bluuebunny/crossref_metadata_2025 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.
Tissue factor pathway inhibitor II as a specific biomarker for pre-operative prediction of clear-cell carcinoma of the ovary.
Authors: Miyagi Etsuko , Arakawa Noriaki , Ruiz Yokota Naho , Yamanaka Takeharu , Sakamaki Kentaro , Miyagi Yohei , Yamaguchi Satoshi , Nagao Shoji , Yamada Yuki , Hirashima Yasuyuki , Kasamatsu Yuka , Kato Hisamori , Kitagawa Masakazu , Kobayashi Hiroshi
Published: May 2020

e18077

Background: Tissue factor pathway inhibitor 2 (TFPI2) is a novel serum biomarker that discriminates ovarian clear cell carcinomas (CCC) from borderline ovarian tumors (BD) and non-CCC epithelial ovarian cancers (EOC). We examined the prediction performances of TFPI2, including high specificity, for preoperative diagnosis of CCC in multi-center settings. Methods: We collected serum samples obtained preoperatively from patients with ovarian masses who needed surgical treatment to confirm pathological diagnoses in five hospitals in Japan. The diagnostic powers of serum levels of TFPI2 (cutoff value 270 pg/mL) and CA125 (cutoff value 35 U/mL) to discriminate CCC from BD, non-CCC-EOC, and benign lesions were compared. Results: A total of 351 patients (77 ovarian benign lesions, 65 BD and 209 EOC including 69 CCC) were analyzed. Serum TFPI2 levels were significantly higher in CCC patients (mean±SD, 508.2±812.0 pg/mL) than in patients with benign lesions (154.7±46.5), BD (181±95.5) and non-CCC EOC (265.4±289.1). TFPI2 had a high diagnostic specificity to CCC (sensitivity and specificity: 43.5% and 79.5%, respectively). The sensitivity of TFPI2 was improved to 71.1% when combined with CA125, and it was increased in Stage II–IV CCC (66.7%) compared with Stage I CCC (33.3%). In patients with benign endometriotic cysts (BEM), no patient was positive for TFPI2 but 71.4% (15/21) were CA125 positive. TFPI2 showed good performance in discriminating Stage II–IV CCC from BD and non-CCC EOC patients (AUC 0.815 for TFPI2 versus 0.505 for CA125) or from BEM (AUC 0.957 for TFPI2 versus 0.748 for CA125). Conclusions: High specificity of TFPI2 for the preoperative detection of CCC was re-verified with the defined cutoff level of TFPI2 in practice. TFPI2 and CA125 may have a substantial contribution to the precise prediction of intractable CCC. [Table: see text]
Immunomodulator in combination treatment of patients with ovarian cancer and its influence on DNA cytometric and immunological parameters.
Authors: Ardzha Anna Yu. , Verenikina Ekaterina V. , Zlatnik Elena Yu. , Nikitina Vera P. , Zhenilo Oksana E. , Nikitin Ivan S. , Kit Oleg I. , Dzhenkova Elena A.
Published: May 2020

