bluuebunny/crossref_metadata_2025_split huggingface dataset:
New biomarkers to predict platinum resistance in ovarian cancer patients.
Authors: Trifanescu Oana , Gales Laurentia Minea , Gruia Maria Iuliana , Gusoiu Bianca Andreea , Torliceanu Florina , Rodica Maricela Anghel 
Published: May 2019

e17085 Background: Epithelial ovarian cancer is the second most common gynecologic malignancy and is characterized by the highest mortality of all gynecological cancers. Despite of initial response, platinum resistance develops and contributes to the poor outcome of advanced stage ovarian cancer patients. The aim of the study was to identify biomarkers helpful in predicting treatment response to platinum salts. Methods: Forty eight patients with advanced ovarian (stage II, III and IV) cancer were prospectively enrolled between 2014 and 2017. All patients underwent surgery followed by platinum-based chemotherapy. Serum reactive oxygen species parameters such as malondialdehyde, ceruloplasmine, and serum VEGF were measured before each cycle of chemotherapy. Results: Mean age at diagnostic was 51.3 +/- 8.1 years, (range 42 - 78). Median follow up was 39 months (range 12-56). Twenty tree percent were platinum resistance. Median progression free survival was 22 months and estimated median overall survival was 84 months, 77% of patients being alive at 3 years. VEGF levels were significantly higher in patients with platinum resistance disease (1210 pg/ml) compare to platinum sensitive (mean VEGF levels 945pg/ml, p = 0.0003). We used a ROC curve to estimate the sensitivity and specificity of VEGF as a predictor to platinum response and find out that the aria under the curve (AUC) was 0.874, p = 0.003, 95% CI 0.734-1 and cut-off value (80% sensibility, 80% specificity) was 1085pg/ml. Malondialdehyde levels were statistically significant higher in patients with platinum resistance disease (mean value 11.1 μmol/100 ml vs. 7.4 μmol/100 ml in platinum sensitive, p = 0.02. The ROC curve for malondialdehyde identify an aria under the curve of 0.818, p = 0.0001 and CI 95% (0.744-0.893) and a cut-off value of 7.74 μmol/100 ml to estimate with 81.3% sensitivity and 64% specificity platinum response validating this bio markers as predicting platinum response. For Ceruloplasmine AUC was 0.706, p = 0.0001, 95% CI (0.617,-0.796). Conclusions: Malondialdehyde, ceruloplasmine and VEGF can estimate with precision the resistance to platinum salts in advanced ovarian cancer patients.
Dynamic of molecular subtypes of high‐grade serous ovarian cancer in paired primary and relapsed biopsies.
Authors: Braicu Elena Ioana , Kulbe Hagen , Dreher Felix , Taube Eliane T , Ringel Frauke , Welsch Gabriele , Darb-Esfahani Silvia , Keunecke Carlotta , Kessler Thomas , Wierling Christoph , Jank Paul , Denkert Carsten , Lammert Hedwig , Hummel Michael , Sehouli Jalid 
Published: May 2019

e17091 Background: Previously four molecular subtypes of high grade serous ovarian cancer (HGSOC) with distinct biological features and clinical outcome have been described: C1 (mesenchymal), C2 (immunoreactive), C4 (differentiated), and C5 (proliferative). Using Nanostring technique and a minimal signature of 39 classifier genes could reproduce the subtypes identified by microarray gene expression profiling (Leong HS et al. Australian Ovarian Cancer Study. J Pathol. 2015). Methods: We characterized paraffin embedded tissue samples from 279 HGSOC patients for molecular subtypes, utilizing the 39 classifier signature and 9 control genes by Nanostring nCounter Analysis System. From 16 patients paired primary and relapsed samples were available. Only chemonaive primary HGSOC patients were included in the study. FFPEs and clinical data were provided by TOC ( www.toc-network.de ). For each sample, probability scores for the four molecular subtypes (C1, C2, C4, and C5) were calculated. The highest calculated score determined the most likely subtype of the tumor. Results: Of all analyzed primary tumor samples, 88 (31.5%) were classified as C1, 83 (29.8%), 53 (19.0%) and 55 (19.7%) as subtypes C2, C4 and C5, respectively. Our results confirmed data by the AOCS study, which described the distribution of HGSOC with 40.2% (C1), 22.5% (C2), 20.1% (C4) and 17.2% (C5), respectively. Within the paired samples, for 12 of the 16 patients dynamic changes in the molecular subtypes between primary and relapse occurred, while in the remaining 4 patients the phenotype was stable. Conclusions: Molecular subtypes of HGSOC using Nanostring technology with a small panel of classifier genes can be confirmed. Furthermore, the data showed that a change of the established molecular subtype might occur during the evolution of the disease, and therefore translate in a different clinical outcome.
