bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gestational trophoblastic neoplasia: 14-year experience from a single institution.
Authors: Roque Perez Katia , Castro-Mollo Melanie Wendy , Vallejos Heberth Daniel , Ruiz Rossana , Galvez-Nino Marco , Valdivieso Natalia , Coanqui Ofelia , Olivera Hurtado de Mendoza Mivael , Perez Joan , Lopez Aldo , Velarde Carlos , De Mello Ramon Andrade , Mas Luis 
Published: June 2022

e17529 Background: Gestational trophoblastic neoplasia (GTN) is a rare tumor with an excellent prognosis. With the advent of multiagent chemotherapy, cure rate improved to nearly 100% in the low-risk group (LR). However, in developing countries it is lower, especially in the high risk (HR) group. Herein, we describe our experience with management and survival of GTN over a 14y period. Methods: Retrospective study based on case review of women with newly diagnosed GTN between 2005 and 2019 at Instituto Nacional de Enfermedades Neoplasicas (INEN), Lima- Peru. Primary outcome measure was complete remission (CR) by 12 months following completion of therapy and 3y overall survival (OS). Risk score was established according to the International Federation of Gynecology and Obstetrics (FIGO) with patients with scores < 7 and ≥7 being classified as LR and HR, respectively. A subgroup with score ≥13 was defined as ultra-high risk (UHR) group. Results: 172 patients with GTN were included, median age was 30 years (range 18-54 y). Choriocarcinoma was the most frequent histology in 54.6%, however, in 38% it was not determined. The most common metastatic sites were lungs (66%) and brain (15%). Median FIGO risk score was 10 points (range 1- 21). Accordingly, 8% and 82% of patients belong to LR and HR group; 41% of patients with HR had a score ≥13. Regarding treatment, 5 patients (16%) in the LR group were treated with surgery only and 84% received oral methotrexate; while all patients in the HR group received multidrug chemotherapy: 85% received etoposide, methotrexate and dactinomycin (EMA)/ cyclophosphamide and vincristine (CO), 10.6% received etoposide, methotrexate, actinomycin-D (EMA)/ etoposide and cisplatin (EP) and 2% received other regimens. CR was ultimately achieved in 83% of cases overall (100%, 80% and 73% in LR, HR and UHR group, respectively). 16% had persistent disease and relapse occurred in 5% of patients who had previously achieved CR. Early death (within 4 weeks of initiating therapy) occurred in 4.6% (8/31). 3y-OS was 82%, after excluding early deaths, the survival rate was 86%. Conclusions: In our series, HR disease is the most frequent presentation and almost half of this cases correspond to the UHR group. Remission rate in the LR group is similar to that reported in other series, however it is lower in HR and UHR group. Having said this, it represents the data of a high-risk cohort of patients in a resource-constraint setting. This data is being used to identify strategies for improvement of results, especially in ultra-high risk group.
Anlotinib suppresses growth and metastasis through MAPK signaling pathway in cisplatin-resistant ovarian cancer cells.