e18079

Background: Immunotherapy in oncology has now proven effective, but standard approaches have not yet been defined. Ways to optimize and increase the effectiveness of treatment with immunomodulators, in particular interferon-gamma preparations, in such patients remain an urgent problem of gynecological oncology. The purpose of the study was to improve direct results of ovarian cancer treatment. Methods: The study included patients aged 50-77 years with inoperable ascitic ovarian cancer (verified by cytological examination of ascitic fluid), stage IIIC-IV, receiving neoadjuvant chemotherapy (CT) in combination with immunotherapy with interferon-gamma (IFNγ). Group I – 26 patients, CT with carboplatin (AUC-6), paclitaxel (175 mg/m2); group II – 22 patients, chemoimmunotherapy and intramuscular IFNγ (ingaron) - 500 000 IU on day 1, 1 million IU on days 2,3,5, a similar CT on day 4; group III – 24 patients, chemoimmunotherapy and intraperitoneal IFNγ (ingaron) - 500 000 IU on day 1, 1 million IU on days 2,3,5, a similar CT on day 4. Patients received on average 2-3 therapy cycles. Results: Progression was registered only in group I in 3.8%; complete response in patients without IFNγ – 7.8%, with intramuscular and intraperitoneal IFNγ – 27.3% and 37.5% (p≤0.05) respectively. Surgical treatment followed in all patients, with total surgeries in 87.5% of patients with intraperitoneal IFNγ. DNA cytometry showed the minimal number of aneuploid tumors in patients with intraperitoneal IFNγ (16.6%), while in patients without immunotherapy 38.4%. The DNA index statistically significantly decreased by 1.3 times in patients with intraperitoneal IFNγ compared with patients without IFNγ (1.11±0.01% vs. 1.4±0.05% respectively) (p≤0.05). Levels of CD3+CD4+ cells elevated by 1.2 times (from 36.2±1.6 to 44.9±3.78%, p≤0.05) in patients with intramuscular IFNγ; intraperitoneal IFNγ caused an increase in CD3+ lymphocytes by 1.3 times (from 62.1±2.8 to 77.9±2.94%, p < 0.05) and CD3+CD4+ by 1.4 times (from 36.2±1.6 to 50.6±5.9%, p≤0.05). Conclusions: Interferon-gamma (ingaron) in combination with CT improves direct results of the treatment; intraperitoneal injections of interferon-gamma demonstrated better outcomes and tolerance confirmed by immunological and DNA cytometric parameters.
Markers of a metastatic niche in the omentum in ovarian cancer.
Authors: Moiseenko Tatiana I. , Frantsiyants Elena M. , Kaplieva Irina V. , Bandovkina Valeria A. , Cheryarina Natalia D. , Menshenina Anna P. , Adamyan Meri L. , Verenikina Ekaterina V. , Yakubova Darya , Boyko Konstantin P. , Ilchenko Maria G. , Gurnak Viktor V. , Agarkova Elena I. , Chalabova Tatiana G. , Kit Oleg I.
Published: May 2020

e18081

Background: Ovarian cancer spreads intraperitoneally due to the interaction of tumor cells and the omental mesothelium, creating a metastatic niche and supporting elements of cancer cell expansion such as adhesion, proliferation, migration, and neoangiogenesis. The purpose of the study was to analyze levels of VEGFA, IGF-I, IGF-II and TGFβ1 in omental tissues in ovarian cancer (OC). Methods: The main group included 23 patients with metastatic OC T3-4аN0-3M1; the comparison group – 21 patients with non-metastatic OC T3-4аN0-3M0; the control group – 19 non-cancer patients. Levels of VEGFA, IGF-I, IGF-II and TGFβ1 were measured by standard ELISA methods in tissues of primary tumors and the omentum. Results: Levels of growth factors in the comparison group were not elevated compared to control values. Growth factors in omental tissues in the main group were increased compared to control values: VEGFA – by 2.5 times, IGF-I – by 3.4 times, IGF-II – by 2.5 times, TGFβ1 - by 3.1 times. In the comparison group, the levels in omental tissues were lower than in the main group: VEGFA – by 1.7 times (p < 0.05), IGF-I – by 2.1 times, IGF-II – by 1.6 times (p < 0.05); TGFβ1 did not differ from the levels in the main group. Conclusions: Higher expression of VEGFА in the omentum with metastases can be considered a significant factor in the formation of signaling pathways between metastatic tumor cells and local non-cancer cells. IGF-I and IGF-II trigger the endothelial growth factor. The TGFβ1 activation in the omentum in metastatic ovarian cancer is necessary for the paracrine induction and transition of disseminated tumor and/or stem cells from the "sleeping" to the active state.
The regulation of RNA Polymerase II mediated transcription by Caspase-8 in ovarian cancer.
Authors: Becker Sven , Mandal Ranadip , Raab Monika , Sanhaji Mourad , Strebhardt Klaus
Published: May 2020