Oncologic outcomes and morbidity following heated intraperitoneal chemotherapy at cytoreductive surgery for primary epithelial ovarian cancer: A systematic review and meta-analysis.
Authors: Bouchard-Fortier Genevieve , Cusimano Maria Christine , Fazelzad Rouhi , Lu Lin , May Taymaa , Bouchard-Fortier Antoine , Ferguson Sarah 
Published: May 2019

e17093 Background: Heated intraperitoneal chemotherapy (HIPEC) following cytoreductive surgery in the treatment of primary epithelial ovarian cancer (EOC) after neoadjuvant chemotherapy was associated with a significant 12 months improved overall survival (OS) in a well-designed randomized controlled trial. Nonetheless, there remains uncertainty about the benefit and safety of HIPEC in ovarian cancer. The aim of this review was to assess efficacy and safety of HIPEC in primary EOC. Methods: We conducted a systematic search in Medline, Embase, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews, from inception to February 22nd 2018 for observational and randomized studies of patients with primary EOC undergoing HIPEC at cytoreductive surgery with no language restrictions . We assessed risk of bias with the Institute of Health Economics Quality Appraisal Checklist for single-arm studies, and Newcastle-Ottawa Quality Scale for double-arm studies. We determined the pooled proportion of 30-day grade 3-4 morbidity, reoperation, and postoperative death. Results: Thirty-five articles including 1937 patients with primary EOC met inclusion criteria. Timing of HIPEC and type of chemotherapy regimens were not consistent between studies. There was significant variation in the reported OS of patients treated with HIPEC at cytoreductive surgery for primary EOC (3-year OS:48-77%; 5-year OS:17-72%). Thirteen articles were including in a meta-analysis to determine to the safety of HIPEC. The pooled proportions for 30-day Grade 3-4 morbidity, 30-day reoperation, and 30-day postoperative death were 33.0% (95% CI 23.0-45.0), 9.0% (95% CI 5.0-17.0) and 3.0% (95% CI 1.0-5.0) respectively. Conclusions: The use of HIPEC in primary EOC is associated with significant morbidity. There is significant heterogeneity in current literature. Higher quality, large prospective randomized control trials are needed to further support the benefit of HIPEC at cytoreductive surgery in the first-line treatment of primary EOC.
Exploring racial disparities of actionable mutations in gynecologic cancers.
