bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical experience with rucaparib after prior PARPi treatment: A subanalysis from the rucaparib access program in Spain by GEICO.
Authors: Yubero-Esteban Alfonso , Reche-Molina Piedad , Salvador Coloma Carmen , Estévez-García Purificación , Manso Luis , Iglesias Campos Marcos , Barquin Arantzazu , Marquez Raul , Santaballa Ana , Calzas Julia , Herrero Ana , Casado Victoria , Madani Julia , Merino Maria , Marquina Gloria , Alarcon Company Jesus , Gaba Lydia , Fuentes Pradera Jose , Gonzalez Martin Antonio , Sanchez Lorenzo Maria Luisa 
Published: June 2022

e17598 Background: Rucaparib is a PARP inhibitor (PARPi) approved as maintenance therapy for platinum (Pt)-sensitive recurrent high-grade ovarian cancer (HGOC), and as treatment for BRCA-mutant HGOC patients. To date, there is little evidence about the efficacy and safety of rucaparib after prior exposure to PARPi. This subanalysis aims to describe the patients’ characteristics and treatment outcomes with rucaparib in women who were included in the rucaparib early access program (RAP) in Spain and had received a prior PARPi. Methods: A retrospective study was conducted by GEICO at 22 hospitals in Spain to analyze data of 51 women treated within the RAP (600 mg BID). Adult women with HGOC, fallopian tube, or primary peritoneal cancer, who had received at least one prior PARPi before rucaparib were analyzed. Patients’ characteristics, medical history, safety, efficacy, and dosing data were collected. Results: A total of 14 women, with a median age of 63 years old (42-78) were included in this subanalysis. Of them, 92.9% were diagnosed of epithelial ovarian cancer and 78.6% had mutations in BRCA1/ 2 genes. The median number of lines before rucaparib was 5 (3-8), while the number of lines before the first PARPi was 3 (2-5). Except for one woman who had received 2 prior PARPis before rucaparib, the others had received just 1. Most patients were given olaparib as the first PARPi (n = 12, 85.8%), while niraparib was the initial PARPi in the remaining cases (n = 2, 14.3%). The outcomes of the treatment with rucaparib in these patients are outlined in table 1. Rucaparib was given as maintenance therapy in 1 patient and as treatment in 13 patients, 12 of them being Pt-resistant. The progression-free survival (PFS) ranged from 0.23 to 9.12 months. Adverse events (AE) of any grade were detected in 78.6% of patients, whereas AE of grade ≥3 affected 28.6% of women. Rucaparib dose was interrupted in 57.1% and reduced in 42.9% of patients. Only 1 patient discontinued rucaparib due to toxicity. No new safety signals were detected. Conclusions: This is one of the first real-word studies reporting the use of rucaparib after treatment with another PARPi. Even in these heavily pre-treated patients who had received prior PARPi, rucaparib efficacy has been notable in some cases, and its safety profile is consistent with that reported in previous clinical trials. Future studies should focus on the selection of patients who could benefit from rucaparib after prior PARPi exposure. [Table: see text]
Multi-omics analysis reveals spatial heterogeneity of infiltrating T cells in high-grade serous ovarian cancer.