e18082

Background: According to the WHO, in 2018, the number of new cases and mortality worldwide due to ovarian cancer, were 295,414 and 184,799, respectively, making it one of the most lethal gynaecological cancers in the world. The standard therapy of ovarian cancers is still comprehensive cytoreductive surgery followed by a combination of platinum-taxane based primary chemotherapy. Second line therapies include Carboplatin or Cisplatin in combination with Paclitaxel, PLD or Gemcitabine, with or without Bevacizumab. Unfortunately, late stage ovarian cancer cases are still incurable, however, several new drugs are under development or are undergoing clinical trials. At present, these new approaches can only stabilize the disease or delay its recurrence. Caspase-8, the predominant initiator of the extrinsic apoptotic pathway, also plays critical roles in a number of other non-apoptotic functions. It is also frequently down-regulated in ovarian cancer and we wanted to understand how this down-regulation could support the development of ovarian cancer. Methods: The analysis of the association between CASP8 expression and patient prognosis in ovarian cancer patients found that low CASP8 expression was significantly correlated with poor OS, with a median OS of 37.43 (low expression) and 49.97 (high expression) months, and higher clinical stages. CRISPR/Cas9 mediated CASP8 KO in multiple high- and low-grade ovarian cancer cell lines resulted in significant increases in their invasiveness. Results: Caspase-8 interactome analysis revealed that it can regulate the RNA Pol II mediated transcription, which was corroborated through multiple in vitro and ex vivo experiments. Global Transcriptomics and Proteomics analysis of the KO cells revealed significant upregulation of genes involved in metastasis, which was again verified in in vitro and ex vivo experiments. Additionally, the KO cells were significantly resistant towards standard chemotherapeutics like Carboplatin, a transcription inhibitor, either alone or in combination with Paclitaxel. Conclusions: Presently, we are working on orthotopic ovarian cancer mouse models to validate - the potential of Caspase-8 to regulate metastasis; and the targeting of RNA Pol II to sensitize them to standard chemotherapeutics. We are also developing organoid banks from patient derived ovarian cancer tissues, with low Caspase-8 expression, to validate the upregulation of genes identified in our ‘omics’ data and the potential of targeting them, along with RNA Pol II, to sensitize them to standard chemotherapeutics.
Adult ovarian granulosa cell tumor: Role of systemic chemotherapy and surgical treatment.
Authors: Beliaeva Anna , Bakhidze Elena
Published: May 2020

e18083

Background: Granulosa cell tumor (GCT) are rare sex cord-stromal tumours. Their frequency is approximately 3% - 5% of all malignant ovarian tumors, and the incidence is from 0.6 to 2.1 cases per 100 000 women per year. According to the histological features, GCT are divided into two types: adult and juvenile. In the 2014 WHO histological classification, GCT were divided into borderline, which included the GCT of the juvenile type, and the malignant GCT of the adult type (AGCT). Despite the definition of AGCT not as borderline, but as low-grade malignant tumors, there are no specific recommendations for the surgical and drug treatment in such patients. Main method of treatment is surgical. Role of systemic treatment due to rarity of AGCT and late recurrence still has not determined. Methods: Data of 93 patients in our institution who were diagnosed with AGCT I-IV stage of the disease between 1980 and 2017 were evaluated. The data were obtained from the files of the patients, electronic database of the gynecologic oncology clinic, operation notes, and pathology records. Results: Stage of the disease, the spread of the tumor beyond the capsule and the number of mitoses of more than 10 significantly influenced the OS rates (p < 0.05). The average time before the onset of the first relapse in IA, IB stage was 134.5 months, in IC stage - 67.4 months, in II-IV stage - 34.3 months. Stage of the disease is an independent prognostic factor for the occurrence of a relapse of the disease. In stage I disease there was no influence of the volume of surgical treatment and adjuvant chemotherapy on DFS and the duration of disease-free period (p > 0.05). The duration of the non-progressive period was some, but not significantly more when performing optimal cytoreduction for the recurrence of the disease, and did not depend on the implementation regimen and adjuvant chemotherapy. Conclusions: There were not found significant difference in the overall and relapse-free survival of patients with ovarian AGCT, depending on the options of surgical and drug treatment they underwent. Studies showed that hormones play a critical role in the pathogenesis and treatment of GCT, especially in some ineffective cases for radiotherapy and chemotherapy. Additional multicenter randomized trials are needed to clarify the effectiveness of the various options for surgical and drug treatment of adult GCT patients.
Germline and somatic mutations in 25 hereditary breast and ovarian cancer related genes and platinum-based chemotherapy response among Chinese patients with epithelial ovarian cancer.
Authors: Li Lei , Wu Ming , Zhu Changbin , Shao Di , Liu Meng ,   Xiehe
Published: May 2020

