bluuebunny/crossref_metadata_2025_split huggingface dataset:
Detection rate and diagnostic accuracy of sentinel-node biopsy in early stage ovarian cancer: A prospective multicentre study (SELLY).
Authors: Nero Camilla , Bizzarri Nicolò , Di Berardino Stefano , Sillano Francesca , Vizzielli Giuseppe , Cosentino Francesco , Vargiu Virginia , De Iaco Pierandrea , Perrone Myriam , Vizza Enrico , Chiofalo Benito , Uccella Stefano , Ghezzi Fabio , Turco Luigi Carlo , Corrado Giacomo , Giannarelli Diana , Pasciuto Tina , Fagotti Anna , Scambia Giovanni 
Published: June 2023

e17579 Background: Comprehensive surgical staging of early epithelial ovarian cancer includes systematic paraaortic and bilateral pelvic lymphadenectomy but its therapeutic role is controversial and it is associated with potential severe morbidity. The feasibility of sentinel lymph-node (SLN) identification in early stage ovarian cancer has been shown only. We did a prospective multicenter study to assess the feasibility, detection rate and diagnostic accuracy of the SLN procedure in predicting the pathological pelvic-node status in patients with early stage ovarian cancer. Methods: This is a phase II single arm study (EUDRACT 2019-001088-58) including patients with presumed stage I-II epithelial ovarian cancer planned for immediate or delayed minimally-invasive comprehensive staging. The ovarian pedicle is injected with 2 mL of a 1.25 mg/mL indocyanine green (ICG) solution. The pelvic and lumbo-aortic retroperitoneum is then accessed and inspected to identify and remove SLNs. Staging is then completed including systematic pelvic and para-aortic lymphadenectomy and an histopathological examination of all nodes is performed. The primary endpoint was estimation of the sensitivity and sensibility of SLN in predicting nodal status. Assuming a sensitivity of 98.5% in predicting positive sentinel lymph nodes at histology, a pathological lymph node prevalence of 14.2%, a precision of estimate (i.e. the maximum marginal error) d=5%, a type I error α = 0.05, a sample size of 141 patients is needed to test the general hypothesis (i.e. to answer whether SLN(s) identified with ICG can accurately predict nodal status at histology of patients with apparently early EOC). Assuming a drop-out rate of 20%, a total of 176 patients will be enrolled in the study. Results: One-hundred and seventy-six patients were included with a drop-out rate of 22%. Sentinel node was identified in 102 patients (detection rate, 58%, [95% CI: 51-65]). There were no clinical differences between patients with successful or unsuccessful mapping. Both the infundibolopelvic ligament and the legamentum ovarii proprium were injected in 29.0% of cases. Twenty-one patients had positive nodes and 71% of them showed successful mapping. