bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell cycle progression score and PTEN as prognostic factors for metastasis in intermediate and high-risk prostate cancer.
Authors: Trock Bruce J. , Rajamani Saradha , Vidal Igor , Glavaris Stephanie , Jones Tracy , Han Misop , Partin Alan W. , Cohen Todd , Stone Steven , De Marzo Angelo M
Published: May 2019

e16575

Background: To evaluate the cell cycle progression (CCP) score and PTEN as prognostic markers for risk of metastasis in a radical prostatectomy (RP) cohort of NCCN intermediate and high risk prostate cancer. Methods: This IRB-approved case-cohort study included men treated with RP at Johns Hopkins from 2007-2015. Paraffin-embedded RP tissue was analyzed blind to study outcome at Myriad Genetics, for CCP score using qRT-PCR, and PTEN by immunohistochemistry. Metastasis-free survival (MFS) was analyzed with the Cox proportional hazards model, weighted for case-cohort design. CCP and PTEN were analyzed independently, and adjusted for CAPRA-S. The CCR score, which combines CCP and CAPRA-S, was also analyzed. Data were analyzed independently by Johns Hopkins and Myriad Genetics. Results: There were 209 patients, of whom 42 were cases (metastasis). Median age was 59 years, 47% had Gleason 4+3 or higher, 48% had non-organ confined tumor, and 18% had seminal vesicle or lymph node involvement. NCCN risk was intermediate in 77% and high in 23%. Median follow-up was 4 years. Both CCP and PTEN, as well as CCR score, were statistically significant in univariate analyses, but only CCP retained statistical significance in a multivariable model of CCP, PTEN, and CAPRA-S (Table). Conclusions: This is the first comparison of the CCP score and PTEN as risk factors for metastasis in a recent RP cohort of patients at NCCN intermediate or high risk. Both CCP score and PTEN were strongly associated with MFS in univariate analyses, but only CCP score retained significance in a multivariable analysis with both biomarkers adjusted for CAPRA-S. [Table: see text]
Simple and rapid enrichment of circulating tumor cells (CTCs) for RNAseq in metastatic castrate resistant prostate cancer (mCRPC).
Authors: Morrison Gareth , Cunha Alexander , Jojo Nita , Manojlovic Zarko , Xu Yucheng , Robinson Peggy S. , Dorff Tanya B. , Quinn David I. , Goldkorn Amir
Published: May 2019

e16587

Background: CTCs have the potential to reflect not only genomic alterations but also cancer-relevant transcriptomic phenotypes. However, CTC gene expression has been hampered by signal-to-noise: rare CTC-derived transcripts are drowned out by abundant leukocyte-derived RNA. To date, a few specialized labs have achieved CTC RNAseq by capturing and analyzing single cells, a laborious and expensive approach not suitable for routine analysis of numerous samples. To address this need, we developed and validated a simple, rapid method for enrichment of live CTCs for RNAseq. Methods: Blood was drawn with informed consent under an IRB-approved protocol. Prostate cancer cell line spike-in samples were used to optimize live CTC enrichment by sequential leukocyte depletion (RosetteSep, Stem Cell Technologies) and size-based enrichment (Parsortix, Angle). Cancer-specific gene expression was first measured by multiplexed prostate specific qRT-PCR and subsequently by whole transcriptome amplification (WTA, SMARTer V2, Clontech) and RNAseq. Four patient samples were similarly analyzed by enrichment and RNAseq, along with spike-in positive controls and matched unenriched buffy coat negative controls. Results: Processing “from patient to RNA” took < 3 hrs. and achieved mean CTC recovery of 30% (range 28-33%) and mean leukocyte background of 100 (range 47-179), a 100,000-fold enrichment. Prostate specific genes (AR, PSA, PSMA) were consistently detected by qRT-PCR from enriched samples but not from unenriched samples. When analyzed by RNAseq, patient samples clustered with spike-in positive controls and away from matched buffy coat controls by principle component analysis and by unsupervised hierarchical clustering. Differential gene expression (enriched vs. matched buffy coat) identified prostate cancer-relevant transcripts. Conclusions: We developed a simple and efficient method for live CTC enrichment and expression profiling, applicable to large numbers of patient samples. This approach can be used serially over time to detect known cancer-specific transcripts and to discover new gene expression signatures that reflect tumor biology and inform disease management.
Automated prostate lesion detection and PI-RADS assessment with deep learning.
Authors: Yoon Choongheon , Van Jasper , Bardis Michelle , Bhatter Param , Ushinsky Alexander , Glavis-Bloom Justin , Chantaduly Chanon , Chow Daniel S. , Houshyar Roozbeh , Chang Peter
Published: May 2019

