bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of LINC00858 with clinical outcome of patients with cervical cancer who received standard concurrent chemo-radiotherapy.
Authors: Lu Shun , Deng Siyao , Zhang Jiayu , Lang Jin Yi 
Published: May 2020

e18002 Background: Cervical cancer is the second most common malignant tumour threatening women’s health and remains a vast challenge for many underdeveloped nations. Combination of concurrent chemotherapy with external beam radiation therapy (EBRT) followed by intracavitary brachytherapy (ICBT) boost achieved a favorable outcome for cervical cancer patients. However, the reduced sensitivity of cancer cells to radiotherapy is an important cause of re-currence and metastasis in some patients, it is necessary to constantly improve the radiotherapy technology and the treatment effect. Long noncoding RNAs (lncRNA) are noncoding RNA molecules greater than 200 nucleotides in size that are often critical regulators of gene expression, lncRNAs were implicated in stem cell pluripotency by examining the expression. Methods: Whole-exome sequencing and RNA sequencing were conducted in patients with locally advanced cervical cancer (LACC) to identify prognostic variants by using a two-stage case-control design. Patients developed local recurrences in 3 years after standard concurrent chemotherapy with EBRT followed by ICBT were divided in case group. While patients did not show local recurrences were regarded as a radio-sensitive group. In the first stage, DNA and RNA were extracted from formalin-fixed paraffin-embedded tumor tissues of 32 patients. In the second stage, to validate the significant association between LincRNA and Local control rate of patients found in first stage, RT-PCR was carried out in RNA samples from an independent 100 patients (with same criteria of selection). Cox regression models were used to analyze the association between genetic variants and time-to-event outcomes. Results: In the first stage, expression of 7 LincRNAs: RP11-335O4.(P = 0.01,HR = 10.86), CTD-2292M14.1(P = 0.01,HR = 9.47),RP11-94H6.1(P = 0.02,HR = 9.47), RP11-417L19.2(P = 0.0,HR = 9.36), RP4-683M8.2(P = 0.02,HR = 10.82), RP11-20B24.3(P = 0.02,HR = 8.90) and LINC00858(P = 0.03,HR = 6.41) were found to be markedly correlated with relapse-free survival in 32 patients. Among these LincRNAs, LINC00858 (P = 0.01, HR = 11.23) remained significant association with relapse-free survival in 100 independent patients. Conclusions: Our data suggest that LincRNA may be a useful predict marker for radiosencetivity of cervical cancer patients.
Prognostic factors and treatment comparison in small cell neuroendocrine carcinoma of the uterine cervix in the surveillance, epidemiology, and end results database.
Authors: Li Jinluan , Lin Limei , Zhang Zongkai , Huang Yunxia , Lin Qin 
Published: May 2020

e18015 Background: The purpose of this study was to evaluate the impact of treatment modality to survival outcome in small cell neuroendocrine carcinoma of the uterine cervix (SCNEC) using the Surveillance Epidemiology and End Results (SEER) database. Methods: We identified patients with SCNEC from the SEER program during 1981 to 2014and analyzed significant factors for cause-specific survival (CSS) and overall (OS) using Kaplan–Meier survival and Cox regression proportional hazard methods. Results: A total of 503 SCNEC patients were identified. The median follow- up time was 31 months. The 5-year cause specific survival and overall survival were 36.6% and 30.6%, respectively. The FIGO stages I to IV distributions were 189(37.6%), 108 (21.4%),95 (18.9%), and 111 patients (22.1%), respectively. Of the patients with known local treatment strategies, 177 patients (45.9%) were treated with radical surgery and 209 (54.1%) patients underwent primary radiotherapy. In multivariate analysis, local treatment strategies were independent prognostic factors for CSS and OS. The 5- year CSS according to radical surgery and primary radiotherapy were 50.0% and 27.9%, respectively (P < 0.001). The 5-year OS in patients received radical surgery and primary radiotherapy were 57.8%, and 29.6%, respectively (P < 0.001). In FIGO stage I SCNEC, patients treated with radical surgery had superior CSS (P = 0.001) and OS (P = 0.003) than those with primary radiotherapy. However, in FIGO stage II and III SCNEC, there are no differences observed in CSS and OS according to different local treatment strategies. The results also observed that the addition of brachytherapy impact OS (P = 0.002) in FIGO stage III SENCE. The 5-year cause specific survival and overall survival of patients with FIGO IV were only 11.7% and 7.1%, respectively. Conclusions: Small cell neuroendocrine carcinoma of the cervix is a rare disease with aggressive clinical behavior. The results suggested that radical surgery is the optimal local treatment for early-stage SCNEC and combining radiation therapy with brachytherapy should be suitable for patients with advanced stage.