Authors: Jhaveri Vasanti , Fanfan Dino , Cotta Jared Addison , George Sophia , Slomovitz Brian M. , Huang Marilyn 
Published: May 2019

e17098 Background: Next Generation Sequencing (NGS) guides targeted therapy and clinical trial enrollment for patients with gynecologic malignancies. South Florida is a key region to explore biomarkers and molecular alterations common in Hispanic (H) patients due to the high proportion of H individuals. While NGS testing is increasingly used in clinical practice to aid in treatment planning, ethnic minorities are at risk for health disparity including clinical trial enrollment. The objective of this study was to determine if frequently reported mutations are also common in a predominantly H population with gynecologic cancers. Methods: Clinicopathologic data was obtained from women treated at our institution from Jan. 2014 to Jan 2019 for gynecologic malignancies. Women with ovarian (OC), endometrial (EC), and cervical cancer (CC) with NGS results from Caris Life Sciences were included for analysis. Women self-report ethnicity based on initial hospital intake form. Mutations based on point mutations, indels, fusions and copy number variations were identified. Descriptive statistics are reported. IRB approval was obtained. Results: A total of 233 patients with 117 ovarian (OC), 24 cervical (CC) and 92 endometrial cancers (EC) were included. Among the 233 women, 96 (41%) were H, 137 (59%) identified as NH. There were 38 H and 48 NH patients with EC; 50 H and 62 NH OC patients; and 8 H and 13 NH CC patients. Among EC patients, TP53 appeared in 42% vs. 47%, PTEN 26% vs. 30% , PIK3CA 32% vs. 17%, CTNNB1 32% vs. 17% , and KRAS 16% vs. 21% of H and NH cases respectively. In the OC cohort, TP53 appeared in 74% vs. 75% , BRCA1/2 10% vs. 19%, KRAS 16% vs. 16% and PIK3CA 8% vs. 6% of H and NH cases respectively. In CC patients, TP53 appeared in 25% vs. 23%, KMT2C 12.5% vs. 7.6% and PIK3CA 0 vs. 38% of H and NH cases respectively. There were no statistical differences in the mutation rates between the two groups. Conclusions: There is limited data reported on the variation of mutations based on ethnicity in women with gynecologic cancers. Our study suggests there may be different driver mutations based on ethnicity. Future studies in larger cohorts are needed to further assess genomic differences, potential responses to treatment and further increase H population enrollment into clinical trials.
Predictive factors of cytoreductive surgery in epithelial ovarian cancer in a Mexican women cohort.
Authors: Vasquez Flavia Morales , Gonzalez Ricardo Raziel Peña , López Basave Horacio Noé 
Published: May 2019

e17099 Background: Cytoreductive surgery is the most important prognostic factor in ovarian cancer. To identify in a timely manner the patients who are not candidates for optimal debulking, does not delay and optimize the treatment. Objetive: Identify the presurgical factors that characterize patients in whom optimal cytoreduction is not possible. Methods: Observational study in a retrospective cohort (n = 255) that compared pre-surgical factors between patients with optimal debulking (n = 65) and suboptimal (n = 190). Non-parametric tests were used, a Cox proportional hazards model was constructed and survival curves were drawn by method of Kaplan y Meier. Results: 255 patients were included. 75% achieved optimal debulking. 9 out of 10 evaluated tomography criteria showed association (p < 0.001) with suboptimal cytoreduction. The best cut-off value of Ca-125 to predict suboptimal surgery was 774 IU / mL. Only clinical ascites showed association with the result of the surgery (p < 0.001). There was no difference in complications between both groups (p = 0.267). The rate of optimal debulking has improved over time (p = 0.049). The turn of the surgeries has no impact on the overall survival of the patients (p = 0.792). Conclusions: Objective parameters (tomography and laboratory) should be used to select patients who are not candidates for surgery. The Clinical evaluation without objective parameters is not enough
Half-dose olaparib reduction: Safe and efficient dose in multi-treated Mexican ovarian cancer patients.