e16605

Background: Prostate Cancer is the most commonly diagnosed male cancer in the U.S. Multiparametric magnetic resonance imaging (mpMRI) is increasingly used for both prostate cancer evaluation and biopsy guidance. The PI-RADS v2 scoring paradigm was developed to stratify prostate lesions on MRI and to predict lesion grade. Prostate organ and lesion segmentation is an essential step in pre-biopsy surgical planning. Deep learning convolutional neural networks (CNN) for image recognition are becoming a more common method of machine learning. In this study, we develop a comprehensive deep learning pipeline of 3D/2D CNN based on U-Net architecture for automatic localization and segmentation of prostates, detection of prostate lesions and PI-RADS v2 lesion scoring of mpMRIs. Methods: This IRB approved retrospective review included a total of 303 prostate nodules from 217 patients who had a prostate mpMRI between September 2014 and December 2016 and an MR-guided transrectal biopsy. For each T2 weighted image, a board-certified abdominal radiologist manually segmented the prostate and each prostate lesion. The T2 weighted and ADC series were co-registered and each lesion was assigned an overall PI-RADS score, T2 weighted PI-RADS score, and ADC PI-RADS score. After a U-Net neural network segmented the prostate organ, a mask regional convolutional neural network (R-CNN) was applied. The mask R-CNN is composed of three neural networks: feature pyramid network, region proposal network, and head network. The mask R-CNN detected the prostate lesion, segmented it, and estimated its PI-RADS score. Instead, the mask R-CNN was implemented to regress along dimensions of the PI-RADS criteria. The mask R-CNN performance was assessed with AUC, Sørensen–Dice coefficient, and Cohen’s Kappa for PI-RADS scoring agreement. Results: The AUC for prostate nodule detection was 0.79. By varying detection thresholds, sensitivity/PPV were 0.94/.54 and 0.60/0.87 at either ends of the spectrum. For detected nodules, the segmentation Sørensen–Dice coefficient was 0.76 (0.72 – 0.80). Weighted Cohen’s Kappa for PI-RADS scoring agreement was 0.63, 0.71, and 0.51 for composite, T2 weighted, and ADC respectively. Conclusions: These results demonstrate the feasibility of implementing a comprehensive 3D/2D CNN-based deep learning pipeline for evaluation of prostate mpMRI. This method is highly accurate for organ segmentation. The results for lesion detection and categorization are modest; however, the PI-RADS v2 score accuracy is comparable to previously published human interobserver agreement.
Multiparametric magnetic resonance imaging (mpMRI) and PSA density for the prediction of reclassification among patients under active surveillance.
Authors: Viana Públio , Horvat Natally , Pessoa Rodrigo Rodrigues , Horvat Joao , Park Rubens , Guglielmetti Giuliano , Bastos Diogo Assed , Cordeiro Mauricio , Coelho Rafael , Vargas Hebert Alberto , Nahas William Carlos
Published: May 2019

e16606

Background: To study the role of mpMRI and PSA density in predicting the likelihood of disease reclassification on re-biopsy and on final pathology among men with low-risk prostate cancer (PCa) enrolled in active surveillance (AS) protocol. Methods: In this IRB-approved prospective study, consecutive patients on AS for low-risk PCa (clinical stage cT1–T2a, Gleason score ≤6, serum PSA < 10 ng/mL, no more than 3 positive cores on biopsy, and all biopsy cores with < 50% of tumor involvement) from March 2015 to August 2017 were selected. The exclusion criteria were previous PCa treatment, contraindication to mpMRI or transrectal ultrasound-guided (TRUS) biopsy. All patients underwent mpMRI ≥3 months from initial biopsy and MRI-targeted TRUS-guided re-biopsy within 6-12 months. One experienced radiologist evaluated all mpMRI studies using the PI-RADS v2. The performance of mpMRI and PSA density for the prediction of reclassification on re-biopsy and final pathology was assessed. A single genitourinary pathologist reviewed all the final specimens who was blinded to the initial biopsy results. Results: A total of 154 patients were included in the final analysis. Among patients classified as PI-RADS ≤3, 11/69 (15.9%) were upgraded on re-biopsy whereas 65/85 (76.5%) were upgraded among those with PI-RADS 4 or 5 lesions. With regards to prostatectomy 7/49 (14.2%) patients classified as PI-RADS ≤3 were upgraded, while 42/49 (85.7%) were upgraded among those with PI-RADS 4 or 5. mpMRI sensitivity was 85.5% and specificity 74.4% on re-biopsy and 85.7% and in predicting upgrade on reclassification. Patients with PI-RADS 4 or 5 and PSA density > 0.15 ng/mL/cm3 had 94.6% of chance of having clinically significant PCa, while patients with PI-RADS 1, 2 or 3 and PSA density ≤ 0.08 ng/mL/cm3 had only 4.2% probability. Conclusions: mpMRI and PSA density are significant tools for predicting severity reclassification on re-biopsy and final pathology among patients under active surveillance. Reclassification was low among patients with PI-RADS ≤3 and low PSA density. Overall, patients with PI-RADS 4 or 5 and PSA density > 0.15 were almost invariably found to harbor significant prostate cancer.
Interdisciplinary surgery for advanced gynecologic malignancies: Outcome and complication rate.
Authors: Boeckhoff Jelena , terGlane Luisa , Wagner Uwe A. G. , Hofmann Rainer , Hegele Axel
Published: May 2019

e17002

Background: Advanced gynecologic malignancies are known to have a poor prognosis. Due to local invasion in adjacent organs, finding the most suitable therapeutic option is often difficult. This study aims to assess the outcome of interdisciplinary surgery for locally advanced gynecologic malignancies focusing on women treated by pelvic exenteration (PE). Methods: All women that were treated with PE at the University Hospital Marburg between 04/2011 and 06/2016, were enrolled in this retrospective study. A data sheet was prepared assessing e.g. demographic informations, tumor type and previous therapies. Furthermore, complication rate (Clavien Dindo, follow-up and outcome were evaluated. Results: From the 57 women identified, the indications for PE were malignancies of the cervix (47.2%), vagina (15.1%), vulva (13.2%), endometrium (11.3%), ovaries (5.7%) and undifferentiated (uterus) (1.9%). 51.9% were treated for recurrent cancer. 26% received no treatment prior to PE, 16%, 38%, 20% received 1, 2 or 3 previous treatments respectively (chemotherapy, radiation, surgery). 54.7% of the patients underwent anterior, 37.8% total and 7.5% posterior PE. Urinary diversion was predominantly ileum conduit (76%). Major complications (Clavien Dindo > 2) were observed for 40.4%, 19.2% had no complications. No correlation with clinical parameters (e.g. BMI, age, time of surgery), previous therapy or urinary diversion could be shown. Renal function improved significantly postoperatively (p < 0.05). Mean hospital stay was 25 d. Median overall survival (OS) was 15.2 months. It was not influenced by the entity of the tumor. Two years survival rate (SR) was 38.2%; 3 years SR 27.3%. After 47 months median follow-up time, 23.7% of the treated women were still alive. Conclusions: PE remains to be a meaningful treatment option for women with invasive gynecologic malignancies also after multiple previous therapies, showing acceptable complication rates and satisfactory OS in regard to the extensive nature of the malignancies and the procedure.
Post-treatment clinical status of patients with cervical cancer.
Authors: Kruze Polina A. , Verenikina Ekaterina V. , Nikitina Vera P. , Cherkasova Anna A. , Selezneva Olga G. , Poryvaev Yuriy A. , Chernikova Natalia V. , Chalabova Tatiana G. , Nikitin Ivan S. , Menshenina Anna P. , Zhenilo Oksana E. , Adamyan Meri L.
Published: May 2019