Novel HPV-E7 immune modulators to activate HPV-specific T cells to eliminate cervical cancer.
Authors: Shi Lihua , Zhang Di , Tam Susan , Fung Man-Cheong 
Published: May 2020

e18027 Background: Human papilloma virus (HPV) infection can lead to several types of cancers in both men and women. HPV+ tumor cells constitutively express the HPV-E7 antigen which can act as an oncogene to promote tumor growth and malignant transformation. Here, we report the application of novel Tavo Immune Modulator (TIM) biologics molecules which are consisted of a pMHC complex with an epitope peptide derived from HPV-E7 and co-stimulatory modulators of T cell activity. The HPV-E7 TIM molecules can specifically recognize and activate HPV-E7-specific T cells for the elimination of HPV affected cells. Methods: HPV-E7 TIM molecules were engineered as fusion molecules with HLA-A*02:01 MHC complexed with an HPV-E7 (11-20) epitope peptide at the N-termini, and various T cell costimulatory modulators at the C-termini of IgG heavy and light chains. TIM molecules were expressed in Expi293 cells and purified by Protein A affinity chromatography. Specific binding of TIM with HPV-E7 specific T cells was confirmed by immunostaining and flow cytometry. The activation and expansion of antigen specific CD8+ T cells were elucidated in T cell activation and recall assays. Results: HPV-E7 TIM molecules with various T cell co-stimulator molecules were engineered to specifically recognize HPV-specific T cells. Activation of T cells was antigen-specific and depended on the presence of an engineered T cell modulatory component on the TIM framework. The effects of various costimulatory molecules in different combinations on T cell activation were explored and an optimal combination was identified which facilitated high potency antigen-specific T cell activation. Such molecular combinations could facilitate T cell expansion and activation in T cell recall assays. Efficacy of HPV-E7 TIM molecules by inhibiting tumor growth in a syngeneic tumor model is ongoing. Conclusions: This study demonstrates that HPV-E7 TIM molecules selectively recognize and activate HPV-specific CD8+ T cells in the presence of a combination of two T cell costimulatory factors. Such novel biologics provide distinctive approaches in the treatment of HPV-related cancers and warrant further investigation. Additional in vitro and in vivo studies are ongoing to demonstrate the utility in eliminating HPV-infected tumor cells. Full data will be presented at the meeting.
Association of time interval from neoadjuvant chemotherapy to interval cytoreduction and interval cytoreduction to adjuvant chemotherapy with survival outcomes and risk of platinum resistance.
Authors: Alencar Viviane , Pirolli Rafaela , Estati Felipe Leonardo , Ribeiro Adriana Regina Goncalves , Guimaraes Andrea Paiva , Baiocchi Glauco , Da Costa Alexandre Andre B. A. 