Authors: Chen Gang , Yang Bin , Li Xiong , Zhang Wei , Fan Junpeng , Sun Chaoyang 
Published: June 2022

e17603 Background: The effect of spatial immunologic variation, especially in T cell infiltration, recognition and expansion, across various tumor foci in the ovary (primary) and distant metastatic foci in the peritoneal cavity and their contribution to the limited response to immune therapy in High-Grade Serous Ovarian Cancer(HGSOC) remains unexplored. We aim to provide a detailed analysis of the landscape of heterogeneity of infiltrating T cells in primary and metastatic lesions and their differential characteristics in HGSOC. Methods: We performed multi-site sampling and simultaneous RNA sequencing (RNA-seq), whole-genome sequencing (WGS) and bulk T cell receptor (TCR) sequencing as well as single cell RNA sequencing (scRNA-seq) and paired TCR sequencing (scTCR-seq) in 9 patients (48 sites, including 19 ovarian, 11 omental, 18 other metastasis lesions) with untreated primary HGSOC. Validation by IHC, flow cytometry, another scRNA-seq data from 7 patients (32 sites, including 9 ovarian, 6 omental, 6 ascites and 11 other metastasis lesions) and spatial transcriptomics. Results: CD8 exhausted clusters that are enriched in ovarian tumors exhibited high exhaustion, tumor-specific score and low bystander score, whereas CD8 transition and NK-like clusters that are enriched in omental tumors exhibited the opposite characteristics, which was confirmed by flow cytometry. Of note, the exhausted CD8+ T cells exhibited GZMB, PRF1, FASLG and IFNG effector genes despite the expression of exhaustion markers, developing from an early differentiation state with high proliferative capacity and the process preferentially occurs in primary ovarian sites. Besides, T cells corresponding to the selected TCRs that had the same distribution as neoantigens were enriched in ovarian lesions, while the virus-specific TCR preferentially enriched in omentum samples. The association of TMB, HRD score, and COSMIC mutational signatures with antigen-engaged T cell subsets was not observed at the site level within individual patients. STARTRAC-migration analysis showed that T cell clusters in blood or other sites migrating to ovarian was extremely low or vice versa. The expression of MHC-I processing and presentation genes and MHC-I protein were higher in omental lesions, along with T cells were preferentially located in tumor region of ovarian tumors. Conclusions: We identify two different immune patterns in ovarian cancer: 1) ovarian lesions with low infiltration of mainly dysfunctional T cells and immunosuppressive Treg cells. These exhausted CD8 T cells with cytotoxic function are clonal expanded; 2) omental lesions infiltrated with non-tumor-specific bystander cells. Decreased major histocompatibility complex (MHC)-I antigen presentation ability and failure of T cell infiltration into omental tumors may contribute to lack of tumor-specific T cells in omental metastasis.
Diagnosis of first relapse and its impact on quality of life in patients with advanced ovarian cancer (AGO-OVAR 19/II).
Authors: Harter Philipp , Ataseven Beyhan , Burges Alexander , Reuss Alexander , Kommoss Stefan , Sehouli Jalid , Lampe Bjoern , Schmalfeldt Barbara , Wimberger Pauline , Witteler Ralf , Buderath Paul , Herwig Uwe , Bronger Holger , Emons Guenter , Klar Maximillian , Hasenburg Annette , de Gregorio Nikolaus , Hilpert Felix , Du Bois Andreas , Mahner Sven 
Published: June 2022

e17609 Background: Maintenance or improvement of health-related quality of life (QoL) is one of the major goals for patients with advanced ovarian cancer (OC). QoL is influenced by symptoms of disease on the one and beneficial or adverse effects of surgical and systemic treatment on the other side. In addition, QoL is also an important patient centered endpoint in clinical trials to support primary endpoints such as progression-free survival (PFS). This analysis evaluates the impact of the diagnosis of first relapse on QoL. Methods: Patients with primary OC were included before start of treatment. QoL was assessed by the cancer-specific questionnaires EORTC QLQ‐C30 and QLQ‐OV28 and the generic EQ‐5D 3L at baseline and every 3 months thereafter, to describe the influence of treatment and course of disease on QoL. QoL data within 100 days before and after the first relapse were compared (part 2 of NCT02828618). QoL scales were analyzed by repeated measures regression. We report model-based pre- and post-recurrence means and p-values for the difference in means. Results: In total, 269 had a PFS event with a median PFS of 20.3 months. This analysis includes 186 patients; 122 with QoL assessment before and after relapse and 50 and 14 with assessment only before or after relapse. Median age was 62.5 years (range 31 – 90). The number of evaluable answers for each domain ranged between 166 and 172 before recurrence and 135 and 137 after recurrence. Global QoL decreased from 61.4 to 48.4 points (p < 0.001) with the diagnosis of recurrence. The following scales showed a deterioration of at least 10 points: Social functioning (65.7- > 52.6), fatigue (55.8 - > 44.5), appetite loss (22.5 - > 33.4), emotional functioning (65.2 - > 54.9), role functioning (56.5 - > 46.4); (all p < 0.001). EQ-5D 3L visual analogue scale showed a deterioration from 66.4 to 55.0 (p < 0.001). Conclusions: The event of first relapse is associated with a significant and clinically relevant deterioration of global QoL including several subscales. Therefore, prolongation of PFS preserves QoL, which supports the role of PFS as meaningful primary endpoint in ovarian cancer trials. Clinical trial information: NCT02828618.
End-of-life care for patients with advanced ovarian cancer in the Netherlands: A retrospective registry-based analysis.
Authors: Broekman Esther , Van Der Aa Maaike , Nijman Hans , Jalving Mathilde , Reyners An K.L 
Published: June 2022

e17612 Background: Patients with advanced ovarian cancer have a poor prognosis and can experience debilitating abdominal symptoms in the last phase of life. Several analyses, mainly performed in the United States (US), show high rates of chemotherapy administration, and emergency room and hospital visits near the end-of-life in this patient category. No large European studies are available, while the organisation of palliative care differs between the US and Europe and between European countries. We aimed to analyse the intensity of inpatient care near the end-of-life in the Netherlands and perform a cross-study comparison with previous reports. Methods: All patients with ovarian cancer that died in 2016 and 2017 were identified from the database of the foundation Dutch Hospital Data (DHD). For the last six months of life the following parameters of aggressive care were extracted: administration of chemotherapy, emergency room (ER) visits, surgical procedures, hospital and intensive care unit (ICU) admissions. Data were analysed for the cohort as a whole and separately for three age categories: < 60, 60-75 and > 75 years of age. The intensity of inpatient care was compared to previously reported European and US data. Results: A total of 2172 patients died with ovarian cancer in 2016 and 2017 in the Netherlands. Data on medical care use was available for 1775 patients. During the last 6 months of life, chemotherapy was given to half of the ovarian cancer patients and the same percentage of patients was admitted to hospital. Chemotherapy administration near the end-of-life was infrequent, with only 12% of patients receiving chemotherapy in the last month of life. Surgery and ICU admissions in the final 6 months of life were rare (< 10%). Our cohort showed the lowest percentages of all five indicators of aggressive care reported thus far. The use of chemotherapy in the six months prior to death was highest in patients 60-75 years of age compared to younger or older patients. ER visits and hospital admissions were less frequent in patients > 75 years of age compared to the younger age groups. Conclusions: Aggressive medical care use in the final 6 months of life in this Dutch cohort of ovarian cancer patients was lower than in other previously reported cohorts.
Cancer-associated fibroblasts in uterine corpus endometrial carcinoma.