e17007

Background: Extended hysterectomy with fixation of preserved ovaries to the round ligaments of the uterus and subsequent transposition of the gonads from the irradiation area have already become a routine procedure in the treatment of cervical cancer in young women in order to avoid castration syndrome. The aim of the study was to analyze clinical characteristics of patients with cervical cancer 10 years after treatment. Methods: Clinical and hormonal status of 216 patients with stage Ib cervical cancer after complex treatment was studied. The majority of women (160 patients, 74%) remained fertile at the time of the study, and 56 patients (26%) were peri- and postmenopausal (from 46-55 years). The presence or absence of climacteric symptoms was assessed by a questionnaire; functional ovarian insufficiency (FNU) was determined as mild, moderate, and severe. Plasma levels of steroid and gonadotropic hormones were evaluated by radioimmunoassay. Results: Analysis of menopausal complaints according to questionnaires showed that the symptoms increased with the age of patients. Only 8 patients of the reproductive age reported hot flashes (Table 1). In this group of patients, levels of sex and gonadotropic hormones were common for this age. Patients aged 45-50 years reported also dry skin and mucous membranes, dyspareunia and dysuric disorders, which indicated perimenopause. And in postmenopause, urogenital disorders were very persistent. This group included patients treated 6 and 10 years ago. Conclusions: Thus, the function of preserved ovaries "faded away" independently according to the age, providing a smooth transition to menopause and optimal medical and social rehabilitation of patients.[Table: see text]
Inpatient burden of cervical and uterine cancer in the United States.
Authors: Corman Shelby , Nwankwo Chizoba , Kebede Nehemiah , Shah Ruchit
Published: May 2019

e17009

Background: Limited data on the inpatient burden of cervical and uterine cancer exist. Therefore, this study assessed inpatient mortality, length of stay (LOS), and costs among hospitalized cervical and uterine cancer patients. Methods: This was a retrospective analysis of the 2006–2015 Healthcare Cost and Utilization Project – Nationwide Inpatient Sample (HCUP-NIS). Cervical and uterine cancer cases were identified using ICD-9 codes of 180.9 and 182.0 respectively. Patient demographics, hospital characteristics, and hospital outcomes (hospitalization rates, inpatient mortality, LOS, and costs) were examined. Multivariate logistic regression models were used to determine predictors of inpatient mortality. Generalized linear models were used to determine predictors of LOS and costs. Results: The analytic cohort included 67,429 cervical cancer and 74,394 uterine cancer cases resulting in 55.92 (±1.51) and 61.69 (±1.78) annual hospitalizations (per 100,000 women), respectively. The highest proportion of hospitalizations related to cervical and uterine cancer were among patients aged 45-65 years (38.9%, 45.7%), Caucasians (70.3%, 78.1%), having public insurance (59.6%, 67.4%), and admitted at large (63.3%, 63.1%), urban teaching (54.8%, 56.5%) hospitals. The mean LOS, proportion of patients who died during hospitalization, and hospital charges per stay were 4.22 (±0.02) days, 1.02%, and $9,646 (±$63.06) for cervical cancer and 4.39 (±0.02) days, 1.43%, and $10,790 (±65.47) for uterine cancer related hospitalizations. Age > 65 years (vs 18-45 years) (OR: 3.656; 95% CI: 2.99 – 4.47), and higher Elixhauser mortality score (OR: 1.097; 95% CI: 1.09 – 1.10) were associated with higher inpatient mortality among cervical cancer patients. Predictors of inpatient mortality for uterine cancer were similar. Patient age, insurance, race, hospital size, urban (vs rural) location, region of the country, and Elixhauser mortality score emerged as significant predictors of LOS and cost per hospital discharge across both cancers. Conclusions: Cervical and uterine cancer are associated with considerable inpatient burden. There was considerable variation in inpatient mortality, LOS, and costs based on patient, hospital, and discharge level characteristics.
Comparison of HPV detection in HIV-infected and HIV-uninfected Kenyan women with or without cervical dysplasia.
Authors: Omenge Elkanah , Tong Yan , Tonui Philip , Ong’echa John M. , Muthoka Kapten , Kiptoo Stephen , Maina Titus , Itsura Peter , Moormann Ann , Wong YeungChing , Ermel Aaron , Liu Tao , Hogan Joseph , Loehrer Patrick J. , Brown Darron , Cu-Uvin Susan
Published: May 2019

