cancer debulking may reflect a d... more Objective-The presence of miliary disease during initial ovarian cancer debulking may reflect a distinct mode of peritoneal spread independent from size-based tumor staging and may explain variation in response to treatment and survival outcomes. To infer the prevalence, presentation and clinical implications of miliary disease we reviewed existing surgical records. Methods-Reports were available for 1008 primary debulking surgeries for ovarian, primary peritoneal or fallopian tube cancer between 2001 and 2015 (685 reports from 2005 to 2015). Clinical outcome data was available for 938 patients. We analyzed a high-stage sub-cohort for survival (N=436). Results-Most records were evaluable for miliary disease (761/938); for these, the miliary phenotype was highly prevalent (249/761, 32.7%) and often accompanied by ascites (185/249, 74%). While optimal debulking rates were unaffected by miliary disease, total resection (R0) rates were poorer. Liver, stomach, spleen or bladder appeared to be sporadically involved while the omentum, mesentery, bowel, peritoneum and diaphragm were affected simultaneously (Spearman rho > 0.5). Overall, miliary disease was associated with worse progression free survival, overall survival, and time from relapse to death independent of stage. Survival effects were particularly strong for Stage IV disease where median overall survival varied by over 30 months (log-rank p=0.002).
Gynecologic Oncology, Oct 1, 2015
Evaluate rates of chemotherapy and radiotherapy delivery in the treatment of uterine carcinosarco... more Evaluate rates of chemotherapy and radiotherapy delivery in the treatment of uterine carcinosarcoma, and compare clinical outcomes of treated and untreated patients. The National Cancer Database was queried to identify patients diagnosed with uterine carcinosarcoma between 2003 and 2011. The impact of chemotherapy on survival was analyzed using the Kaplan-Meier method. Factors predictive of outcome were compared using the Cox proportional hazards model. A total of 10,609 patients met study eligibility criteria. Stages I, II, III, and IV disease accounted for 2997 (28.2%), 642 (6.1%), 2037 (19.2%), and 1316 (12.4%) of the study population, respectively. Most patients (91.0%) underwent definitive surgery, and lymphadenectomy was performed in 68.7% of the patients. Chemotherapy was administered in 2378 (22.4%) patients, radiotherapy to 2196 (20.7%), adjuvant chemo-radiation to 1804 (17.0%), and 4231 (39.9%) of women did not received adjuvant therapy. Utilization of chemotherapy became more frequent over time. Over the entire study period, after adjusting for race, period of diagnosis, facility location, facility type, insurance provider, stage, age, treatment modality, lymph node dissection, socioeconomic status, and comorbidity index, there was an association between treatment modality and survival. The lowest hazard ratio observed was in patients that received chemo-radiation. The strongest quantitative predictor of death was stage at the time of diagnosis. In addition, surgical treatment, lymph node dissection, most recent time-periods, lower comorbidity index, and higher socioeconomic status were associated with improved survival. The overall rates of chemotherapy use have increased over time. Adjuvant chemotherapy and chemo-radiation were associated with improved survival.
Cancer immunotherapies, particularly checkpoint inhibitors, have emerged as highly promising appr... more Cancer immunotherapies, particularly checkpoint inhibitors, have emerged as highly promising approaches for treatment of a variety of solid tumors, including recurrent ovarian cancer. While dramatic clinical benefit is observed in a subset of patients with ovarian cancer, the majority of ovarian cancer patients do not respond to checkpoint inhibitors, thus combinatorial treatments are sorely needed. Immune competent pre-clinical animal models are crucial to test emerging treatment strategies and for the identification of biomarkers to predict response to therapy. As results from immune competent preclinical models are often translated into clinical trials, we sought to investigate whether slight variability related to animal housing and/or breeding practices in the same strain could impact experimental outcomes related to immunotherapy. We conducted animal studies using C57BL/6J mice purchased from Jackson Laboratories (Cat# 000664) 2 weeks prior to experimental use (Jax) and using the same mouse strain purchased from Jackson Laboratories but bred within our institution for a period of 6 months prior to use (Jax-R). Using the gold standard ID8 murine metastatic intraperitoneal ovarian cancer model we tested the therapeutic efficacy of anti-PD-1 monotherapy in both Jax and Jax-R animals. Aged-matched female mice were housed under the same conditions for 2 weeks prior to tumor inoculation and for the duration of study. Strikingly, we noted that while anti-PD-1 monotherapy had absolutely no effect on tumor growth or survival of Jax mice, the Jax-R animals showed dramatic tumor growth control and significantly improved long term survival. Tumor progression and survival was similar across sub-strains in untreated control animals, suggesting that the observed differences in treatment outcome following anti-PD-1 treatment were not simply due to intrinsic differences between the animals. Response to treatment was also associated with increased frequencies of circulating CD4+ and CD8+ T cells in the Jax-R mice compared with the Jax animals. Although major variations in age, animal strain and gut microbiome can dramatically impact upon the efficacy of checkpoint inhibitors, our findings demonstrate that even minute changes within sub-strains recently derived from the same founder animals could result in significantly different survival and pre-clinical outcome. Thus, immunotherapy results obtained from immune competent animal studies need to be interpreted with caution when designing future immunotherapy trials. Citation Format: AJ Robert Mcgray, Kristen Starbuck, Samar Masoumi-Moghaddam, Ariel Francois, Kunle Odunsi, Emese Zsiros. Minute variation in murine ovarian cancer preclinical models significantly impact immunotherapy results obtained for clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1623. doi:10.1158/1538-7445.AM2017-1623
Key words: Sialyl Tn, drug resistance, antibody-drug conjugates, cancer stem cells OBJECTIVES: A ... more Key words: Sialyl Tn, drug resistance, antibody-drug conjugates, cancer stem cells OBJECTIVES: A successful therapeutic strategy for ovarian cancer will require direct targeting of inherently chemoresistant tumor cells which are comprised in part of cancer stem cells (CSCs) that survive current cytotoxic treatment regimes and drive tumor resurgence. The sialyl-Tn (STn) antigen is a carbohydrate moiety present on tumor cells but rarely seen in normal adult tissue. Importantly, STn has been shown to be present on CSCs in pancreatic, colon, and gastric malignancies. Our objective was to assess the expression of STn and the known CSC marker CD133 in human ovarian cancer (OvCa) cell lines and primary serous carcinomas, and evaluate the ability of STn+ and STn- cells to both grow in an anchorage independent manner and survive standard-of-care cytotoxic therapy. Furthermore, we sought to assess the effect of murine and humanized α -STn antibody-drug conjugates (ADCs) on OvCa cells in vitro and tumor viability in vivo. METHODS: STn and CD133 expression in established OvCa cell lines was analyzed by flow cytometry. STn-CD133-, STn+CD133-, STn-CD133+ and STn+CD133+ cells were purified from OVCAR3 and OVCAR4 by FACS, plated in soft agar, and incubated for 21 days. Colony forming efficiency of each sub-population was calculated. Unsorted cells were treated in vitro with either murine α -STn-monomethyl auristatin E (MMAE) ADC or vehicle control and cell viability was assessed by MTT assay. Subsequently, cells were treated in vitro with α -STn-MMAE, paclitaxel and carboplatin, or