Published: May 2020

e18043 Background: Neoadjuvant chemotherapy (NACT), followed by interval debulking surgery (IDS), is a possible approach to patients with stages IIIC and IV epithelial ovarian cancer who are most likely to have suboptimal results with upfront surgery. Delay in initiation of adjuvant chemotherapy has been associated with worse outcomes. Our study aimed to evaluate whether time from NACT to surgery (TNS) and from surgery to adjuvant chemotherapy (TSA) were associated with survival outcomes and with platinum-resistant relapse. Methods: We did a retrospective analysis of medical records from 194 patients with EOC treated with IDS at a single institution from 2007 to 2018. We calculated the median TNS and TSA and evaluated its relation to progression free survival (PFS), overall survival (OS) and time to platinum-resistant relapse (TTPR) through Kaplan-Meier and Cox regression analysis. Results: After a median follow-up of 62 months, OS was 58 months and PFS was 18 months. Most patients received at least 3 cycles of NACT (21.1% 3 cycles, 16.0% 4 cycles and 39.7% 6 cycles); and the rate of optimal cytoreduction was 75,8%. Optimal surgery was associated with survival (p < 0.001). TNS over 8 weeks and TSA over 7 weeks were associated with worse PFS (HR 1.57, 95%CI 1.07-2.31; HR 1.52, 95%CI 1.00-2.32, respectively) and OS (HR 1.83, 95%CI 1.13-2.96; HR 1.57, 95%CI 0.93-2.65, respectively) in univariate analysis but not in a multivariate analysis including residual disease as a covariate. In the subgroup of patients with residual disease < 10mm a multivariate analysis showed shorter PFS (HR 2.06, CI95% 1.16-3.66, p = 0.014) and OS (HR 2.20, CI95% 1.05-4.59, p = 0.035) for patients with TSA longer than 7 weeks. Longer TNS was associated with PFS (HR 1.66, 95%CI 1.06-2.59, p = 0.026) in univariate analysis but not in multivariate analysis. Interestingly, longer TNS was associated with shorter TTPR (65.6 vs. 35.0 months, p = 0.049) and a higher frequency of platinum resistant relapse at first relapse (48.8% versus 26.5%, p = 0.012). Conclusions: Our study provides evidence that delayed TSA is an independent prognostic factor for worse PFS and OS only in the subgroup of patients with residual disease ≤ 10mm. Longer TNS was associated with higher risk of platinum resistant relapse. One possible explanation is that NACT may select chemoresistant clones, which would have more time to grow and spread with longer intervals until surgery. Further studies are necessary to corroborate this hypothesis.
Hrd in ovarian cancer: Defined today, evolving for the future.
Authors: Eckstein Markus , Bloom Kenneth Joel , Riccelli Peter , Policht Frank , Keeling Derry Mae , Clark Jordan 
Published: May 2020

e18052 Background: Homologous Recombination Repair (HRR) gene mutations result in Homologous Recombination Deficiency (HRD) associated with increased risk of high grade serous ovarian (HGOC) cancer and subsequent response to PARP inhibitors (PARPi). Traditionally, HRD has been determined by testing for germline and/or somatic BRCA1/2 mutations. Today, a growing number of HRR gene mutations are known to result in HRD and genomic instability, thus being a suitable target for PARPi. Therapy response to PARPi is highest in BRCA-mutant followed by HRD+/non-BRCA-mutant HGOC. Today, no standard HRD testing methods exist, causing confusion for physicians, and leading to poor outcomes for missed PARPi eligible patients. Thus, there is need to understand HRD testing utilization and methods in HGOC to inform best practices and optimize HRD testing in the clinic. Methods: We assessed the testing landscape for determining HRD status in ovarian cancer using a data set of 8,400 newly diagnosed and metastatic ovarian cancer patients in the US from Q3-2018 through Q2-2019 identified from Diaceutics’ proprietary Global Diagnostic Index (GDI). Analysis of real-world BRCA1/2 and NGS associated testing data and laboratory profile mapping exercise of 82 US labs was carried out using Diaceutics proprietary methods and data sources to evaluate BRCA1/2 and/or HRD germline/somatic testing rates, test availability, and test panel HRR gene composition. Results: Overall, germline mutation testing rates were 3x greater than somatic testing rates. Excluding BRCA1/2, 67 labs offered comprehensive solid tumor NGS panels capable of measuring HRD with varied HRR gene target composition. Across 34 labs, 5 HRR genes were commonly found on panels: PALB2, ATM, BARD1, BRIP1 and CHEK2. 3 labs currently offering panels explicitly intended for HRD determination only include BRCA1/2 and at least one genomic instability marker (loss of heterozygosity, large-scale state transitions or telomeric allelic imbalance). Conclusions: Lack of standardized HRD panels and low testing rate identifying patients with somatic mutations in BRCA1/2 and other HRR genes is leading to poorer outcomes for missed patients eligible for PARPi’s. As clinical evidence linking HRD status with PARPi efficacy grows in ovarian as well as prostate and pancreatic cancer, Diaceutics recommends organizations such as ASCO, CAP or AMP establish defined universal HRD testing panels including relevant somatic/germline HRR genes and BRCA1/2 as well as genomic instability markers and educate stake holders aiding harmonization and ultimately, better treatment outcomes.