e17015

Background: Cervical cancer, a malignancy caused by human papillomavirus (HPV) infection, is the most common malignancy in women living in sub-Saharan African countries including Kenya. HIV co-infection accelerates the natural course of cervical cancer. To determine the specific HPV type distribution in HIV-infected women compared to HIV-uninfected women, with and without evidence of cervical dysplasia. Methods: Demographic information, behavioral data, and a cervical swab were collected from women 18 and 45 years of age, HIV-infected or HIV-uninfected, who presented for cervical cancer screening at Moi Referral and Teaching Hospital in Eldoret, Kenya. Women were triaged based on the presence or absence of cervical dysplasia. HPV testing was performed using the Roche Linear Array Assay. Results were compared between women with or without HIV co-infection and between those with or without cervical dysplasia, using Chi-square tests or Fisher’s exact tests. Results: 223 women had normal VIAs. All had HPV testing, 221 had valid results: 115 HIV-infected women (mean age 37 years) and 106 HIV-uninfected (mean age 33 years). 175 women had abnormal VIAs. 143 women had HPV testing performed, 140 had valid results: 70 HIV-infected women (mean age 38.5 years) and 70 HIV-uninfected (mean age 31.3 years). Greater than 90% of all HIV-infected women in both projects were receiving anti-retroviral therapy at enrollment. HPV of any type was detected in 48% of all women with normal VIA vs. 61% of women with abnormal VIA (P = 0.018). High risk (HR)-HPV was detected in 38% of all women with normal VIA vs. 51% of all women with abnormal VIA (P = 0.012). HIV-uninfected women with normal VIA had significantly lower detection of all HPV (P = 0.026), high risk-HPV (P = 0.018), IARC high risk-HPV (P = 0.047), A9 types (P = 0.050), and individual types HPV 16 (P = 0.0274), HPV 18 (P = 0.007), and HPV 51 (P = 0.009) than HIV-uninfected women with abnormal VIA. Among HIV-infected women, there was no difference in detection of any group of HPV types or individual types with respect to VIA results. Conclusions: HIV-uninfected women without cervical dysplasia had lower detection of oncogenic HPV than HIV-uninfected women with dysplasia. In contrast, HPV detection did not differ among HIV-infected women between those with or without cervical dysplasia. In addition, VIA appears to lack specificity for HPV-associated cervical dysplasia, as 39% of women with abnormal VIA examinations did not have any HPV detected, and 49% of women with abnormal VIA examinations did not have any HR-HPV detected.
Visceral adiposity as a predictor of survival in patients with epithelial ovarian cancer receiving platinum and taxane-based chemotherapy.
Authors: Staley Stuart-Allison Moffat , Tucker Katherine , Oldan Jorge , Moore Dominic T. , Newton Meredith , Ertel Michelle , West Lindsay , Bae-Jump Victoria
Published: May 2019

e17031

Background: Obesity has been linked to worse outcomes in epithelial ovarian cancer (EOC), due to underlying metabolic dysfunction. Visceral fat (i.e. central obesity) compared to subcutaneous fat is more metabolically active and has been linked to higher rates of obesity-related comorbidities such as hypertension and diabetes, but less is known of the impact of increased visceral adiposity on EOC outcomes. Thus, our goal was to evaluate if visceral adiposity, as determined by computed tomography (CT) morphometric measurements, was associated with worse outcomes in EOC patients undergoing platinum and taxane-based chemotherapy. Methods: EOC patients diagnosed between 12/2004 and 5/2016 who received neoadjuvant or adjuvant treatment with platinum and taxane-based chemotherapy were included. Data on age, stage, grade, histology, BMI, comorbidities, treatment approaches and outcomes were collected. CT images closest to the time of diagnosis were retrospectively evaluated for mid-waist visceral fat volume (VFV), mid-waist subcutaneous fat volume (SFV) and the ratio of mid-waist VFV/SFV. Visceral adiposity is commonly defined as a VFV/SFV ≥ 0.4. Cox regression models were used to analyze time-to-event outcomes. Results: Two hundred fifty-eight EOC patients were evaluated. Seventy-five percent of patients were diagnosed with Stage III or IV disease, with high grade serous as the most common histology (72%). Median age at diagnosis was 62.4 years. Approximately 65% were obese; the median BMI was 26.8 (IQR 23.1 – 32.6). The median VFV/SFV ratio was 0.46 (IQR 0.32 – 0.70). Patients were categorized into those with a VFV/SFV ratio greater than 0.4 or a ratio less than 0.4. When comparing these two groups, there was no difference in progression free survival (PFS) for women with a VFV/SFV ratio greater or less than 0.4 (p = 0.22). However, a VFV/SFV ratio of greater than 0.4 was associated with worse overall survival (OS) (p = 0.01). Conclusions: We found that visceral adiposity, defined as a VFV/SFV ratio greater than 0.4, appeared to be associated with decreased OS, but not PFS. These findings suggest that body fat distribution may be an important prognostic factor for EOC and should be further explored as we expect the obesity epidemic to continue and influence EOC oncologic outcomes.
Sarcopenia as a predictor of chemotherapy toxicity in patients with ovarian cancer receiving platinum and taxane-based chemotherapy.
Authors: Tucker Katherine , Staley Stuart-Allison Moffat , Newton Meredith , Ertel Michelle , Zhang Yingao , Doherty Irene , Gehrig Paola A.
Published: May 2019