Authors: Ji Yurou , Qu Pengpeng 
Published: June 2022

e17542 Background: Anlotinib is a highly potent multi-target tyrosine kinase inhibitor. Increasing evidence suggests that anlotinib exhibits effective anti-tumor activity in various cancer types. However, the functional roles of anlotinib on cisplatin-resistant ovarian cancer are yet to be elucidated. The objective of this study was to investigate the anti-tumor effects of anlotinib in the pathogenesis of cisplatin-resistant ovarian cancer cells and tried to explore the related molecular mechanisms. Methods: Human ovarian cancer cells (A2780 and A2780 CIS) were cultured and treated with or without anlotinib. The effects of anlotinib on cells proliferation were determined by CCK-8 assay and colony formation assay. To evaluate the invasion and metastasis of ovarian cancer cells, we conducted wound healing and trans-well assay. Cell cycle was detected by flow cytometry. Moreover, the xenograft mouse model was used for conducting in vivo studies to verify the effect of anlotinib. The expression of Ki-67 in the tumor tissue was detected by immunohistochemistry. In GSE15372, differential expressed genes (DEGs) between cisplatin-sensitive and cisplatin-resistant groups were analyzed and enriched pathways were identified. Real-time qPCR and Western blot were used to measure the mRNA or protein level. Results: In vitro experiments, we found that anlotinib had significant effects on proliferation inhibition, migration, and invasion restraint. Meanwhile, xenograft cisplatin-resistant ovarian tumor models revealed that anlotinib treatment dramatically hindered in vivo tumor cells growth. HE and Ki-67 staining showed anlotinib markedly inhibited cisplatin-resistant ovarian cancer cells proliferation. Polo-like kinase 2 (Plk2) was identified as the main target gene of cisplatin-resistant ovarian cancer cells through bioinformatics analysis. Furthermore, we found that anlotinib upregulated the expression of Plk2 and suppressed the MAPK signaling pathway activation. The high expression of Plk2 might serve as a promising indicator when used to predict a favorable therapeutic response. Conclusions: In this study, we found that anlotinib had excellent anti-tumor effects in cisplatin-resistant ovarian cancer cells both in vitro and in vivo. These present results add to the growing body of evidence supporting anlotinib as a potential anti-cancer agent in ovarian cancer.
ChosenHRDw: A novel tool for the detection of homologous recombination deficiency(HRD) using low-pass whole-genome sequencing.
Authors: Zhang Xiaotian , Tian Weiwei , Wang Yakun , Bing Wang , Pengyan Chen , Yukai Hu , Zhang Yiqun , Cheng Wu , Xiumin Huang , Wan Qianhui , Xinying Shi , Pei Zhihua , Qiming Zhou , Wang Dongliang , Shen Lin 
Published: June 2022

e17573 Background: Homologous recombination deficiency(HRD) as a promising biomarker holds predictive and prognostic value in anticancer therapies, especially in ovarian cancer. Although next-generation sequencing techniques such as whole-exome sequencing (WES) and targeted sequencing have proven to be powerful detection of HRD, the latest low-pass (1x) whole-genome sequencing (WGS) with characteristic large-scale patterns for HRD detection status, as a cost-effective screening strategy, have established feasibility. In this study, we developed the ChosenHRDw, a comprehensive algorithm, which utilizing low-pass WGS to effectively classify the HRD status by defining the high or low HRD score. Methods: In this work, a correction method base on GC-content was applied. Then we took a window size of 1Mb resolution, and removed the error alignments genome bins basing on the healthy cohort data. Baseline of each bins was constructed from the data of 100 healthy volunteers. We characterized and quantified 8 HRD-related signatures: LOH score, TAI score, LST score, chromosomal instability index(CIN index), wGII(weighted genome instability index), CNV ratio (copy number ratio in bins), HRR index (HRR gene instability index), TFBS ratio (copy number ratio in transcription factor binding sites) as the variables in a random forest model. Results: A total of 140 patients (pts) were enrolled in the discovery cohort, which including 70 high HRD score and 70 low HRD pts were confirmed by HRDetect on paired tumor/normal samples via 1123plus-genes panel targeted sequencing. The AUC was 0.93. Independent validation was conducted in a validation cohort of 60 pts, which HRD high or low pts were 30 and 30, respectively. The sensitivity = 0.87 and specificity = 0.9. Conclusions: We classified HRD into high vs low using ChosenHRDw, which showing strong concordance. Our analyses demonstrated that the prediction of HRD status can be achieved from low-pass WGS. Due to the limitation of relatively small sample size, real-world studies with a larger number of patients are needed to verify our algorithm in the future.
Exploratory hrd and PD-L1 analysis of l-MOCA study: Olaparib maintenance monotherapy in Asian patients with platinum-sensitive relapsed ovarian cancer.