Authors: Li Yingqiang , Zhou Jie , Zhang Jing , Liu Ming , Chen Shifu , Liu Yaqiong 
Published: June 2022

e17618 Background: The general role of cancer-associated fibroblasts (CAFs) and their invasive characteristics in Uterine Corpus Endometrial Carcinoma (UCEC) remain unknown. CAFs serve as an important component of the tumor microenvironment and promote tumorigenesis and cancer aggressiveness. Methods: UCEC mRNA data were downloaded from TCGA cBioPortal ( http://www.cbioportal.org/ ). CAF levels were estimated by three algorithms: MCPCOUNTER, XCELL, and EPIC, so three CAF scores were gotten and ranked. Then, the data of CAF scores in each cohort were divided into quarters, and we labeled the sample by upper quartile and lower quartile with “high”, “medium”, and “low”. To mitigate the possible classification error from each estimation method, we defined samples as “high” by at least two methods consistently labeling “high”. Samples labeled with “low” by at least two methods were assigned to the consensual low CAF group. The high and low group were analysis using GSEA software, Survival analysis was performed using the R package “survival”. Results: There were 129, 118 and 280 samples in the high, low and middle CAFs group, respectively. GSEA results showed extensive gene expression differences between the high and low CAF groups. 193 gene sets were significantly enriched at nominal p value < 0.01 in the low group, 869 gene sets were significantly enriched at nominal p value < 0.01 in the high group. In the low group, obvious differences, included lim mammary stem cell up, reactome degradation of the extracellular matrix, bertucci medullary vs ductal breast cancer dn etc. are enriched in the high group. xu akt1 targets 6hr, OUELLET (Gene Set) ovarian cancer invasive vs lmp up etc. are enriched in the low group. OS and PFS survival analysis showed there was no significant difference between these two groups. Conclusions: Our study analyzed the relationship between CAFs with UCEC, CAFs were associated with an immunosuppressive microenvironment. Larger transcriptomic alterations occurred in UCECs with high CAF infiltration, and with AKT, ALCALA APOPTOSIS and SPLICEOSOME pathways prominent in this process. But Survival analysis showed no difference between the two groups.
DACH1 mutation frequency in endometrial cancer is associated with high tumor mutation burden in a nationwide cohort.
Authors: Riggs McKayla J , Lin Nan , Miller Rachel W. , Piecoro Dava West , Schneider Bryan P. , Chon Hye Sook , Carpten John D. , Churchman Michelle L. , Corr Bradley , Washington Christina , Dood Robert , Edge Stephen B. , Leiser Aliza L. , Siegel Erin M. , Ueland Frederick West , Kolesar Jill 
Published: June 2022

e17634 Background: DACH1 is a novel transcriptional repressor and tumor suppressor gene. DACH1 mutations are associated with poor prognostic features and reduced overall survival in endometrial cancer, with an increased prevalence in the Appalachian region of Kentucky. Preliminary studies have suggested an association with an increase in tumor mutation burden. In this follow up study, we utilized the nationwide Oncology Research Information Exchange Network (ORIEN) to determine the frequency of DACH1 mutations in patients with endometrial cancer through a multi-institution analysis and evaluate its impact on RNA expression, clinical correlates, and outcomes. Methods: We obtained clinical and genomic data for 691 patients with endometrial cancer from nine U.S. institutions within the ORIEN collaborative. We examined the clinical attributes of the cancers with DACH1 status by comparing whole-exome sequencing (WES), RNA Sequencing (RNASeq), microsatellite instability (MSI), and tumor mutational burden (TMB). Results: Appalachian women with endometrial cancer had an increased frequency of DACH1 mutations (6/41 patients, 15%) compared to the non-Appalachian endometrial cancer population (24/581 patients, 4.1%) with p-value = 0.010, with the non-Appalachian DACH1 mutation frequency mirroring the rate of DACH1 gene mutation seen in TCGA at 3.8%. DACH1 mutated patients have a higher tumor mutation burden compared to DACH1 wild-type (32.2 vs. 4.62, p-value = 0.001) though no differences in microsatellite instability between DACH1 mutated and wild-type were present (p-value = 0.350). DACH1 mutations showed significant gene co-occurrence patterns with POLE, MLH1, MSH2, MSH6 and PMS2. Conclusions: DACH1 mutations are prevalent in Kentucky patients with endometrial cancer, particularly those from the Appalachian region. These results were again reflected in the TCGA PanCancer Atlas as well as the ORIEN multi-institution cohort. These mutations are associated with high tumor mutational burden and co-occur with genome destabilizing gene mutations. These findings suggest DACH1 as a candidate biomarker for future trials with immunotherapy, particularly in endometrial cancers.
Apatinib in recurrent or metastatic head and neck cancer patients.