Authors: Gallardo-Rincon Dolores , Alamilla Gabriela , Montes-Servín Edgar , Michel-Tello David , Montes-Servín Elizabeth , Toledo-Leyva Alfredo , Bahena-Gonzalez Antonio , Gonzalez-Ibarra Ernesto , Morales-Vasquez Flavia , Cano Blanco Claudia , Espinosa-Romero Raquel 
Published: May 2019

e17101 Background: Ovarian cancer (OC) is the most common gynecological cancer worldwide, and in Mexico stands as the 2nd gynecological cancer-related death cause with 4,759 new cases yearly. PARP inhibitors in BRCA1/2 mutated patients offer disease control after response to chemotherapy with few side effects and minimal impact on quality of life. The primary objective of this study was to evaluate the clinical benefit of Olaparib half-dose reduction in multi-treated Mexican OC patients. Methods: Nineteen OC BRCA1/2 positive patients were enrolled (Nov 2016-Dec 2018), at the Instituto Nacional de Cancerología, Mexico. Eligible patients had received > 2 previous platinum-based lines. Olaparib dose was 800 mg/day, as maintenance therapy after complete or partial response. Half-dose administration was allowed in grade 3 toxicity events. Median PFS curves were estimated by the Kaplan–Meier method. Results: The most common mutation in OC patients was BRCA1 (78.9%), four patients had founder mutation (Del9-12). Eleven patients (57.9%) received Olaparib in ≥4 lines. Nine patients required dose adjustment following hematological (42.1%) and gastrointestinal toxicity (5.2%). There was not statistical differences between complete-dose and half-dose administration groups. However patients with founder BRCA1 mutation did not require dose adjustment ( P= 0.033) and multi-treated (≥4 lines) patients were more susceptible to develop hematological toxicity ( P= 0.030). The median PFS was 12.02 months, patients HGSP histology had a better PFS compared with endometroid histology (14.8 Vs 5.19; P= 0.020). BRCA1 founder mutated patients had a better PFS compared with other BRCA mutations (NR Vs 11.30; P= 0.050). The median PFS in first, second and third or more recurrence was NR Vs 14.8 Vs 8.3; P= 0.050. We did not find statistical difference in the PFS in half-dose reduction compared with complete-dose groups (9.6 Vs NR; P= 0.221). Conclusions: We provide evidence that using Olaparib in first and second recurrence had better outcome compared with third or more recurrence. However the recommended dose exhibits a high toxicity profile; therefore half-dose reduction in multi-treated patients needs to be suggested in Olaparib OC guidelines as a safety and effective strategy.
Effect of postoperative adjuvant treatment in the therapeutic management of stage I, morcellated uterine leiomyosarcoma: A Korean multicenter study.
Authors: Kim Se Ik , Choi Chel Hun , Kim Kidong , Hong Deok Ho , Park Jeong-Yeol , Kwon Byung Su , Lee Keun Ho , Hong Dae Gy , Shin So-Jin , Park Sang-Il , Kim Yun Hwan , Lee Seung-Ho , Lee Sanghoon , Hong Jin Hwa , Lee Jung-Yun , Kim Yong Beom , No Jae Hong , Suh Dong-Hoon 
Published: May 2019

e17106 Background: To evaluate the effectiveness of postoperative adjuvant treatment for morcellated, uterus-limited leiomyosarcoma in a multicenter setting. Methods: We included primary FIGO stage I uterine leiomyosarcoma patients treated between 2003 and 2016. All received one of the following morcellation methods: (1) intracorporeal morcellation using motorized device; (2) intracorporeal morcellation using surgical knife or electrocautery; and (3) vaginal morcellation. Patients’ survival outcomes were compared according to the implementation of postoperative adjuvant treatment. Results: In total, 55 patients were enrolled from 13 institutions, and 24 and 31 patients were assigned to surgery alone group and adjuvant treatment group, respectively. Characteristics including age, mass size, morcellation methods, and extent of surgery were similar between the two groups. On pathologic examination, there were no differences in degree of nuclear pleomorphism, necrosis, and lymphovascular space invasion. In adjuvant treatment group, 67.7%, 19.4%, and 12.9% received chemotherapy, concurrent chemoradiation therapy, and radiation, respectively. While the two groups showed similar overall survival ( P= 0.959) after a median follow up of 50.5 months, adjuvant treatment group showed a trend towards worse progression-free survival (PFS; 3-year survival rate, 78.2% vs. 46.1%; P= 0.060). However, in multivariate analyses, adjuvant treatment did not influence PFS (adjusted HR, 3.478; 95% CI, 0.659–18.367; P= 0.142). Confined to 17 cases where motorized morcellation device was used, surgery only and adjuvant treatment groups also showed similar PFS (3-year survival rate, 57.1% vs. 44.4%; P= 0.874). Conclusions: In FIGO stage I, morcellated uterine leiomyosarcoma, post-operative adjuvant treatment did not improve patients’ survival outcomes. Further prospective cohort studies are warranted.