e17035

Background: Sarcopenia (age-related loss of skeletal muscle mass) is associated with worse oncologic outcomes and adverse events in patients with solid tumors. Limited research in epithelial ovarian cancer (EOC) has shown that sarcopenia is associated with worse patient outcomes. The purpose of this study was to investigate the association of sarcopenia with chemotherapy toxicity in patients with EOC. Methods: EOC patients diagnosed between 6/2000 and 2/2017 who received platinum and taxane-based chemotherapy were included. Age, race, stage, grade, BMI, comorbidities, treatment, and outcomes were collected. Chemotherapy toxicities and associated grades, as well as treatment modifications were recorded. Computed tomography (CT) images within 3 months of diagnosis were evaluated for Skeletal Muscle Area (SMA) at the 3rd lumbar vertebrae. Measurements were obtained with use of TomoVision(R) radiological software (SliceOmatic – version 5.0, Quebec, Canada). Sarcopenia was defined as Skeletal Muscle Index (SMI = SMA/height2) ≤ 41. This preliminary analysis generated descriptive statistics and compared the distributions of toxicity assessments by sarcopenia, with t-tests, rank-sum, chi-square and fisher’s exact tests. Results: 144 patients were evaluated. The majority presented with Stage III /IV, HGSOC (75%, 73%). Median age was 63 yrs and median BMI was 27.2 (IQR = 23.7-32.8). 61% of patients were sarcopenic. The median SMI was 40 (IQR = 34.2-46.2). There was no significant difference between sarcopenic (S) and nonsarcopenic (NS) patients with respect to dose adjustment (p = 0.37), regimen change (p = 0.998), need for blood transfusion (p = 0.60), toxicity-related hospitalization (p = 0.84) or delay in treatment (p = 0.37). Grade 3-4 toxicity was found in 56.8% of S and 58.9% of NS patients (p = 0.992). Similarly, the distributions of grade 1-2 toxicities in S and NS patients were comparable. Conclusions: In this cohort of patients, there was no significant association between sarcopenia and chemotherapy related toxicities. However, given high prevalence of sarcopenia in ovarian cancer patients, our relatively small sample size, and challenges with retrospective collection of chemotherapy toxicity, further prospective exploration is warranted.
FLABRA, frontline approach for BRCA testing in ovarian cancer (OC) treatment naïve population: A Latin America (LA) epidemiologic study.
Authors: Goncalves Susana Beatriz , Giornelli Gonzalo , Pereira Marcelo Horacio , Gallardo-Rincon Dolores , Estevez-Diz Maria Del Pilar
Published: May 2019

e17050

Background: The majority of OC cases are sporadic, but it is estimated that in 17%, germline mutations in BRCA1 or BRCA2 genes can be identified. BRCA mutated OC has distinct clinical characteristics, increased sensitivity to platinum and non-platinum agents, and to DNA damage repair (DDR) targeting agents like PARP inhibitors. Additionally, somatic BRCA mutations could be identified in tumor tissue. The prevalence of germline BRCA mutations (gBRCAm) and somatic mutations (sBRCAm) has been not been characterized in Latin-american population, which is a paradigm of poly-ethnicity, where prevalence of germline, but especially somatic BRCA mutations in OC, has not been studied. Furthermore, tumor testing as first step may be a new option in BRCA testing algorithm that could avoid the necessity for double testing (gBRCA, then sBRCA testing), in case of gBRCAm negative result. Methods: FLABRA is a cross-sectional, multi-center, study designed to determine the prevalence of sBRCAm in newly diagnosed OC patients versus gBRCAm, and to describe different treatment approaches at front line in LA, as well as current OC genetic counselling. We enrolled 400 consecutive patients from 40 institutions in Argentina, Brazil, Colombia, Mexico, Peru and Panama, diagnosed with OC. Tumor blocks were tested for sBRCA (Myriad Tumor BRACAnalysis CDx™). In sBRCA positive patients, blood samples were analyzed to confirm if the mutation was germline or somatic in origin. In gBRCAm, genetic counseling was advised. Medical records were reviewed for data relevant to medical history, surgery results, treatment approach and genetic counseling. Results: We present the preliminary results with 291 patients already tested. For this first subset of patients, 85/291 (29%) had BRCA mutations identified in their tumors. Preliminary results confirm that starting with tumor testing enlarges the population eligible for PARP inhibitors, by identifying additional patients with somatic mutations only detectable in the tumor. Although preliminary, our data confirms the possibility of identifying additional patients with sBRCA mutations by testing in tumor, with a more cost-effective approach, avoiding a second round of gBRCA testing in patients with BRCA negative results in tumor. Conclusions: In this preliminary analysis we found that somatic BRCA mutations account for a significant proportion from total BRCA mutations within LA population studied.
The association of marital status, socioeconomic status, and race on the survival of ovarian cancer patients.
Authors: Gardner Austin Blake , Sanders Brooke , Mann Amandeep Kaur , Liao Cheng-I , Kapp Daniel Stuart , Chan John K.
Published: May 2019

e17056

Background: To evaluate the influence of marital status, socioeconomic status, and race on the survival of ovarian cancer patients. Methods: Data were obtained from the SEER database from 2010 to 2015. Analyses were performed with Kaplan–Meier and multivariate Cox proportional hazard models. Results: Of 19,772 patients with ovarian cancer (median age: 60), 82.8%, 7.1%, 9.4%, and 0.7% were White, Black, Asian, and Native American, respectively. 54.5%, 21.7%, 11.5%, and 12.3% were married, single, divorced, and widowed. Married patients were older than single patients but younger than divorced and widowed patients (59 vs. 54 vs. 61 vs. 75 years; p < 0.001). 55.5%, 30.7%, 64.1%, and 38.8% of White, Black, Asian, and Native American patients were married (p < 0.001). 90.6% of married patients were insured compared to 71.8% single, 78% divorced, and 86.1% widowed (p < 0.001). Patients who were married presented at earlier clinical stages (I-II) and lower tumor grades (I-II) compared to widowed and divorced patients (p < 0.001). Married patients were more likely to receive chemotherapy compared to single, divorced, and widowed patients (79.1% vs. 71.3% vs. 76.7% vs. 67.6%; p < 0.001). The 5-year disease-specific survival (DSS) of the overall group was 60.1%. Married patients had similar DSS compared to single patients at 62.3% vs. 65.0%, but improved survival vs 53.7% divorced and 46.6% widowed (p < 0.001). In multivariate analysis, patients with stage II-IV or grade III-IV disease, older age (HR: 1.002, 95% CI: 1.001 to 1.003, p < 0.01), Medicaid (HR:1.16, 95% CI: 1.11-1.22 p < 0.0001) or no insurance (HR:1.20, 95% CI: 1.11-1.30, p < 0.0001) had worse prognosis. Married patients had improved survival relative to widowed patients (widowed HR = 1.08; 95% CI: 1.03-1.14; p < 0.01). Race did not influence DSS when controlling for surgery, chemotherapy, and radiation. Conclusions: Married patients were younger, had less advanced diseases relative to divorced and widowed patients, and were more likely to receive adjuvant chemotherapy compared to unmarried patients. Marital status is an independent predictor for survival relative to widowed status. DSS among races was not significant.
Prognostic factors of overall survival for patients with FIGO stage IIIc or IVa ovarian cancer treated with neo-adjuvant chemotherapy followed by interval debulking surgery.
Authors: Vincent Laura , Jankowski Clémentine , Ouldamer Lobna , Ballester Marcos , Bendifallah Sofiane , Bolze Pierre-Adrien , Akladios Cherif , Costaz Hélène , Lavoué Vincent , Uzan Catherine , Collinet Pierre , Touboul Cyril , Huchon Cyrille , Bricou Alexandre , Dridi Sabrina , Padeano Marie-Martine , Fraisse Jean , Bengrine Leila , Arnould Laurent , Coutant Charles
Published: May 2019