Authors: WU Qiuji , Liu Jia , Li Shaojie , Wang Juan , Zhong Yahua 
Published: June 2022

e18010 Background: Apatinib is a small tyrosine kinase inhibitor targeting the vascular endogenous growth receptor 2 (VEGFR-2) that shows potent antitumor activities in various advanced cancers via the inhibition of neo-angiogenesis. The effect of apatinib in recurrent or metastatic head and neck cancers has not been fully demonstrated. Methods: Patients with recurrent or metastatic head and neck cancers consecutively treated in our institute by apatinib from January 2015 to December 2020 were enrolled. Daily 250 mg or 500 mg apatinib was given with or without chemotherapy according to patients' tolerance. A part of the patients also received palliative radiotherapy. Disease response, treatment-related toxicities and patient survival were analyzed. Toxicity was assessed by CTCAE v4.0. Kaplan-Meier analysis was used to estimate patients' overall survival. The R software (version 3.6.3) were used for statistical analysis. Results: A total of 73 patients were enrolled in this study. There were 59 males and 14 females with the median age of 55 (range: 27-80) years. Most patients had a performance status of 0 (15/73, 20.5%) and 1 (51/73, 69.9%). There were 29 oral cavity cancers, 20 nasopharyngeal carcinomas, 8 salivary gland cancers, 7 nasal and paranasal sinus cancers and 9 other malignancies. Pathologically, 47 were squamous cell carcinoma, 18 were adenoid cystic carcinoma, and the rest 8 were adenocarcinoma, sarcoma and melanoma. The majority of patients were with metastatic diseases (57/74, 78.1%). Nine of the 73 (12.3%) received apatinib as first-line treatment, 22 (30.1%) as second-line and 42 (57.5%) as more than second-line treatments. Forty patients received S-1 or capecitabine chemotherapy, 2 received nab-paclitaxel and 1 received gemcitabine. Ten patients received palliative radiotherapy. The most frequent toxicities were anemia (37/73, 50.7%), leucopenia (27/73, 37.0%), thrombocytopenia (20/73, 27.4%), proteinuria (20/73, 27.4%), arterial hypertension (17/73, 23.3%), hand-foot syndrome (17/73, 23.3%). Hemorrhage occurred in 10 (13.7%) patients. No treatment-associated death was noted. The median follow-up was 29.9 months. Fifty-six patients had evaluable tumor response. Complete response occurred in 1 patients. Partial response was seen in 3 patients. Most patients had stable disease (29/56, 51.8%) or progressive disease (23/56, 41.1%). By the end of the last follow-up, 33 patients died of disease progression. The median overall survival was 29.6 months. Conclusions: Apatinib showed modest antitumor activities in recurrent or metastatic head and neck cancers. The side effects were manageable. The effect of apatinib in recurrent or metastatic head and neck cancers warrants further studies in larger-scale randomized studies.
Long-term toxicity and tolerance of concurrent docetaxel with radiotherapy in cisplatin ineligible head and neck cancer patients.
Authors: Kolkur Manali , Patil Vijay Maruti , Menon Nandini Sharrel , Noronha Vanita , Prabhash Kumar , Simha Vijai , Talreja Vikas , Chandrasekharan Arun , Dhumal Sachin 
Published: June 2022

e18037 Background: Docetaxel can be administered in several situations like low creatinine clearance or pre-existing grade 3-4 ototoxicity, where cisplatin is contraindicated. In this analysis, we present our data on toxicity and tolerance to docetaxel-based chemoradiation in cisplatin-ineligible patients. Methods: Patients who underwent docetaxel-based chemoradiation between January 2015 to December 2017 for locally advanced head and neck cancer, either in the radical or adjuvant setting were selected for this analysis. SPSS version 16 was used for analysis. Results: Nineteen patients were identified and the median age of the cohort was 58 years (range 41-71 years). The most common site of the primary was the oral cavity (n = 9, 47.4%). Sixteen patients (84.2%) had stage IV disease and 3 patients (15.8%) had stage 3 disease. The intent of chemoradiation was radical in 12 (63.9%) patients and adjuvant in 7 (36.1%) patients. Any grade 3 or above adverse events were seen in 12 patients (63.2%). The most common grade 3 or above adverse events observed were mucositis and hyponatremia in 9 patients (47.4%) each. At a median follow up of 5.3 years, the 2-year and 5-year PFS were 26.3% (Standard error-10.1) and 15.8% (Standard error- 8.4) while 2-year and 5-year OS were 36.8% (Standard error-11.1) and 15.8% (Standard error- 8.4). Conclusions: Docetaxel based chemoradiation is a feasible and tolerated option in cisplatin unfit patients and needs further testing in large randomized studies to prove its worth.