appropriate controls, and the profile of cells surviving 72 hours post-treatment was determined by flow cytometric analysis. Finally, OVCAR3-derived mouse xenografts were treated with murine and humanized α-STn-MMAE, unconjugated mAbs alone, and vehicle control. Mice were assessed regularly for tumor growth and cytotoxic effects. RESULTS: In the OvCa cell lines OV90, OVCAR3 and OVCAR4, when grown in traditional 2D culture, STn+ cells comprised 98.4%, 40.0%, and 26.4% of the total cell population, respectively. In each of these cell lines, we readily detected STn+CD133+ sub-populations suggesting that STn is expressed on CD133+ ovarian CSCs. Colony formation assays analyzing FACS-purified STn-CD133-, STn+CD133-, STn-CD133+ and STn+ CD133+ sub-populations suggest that STn expression correlates with anchorage independent growth, a characteristic of cell stemness. Paclitaxel and carboplatin treatment in vitro significantly increased the proportion of STn+ and CD133+ cells, demonstrating the chemoresistant characteristics of these cells. Treatment with the murine α-STn-MMAE ADCs reduced the viability of OvCa cell lines in vitro in a dose-dependent manner. Treatment with murine and humanized α -STn- MMAE antibodies in vivo reduced tumor volumes, whereas vehicle treatment did not impede tumor growth. Interestingly, the unconjugated antibody also had a modest negative impact on tumor volume. CONCLUSION: A novel, highly specific STn antibody identifies the STn antigen in OvCa cell lines and patient samples. STn+ and CD133+ cells demonstrate stem-like characteristics such as anchorage-independent growth and chemoresistance. STn ADCs decreased cell viability in vitro and reduced tumor volumes in vivo, suggesting that specific therapeutic targeting of STn in ovarian tumors may be an effective clinical strategy to eliminate quiescent CSCs. Citation Format: B.R. Rueda, K. Starbuck, D. Eavarone, J. Prendergast, J. Stein, R. Foster, J. Behrens. TARGETING A CHEMORESISTANT OVARIAN CANCER CELL POPULATION VIA THE CARBOHYDRATE ANTIGEN SIALYL TN [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-071.
Cancer Research, Jul 1, 2017
Chemokine CXCL12 and its receptor CXCR4 are the most highly expressed chemokine axis in serous ov... more Chemokine CXCL12 and its receptor CXCR4 are the most highly expressed chemokine axis in serous ovarian cancer. CXCR4 promotes tumor growth, angiogenesis, and metastasis. High CXCR4 expression is associated with poor survival, making it an attractive therapeutic target. The objective of this study was to establish an immune competent murine ovarian cancer model with high CXCR4 expression and to test single agent CXCR4 blockade and combination therapy to optimize emerging treatment strategies for future clinical trials. CXCR4 expression was evaluated by flow cytometry in ID8, ID8-VEGF, IE9-MP1, BR5, BR5-Akt, BR5-C2k, and BR5-Kras mouse ovarian cancer cell lines as well as IE9-MP1 tumor samples. Subsequently an exploratory study was undertaken utilizing the ID8 immune competent mouse model to assess the efficacy of AMD3100, the only commercially available CXCR4 inhibitor, alone and in combination with bevacizumab and anti-PD-1. Immune analysis of circulating lymphocytes by flow cytometry was performed during treatment to monitor changes of immune cell subsets. Surface expression of CXCR4 receptor was minimal in ID8 (1.6%), ID8-VEGF (0.9%), IE9-MP1 (1.8%), BR5 (0.9%), BR5-Akt (1.2%), BR5-C2k (2.3%), and BR5-Kras (1.1%), however intracellular staining revealed widespread CXCR4 expression in ID8 (99.6%), ID8-VEGF (99.7%) BR5 (96.7%), BR5-Akt (94.3%), BR5-C2k (98.2%), and BR5-Kras (98.7%) cell lines. Using the ID8 intraperitoneal ovarian cancer mouse model in C57BL/6J mice, treatment with immunotherapy significantly increased cell surface expression of CXCR4 from 2% in the control group to 79.6-91.8% in the treatment group. Treatment with AMD3100 as a single agent showed no improvement in survival over control. However, AMD3100 in combination with anti-PD-1 therapy significantly improved survival. The addition of bevacizumab demonstrated no further survival benefit and bevacizumab as a single agent showed no improvement in survival over control, either alone or in combination with anti-PD-1. Analysis of circulating lymphocytes revealed a trend toward higher CD4 to CD8 ratio in mice who were treated with anti-PD1 therapy. Targeting the CXCL12-CXCR4 axis in combination with other immunotherapies such as immune checkpoint inhibitors is a novel therapeutic strategy which may provide benefit over single-agent immunotherapy and warrant investigation in a clinical trial. Citation Format: Kristen Starbuck, Robert McGray, Samar Masoumi-Moghaddam, Ariel Francois, Kunle Odunsi, Emese Zsiros. CXCR4 in combination with immune check point inhibition in ovarian cancer mouse model demonstrates potential for novel therapeutic strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 947. doi:10.1158/1538-7445.AM2017-947
Cancer Research, Jul 1, 2017
Ovarian cancer continues to be the most lethal gynecologic malignancy with no real cure for patie... more Ovarian cancer continues to be the most lethal gynecologic malignancy with no real cure for patients presenting with advanced stage disease. Immune check point blockade showed modest clinical response in patient with recurrent ovarian cancer, thus additional therapeutic strategies for combination therapy are needed. As chemokines and their receptors drive both immune cell migration and tumor growth, angiogenesis and metastasis formation, they are an attractive target for combinatorial cancer therapy. CXCR4 is the most highly expressed chemokine receptor in advanced stage high grade serous ovarian cancer, thus the objective of this study was to evaluate the efficacy of a novel oral small molecule CXCR4 inhibitor (X4-136) alone and in combination with immune checkpoint inhibition and the anti-angiogenic agent bevacizumab, and characterize the changes in circulating immune cells during treatment in murine ovarian cancer model. The ID8 cell line was used in C57BL/6J mice to establish an immune competent murine model and to compare single agent and combination therapy with oral X4-136 CXCR4 inhibitor, bevacizumab, and anti-PD1. During treatment blood sampling was performed and immune cells were analyzed by flow cytometry. Our results demonstrated that single agent therapies alone with either drug had no significant effect on tumor progression or survival. Combination therapy with the CXCR4 inhibitor and anti-PD1 improved survival compared to control animals and the other combination therapy groups. The addition of bevacizumab to the dual combination did not further prolong survival. Analysis of circulating immune cells revealed elevations in CD11b+Ly6C+ and the ratio of CD11b+Ly6C+ to CD11b+Ly6G+ in groups treated with the CXCR4 inhibitor, indicating an increase in circulating myeloid cells. Bevacizumab had no activity in this mouse model as a single agent, and did not have synergistic effect in combination therapy. For the first time we demonstrated that novel CXCR4 inhibitor X4-136 in combination therapy with anti-PD1 showed improved survival in murine ovarian cancer model. CXCR4 blockade increased the proportion of circulating myeloid cells during active treatment, thus further investigation into this novel therapeutic approach is warranted. Citation Format: Kristen Starbuck, Robert McGray, Samar Masoumi-Moghaddam, Ariel Francois, Kunle Odunsi, Emese Zsiros. Novel oral small molecule CXCR4 inhibitor improves activity of immune checkpoint blockade in ovarian cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 956. doi:10.1158/1538-7445.AM2017-956
Gynecologic Oncology, Dec 1, 2015
Ovarian carcinosarcoma has worse prognosis compared to papillary serous histology. • The survival... more Ovarian carcinosarcoma has worse prognosis compared to papillary serous histology. • The survival difference was noted across all FIGO stages. • Women with ovarian carcinosarcoma are less likely to receive chemotherapy.