e18088

Background: Insight on the germline and somatic mutation in BRCA1/2 was predictable on the sensitivity on platinum-based therapy. The therapeutic impact of mutations in other hereditary breast and ovarian cancer related genes is uncertain. Methods: We sought to investigate the germline and somatic deleterious mutations through all exons in 25 hereditary breast and ovarian cancer related genes in paired blood and frozen tumor samples from 235 Chinese women diagnosed with epithelial ovarian carcinomas. Results: Forty-seven subjects (24.6%) had a germline deleterious mutation, and 126 subjects (66%) had a somatic deleterious mutation. Thirty-four (17.8%) had both a germline and somatic mutation. Of the 203 germline and somatic deleterious mutations, 114 (56.2%) occurred in TP53, 41 (20.2%) in BRCA1, 11 (5.4%) in BRCA2 and 37 (23.6%) in 13 other genes: ATM, BARD1, BRIP1, CDH1, CHEK2, MLH1, MRE11A, MSH2, NF1, PALB2, PTEN, RAD51C and, STK11. In 235 patients, 215 (91.5%) and 20 (8.5%) cases were sensitive and resistant to the platinum-based chemotherapy. In the whole population, homologous recombination repair (HRR) mutations, non- homologous recombination repair(non-HRR) mutations, mismatch repair (MMR) mutations had no impact on the platinum-based chemotherapy response. No significant difference in platinum response were found in HRR, non-HRR and MRR mutation(P = 0.788). In 235 patients, ones with ATM (10), CHEK2(9), NF1(5), PALB2(8), PTEN (8) mutations were available for platinum response information; Among them, there were three patients with either ATM, CHEK2 or PALB2 mutation presented platinum resistance. Conclusions: Multi-gene panel testing of germline and somatic HBOC related gene mutations was feasible to characterize a comprehensive molecular profile of ovarian cancer and showed non-BRCA gene stratification potential value in predicting patient’s response for platinum-based chemotherapy.
Paraneoplastic ataxic syndrome with anti-Yo antibodies in breast and ovarian cancer: A retrospective analysis.
Authors: Puri Akshjot , Khan Usman , Niravath Polly Ann
Published: May 2020

e18089

Background: Paraneoplastic cerebellar syndrome is a rare immunological reaction caused most commonly by Anti-Yo or Purkinje cell cytoplasmic antibody type 1(PCA1) to cerebellar degeneration protein 2(CDR2), found in the cerebellum and ectopically produced by tumor. Most cases are reported in women with HER2+ breast and ovarian cancers with underlying breast cancer patients having relatively better prognosis. Treatment initiation within one month of symptom onset has shown better outcomes. Methods: A retrospective analysis was conducted using a clinical database at a single institution and included 3 patients with a cancer diagnosis and ataxic symptoms diagnosed between 2016 and 2020. Data collection included age, gender, performance status, site of disease, pathology, diagnostic work up, treatment and overall survival (OS). Results: The study included 3 patients who presented with new onset ataxic symptoms with the median time of cancer diagnosis from onset of symptoms being 5 months (range 4-7). Median age was 62 years (range 59-83), all 3 patients were females and functionally independent before symptom onset. Out of 3 patients 2 had HER2+ breast cancer (one with IHC 3+ and one with equivocal IHC but 20 HER2 signals/nucleus) and the third had ovarian carcinoma. All 3 patients had stage IIIA disease as per AJCC 8th edition and presented with bilateral extremity weakness, ataxia, visual disturbances, vertigo and nausea/vomiting. Extensive neurological work up including MRI brain, CSF analysis, EEG were inconclusive except for high titres of anti- Yo antibodies in all patients. All patients were treated with cancer directed therapy and immunomodulation with plasma exchange, IVIG and steroids. The median OS being 22 months (range 12-28) with 2 patients with underlying breast cancer alive at the time of the analysis albeit there has been no neurological recovery, despite IVIG, steroids, and plasma exchange. Conclusions: The anti-Yo associated paraneoplastic ataxic syndrome most commonly associated with breast and pelvic tumors in women has a very poor prognosis despite anti-tumor and immunomodulating therapies, leaving most patients bed-ridden. The neurologic damage is irreparably incurred once the antibodies attack cerebellar cells. Thus, it is critical for clinicians to recognize the potential signs and symptoms as early as possible, so that treatment can be started, and long term symptoms are minimized. Further studies are needed to know the exact mechanism of this syndrome and provide evidence based treatment options.
National patterns and factors predicting employment disruption in women diagnosed with endometrial cancer.
Authors: Nitecki Roni , Fu Shuangshuang , Smith Benjamin D. , Meyer Larissa , Melamed Alexander , Rauh-Hain Jose Alejandro
Published: May 2020