Clinicopathological significance and prognostic value of intratumoral and peritumoral lymphocytes in endometrial cancer patients.
Authors: Ore-Arce Martin , Ballester Carmen Illueca , Lopez-Reig Raquel , Parra-Grande Monica , Romero Ignacio , Lopez-Guerrero Jose Antonio , Poveda Andres 
Published: May 2019

e17116 Background: The characterization and prognostic relevance of immune cells in the tumor microenvironment of endometrial cancer (EC) remain unknown. Our aims are to analyze the presence of tumor infiltrating lymphocytes (TIL) and peritumoral lymphocytes (PTL) in tumoral tissue of patients with EC, and to identify the correlation between TILs and PTLs subsets with clinicopathologic features and its prognostic value Methods: CD3, CD4, CD8, CD20, and FOXP-3 was determined by immunohistochemestry (IHQ). A 4-point score was defined based on TIL counts per highpowered field: (negative, low, moderate, and high). We used 10% positive peritumoral lymphocytes as a low-high cutoff value. POLE mutation was identified by Sanger sequencing of the exonuclease domain (exons 9-14). Analysis of mismatch repair expression and TP53 gene mutation status were assessed. Results from IHQ and analysis mutation were correlated with clinicopathological parameters and survival. Results: We recovered tumor samples from 68 FIGO stage I–IV EC patients. POLE mutations were identified in 5 of 44 (11.4%) EC analyzed. Microsatellite instability (MSI) and TP53 mutation were found in 45% and 25 % of cases respectively. According PTL, MSI tumors were significantly associated with low CD4+ (p = 0.01). High CD8+ was significantly associated with endometrioid grade 1-2 tumors (p = 0.04). Low FOXP3+ was significantly associated with endometrioid grade 1-2 (p = 0.02), MSS tumors (p < 0.01), FIGO stage I-II (p < 0.01), POLE WT (p < 0.01), TP53 WT (p < 0.01), and negative lymphovascular space invasion (p < 0.01). Negative CD20+ TIL was associated with endometrioid grade 1-2 tumors (p < 0.01) and ≥50% myometrial invasion (p = 0.03). Moderate CD8+ TIL was associated with lower tumor stage (p = 0.01). High CD8+ TIL was associated with better 5-year overall survival (OS) rate (high: 100 % vs. low: 53%; p = 0.003). No significant association was observed between POLE status, TP53 status, MMR expression and survival. Conclusions: Regulatory and cytotoxic T cells subsets differs in EC patients. High CD8+ TILs was significantly associated with better 5-year OS.
Does mismatch repair (MMR) deficiency have prognostic significance in low-risk endometrioid endometrial cancers?