e17060

Background: The aim of this study was to identify prognostic factors of overall survival in patients with FIGO stage IIIc or IVa ovarian cancer treated by neo-adjuvant chemotherapy(NAC) followed by interval debulking surgery. Methods: Data of 483 patients from FRANCOGYN database, were retrospectively included in 11 French expert centers between January 2000 and December 2016. Interval cytoreductive surgery was realized in all patients after 2 or 3 or 4 or more than 4 courses of NAC. Completeness of Cancer Resection score led to define residual disease after surgery. Median overall survival was determined using the Kaplan-Meier method. Univariate and multivariate analysis were performed to define prognostic factors of overall survival. Results: The median overall survival was 52 months, after a median follow up of 30 months. 73.5% patients had no residual disease after surgery. After univariate analysis, factors significantly associated with decreased overall survival were; no pelvic and/or lombo-aortic lymphadenectomy (p= 0.002), residual disease after surgery ( p< 0.001), positive cytology after NAC ( p< 0.001), omental disease after NAC ( p= 0.002), no pathologic complete response (pCR) ( p= 0.002). In multivariate analysis, factors significantly associated with decreased overall survival were; residual disease after surgery (HR = 1.93; CI95% (1.16-3.21), p= 0.01) and positive cytology after NAC (HR = 1.59; CI95% (1.01-2.55), p= 0.05). Patients with no residual disease after surgery had a median overall survival of 64 months versus 35 months for patients with residual disease. Patients with negative cytology after NAC had a median overall survival of 71 months versus 43 months for patients with positive cytology after NAC. Conclusions: Residual disease after surgery and positive cytology after NAC are significantly associated with decreased overall survival of FIGO stage IIIc or IVa ovarian cancer. Therefore, complete cytoreductive surgery is ovarian cancer main prognostic factor.
Mutational landscape of ovarian cancers (OC) identified by prospective clinical sequencing in a nationwide cancer network.
Authors: Schink Julian , Alvarez Ricardo H. , Elvin Julia Andrea , Moran Amber , Rollins Rebecca , Geisler John P. , Chura Justin , McIntosh David , Godbee Natalie , Tan Bradford A. , Markman Maurie
Published: May 2019

e17067

Background: Tumor genomic profiling is a critical component of precision oncology allowing the detection of genomic alterations (GA) that have the potential to be targeted therapeutically. We present an analysis of comprehensive genomic profiling (CGP) of a large series of OC assayed in a nationwide cancer network. Methods: 449 Pts with advanced OC underwent CGP with hybrid capture of up to 406 cancer-related genes on tumor tissue or for 62 genes on circulating tumor DNA ordered during clinical care for treatment decision-making between 01-2013 to 05-2018. Clinically relevant (CR) GA were defined as associated with targeted therapies or mechanism-driven clinical trials. Treatment histories for the 449 patients were obtained with IRB-approved retrospective review. Results: Median age was 56 years (range, 23-83), 71% were Caucasian. GA were identified in 94% (420/449) of OC, of which 283 (63%) had a clinically relevant genomic alteration (CRGA). 24.0% in HRD ( BRCA1/2, ATM, PALB2, BRIP1). CRGA in other potentially targetable pathways were identified: 48.0% MEK pathway ( KRAS, NRAS, HRAS, BRAF, RAF1, GNAS, NF1, NF2) CRGA, 33.5% PI3K/AKT/mTOR pathway ( PIK3CA, AKT1/2/3, PIK3R1, PTEN, MTOR, STK11, FBXW7), and 10.6% in ERBB ( ERBB2, ERBB3, ERBB4, EGFR). All OC tested were microsatellite stable and only one patient had a tumor mutational burden > 20 muts/Mb. 21% (59/283) of OC patients were ordered a genomically-matched treatment, 58% (37/64) were agents that were FDA approved in a different tumor type, and 17% (11/64) through referral to a matched mechanism driven clinical trial. With access to the clinical trial TAPUR, the frequency of matched treatment through clinical trials increased over time from 2013 to 2018. For the off label non-study population the median PFS was 19 weeks, and the median OS was 34 weeks. Conclusions: In a large series of OC assayed with CGP, 21% of pts received matched treatment, which was predominantly targeted therapy. The comprehensive sensitive and unbiased nature of CGP, coupled with a multidisciplinary molecular tumor board and staff dedicated to genomic interpretation, assisted in achieving a high frequency of patients’ participation in clinical trials and gene-directed treatment.
Factors associated with one-year mortality after debulking surgery in older women with ovarian cancer.
Authors: Filippova Olga T. , Tew William P. , O'Cearbhaill Roisin Eilish , Sonoda Yukio , Long-Roche Kara C. , Zivanovic Oliver , Gardner Ginger J. , Chi Dennis , Shahrokni Armin
Published: May 2019