e18093

Background: Cancer patients are less likely to return to work after diagnosis. As endometrial cancer is highly curable, it is important to assess whether patients are able to resume work after treatment. We evaluated rates of return to work following endometrial cancer diagnosis and assessed factors associated with a disruption in employment. Methods: A cohort of patients aged 18-63 years who were diagnosed (2010-2015) with endometrial cancer and underwent surgical staging were identified in Truven Marketscan, an insurance claims database of commercially insured patients in the United States. All patients who were working full or part-time when diagnosed were included, and all employment changes during the year following diagnosis were identified. Treatment information, including use of chemotherapy and radiation, and complications of treatment were identified and collected using Common Procedural Terminology codes, and International Statistical Classification of Diseases codes. Univariable analysis and multivariable logistic regression were used to evaluate the impact of treatment and demographic variables on change in employment status. Results: A total of 3547 women with endometrial cancer who held a full-time or part-time job 3 months prior to diagnosis were identified. The median age at diagnosis was 55 years, and the majority of patients (82%) had a Charlson comorbidity index of 0. While most women continued to work following diagnosis, 21% (736) experienced a disruption in employment. The majority (96.7%) held a full-time job prior to going on long-term disability, retirement, or stopping to work. In univariable analysis, chemotherapy recipients were 40% more likely to experience a disruption in employment (Odds ratio (OR) = 1.5, 95% confidence Interval (CI) 1.15-2.11), whereas radiation therapy did not influence employment (OR 1.3, 95% CI 0.99-1.61). In multivariable analysis including age, region of residence, Charlson comorbidity, radiation, chemotherapy, insurance plan and presence of surgical complications, receipt of chemotherapy remained a significant predictor of employment disruption (OR 1.46, p = 0.0257). Conclusions: Twenty-one percent of employed, insured women experienced a change in employment following diagnosis of endometrial cancer, an often-curable disease. Chemotherapy was a significant predictor of employment disruption. This is important to consider in development of interventions to maximize functional recovery following treatment for endometrial cancer.
Diagnosis and treatment of uterine carcinosarcoma.
Authors: Beliaeva Anna , Bakhidze Elena
Published: May 2020

e18111

Background: Uterine carcinosarcoma (UCS) is rare and highly aggressive malignant tumor belonging to mixed epithelial and mesenchymal tumors and classified as high-grade endometrial carcinoma. UCS is more prone to metastasis, especially in the lymph nodes, and 35% of the diagnostics show advanced process and worse treatment results. High UCS aggressiveness, unsatisfactory treatment results and the lack of standard approaches to its treatment require more researches. Methods: Clinical and morphological data of 72 patients from N.N. Petrov National Medical Research Center of Oncology treated from 2004 to 2014 were analysed. 28 patients were included with the UCS I – III stages based on clinical and morphological data. The average age of the patients was 61.5 years (43 to 82). Results: 15 patients had stage I (53.6%), 3 - stage II (10.7%), 10 – stage III (35.7%) with ovarian metastases 14.3% and omental - 18.2%. 5 patients received only surgical treatment; 21 received combined treatment, including surgery and radiation therapy (RT). Postoperative remote RT in combination with brachytherapy was applied in 18 patients, only brachytherapy - 5. Chemotherapy (CT) was used in 6 patients. Metastatic lesion of the iliac lymph was morphologically proven in 6 of 18 patients (31.6%). No correlation between frequency of regional metastasis and depth of tumor invasion to the myometrium was found. Overall survival was 52%, relapse-free - 32%, for stage I – II it reached 72.2%. Five-year survival for stage III was 44.4%. Recurrence rate after total hysterectomy with pelvic lymphadenectomy was 2 times lower compared to that without lymphadenectomy (30 and 62.5%, respectively). The relapse rate in patients with UCS I – II stages after surgical treatment without adjuvant RT reached 33.3%, with brachytherapy - 40%, with remote RT in combination with brachytherapy - 20%. Systemic treatment was applied to 6 patients, 2 of them did not undergo RT (relapses in these 2 patients were noted during the first year of observation). Conclusions: The overall 5-year survival and relapse-free survival of patients with UCS I – III stages is quite low: about 50% and 30%, respectively. Optimal surgical staging (which involves performing pelvic lymphadenectomy) and the use of adjuvant RT, can reduce the frequency of relapses. The use of systemic CT as an adjunct to surgical and radiation treatment is justified for patients with UCS from the standpoint of the same frequency of both local relapses and distant metastases.