Gynecologic Oncology, Jun 1, 2019
predictive of response/resistance to dasatinib. Overall, the ORR was 45% (95% CI 22-72%) with PFS... more predictive of response/resistance to dasatinib. Overall, the ORR was 45% (95% CI 22-72%) with PFS of 10.5 months and OS of 30.4 months. The most common grade 3/4 adverse events were neutropenia (65%), thrombocytopenia (59%), anemia (24%), and fatigue (24%). RPPA analysis demonstrated interactions in Notch pathway signaling. Conclusion: This unique lead-in trial design demonstrated that CAV1 expression in combination with Raf heterodimerization is responsible for resistance to EphA2 targeting by dasatinib. The triplet combination shows interesting clinical activity for this population with acceptable toxicity. The exploration for biomarker-driven and informed therapy is feasible and necessary for improving outcomes in women with advanced-stage and recurrent endometrial cancer.
Gynecology and reproductive endocrinology, 2019
Red blood cell transfusion has been historically used to improve hemoglobin values to 10 g/dL or ... more Red blood cell transfusion has been historically used to improve hemoglobin values to 10 g/dL or greater . Mounting evidence suggests transfusions are not a benign intervention and are associated with increased rates of infection, hemolytic reactions, anaphylaxis, transfusion-associated circulatory overload, sepsis, transfusion-related acute lung injury and death . An estimated 50,000 transfusion reactions occur in the United States annually . Most fatalities are a result of transfusion-associated sepsis, hemolytic transfusion reactions and transfusion-related acute lung injury . Level II evidence has shown that blood transfusion protocols that are not restrictive are associated with increased patient morbidity and mortality . A 2016 Cochrane review of 12,587 patients analyzed the safety of transfusing to maintain hemoglobin of 7-8 g/dL vs 9-10 g/dL . The included studies encompassed orthopedic surgery, critical care, trauma, cardiac surgery, acute coronary syndrome, leukemia, hematological cancer, vascular surgery and pediatric patients. Analyses included 30 day mortality, cardiac events (myocardial infarction and heart failure), stroke, thromboembolism, sepsis, pneumonia, postoperative wound infection, renal failure, mental Objectives: The purpose of this study was to evaluate the impact of a restrictive blood transfusion protocol in a postoperative gynecologic oncology population. The primary objective was the rate of blood transfusions after surgery before and after implementation of a restrictive transfusion protocol (from July 1 st 2011 to December 30 th 2016). Secondary outcomes were patient morbidity and included rates of surgical site infection, pneumonia, sepsis, unplanned intubation, prolonged ventilator use, renal insufficiency, acute renal failure, urinary tract infection, cerebral vascular accident, cardiac complications, venous thromboembolism, and death within 30 days of surgery, readmissions and length of stay. Methods: A restrictive blood transfusion protocol was implemented by the gynecologic oncology service at a National Comprehensive Cancer Network designated Comprehensive Cancer Center on January 1 st , 2014. The restrictive protocol required that no patient receive a blood transfusion for hemoglobin greater than 7.0 g/dL (or hematocrit greater than 21.0%) and that all red blood cells were administered in one unit increments followed by re-evaluation of blood parameters. Exceptions to this protocol were postoperative symptomatic anemia, intraoperative or day of surgery transfusion, active bleeding, postoperative severe sepsis, postoperative active coronary ischemia, and postoperative transfusion after 1.5 liter or greater blood loss. Results: 1482 patients were identified for this study (755 in the pre-protocol group and 727 in the post-protocol group). Patients treated under the restrictive protocol had decreased rates of red blood cell transfusion (11.0% vs 5.9% p<0.001), superficial surgical site infection (7.7% vs 4.1% p=0.005), deep surgical site infection (2.3% vs 0.7% p=0.02), and median length of stay (3.0 days vs 2.0 days p<0.001). Conclusions: A restrictive blood transfusion protocol is associated with reductions in the rates of blood transfusions and postoperative morbidity with a 46.8% reduction in superficial surgical site infection and a 69.6% decrease in deep surgical site infection in the gynecologic oncology patient population.
Gynecologic Oncology, Dec 1, 2020
Members of the transgender community have experienced discrimination and rejection in the communi... more Members of the transgender community have experienced discrimination and rejection in the community and medical setting • Discriminatory experiences may lead to increased cancer-associated risk factors and decreased cancer screening • Transgender men remain at risk for gynecologic malignancies, but face barriers to adequate care • Increased provider education and outreach may improve the care for transgender men in gynecologic oncology
European Heart Journal - Case Reports, Dec 1, 2022
at the time of patient presentation. We would like to thank the surgical team, Drs. Mani Daneshma... more at the time of patient presentation. We would like to thank the surgical team, Drs. Mani Daneshmand (Cardiothoracic Surgery), Shishir Maithel (Surgical Oncology), and Viraj Master (Urologic Oncology) as well as the cardiology team Drs.
Gynecologic Oncology, Jun 1, 2019
from a questionnaire to the participants. We compared the prevalence of HPV type-specific infecti... more from a questionnaire to the participants. We compared the prevalence of HPV type-specific infection between women registered in 2014 (born 1993-1994) and registered in 2015-2017 (born in 1994-1997: post OHPV generation). Results: We collected 2,493 specimens. The rates of vaccination coverage were 28.6%, 74.8%, 76.7%, and 80.0% (P b 0.01) from 2014 to 2017, respectively. The prevalence of HPV16/18 infection was significantly decreased from 1.3% in 2014 to 0.5% in 2015, 0.4% in 2016, and 0% in 2017 (P = 0.02). The 3 most prevalent types were HPV52, 16 and 56 in 2014, and HPV52, 51 and 58 in 2017. See Figure . Conclusion: Our study demonstrates that the profile of type-specific HPV infection was changed after initiation of HPV vaccination in Japan.