e17069

Background: The objective of this study was to assess the factors associated with one-year mortality following cytoreductive surgery among women ≥65 years with epithelial ovarian cancer (EOC). Methods: Since 2011, patients aged 65 and older with advanced EOC, who underwent cytoreductive surgery within two months of initial visit, and had at least one year of follow up were included. Mortality data was retrieved from social security death index. Independent variables of interest were age, American Society of Anesthesiologist Physical Status (ASA-PS) classification, preoperative albumin, Memorial Sloan Kettering Frailty Index (MSK-FI), procedure time, intraoperative blood loss, 30-day minor and major adverse events, 30-day readmission and emergency room visits, stage, rate of suboptimal surgery, and receipt of neoadjuvant chemotherapy (NACT). Univariate analysis was performed to assess relationship between these variables and one-year mortality. Results: In total, 263 women (median age 70, range 65-88), of whom 26% had stage IV disease and 5% suboptimal surgery, were included. One-year mortality was 6.5% (n = 17), with six patients dying within six months. On univariate analysis, patients who died within the first year differed from those who were alive at one year in terms of length of stay (13 vs 9 days, p = 0.01), pre-operative albumin (3.8 vs 4.1, p = 0.01), major adverse events (29.4% vs. 12.2%, p = 0.04), and receipt of NACT (33.3% vs. 14.7%, p = 0.05). Patients who died within one year had an insignificant difference in MSK-FI (1.4 vs. 0.8, p = 0.08), and pre-operative hemoglobin (11.4 vs. 12.1, p = 0.06), as well as no difference in in age, ASA-PS, stage, procedure time, blood loss, minor adverse events, readmission and emergency room visits. Patients with suboptimal surgery did not have significantly higher one-year mortality rates, compared to those with optimal resection (11.8% vs. 4.5%, p = 0.5). Conclusions: Cytoreductive surgery in the selected group of older women is safe. In this cohort, age and ASA PS were not among factors associated with one year mortality. More robust risk stratification for this cohort is needed.
CD49d (high) T cells in the ovarian cancer microenvironment are a potential target for the optimization of immune checkpoint therapy in ovarian cancer.
Authors: De May Henning , Desai Sharina Palencia , Kinjyo Ichiko , Harris Jaryse , Adams Sarah Foster
Published: May 2019

e17075

Background: Despite the correlation between tumor infiltrating lymphocytes and long-term survival, immune-based therapies have underperformed for the treatment of ovarian cancer. This is attributed to an immune suppressive intraperitoneal microenvironment. With evidence that T cell dysfunction in the ovarian tumor environment is not reflected peripherally, we hypothesized that anatomically restricted T cell subsets play a role in local disease regulation. High expression of integrin α4 (CD49d) is selectively seen on peritoneal T cells in patients and healthy mice. Here we tested whether CD49d(high) CD8 T cells also contribute to anti-tumor immunity in ovarian cancer models. Methods: Using a syngeneic immune competent model of high grade serous ovarian cancer (ID8ova), we evaluated the phenotype of CD49d(high) T cells at varying stages of intraperitoneal disease by flow cytometry. Antigen specificity was tested using a SIINFEKL/H-2Kb NIH tetramer assay. Results: CD49d is highly expressed by peritoneal CD8 T cells but not by splenocytes in tumor-bearing mice (29.8% vs. 3.3% of CD8 cells respectively). Supporting a role in anti-tumor immunity, 92% of tumor antigen-specific CD8 T cells in the peritoneal cavity expressed high CD49d. While the proportion of peritoneal CD8 cells that express high CD49d is similar in healthy and tumor-bearing mice, CD49d(high)CD8 cells upregulate the expression of co-inhibitory receptors with tumor progression. At late stages of the disease, PD-1, TIM3, and LAG3 are exclusively expressed by peritoneal CD49d(high) cells (range 94.7 +/- 3.05%). Consistent with our prior data, PD1+TIM3+LAG3+ CD8 T cells were not present in the spleen, confirming the anatomic specificity of this lymphocyte subset. Conclusions: These findings add to the accumulating evidence that tumor immunity is locally regulated and identify an IP specific subset of CD8 T cells that could be selectively targeted with immune checkpoint blockade. We predict that strategies directing immune therapy to the peritoneal tumor microenvironment will enhance treatment efficacy and limit off-target toxicities in women with ovarian cancer.
Hypermetabolic activity by FDG-PET after immunogenic chemotherapy and multi-peptide immunotherapy in ovarian cancer.
Authors: Marquez-Manriquez Juan Pablo , Lucero-Diaz Pedro Alejandro , Durazo Alberto , Matute-Briseno Jose Antonio , Gallardo-Rincon Dolores , Perez-Astorga Mario ALBERTO , Gutierrez-Marquez Michelle ANTONIA , Camacho-Hernandez Alejandro
Published: May 2019