Authors: Ma Ding , Gao Qing-lei , Zhu Jianqing , Zhao Weidong , Huang Yi , An Ruifang , Zheng Hong , Qu Pengpeng , Wang Li , Zhou Qi , Wang Danbo , Lou Ge , Wang Jing , Low John , Kong Beihua , Yin Rutie , Xie Xing , Liu Jihong , Sun Wei , Zang Rongyu 
Published: June 2022

e17578 Background: Olaparib demonstrated its efficacy to prolong progression-free survival (PFS) in platinum-sensitive relapsed ovarian cancer (PSROC) patients (L-MOCA study). Almost half of OC patients harbor homologous recombination deficiencies (HRD). However, there is lack of the HRD prevalence in Asian PSR population. Meanwhile, Immunological processes play a key role in tumorigenesis and PD-L1 status may hinder an effective antitumor immune response in OC. Herein, we analyzed HRD and PD-L1 status in Asian patients with PSROC, and explored Olaparib response to different HRD status. Methods: In this exploratory analysis of L-MOCA trial, HRD and PD-L1 status were analyzed from patients with PSROC. Residual DNA samples of 193 patients were analyzed for HRD status with a local developed HRD assay (Teddy Laboratory, Shanghai, China, which determines two major components, tBRCA1/2 status and LOH score, HRD positive indicates the presence of a deleterious or suspected deleterious BRCA mutation or LOH score ≥0.4). The remaining formalin fixation and paraffin embedded samples were used for PD-L1 expression analysis by immunohistochemistry with SP263. Descriptive statistics were summarized for HRD status, PD-L1 expression status and PFS by different HRD status subgroups. Results: 193 of 224 patients had residual DNA for HRD test. Patients clinical characteristics were similar between those with and without residual DNA for HRD test, in terms of age (mean age 55.5y Vs 54.2y), FIGO stage (stage III 68.9% Vs 61.3%, stage IV 12.4% Vs 22.65%), and time to disease progression to Last prior Platinum Based Chemotherapy (6-12m: 39.9% Vs 41.9%; > 12m: 59.6% Vs 54.8%). Among 193 patients with HRD test conducted, proportion of HRD+ BRCAm, HRD+ BRCAwt, HRD- and HRD unknown were 37.3%, 28.0%, 14.5% and 20.2%, separately. mPFS of the above subgroups was 20.1 months, 15.8 months, 9.2 months and 16.4 months, respectively (Table1). 200 of 224 patients were available for PD-L1 expression analysis. 184 (92%) with TC＜1%, 12 (6%) with TC among 1-25%. These results showed TC expression in all patients were less than 25%, suggesting that ovarian cancer may be an immunologically cold tumor. Conclusions: This is firstly showing the HRD and PD-L1 status in Asian OC patients. The results showed all the PSR patients could benefit from Olaparib treatment, regardless of HRD status. Meanwhile the numerically different mPFS observed across different HRD status subgroups also indicated potential clinical utility of locally developed HRD assay. Clinical trial information: NCT03534453. [Table: see text]
Exploring the mechanism of PARPi resistance in ovarian cancer by integrated analyze of pre- and post-progression samples in 5 patients.