International Journal of Radiation Oncology Biology Physics, Nov 1, 2021
PURPOSE/OBJECTIVE(S) Definitive or adjuvant radiotherapy (RT) for vulvar squamous cell carcinoma ... more PURPOSE/OBJECTIVE(S) Definitive or adjuvant radiotherapy (RT) for vulvar squamous cell carcinoma (VSCC) is associated with significant toxicity that can negatively impact a patient's health-related quality of life (HRQoL). Given the rarity of this disease, data on the incidence of acute and late severe toxicity as well as the real-world late-symptom burden from a modern cohort are lacking. MATERIALS/METHODS Patients with VSCC treated with adjuvant or definitive radiotherapy with curative intent from 2009-2020 within our multi-center academic medical system were retrospectively analyzed. Treatment-related acute and late (≥3 months after RT) grade 3 or greater toxicities assessed by CTCAE version 5.0 were recorded. All provider-reported subjective symptoms (PRSS) documented from the date of RT completion to the date of last follow up were recorded. Kaplan-Meier model was used to estimate one-year overall survival (OS) and progression-free survival (PFS). RESULTS Thirty-nine patients received either definitive (n = 22, 56.4%) or adjuvant (n = 17, 43.6%) RT to a median dose of 64.4 Gy and 59.4 Gy, respectively. Five patients (3 definitive, 2 adjuvant) received a brachytherapy boost with a median total EQD2 of 84.3 Gy. Intensity-modulated or volumetric-modulated arc RT was used in 34 (87.2%) of patients, and 22 patients (56.4%) received concurrent chemotherapy. Median follow up time was 12.5 months (Q1-Q3: 2.8-31.3 months) for all patients and 14.9 months (3.8-33.2) for alive patients. Seventy-four percent of patients (FIGO Stage I; n = 10, II; n = 5, III; n = 10, IVA; n = 4) had a complete response based on clinical (n = 26) or pathologic (n = 3) criteria, including 16 treated with adjuvant RT and 13 treated with definitive RT. The 1-year estimated OS and PFS were 90.4% and 90.5%, respectively. The incidence of acute grade ≥3 toxicity was 35.9% (n = 14). Acute grade ≥3 skin toxicity was most common (n = 10, 25.6%), followed by urinary (n = 1, 2.6%), gastrointestinal (n = 1, 2.6%), hematologic (n = 1, 2.6%), and fatigue (n = 1, 2.6%). Five (12.8%) patients experienced late grade ≥3 toxicity, including 2 patients (5.1%) with grade 3 dermatologic toxicity, 2 patients (5.1%) with grade 4 skin toxicity, and 1 patient (2.6%) with grade 3 gastrointestinal toxicity. Among the 32 patients with PRSS data available, 6 (15.3%) reported dyspareunia or inability to have sexual intercourse, 5 (12.8%) noted skin discoloration or fibrosis, 11 (28.2%) reported long-term vaginal pain or irritation, and 8 (20.5%) required long-term opiate pain medication. CONCLUSION RT for VSCC is associated with considerable rates of severe acute and late toxicity as well as PRSS that affect both a patient's physical functioning and HRQoL. Taken together with the high rates of disease control and survival, these data argue for improved patient-reported outcome measures and investigation of therapeutic de-escalation strategies. AUTHOR DISCLOSURE N.S. McCall: Honoraria; PrecisCA.T.Y. Eng: Stock; Amgen. J.W. Shelton: None. S. Hanasoge: None. P.R. Patel: None. A.B. Patel: Honoraria; American College of Radiology. A. McCook: None. J. Switchenko: None. T. Cole: None. N. Khanna: None. C. Han: None. A.N. Gordon: None. K. Starbuck: None. J.S. Remick: None.
Cancer Causes & Control, Jan 11, 2018
PLOS ONE, Nov 12, 2018
We aimed to investigate the prognostic impact of duration of first-line chemotherapy administrati... more We aimed to investigate the prognostic impact of duration of first-line chemotherapy administration in patients with epithelial ovarian cancer (EOC). Methods Chemotherapy records were abstracted from the electronic medical record. Patients with on-time completion (105 days) were compared to patients finishing early (<105 days), delays of 1-4 weeks, or >4 weeks. For 222 women with stage IIIC/IV, stage-stratified estimates of progression-free survival (PFS) and overall survival (OS) were compared. A delay sub-study was performed with outliers removed. Each week of delay was correlated with the change in PFS and OS to identify time points associated with change in outcome. Results Most women had on-time completion of chemotherapy (23.6%) or a treatment delay of �4 weeks (21.8%); 21.6% of women experienced a delay longer than 4 weeks. R0 resection at initial debulking (OR = 1.99, 95%CI: 1.18-3.36, p = 0.010) and RECIST complete response (OR = 4.88, 95%CI: 2.47-10.63, p<0.001) were strongly associated with on-time completion. Patients with on-time completion and < 1 month delay had similar median survivals of 43.1 months (lower 95% CI bound 33.7 months) and 44.5 months (lower bound 37.0, p = 0.93). Women with >1 month delay had decreased median survival of 18.1 months (14.7-24.9 months), while women with short intervals survived 35.0 months (95%CI: 21.8-49.8 months). Short-term delays lead to progressively decreasing OS. This was significantly different from the on-schedule survival estimate after 6 weeks of delay.
Gynecologic Oncology, Jun 1, 2019
Objective: Molecular determinants of ovarian cancer (OC) racial disparity have been under investi... more Objective: Molecular determinants of ovarian cancer (OC) racial disparity have been under investigation in order to find avenues for improved targeted therapeutics. Our objective was to evaluate and compare the immunologic landscape of primary ovarian cancer stratified by race. Method: Self-reported black and white patients with OC were matched for age, stage, and survival. A full genome RNAseq library was constructed and sequenced on an Illumina HiSeq instrument with differentially expressed genes inferred using DESeq2 software. Candidate gene sets of significantly regulated genes were used for functional and pathway enrichment analyses. Using a global 700-gene panel for immuneoncology, a validated tumor inflammation signature (TIS) algorithm was used to determine the presence of a pre-existing adaptive immune response of "hot" versus "cold" tumors. Results: OC tissue samples from 94 patients with primary advanced-stage OC were identified and matched by survival and platinum sensitivity. Self-reported patients were 55% white (n = 52) and 45% (n = 42) black. Groups were similar in age, BMI, histology, and grade. A total of 4,392 genes demonstrated significant differential expression when races were compared. Subsequent pathway analyses revealed significant upregulation of five genes associated with indoleamine 2.3-dioxygenase (IDO) pathway in black patients (WARS, IDO1, IDO2, AFMID, GCDH, p b 0.01). When compared to IDO low , progression-free survival (PFS) was shown to be worse in IDO high cancers, 18 versus 12 months (P = 0.03). Global immune-oncology gene signature panel showed IDO high cancers exhibited escape from immune control via adaptive resistance by overexpression of T cells and IFN-gamma and enhanced resistance to apoptosis. IDO high cancers served as a surrogate marker for global immune escape with significant correlation to elevated TIS (P = 0.008). Conclusion: In a well-matched cohort, OC from black patients demonstrated higher proportion IDO pathway expression that correlated to worse survivals. Genetic mapping revealed a global immune escape by an adaptive resistance mediated by T-cell secretion of IFN-gamma. These findings support an opportunity to selectively utilize immunotherapy for "hot" tumors preferentially found in black patients and offers the potential to close the disparity gap.