A post-hoc study of relative dose intensity in elderly patients with advanced ovarian cancer (JGOG3016-A3).
Authors: Itani Yoshio , Sakai Hitomi , Asai-Sato Mikiko , Sato Shinya , Futagami Masayuki , Suzuki Nao , Fujimura Masaki , Aoki Yoichi , Hamano Tetsutaro , Yoshida Yoshio ,   JGOG Supportive & Palliative Care Committee
Published: May 2020

e18053 Background: The number of elderly (aged ≥70 years) ovarian cancer patients (OCP) has doubled in the last 40 years. The clinical question is whether equivalent-strength chemotherapy could be administered to both young and fit-elderly OCP with advanced disease who are eligible in a randomized controlled trial setting. Methods: We retrospectively analyzed the cases of 605 OCP who received a dose dense T(PTX)C(CBDCA) (dTC) (n = 301) or conventional TC (cTC) (n = 304) regimen after the initial surgery in the Japanese Gynecologic Oncology Group 3016 trial. The relative dose intensity (RDI)(a treatment strength indicator), overall survival time (OS), and adverse events(NCI-CTC ver.2.0) of the elderly (≥70 years old) (E) and young ( < 70 years old) patients (Y) were compared, and prognostic factors were analyzed. Results: 1) Mean RDI of the Y and E: dTC group: CBDCA: 80.1% and 79.0%, respectively (p = 0.648); PTX: 81.5% and 79.8%, respectively (p = 0.384); cTC group: CBDCA: 89.6% and 88.1%, respectively (p = 0.429); PTX: 90.4% and 88.5%, respectively (p = 0.262). 2) Three-year survival rates of the Y and E: dTC: 75.5% (95% confidence interval (CI): 70.3–81.0) and 57.6% (95%CI: 44.5–74.6) ( p = 0.004, Log-rank), respectively; cTC: 67.7% (95%CI: 62.2–73.6) and 49.7% (95%CI: 36.5–67.5) ( p = 0.002, Log-rank), respectively. 3) Univariate analyses demonstrated that the RDI-related hazard ratio for OS was 0.95 (95%CI: 0.83–1.08; p = 0.425) and 0.94 (95%CI: 0.81–1.08; p = 0.396) in the dTC and cTC groups, respectively. 4) Age (≥70 vs. < 70 years old; p = 0.049) in the cTC group was an independent prognostic factor. The serum albumin level (p = 0.005) in the dTC group and the WBC (p < 0.001) in the cTC group within 2 weeks from the chemotherapy introduction were identified as independent prognostic factors. The ECOG-PS (≥2 vs. 1), clinical stage (III&IV vs. II), and residual tumor size (≤1 cm vs. > 1 cm) also acted as independent prognostic factors in both groups. 5)Toxicities of G3 or G4 occurred higher in the E: arthralgia (p = 0.003) in the dTC group; creatinine (p = 0.02), febrile neutropenia (p = 0.011), and infection (p = 0.028) in the cTC group. Conclusions: There was no difference in RDI by age among the subjects, but the prognosis of fit-elderly OCP was worse than that of young OCP. It is suggested that the worse prognosis of fit-elderly OCP with advanced disease is caused not by chemotherapy strength, but by the smaller physiological reserves possessed by such patients after debulking surgery. Both hematologic and non-hematologic toxicities occurred higher in fit-elderly than young OCP.