Authors: Li Qingli , Song Liang , Lin Xiaojuan , Zhang Wenhao , Cheng Peng , Zhu Changbin , Yin Rutie 
Published: June 2022

e17582 Background: PARP inhibitors (PARPi) have been widely used in the treatment of homologous recombination repair-deficient tumors. Comprehensive investigations on the resistance mechanisms of PARPi and tumor microenvironment alterations after PARPi therapy are largely insufficient. Methods: 5 ovarian cancer patients (pts) treated with PARPi at West China Second University Hospital were enrolled in this study (Ethical Lot Number: 20200076). Clinicopathological information of the pts are shown in table below. Paired PARPi treatment-naive surgical samples (TNS) and the biopsy samples that progressed after PARPi maintenance therapy (PPS) were obtained. Multi-omic profiling was conducted by an NGS panel (Master Panel, AmoyDx) containing DNA exon regions of 563 genes and RNA expression of 1831 genes analyzing genetic mutations and dynamics of gene expression profile in these paired tumor samples. Results: Median duration of treatment with PARPi was 18 months (11-22). Comprehensive genomic profiling discovered MYC amplification (n = 3), ZFHX4 mutation (n = 2) and IDH1 mutation (n = 1) in PPS. One PPS harbored simultaneous amplification of PDCD1, FGF3, MYC, FGF19 and ZFHX4 mutation. In addition, BRCA1 intron11: c.4096+1G > T mutation was detected in one PPS carrying germline BRCA1 mutation (E1066*), which putatively resulted in restoration of BRCA1 function. At RNA level, single-sample enrichment analysis showed that B cells, T cells, and co-activation factors were significantly up-regulated in PPS. In addition, expression of CXCL13 and activation of CCL19/21-CCR7 axis were significantly increased, which indicated a PARPi-triggered “hot” immune-microenvironment. Moreover, immune-checkpoint TIGIT was significantly upregulated, paved the way for immunotherapy. Nevertheless, stromal remodeling, and tumor proliferation signatures were also up-regulated in PPS. In parallel, cancer-related pathways, PI3K/AKT, Epithelial-Mesenchymal transition, cell-cycle as well as G2M checkpoint were observed in the pathway enrichment analysis, which further verified the aforementioned findings. Conclusions: This small sample size study confirmed the complexity of the resistance mechanisms to PARPi, including BRCA reversion mutation, oncogene activation and bypass signaling activation. The activation of both positive and negative immune regulators in the tumor microenvironment shed light on future clinical management for patients with PARPi resistance.[Table: see text]
Changes in focal adhesion protein Talin-1 expression during malignant transformation leading to ovarian high-grade serous carcinoma.
Authors: Paris Elizabeth , Bitterman Pincas , Sharma Sameer , Basu Sanjib , Bahr Janice M , Barua Animesh 
Published: June 2022

e17586 Background: Ovarian high-grade serous carcinoma (HGSC), the most lethal form of ovarian cancer, is often detected at late stages due to the lack of an early detection test resulting in low 5-year survival rates. Information on factors associated with malignant transformation and early metastasis is critical in developing interventional strategies to reduce the incidence and death due to HGSC. Talin-1, a focal adhesion protein, regulates cell–cell adhesion, and induces cytoskeletal remodeling leading to tumor cell migration and adhesion. Destabilization of the cell membrane during malignant development may shed Talin-1 in circulation which may be a potential early marker of progression of HGSC. Objective: The goal of this study was to examine the changes in Talin-1 expression during malignant transformation in ovaries and fimbria of the fallopian tube and its prevalence in serum. Difficulty in accessing patients with early-stage HGSC is a significant barrier to study malignant transformation and progression. Laying hen model of spontaneous ovarian HGSC was used together with clinical specimens. Methods: Two experiments were conducted. Exploratory study:Archived normal ovaries (n = 10), ovaries with HGSC at early (n = 10) and late (n = 10) stages from patients and their serum samples were used. Prospective study: Laying hens with no detectable abnormalities were selected and monitored using transvaginal ultrasound (TVUS) imaging at 10 week intervals for 10 months and sera were collected at each scan. Hens were euthanized at diagnosis of solid mass during scanning or at the end of the study; ovaries, fimbria and serum samples were collected. Normal hens (n = 10), hens with early (n = 7) and late-stage (n = 8) tumors were selected. Talin-1 expression in tissues and serum was determined by immunohistochemistry (IHC), Western blotting (WB), gene expression (qPCR), and immunoassay (ELISA). Significant differences in Talin-1 expression among all groups were determined by ANOVA and/or paired/unpaired t-tests, significance was taken when P< 0.05. Results: Expression of Talin-1was detected in all tissues with various intensities. Compared with normal, ovarian HGSC tissues showed intense expression of Talin-1 in IHC, WB and qPCRs ( P< 0.05). Similar patterns were observed in serum levels in ELISA ( P< 0.01) in the exploratory study. Prospective study in hens showed significant increase in serum Talin-1 levels even before the formation of a solid tumor mass in the ovary or fimbria detectable by TVUS. Conclusions: Elevated Talin-1 expression in early-stage ovarian HGSC tumors suggests its association with malignant development. Serum prevalence of Talin-1 during malignant transformation makes it a potential marker for early detection of HGSC and its progression. These results will serve as foundation for a clinical study with larger cohorts. Support: NIH R01 CA210370 (AB)
Prognostic factors of stage I endometrioid or clear cell or mucinous ovarian cancer: Analysis based on surveillance, epidemiology, and end result program, 2000-2016.