Gynecologic Oncology, Jun 1, 2018
Gynecologic Oncology, Jun 1, 2018
Gynecologic Oncology, Jul 1, 2017
Objective-The presence of miliary disease during initial ovarian cancer debulking may reflect a d... more Objective-The presence of miliary disease during initial ovarian cancer debulking may reflect a distinct mode of peritoneal spread independent from size-based tumor staging and may explain variation in response to treatment and survival outcomes. To infer the prevalence, presentation and clinical implications of miliary disease we reviewed existing surgical records. Methods-Reports were available for 1008 primary debulking surgeries for ovarian, primary peritoneal or fallopian tube cancer between 2001 and 2015 (685 reports from 2005 to 2015). Clinical outcome data was available for 938 patients. We analyzed a high-stage sub-cohort for survival (N=436). Results-Most records were evaluable for miliary disease (761/938); for these, the miliary phenotype was highly prevalent (249/761, 32.7%) and often accompanied by ascites (185/249, 74%). While optimal debulking rates were unaffected by miliary disease, total resection (R0) rates were poorer. Liver, stomach, spleen or bladder appeared to be sporadically involved while the omentum, mesentery, bowel, peritoneum and diaphragm were affected simultaneously (Spearman rho > 0.5). Overall, miliary disease was associated with worse progression free survival, overall survival, and time from relapse to death independent of stage. Survival effects were particularly strong for Stage IV disease where median overall survival varied by over 30 months (log-rank p=0.002).
Gynecologic Oncology, Oct 1, 2015
Evaluate rates of chemotherapy and radiotherapy delivery in the treatment of uterine carcinosarco... more Evaluate rates of chemotherapy and radiotherapy delivery in the treatment of uterine carcinosarcoma, and compare clinical outcomes of treated and untreated patients. The National Cancer Database was queried to identify patients diagnosed with uterine carcinosarcoma between 2003 and 2011. The impact of chemotherapy on survival was analyzed using the Kaplan-Meier method. Factors predictive of outcome were compared using the Cox proportional hazards model. A total of 10,609 patients met study eligibility criteria. Stages I, II, III, and IV disease accounted for 2997 (28.2%), 642 (6.1%), 2037 (19.2%), and 1316 (12.4%) of the study population, respectively. Most patients (91.0%) underwent definitive surgery, and lymphadenectomy was performed in 68.7% of the patients. Chemotherapy was administered in 2378 (22.4%) patients, radiotherapy to 2196 (20.7%), adjuvant chemo-radiation to 1804 (17.0%), and 4231 (39.9%) of women did not received adjuvant therapy. Utilization of chemotherapy became more frequent over time. Over the entire study period, after adjusting for race, period of diagnosis, facility location, facility type, insurance provider, stage, age, treatment modality, lymph node dissection, socioeconomic status, and comorbidity index, there was an association between treatment modality and survival. The lowest hazard ratio observed was in patients that received chemo-radiation. The strongest quantitative predictor of death was stage at the time of diagnosis. In addition, surgical treatment, lymph node dissection, most recent time-periods, lower comorbidity index, and higher socioeconomic status were associated with improved survival. The overall rates of chemotherapy use have increased over time. Adjuvant chemotherapy and chemo-radiation were associated with improved survival.
Cancer immunotherapies, particularly checkpoint inhibitors, have emerged as highly promising appr... more Cancer immunotherapies, particularly checkpoint inhibitors, have emerged as highly promising approaches for treatment of a variety of solid tumors, including recurrent ovarian cancer. While dramatic clinical benefit is observed in a subset of patients with ovarian cancer, the majority of ovarian cancer patients do not respond to checkpoint inhibitors, thus combinatorial treatments are sorely needed. Immune competent pre-clinical animal models are crucial to test emerging treatment strategies and for the identification of biomarkers to predict response to therapy. As results from immune competent preclinical models are often translated into clinical trials, we sought to investigate whether slight variability related to animal housing and/or breeding practices in the same strain could impact experimental outcomes related to immunotherapy. We conducted animal studies using C57BL/6J mice purchased from Jackson Laboratories (Cat# 000664) 2 weeks prior to experimental use (Jax) and using the same mouse strain purchased from Jackson Laboratories but bred within our institution for a period of 6 months prior to use (Jax-R). Using the gold standard ID8 murine metastatic intraperitoneal ovarian cancer model we tested the therapeutic efficacy of anti-PD-1 monotherapy in both Jax and Jax-R animals. Aged-matched female mice were housed under the same conditions for 2 weeks prior to tumor inoculation and for the duration of study. Strikingly, we noted that while anti-PD-1 monotherapy had absolutely no effect on tumor growth or survival of Jax mice, the Jax-R animals showed dramatic tumor growth control and significantly improved long term survival. Tumor progression and survival was similar across sub-strains in untreated control animals, suggesting that the observed differences in treatment outcome following anti-PD-1 treatment were not simply due to intrinsic differences between the animals. Response to treatment was also associated with increased frequencies of circulating CD4+ and CD8+ T cells in the Jax-R mice compared with the Jax animals. Although major variations in age, animal strain and gut microbiome can dramatically impact upon the efficacy of checkpoint inhibitors, our findings demonstrate that even minute changes within sub-strains recently derived from the same founder animals could result in significantly different survival and pre-clinical outcome. Thus, immunotherapy results obtained from immune competent animal studies need to be interpreted with caution when designing future immunotherapy trials. Citation Format: AJ Robert Mcgray, Kristen Starbuck, Samar Masoumi-Moghaddam, Ariel Francois, Kunle Odunsi, Emese Zsiros. Minute variation in murine ovarian cancer preclinical models significantly impact immunotherapy results obtained for clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1623. doi:10.1158/1538-7445.AM2017-1623