Human papillomavirus DNA resides in surgical drain fluid exosomes from HPV+ oropharyngeal squamous cell carcinoma patients and can be spread to neighboring HPV-negative cells.
Authors: Xu Zhongping , Earland Noah , Harris Peter K. , Gerndt Sophie P. , Ramirez Ricardo J. , Hearn Andrew I. , Semenkovich Nicholas P. , Chaudhuri Aadel A , Zevallos Jose P. 
Published: June 2022

e18050 Background: Human papillomavirus (HPV) is the primary driver of oropharyngeal squamous cell carcinoma (OPC) in the US. Previous studies have investigated the role of plasma and saliva-based cell-free HPV DNA in OPC, yet the pathophysiological impact of exosomes in HPV+ OPC remains unknown. Exosomes are nanometer-sized membrane vesicles of endocytic origin carrying DNA, RNA and proteins, and have been shown to exist in blood, plasma, and in urine. We hypothesize that serosanguinous fluid drained from the postoperative bed, which we call “surgical drain fluid” (SDF) also contains exosomes. We further hypothesize that exosomes derived from SDF in HPV+ OPC patients contain HPV DNA that can be directly transmitted into HPV-negative cells. Methods: Twenty-six 5-mL SDF samples were collected following surgical neck dissections directly from the surgical drain; 21 from HPV+ and 5 from HPV- OPC patients. Exosomes were isolated from SDF using the Qiagen exoEasy kit. Exosome structure was characterized by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). Western blotting (WB) targeted known exosomal surface markers. Exosomes were pretreated with DNase (New England Biolabs) to cleave the surface DNA, then exosomal DNA was extracted using a cell-free DNA isolation kit (Sigma). TaqMan real-time PCR was employed to detect HPV16 copy numbers. Lastly, exosomes isolated from 3 HPV+ patients’ SDF and 1 HPV- patient’s SDF were incubated with HPV- cell lines, SCC22A and SCC25, in order to query exosome-mediated HPV transmission. Results: TEM identified exosomes as round/oval-shaped vesicles measuring between 70 and 150 nm. NTA enumerated an average of 1.5 x 1011 particles per mL of SDF. WB further confirmed exosomal identity with strong CD63, CD9, and TSG101 signal detected. Among SDF exosomes from HPV+ OPC, 81% (n = 17) had detectable HPV16 DNA by real-time PCR, while all HPV- SDF exosomes (n = 5) showed undetectable HPV16. Paired comparison of HPV16 levels within exosomes to total HPV16 in SDF revealed an average of 90% of HPV16 in SDF was contained within exosomes. In an in vitro assay, SCC22A and SCC25 cells treated with HPV16 + exosomes became real-time PCR-positive for HPV16, while cells treated with HPV16- exosomes remained HPV16 negative. Conclusions: This study demonstrates that SDF, a novel post-surgical biofluid analyte, is enriched for HPV-containing exosomes in HPV+ OPC patients. We also found that exosomes from HPV+ OPC patients can transmit HPV to HPV-negative cells, suggesting a novel mode of virus-mediated spread of disease.