Authors: Li Jing , Lin Zhongqiu , Qiao Huimin , Wang Lijuan , Liu Yunyun , Lu Huaiwu 
Published: June 2022

e17589 Background: Endometrioid (EEOC), clear cell (OCCC) or mucinous ovarian cancer (MOC) had the highest incidence of Less Common Ovarian Cancers (LCOC). The benefit of adjuvant chemotherapy, lymphadenectomy or fertility-sparing surgery (FSS) for Stage I of these rare cancers remains unclear. Methods: We conducted a retrospective case-controlled study examining the Surveillance, Epidemiology, and End Result (SEER) database between 2000 and 2016. Propensity score matching is used to avoid the selection bias caused by the heterogeneity of demographic and clinical characteristics. Adjuvant chemotherapy or lymphadenectomy or fertility-sparing surgery on overall survival (OS) was compared with log-rank tests. A univariate and multivariate Cox analysis was performed to control for confounders. A nomogram was developed and the discriminatory ability of the model was analyzed. Results: The study identified 4,681 patients with FIGO stage I EEOC, 2,450 with stage I OCCC, and 2,839 with stage I MOC. After the propensity score matching, there was an equally comparable number of patients with or without adjuvant chemotherapy. The results showed that adjuvant chemotherapy could not prolong the 5-year OS of patients with stage I OCCC (86.7% vs. 85.9%, p = 0.732) and MOC (87.6% vs. 88.2%, p = 0.843). Adjuvant chemotherapy was associated with a 5-year OS benefit only in the subgroup of patients with substage IC, grade 3 EEOC (85.2% vs. 67.7%, p = 0.008). We also found that lymphadenectomy improved the 5-year OS of stage I EEOC (93.5% vs. 86.3%, P = 0.000), OCCC (87.8% vs. 82.8%, P = 0.040) and MOC patients (91.8% vs. 84.2%, P = 0.000). Furthermore, we observed that the 5-year OS raised in stage I EEOC (91.9%vs. 87.7%, P = 0.029) and OCCC (87.6% vs. 81.3%, P = 0.051) patients when conducted the non-fertility-sparing surgery (non-FSS) rather than the FSS. However, FSS did not significantly impact the 5-year OS of MOC patients (91.3% vs. 88.8%, P = 0.181). The nomogram survival prediction model showed that the area under the receiver operating characteristic (ROC) curve (AUC) was 0.650, 0.640 and 0.710 in EEOC, OCCC and MOC, respectively. The C-indexes for the OS were 0.666 (95%CI:0.638-0.694), 0.613 (95% CI:0.575-0.650) and 0.677 (95% CI:0.637-0.716), respectively. Conclusions: Adjuvant chemotherapy was associated with a 5-year OS benefit for patients with stage IC, grade 3 EEOC, but it was unnecessary for patients with stage I OCCC and MOC. Lymphadenectomy was associated with a survival benefit for these early cancer patients. FSS is appropriate for stage I MOC but needs to be discussed for stage I EEOC and OCCC. We constructed predictive nomograms to evaluate the OS of patients with stage I EEOC, OCCC or MOC, and it will provide an individualized evaluation of OS for suitable treatments.