e17079

Background: There are several reports of increased of SUV in the lymph nodes of cancer patients after immune manipulation such as the administration of vaccines and checkpoint inhibitors. However the clinical importance of these phenomena is poorly understood. The administration of two immunogenic drugs and eight peptides in HGSOC induced atypical bright zones in multiple lymph nodes and, in areas with microscopic disease where potentially we can have cancer stem cells (CSC’s). Methods: We enrolled N = 10 HGSOC after the local IRB ethic committee approval. All the patients had 3 recurrences with mPFS = 8 months of the third relapse. The last FDG-PET scan was used as basal image for the study. Blood was collected for cellular and humoral immunology analysis such as Granzyme B ELISPOT and ELISA. Tissue was used for IHC analysis for the evaluation of CD8, FOXP3, Th1, and proteins related with CSC’s. The patients received 50 mg of oxaliplatin and 30 mg of doxorubicin total dose every week four times simultaneously with multi peptide immunotherapy. A second FDG-PET scan was performed after the termination of the treatment. Results: After the treatment 100% of the patients showed intense atypical bright uptake areas in lymph nodes and in the peritoneum. There was a correlation between the brightness intensity (SUV), and the Granzyme B production (p = 0.001). We found multiple bright small lesions in the peritoneum that were not visible before treatment. We demonstrated the presence of proteins related with CSC’s in the original tumor tissue and an antibody immune response against EGFR (P = 0.005), Ape-1 (p = 0.003) and Bcl-2 (p = 0.05). Conclusions: Immunotherapy may produce hypermetabolic activity that could lead to overtreatment when evaluated by FDG-PET in HGSOC. Vaccination may activate lymph nodes and anti-cancer immune interventions may also activate CD8 and Th1 cells able to accumulate in CSC’s clusters and increased notably the SUV, which may lead to false relapse interpretation by the radiologists and oncologists.
Association between time to first subsequent therapy (TFST) and overall survival (OS) in previously untreated patients with ovarian cancer (OC): A SEER Medicare database analysis.
Authors: Desai Kaushal , Muston Dominic , Adeboyeje Gboyega , Monberg Matthew J.
Published: May 2019

e17095

Background: TFST may be a patient-relevant indicator of efficacy beyond progression in OC, however, the association between TFST and OS is unknown. We analyzed the SEER Medicare database to determine whether OS varied by TFST in previously untreated patients with OC. Methods: From the SEER-Medicare linked database, we identified newly diagnosed OC patients (≥66 years) who initiated first-line chemotherapy between 2009 and 2015. Patients were followed through the end of 2016. TFST was defined as the time from initiation of first-line chemotherapy until the start of subsequent therapy or death. Cox models summarized the overall association between TFST and OS through hazard ratios (HRs), and by TFST strata for patients who had a TFST event. In case hazards were non-proportional, we examined the fit of independent parametric survival curves. Results: In the cohort of 1407 patients, 1005 patients had a TFST event. Median age was 74 years and 34.9% were alive at the time of this analysis. For population with a TFST, the median TFST was 13.1 months and median OS was 30.88 months (HR = 0.29, 95% CI: 0.26, 0.32). Among patients < 75 years, the median TFST was 13.65 months and the median OS was 37.07 months (HR = 0.24, 95% CI: 0.21, 0.28). In the full cohort of 1407 patients, the best-fitting distributions accelerated failure time models under which the (unrestricted) mean TFST and OS were 44.9 and 73.8 months respectively. This indicated that on average TFST was an acceleration of OS by a factor of 39%. Conclusions: In this elderly population of previously untreated OC, longer TFST was associated with longer OS. Limitations of this analysis include censoring of OS and immortal time bias. [Table: see text]
Clinical benefit of bevacizumab in Mexican ovarian cancer patients according to the intention of treatment by the oncologist.
Authors: Gallardo-Rincon Dolores , Bahena-Gonzalez Antonio , Montes-Servín Edgar , Montes-Servín Elizabeth , Michel-Tello David , Toledo-Leyva Alfredo , Alamilla Gabriela , Espinosa-Romero Raquel , Gonzalez-Ibarra Ernesto , Morales-Vasquez Flavia , Cano Blanco Claudia , Coronel-Martinez Jaime A , Cetina-Perez Lucely Del Carmen
Published: May 2019

e17097

Background: Ovarian cancer (OC) is the first cause of gynecological cancer, and the fifth cause of women cancer-death in US. In Mexico, more than 4,500 new cases of ovarian cancer are diagnosed yearly and it represents the second cause of gynecological cancer mortality. Bevacizumab (BVZ) is an antiangiogenic antibody that has been approved for first-line and recurrence therapy in OC patients. The aim of the study was to evaluate the clinical benefit of BVZ in different lines of treatment in Mexican OC patients. Methods: A total of 94 OC patients treated with BVZ were recruited at the Ovarian Cancer Program of the Instituto Nacional de Cancerología, from February 2012 to September 2018. Clinicopathological characteristics and toxicity was correlated with line of treatment. PFS curves were estimated by the Kaplan–Meier method, while comparisons among groups were analyzed with log-rank or Breslow tests. Results: Most of the patients were stage IIIC (69.1%) with HGSP histology (73.4%). 24 patients (25.5%) received BVZ as first-line treatment before debulking surgery (50% for suboptimal and 45.8% for optimal cytoreduction). 48 patients (51.1%) received BVZ for second-line (72.9% after a platinum-resistant and 27.1% after a platinum-sensitive recurrence) and 22 patients (23.4%) for three or more lines of treatment. Venous thromboembolic events (VTE) were more frequent in multi-treated patients ( P= 0.030). The median PFS was 23.7, 11.7 and 5.8 months for first, second and third or more lines, respectively. Patients with optimal debulking surgery had a better PFS compared with suboptimal and BVZ in first-line patients (24.8 vs 20.9; P= 0.050). Patients with BVZ in second-line who are a platinum-sensitive recurrence had better PFS compared to those with a platinum-resistant disease (15.1 vs 7.6; P= 0.040). Conclusions: OC patients had clinical benefit from treatment with BVZ when used as first-line and first recurrence treatments. The use of BVZ for third or later line treatment has a questionable benefit and is associated with a higher rate of VTE. Also, we highlight that 77% of the patients had the greatest-benefit while 33% had limited-benefit.