Dose-dense carboplatin and paclitaxel versus three weekly regimen in the first-line treatment of ovarian carcinoma.
Authors: Pirolli Rafaela , Estati Felipe Leonardo , Alencar Viviane , de Oliveira Mariana Romero , Ribeiro Adriana Regina Goncalves , Baiocchi Glauco , Guimaraes Andrea Paiva , Da Costa Alexandre Andre B. A. 
Published: May 2020

e18059 Background: The benefit of dose dense chemotherapy (ddCT) in the adjuvant treatment of ovarian carcinoma (OC) is not clear. There is one positive Japanese trial and two negative trials in non-Asian patients, which differed from the JGOG 3016 trial for the use of bevacizumab in one of them and the use of neoadjuvant CT (NCT) in half the patients in the other. In this study, we aimed to compare progression free survival (PFS) of ddCT to conventional regimen. Methods: We did a retrospective review of medical records from patients with OC treated in a Brazilian cancer center from 2007 to 2018. All patients treated with ddCT or conventional carboplatin and paclitaxel regimen (3wCT) in the first line setting were included. PFS and overall survival (OS) were compared. To address selection bias we performed a second analysis in a propensity score matched cohort. Patients were matched according to age, ECOG performance status, CA 125, stage, residual disease and histological subtype, in a 1:2 ratio. Results: A total of 615 cases were enrolled for analysis, 62 were treated with ddCT. Patients treated with ddCT presented better ECOG and more frequently presented advanced stage, high-grade serous carcinoma and residual disease ≤ 1cm. Only 10% of patients were treated with NCT in both groups. In the multivariate analysis ddCT showed a non-significant benefit over conventional CT (PFS HR 0.646, 95% CI 0.384–1.087, p = 0.10). In the propensity score matched cohort 186 patients were included, 62 treated with ddCT and 124 3wCT. Groups were well balanced. After a median follow-up of 48.1 months, median PFS was 32 (18-45.9) versus 22.7 (18.8-26.6) months, favoring dose dense treatment (p = 0.059). In the multivariate cox regression ddCT showed a 45% lower risk of progression (HR 0.55, 95% CI 0.35–0.88, p = 0.01). Overall survival data is immature, but suggested better outcomes for ddCT (NR versus 76.1 months; p = 0.02). Conclusions: There is no prospective study in a Western population with the same design as the JGOG 3016 trial. In our study, in a population with the same treatment schedules of the Japanese trial, ddCT was associated with longer PFS. This finding suggests that a weekly regimen of paclitaxel might still be a reasonable option for first-line treatment for women with advanced ovarian cancer, and should be further prospectively evaluated.
Impact of the timing and extent of debulking surgery on progression-free survival (PFS) and overall survival (OS) in advanced epithelial ovarian cancer (EOC): Single-center experience.