Key words: Sialyl Tn, drug resistance, antibody-drug conjugates, cancer stem cells OBJECTIVES: A ... more Key words: Sialyl Tn, drug resistance, antibody-drug conjugates, cancer stem cells OBJECTIVES: A successful therapeutic strategy for ovarian cancer will require direct targeting of inherently chemoresistant tumor cells which are comprised in part of cancer stem cells (CSCs) that survive current cytotoxic treatment regimes and drive tumor resurgence. The sialyl-Tn (STn) antigen is a carbohydrate moiety present on tumor cells but rarely seen in normal adult tissue. Importantly, STn has been shown to be present on CSCs in pancreatic, colon, and gastric malignancies. Our objective was to assess the expression of STn and the known CSC marker CD133 in human ovarian cancer (OvCa) cell lines and primary serous carcinomas, and evaluate the ability of STn+ and STn- cells to both grow in an anchorage independent manner and survive standard-of-care cytotoxic therapy. Furthermore, we sought to assess the effect of murine and humanized α -STn antibody-drug conjugates (ADCs) on OvCa cells in vitro and tumor viability in vivo. METHODS: STn and CD133 expression in established OvCa cell lines was analyzed by flow cytometry. STn-CD133-, STn+CD133-, STn-CD133+ and STn+CD133+ cells were purified from OVCAR3 and OVCAR4 by FACS, plated in soft agar, and incubated for 21 days. Colony forming efficiency of each sub-population was calculated. Unsorted cells were treated in vitro with either murine α -STn-monomethyl auristatin E (MMAE) ADC or vehicle control and cell viability was assessed by MTT assay. Subsequently, cells were treated in vitro with α -STn-MMAE, paclitaxel and carboplatin, or appropriate controls, and the profile of cells surviving 72 hours post-treatment was determined by flow cytometric analysis. Finally, OVCAR3-derived mouse xenografts were treated with murine and humanized α-STn-MMAE, unconjugated mAbs alone, and vehicle control. Mice were assessed regularly for tumor growth and cytotoxic effects. RESULTS: In the OvCa cell lines OV90, OVCAR3 and OVCAR4, when grown in traditional 2D culture, STn+ cells comprised 98.4%, 40.0%, and 26.4% of the total cell population, respectively. In each of these cell lines, we readily detected STn+CD133+ sub-populations suggesting that STn is expressed on CD133+ ovarian CSCs. Colony formation assays analyzing FACS-purified STn-CD133-, STn+CD133-, STn-CD133+ and STn+ CD133+ sub-populations suggest that STn expression correlates with anchorage independent growth, a characteristic of cell stemness. Paclitaxel and carboplatin treatment in vitro significantly increased the proportion of STn+ and CD133+ cells, demonstrating the chemoresistant characteristics of these cells. Treatment with the murine α-STn-MMAE ADCs reduced the viability of OvCa cell lines in vitro in a dose-dependent manner. Treatment with murine and humanized α -STn- MMAE antibodies in vivo reduced tumor volumes, whereas vehicle treatment did not impede tumor growth. Interestingly, the unconjugated antibody also had a modest negative impact on tumor volume. CONCLUSION: A novel, highly specific STn antibody identifies the STn antigen in OvCa cell lines and patient samples. STn+ and CD133+ cells demonstrate stem-like characteristics such as anchorage-independent growth and chemoresistance. STn ADCs decreased cell viability in vitro and reduced tumor volumes in vivo, suggesting that specific therapeutic targeting of STn in ovarian tumors may be an effective clinical strategy to eliminate quiescent CSCs. Citation Format: B.R. Rueda, K. Starbuck, D. Eavarone, J. Prendergast, J. Stein, R. Foster, J. Behrens. TARGETING A CHEMORESISTANT OVARIAN CANCER CELL POPULATION VIA THE CARBOHYDRATE ANTIGEN SIALYL TN [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr MIP-071.
Cancer Research, Jul 1, 2017
Chemokine CXCL12 and its receptor CXCR4 are the most highly expressed chemokine axis in serous ov... more Chemokine CXCL12 and its receptor CXCR4 are the most highly expressed chemokine axis in serous ovarian cancer. CXCR4 promotes tumor growth, angiogenesis, and metastasis. High CXCR4 expression is associated with poor survival, making it an attractive therapeutic target. The objective of this study was to establish an immune competent murine ovarian cancer model with high CXCR4 expression and to test single agent CXCR4 blockade and combination therapy to optimize emerging treatment strategies for future clinical trials. CXCR4 expression was evaluated by flow cytometry in ID8, ID8-VEGF, IE9-MP1, BR5, BR5-Akt, BR5-C2k, and BR5-Kras mouse ovarian cancer cell lines as well as IE9-MP1 tumor samples. Subsequently an exploratory study was undertaken utilizing the ID8 immune competent mouse model to assess the efficacy of AMD3100, the only commercially available CXCR4 inhibitor, alone and in combination with bevacizumab and anti-PD-1. Immune analysis of circulating lymphocytes by flow cytometry was performed during treatment to monitor changes of immune cell subsets. Surface expression of CXCR4 receptor was minimal in ID8 (1.6%), ID8-VEGF (0.9%), IE9-MP1 (1.8%), BR5 (0.9%), BR5-Akt (1.2%), BR5-C2k (2.3%), and BR5-Kras (1.1%), however intracellular staining revealed widespread CXCR4 expression in ID8 (99.6%), ID8-VEGF (99.7%) BR5 (96.7%), BR5-Akt (94.3%), BR5-C2k (98.2%), and BR5-Kras (98.7%) cell lines. Using the ID8 intraperitoneal ovarian cancer mouse model in C57BL/6J mice, treatment with immunotherapy significantly increased cell surface expression of CXCR4 from 2% in the control group to 79.6-91.8% in the treatment group. Treatment with AMD3100 as a single agent showed no improvement in survival over control. However, AMD3100 in combination with anti-PD-1 therapy significantly improved survival. The addition of bevacizumab demonstrated no further survival benefit and bevacizumab as a single agent showed no improvement in survival over control, either alone or in combination with anti-PD-1. Analysis of circulating lymphocytes revealed a trend toward higher CD4 to CD8 ratio in mice who were treated with anti-PD1 therapy. Targeting the CXCL12-CXCR4 axis in combination with other immunotherapies such as immune checkpoint inhibitors is a novel therapeutic strategy which may provide benefit over single-agent immunotherapy and warrant investigation in a clinical trial. Citation Format: Kristen Starbuck, Robert McGray, Samar Masoumi-Moghaddam, Ariel Francois, Kunle Odunsi, Emese Zsiros. CXCR4 in combination with immune check point inhibition in ovarian cancer mouse model demonstrates potential for novel therapeutic strategies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 947. doi:10.1158/1538-7445.AM2017-947
Cancer Research, Jul 1, 2017