Molecular classification of endometrial cancer of Chinese population.
Authors: Kang Nan , Wang Zhiqi , Gai Fei , Su Wenqing , Shen Danhua , Wang Jianliu 
Published: June 2022

e17623 Background: Endometrial cancer (EC) is one of the most prevalent gynecologic tumors. Current diagnosis and treatment of EC no longer rely solely on traditional histopathological classification. Nevertheless, molecular classification of EC demonstrated clear prognostic value and may guide clinical decision. Methods: In this study, archived tissue specimens from 240 EC patients from Department of Pathology, Peking University People’s Hospital. Four subtypes [POLE ultramutated (POLE mut), microsatellite instability high (MSI-H), copy number low (CNL), and copy number high (CNH)] were stratified by next-generation sequencing (NGS) panel (Amoy Diagnostics, Xiamen, China) targeting POLE, TP53, BRCA1, and BRCA2 genes and microsatellite instability (MSI) status. Immunohistochemistry (IHC) was applied to detect the expression of P53, MMR and other related proteins. Results: Distribution of the EC subtypes in 240 patients was 13 (5.42%) of POLE mut, 36 (15.00%) of MSI-H, 41 (17.08%) of CNH, and 150 (62.50%) of CNL. Compared to published results of EC subtypes in Caucasian including TCGA, ProMisE as well as TransPORTEC, real-world data on Chinese ECs displayed a significantly larger proportion of CNL. In addition, novel biomarkers such as DUSP1, MCF7 and BUB1, which were independent prognostic marker from our previous research were validated. Also, it was found that BRCA2 appeared to be more prevalent in EC than BRCA1. Further analysis revealed that the overall consistency for NGS-based and IHC-based TP53 abnormalities detection and MSI/MMR status assessment were as high as 87.5% and 100%, respectively. Conclusions: Chinese ECs have unique molecular characteristics. In order to perform accurate molecular typing of Chinese ECs, more molecular indicators that match the characteristics of the Chinese population need to be added to the existing classifiers. NGS-based panel is easy to operate and replicate with high accuracy. Thus, it is a viable alternative to IHC in EC molecular classification.
Five years survival outcomes of head and neck cancer patients treated with palliative metronomic chemotherapy.
Authors: Naidu Priyanka Dhanraj , Patil Vijay Maruti , Noronha Vanita , Nawale Kavita Prakash , Dhumal Sachin Babanrao , Jogdhankar Shweta , Menon Nandini Sharrel , Prabhash Kumar 
Published: June 2022

e18009 Background: Palliative metronomic chemotherapy improved overall survival over intravenous chemotherapy in head and neck cancers. However, there is no data available about the 5-year outcomes with this regimen. Methods: This was a single-arm prospective study that enrolled head and neck squamous cell carcinoma patients warranting palliative chemotherapy. The chemotherapy administered was methotrexate 15 mg/m2 per oral weekly and celecoxib 200 mg per oral daily till the development of intolerable side effects or progression. Kaplan Meier method was used for estimation of OS and factors impacting the same were sought. A p-value of 0.05 was considered significant. Results: 200 patients were enrolled with a median age was 49.5 years (Range 22-85 years) and preponderance of male gender (175, 87.5%). The predominant site of malignancy was oral cavity in 144 patients (72.2%). Prior chemotherapy exposure was present in 78 patients (39%). The median FACT trial outcome index score was 43.7 (16.7-80.7). The median OS was 194 days (95%CI 181.7-206.3) . The 1-year, 3-years and 5-years OS were 17 %(Standard error-2.8%), 7.9% (Standard error-2.5%), and 3.9% (Standard error- 2%) respectively. The details of factors impacting OS are given in Table. Conclusions: Oral metronomic chemotherapy leads to a small proportion of patients having long term survival with metronomic chemotherapy. Clinical trial information: CTRI/2015/11/006392. [Table: see text]