Authors: Seoud Muhieddine A-F , Husheimi Alaa , Jaafar Iman , Jamali Faek , Hamed Karam , Khalil Ali , Abdallah Reem 
Published: May 2020

e18060 Background: To evaluate the impact of timing and extent of cytoreduction on the survival of patients with EOC before (2002-2008) and after (2009-2018) the introduction of aggressive debulking. Methods: A retrospective review of 195 patients with Stages IIIC and IV EOC who underwent debulking between 2002-2018 (Group#1: G1:(2002-2008), and Group#2: G2:(2009-2018). Medical and surgical variables related to PFS and OS were analyzed. Results: Compared to patients in G1, more patients in G2 had neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) [56%(39/70 Vs. 76%(95/125) Vs), p = 0.003], had complete debulking (CD) [44%(31/71) Vs. 79%(103/131), P-value < 0.001]including [diaphragmatic resection [6%(4/72) Vs. 48%(63/131) p < 0.001], bowel ressection [15%(11/72) Vs. 37%(48/131), p = 0.001], peritnoectomy [11%(8/72) Vs. 62%(81/131) p < 0.001], and lymph node dissection [8%(6/72) Vs. 26%(34/131) p = 0.003] .More patients in G2 received Bevacizumab than in G1 [59%(38/65) Vs. 14%(4/29), p < 0.001]. More patients who had ACT and IDS had CD than optimal debulking (OD) than patients who had (PDS) (adjusted odds ratio (aOR) = 1.89, 95% CI: 0.98,3.6). After 2008, there was an increase in the number of patients with high tumor load and lower performance status who were referred for NACT and IDS. In patients with stage IIIC and IV, median PFS was longer in patients who had CD Vs. OD [in stage IIIC: 24 months, 95% CI: 21,27 Vs. 19 months, 95% CI: 17, 21, HR = 0.4, p = 0.006 respectively] [in stage IV: 18 months, 95% CI: 16,20 Vs. 14 months, 95% CI: 9,18, HR = 0.4, p = 0.1 respectively].Patients with stage IIIC who had PDS Vs. NACT and IDS had a non-statistically significant longer PFS [24 months, 95% CI; 20,27 Vs. 19 months, 95% CI: 17,21, HR = 0.8, p = 0.3]. Moreover, in stage IV, there was no difference in PFS in NACT and IDS Vs. PDS [16 months, 95% CI: 12,20 Vs. 17 months, 95% CI: 15,19 HR = 0.8, p = 0.7 respectively]. However, the timing and extent of the cytoreductive surgery did not significantly affect OS in both stages IIIC and IV. Conclusions: In Stage IIIC EOC, the extent but not timing of debulking surgery has the greatest impact on PFS. Longer follow-up is needed to assess the impact on OS.
Boosting the apoptotic response of high-grade serous ovarian cancers with CCNE1-amplification to paclitaxel by targeting APC/C and the pro-survival protein MCL-1.
Authors: Becker Sven , Strebhardt Klaus , Mandal Ranadip , Sanhaji Mourad 
Published: May 2020

e18065 Background: Ovarian cancer exhibits the highest mortality rate among gynecological malignancies. Antimitotic agents, such as paclitaxel, are frontline drugs for the treatment of ovarian cancer. They inhibit microtubule dynamics and their efficiency relies on a prolonged mitotic arrest and the strong activation of the spindle assembly checkpoint (SAC). Although ovarian cancers respond well to paclitaxel, the clinical efficacy is limited due to an early onset of drug resistance, which may rely on a compromised mitosis exit associated with weakend intrinsic apoptosis. Accordingly, we aimed at overcoming SAC silencing that occurs rapidly during paclitaxel-induced mitotic arrest. Methods: To do this, we used a specific anaphase-promoting complex/ cyclosome (APC/C) inhibitor to prevent a premature mitotic exit upon paclitaxel treatment. Furthermore, we investigated the role of the anti-apoptotic BCL-2 family member MCL-1 in determining the fate of ovarian cancer cells with CCNE1-amplification that are challenged with clinically relevant dose of paclitaxel. Results: Using time-laps microscopy we demonstrated that APC/C and MCL-1 inhibition under paclitaxel prevents mitotic slippage in ovarian cancer cells and restores death in mitosis (DIM). Consistent with this, the combinatorial treatment reduced the survival of ovarian cancer cells in 2D and 3D cell models. Since a therapeutic ceiling has been reached with taxanes, it is of utmost importance to develop alternative strategies to improve the patient´s survival. Conclusions: Our study provides not only elements to understand the causes of taxane resistance in CCNE1-amplified ovarian cancers but also suggests a new combinatorial strategy that may improve paclitaxel efficacy in this highly lethal gynecological disease.