Ovarian cancer continues to be the most lethal gynecologic malignancy with no real cure for patie... more Ovarian cancer continues to be the most lethal gynecologic malignancy with no real cure for patients presenting with advanced stage disease. Immune check point blockade showed modest clinical response in patient with recurrent ovarian cancer, thus additional therapeutic strategies for combination therapy are needed. As chemokines and their receptors drive both immune cell migration and tumor growth, angiogenesis and metastasis formation, they are an attractive target for combinatorial cancer therapy. CXCR4 is the most highly expressed chemokine receptor in advanced stage high grade serous ovarian cancer, thus the objective of this study was to evaluate the efficacy of a novel oral small molecule CXCR4 inhibitor (X4-136) alone and in combination with immune checkpoint inhibition and the anti-angiogenic agent bevacizumab, and characterize the changes in circulating immune cells during treatment in murine ovarian cancer model. The ID8 cell line was used in C57BL/6J mice to establish an immune competent murine model and to compare single agent and combination therapy with oral X4-136 CXCR4 inhibitor, bevacizumab, and anti-PD1. During treatment blood sampling was performed and immune cells were analyzed by flow cytometry. Our results demonstrated that single agent therapies alone with either drug had no significant effect on tumor progression or survival. Combination therapy with the CXCR4 inhibitor and anti-PD1 improved survival compared to control animals and the other combination therapy groups. The addition of bevacizumab to the dual combination did not further prolong survival. Analysis of circulating immune cells revealed elevations in CD11b+Ly6C+ and the ratio of CD11b+Ly6C+ to CD11b+Ly6G+ in groups treated with the CXCR4 inhibitor, indicating an increase in circulating myeloid cells. Bevacizumab had no activity in this mouse model as a single agent, and did not have synergistic effect in combination therapy. For the first time we demonstrated that novel CXCR4 inhibitor X4-136 in combination therapy with anti-PD1 showed improved survival in murine ovarian cancer model. CXCR4 blockade increased the proportion of circulating myeloid cells during active treatment, thus further investigation into this novel therapeutic approach is warranted. Citation Format: Kristen Starbuck, Robert McGray, Samar Masoumi-Moghaddam, Ariel Francois, Kunle Odunsi, Emese Zsiros. Novel oral small molecule CXCR4 inhibitor improves activity of immune checkpoint blockade in ovarian cancer mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 956. doi:10.1158/1538-7445.AM2017-956
Gynecologic Oncology, Dec 1, 2015
Ovarian carcinosarcoma has worse prognosis compared to papillary serous histology. • The survival... more Ovarian carcinosarcoma has worse prognosis compared to papillary serous histology. • The survival difference was noted across all FIGO stages. • Women with ovarian carcinosarcoma are less likely to receive chemotherapy.
Gynecologic Oncology, Jun 1, 2019
predictive of response/resistance to dasatinib. Overall, the ORR was 45% (95% CI 22-72%) with PFS... more predictive of response/resistance to dasatinib. Overall, the ORR was 45% (95% CI 22-72%) with PFS of 10.5 months and OS of 30.4 months. The most common grade 3/4 adverse events were neutropenia (65%), thrombocytopenia (59%), anemia (24%), and fatigue (24%). RPPA analysis demonstrated interactions in Notch pathway signaling. Conclusion: This unique lead-in trial design demonstrated that CAV1 expression in combination with Raf heterodimerization is responsible for resistance to EphA2 targeting by dasatinib. The triplet combination shows interesting clinical activity for this population with acceptable toxicity. The exploration for biomarker-driven and informed therapy is feasible and necessary for improving outcomes in women with advanced-stage and recurrent endometrial cancer.
Gynecology and reproductive endocrinology, 2019
Red blood cell transfusion has been historically used to improve hemoglobin values to 10 g/dL or ... more Red blood cell transfusion has been historically used to improve hemoglobin values to 10 g/dL or greater . Mounting evidence suggests transfusions are not a benign intervention and are associated with increased rates of infection, hemolytic reactions, anaphylaxis, transfusion-associated circulatory overload, sepsis, transfusion-related acute lung injury and death . An estimated 50,000 transfusion reactions occur in the United States annually . Most fatalities are a result of transfusion-associated sepsis, hemolytic transfusion reactions and transfusion-related acute lung injury . Level II evidence has shown that blood transfusion protocols that are not restrictive are associated with increased patient morbidity and mortality . A 2016 Cochrane review of 12,587 patients analyzed the safety of transfusing to maintain hemoglobin of 7-8 g/dL vs 9-10 g/dL . The included studies encompassed orthopedic surgery, critical care, trauma, cardiac surgery, acute coronary syndrome, leukemia, hematological cancer, vascular surgery and pediatric patients. Analyses included 30 day mortality, cardiac events (myocardial infarction and heart failure), stroke, thromboembolism, sepsis, pneumonia, postoperative wound infection, renal failure, mental Objectives: The purpose of this study was to evaluate the impact of a restrictive blood transfusion protocol in a postoperative gynecologic oncology population. The primary objective was the rate of blood transfusions after surgery before and after implementation of a restrictive transfusion protocol (from July 1 st 2011 to December 30 th 2016). Secondary outcomes were patient morbidity and included rates of surgical site infection, pneumonia, sepsis, unplanned intubation, prolonged ventilator use, renal insufficiency, acute renal failure, urinary tract infection, cerebral vascular accident, cardiac complications, venous thromboembolism, and death within 30 days of surgery, readmissions and length of stay. Methods: A restrictive blood transfusion protocol was implemented by the gynecologic oncology service at a National Comprehensive Cancer Network designated Comprehensive Cancer Center on January 1 st , 2014. The restrictive protocol required that no patient receive a blood transfusion for hemoglobin greater than 7.0 g/dL (or hematocrit greater than 21.0%) and that all red blood cells were administered in one unit increments followed by re-evaluation of blood parameters. Exceptions to this protocol were postoperative symptomatic anemia, intraoperative or day of surgery transfusion, active bleeding, postoperative severe sepsis, postoperative active coronary ischemia, and postoperative transfusion after 1.5 liter or greater blood loss. Results: 1482 patients were identified for this study (755 in the pre-protocol group and 727 in the post-protocol group). Patients treated under the restrictive protocol had decreased rates of red blood cell transfusion (11.0% vs 5.9% p<0.001), superficial surgical site infection (7.7% vs 4.1% p=0.005), deep surgical site infection (2.3% vs 0.7% p=0.02), and median length of stay (3.0 days vs 2.0 days p<0.001). Conclusions: A restrictive blood transfusion protocol is associated with reductions in the rates of blood transfusions and postoperative morbidity with a 46.8% reduction in superficial surgical site infection and a 69.6% decrease in deep surgical site infection in the gynecologic oncology patient population.