Authors: Kim Soyoun Rachel , Pina Annick , Albert Arianne , McAlpine Jessica N. , Wolber Robert , Gilks Cyril Blake , Carey Mark S , Kwon Janice S 
Published: May 2019

e17122 Background: Mismatch repair (MMR) deficiency is observed in 25-30% of all endometrial cancers. This can be detected by the absence of MMR protein staining on immunohistochemistry (IHC), and is used in many jurisdictions as a screen for an inherited mutation in one of the MMR genes (Lynch Syndrome). Only 10% of women with MMR deficiency (MMRd) have Lynch syndrome, but MMRd may still have prognostic significance. The objective of this study was to compare clinical outcomes between MMR deficient and proficient low-risk endometrioid endometrial cancers (stage IA, grade 1/2). Methods: This was a retrospective population-based cohort study of all low-risk endometrial cancers from Vancouver Coastal Health authority region from 2011 to 2016 that were assessed for MMR deficiency (MMRd). Primary outcome measures were recurrence rates expressed per person-years (py), progression free survival (PFS) and overall survival (OS) calculated using Kaplan-Meier method and log-rank tests. Cox proportional hazards model estimated the association between MMRd and recurrence and death after adjustment for covariates, expressed as hazard ratios (HR). Results: There were 475 low-risk patients, including 131 MMRd (27.6%) and 345 MMRp (proficient) patients. Women with MMRd tumors had higher recurrence rates (3.53p100py vs 1.21p100py) and worse PFS (p = 0.0082) compared to women with MMRp tumors. After adjustment for age, LVSI status, adjuvant therapy, and post-operative grade, MMRd status remained associated with a higher risk of recurrence (HR 2.99, 95% CI 1.27-7.04). There was no significant difference in OS between MMR groups (HR 1.38, 95% CI 0.57-3.33). Conclusions: In low-risk stage IA grade 1 or 2 endometrioid endometrial cancers, MMR deficiency is associated with a higher recurrence rate than in MMR proficient cases, after adjustment for covariates, implying that MMR deficiency reflects a different biology in endometrial cancer.
Effects of nivolumab alone or combination with molecular targeting agents for recurrent and refractory endometrial cancers with biomarker analyses.
Authors: Takano Masashi , Yoshikawa Tomoyuki , Kouta Hiroko , Horikoshi Miyuki , Asakawa Takayoshi , Kudoh Kazuya , Kita Tsunekazu , Miyamoto Morikazu , Aoyama Tadashi , Matsuura Hiroko , Ishibashi Hiroki , Iwahashi Hideki , Kakimoto Souichirou , Ikeda Sayaka , Takasaki Kazuki , Suminokura Jin , Kikuchi Yoshihiro 
Published: May 2019

e17124 Background: The immunotherapy drug, nivolumab, is now approved for several metastatic cancers, and has resulted in responses previously not seen with these cancers. Molecular targeting agents, such as mammalian target of rapamycin (mTOR) inhibitor, have also recently been shown to have modest activity for endometrial cancers, however, the efficacy was limited.　The present retrospective analysis is to evaluate the efficacy of Nivolumab alone or combination with molecular targeting agents for recurrent and refractory endometrial cancers. Methods: A retrospective evaluation for medical charts of the patients were conducted: (a) the cases with histologically confirmed endometrial cancers, (b) those that had recurrent diseases, (c) diagnosed as refractory for the previous chemotherapy, (d) those that were treated with combination therapy using tri-weekly Nivolumab (100mg/body, every 3 weeks) alone, or combination with molecular targeting agents. The association with serum markers and response was also investigated. Results: A total of 16 patients were identified: 5 cases with endometrioid G1/2, 4 cases with endometrioid G3, and the 6 cases with serous, and one case with mucinous histology. Median age was 61 years old (range:43-76), and median number of the previous chemotherapy was 4 regimens (range:1-5). Combined drugs included everolimus (n = 9), temozolomide (n = 1), trametinib (n = 1), and nintedanib (n = 1). Among 12 cases with evaluable disease, a complete response over 20 months was observed in one case: a case with endometrial carcinoma G2 treated with Nivolumab and evelorimus (5mg/day, continuously). Stable disease more than three months was achieved in 8 cases (67%), and clinical benefit rate (CR+SD > 3months) was achieved in 75% of the cases. Median progression-free survival was 5 months (range: 3-20+). Non-hematological adverse events included general fatigue, mucositis, dysgeusia, skin rash, edema, and liver dysfunction, but the toxicity greater than grade2 was observed and in a case with liver dysfunction (G3). There was no significant relationship between response and serum levels of VEGF, p53, and IL-6, however, clinical benefit was observed in higher abundance of endometrioid histology compared with serous subtype (86% vs. 50%). Conclusions: Combination therapy using Nivolumab with evelolimus could be a candidate for recurrent and refractory endometrial cancers. Biomarker analyses for the responders are mandatory for further investigation for larger clinical studies.