Gynecologic Oncology, Dec 1, 2020
Members of the transgender community have experienced discrimination and rejection in the communi... more Members of the transgender community have experienced discrimination and rejection in the community and medical setting • Discriminatory experiences may lead to increased cancer-associated risk factors and decreased cancer screening • Transgender men remain at risk for gynecologic malignancies, but face barriers to adequate care • Increased provider education and outreach may improve the care for transgender men in gynecologic oncology
European Heart Journal - Case Reports, Dec 1, 2022
at the time of patient presentation. We would like to thank the surgical team, Drs. Mani Daneshma... more at the time of patient presentation. We would like to thank the surgical team, Drs. Mani Daneshmand (Cardiothoracic Surgery), Shishir Maithel (Surgical Oncology), and Viraj Master (Urologic Oncology) as well as the cardiology team Drs.
Gynecologic Oncology, Jun 1, 2019
from a questionnaire to the participants. We compared the prevalence of HPV type-specific infecti... more from a questionnaire to the participants. We compared the prevalence of HPV type-specific infection between women registered in 2014 (born 1993-1994) and registered in 2015-2017 (born in 1994-1997: post OHPV generation). Results: We collected 2,493 specimens. The rates of vaccination coverage were 28.6%, 74.8%, 76.7%, and 80.0% (P b 0.01) from 2014 to 2017, respectively. The prevalence of HPV16/18 infection was significantly decreased from 1.3% in 2014 to 0.5% in 2015, 0.4% in 2016, and 0% in 2017 (P = 0.02). The 3 most prevalent types were HPV52, 16 and 56 in 2014, and HPV52, 51 and 58 in 2017. See Figure . Conclusion: Our study demonstrates that the profile of type-specific HPV infection was changed after initiation of HPV vaccination in Japan.
International Journal of Radiation Oncology Biology Physics, Nov 1, 2021
PURPOSE/OBJECTIVE(S) Definitive or adjuvant radiotherapy (RT) for vulvar squamous cell carcinoma ... more PURPOSE/OBJECTIVE(S) Definitive or adjuvant radiotherapy (RT) for vulvar squamous cell carcinoma (VSCC) is associated with significant toxicity that can negatively impact a patient's health-related quality of life (HRQoL). Given the rarity of this disease, data on the incidence of acute and late severe toxicity as well as the real-world late-symptom burden from a modern cohort are lacking. MATERIALS/METHODS Patients with VSCC treated with adjuvant or definitive radiotherapy with curative intent from 2009-2020 within our multi-center academic medical system were retrospectively analyzed. Treatment-related acute and late (≥3 months after RT) grade 3 or greater toxicities assessed by CTCAE version 5.0 were recorded. All provider-reported subjective symptoms (PRSS) documented from the date of RT completion to the date of last follow up were recorded. Kaplan-Meier model was used to estimate one-year overall survival (OS) and progression-free survival (PFS). RESULTS Thirty-nine patients received either definitive (n = 22, 56.4%) or adjuvant (n = 17, 43.6%) RT to a median dose of 64.4 Gy and 59.4 Gy, respectively. Five patients (3 definitive, 2 adjuvant) received a brachytherapy boost with a median total EQD2 of 84.3 Gy. Intensity-modulated or volumetric-modulated arc RT was used in 34 (87.2%) of patients, and 22 patients (56.4%) received concurrent chemotherapy. Median follow up time was 12.5 months (Q1-Q3: 2.8-31.3 months) for all patients and 14.9 months (3.8-33.2) for alive patients. Seventy-four percent of patients (FIGO Stage I; n = 10, II; n = 5, III; n = 10, IVA; n = 4) had a complete response based on clinical (n = 26) or pathologic (n = 3) criteria, including 16 treated with adjuvant RT and 13 treated with definitive RT. The 1-year estimated OS and PFS were 90.4% and 90.5%, respectively. The incidence of acute grade ≥3 toxicity was 35.9% (n = 14). Acute grade ≥3 skin toxicity was most common (n = 10, 25.6%), followed by urinary (n = 1, 2.6%), gastrointestinal (n = 1, 2.6%), hematologic (n = 1, 2.6%), and fatigue (n = 1, 2.6%). Five (12.8%) patients experienced late grade ≥3 toxicity, including 2 patients (5.1%) with grade 3 dermatologic toxicity, 2 patients (5.1%) with grade 4 skin toxicity, and 1 patient (2.6%) with grade 3 gastrointestinal toxicity. Among the 32 patients with PRSS data available, 6 (15.3%) reported dyspareunia or inability to have sexual intercourse, 5 (12.8%) noted skin discoloration or fibrosis, 11 (28.2%) reported long-term vaginal pain or irritation, and 8 (20.5%) required long-term opiate pain medication. CONCLUSION RT for VSCC is associated with considerable rates of severe acute and late toxicity as well as PRSS that affect both a patient's physical functioning and HRQoL. Taken together with the high rates of disease control and survival, these data argue for improved patient-reported outcome measures and investigation of therapeutic de-escalation strategies. AUTHOR DISCLOSURE N.S. McCall: Honoraria; PrecisCA.T.Y. Eng: Stock; Amgen. J.W. Shelton: None. S. Hanasoge: None. P.R. Patel: None. A.B. Patel: Honoraria; American College of Radiology. A. McCook: None. J. Switchenko: None. T. Cole: None. N. Khanna: None. C. Han: None. A.N. Gordon: None. K. Starbuck: None. J.S. Remick: None.
Cancer Causes & Control, Jan 11, 2018
PLOS ONE, Nov 12, 2018
We aimed to investigate the prognostic impact of duration of first-line chemotherapy administrati... more We aimed to investigate the prognostic impact of duration of first-line chemotherapy administration in patients with epithelial ovarian cancer (EOC). Methods Chemotherapy records were abstracted from the electronic medical record. Patients with on-time completion (105 days) were compared to patients finishing early (<105 days), delays of 1-4 weeks, or >4 weeks. For 222 women with stage IIIC/IV, stage-stratified estimates of progression-free survival (PFS) and overall survival (OS) were compared. A delay sub-study was performed with outliers removed. Each week of delay was correlated with the change in PFS and OS to identify time points associated with change in outcome. Results Most women had on-time completion of chemotherapy (23.6%) or a treatment delay of �4 weeks (21.8%); 21.6% of women experienced a delay longer than 4 weeks. R0 resection at initial debulking (OR = 1.99, 95%CI: 1.18-3.36, p = 0.010) and RECIST complete response (OR = 4.88, 95%CI: 2.47-10.63, p<0.001) were strongly associated with on-time completion. Patients with on-time completion and < 1 month delay had similar median survivals of 43.1 months (lower 95% CI bound 33.7 months) and 44.5 months (lower bound 37.0, p = 0.93). Women with >1 month delay had decreased median survival of 18.1 months (14.7-24.9 months), while women with short intervals survived 35.0 months (95%CI: 21.8-49.8 months). Short-term delays lead to progressively decreasing OS. This was significantly different from the on-schedule survival estimate after 6 weeks of delay.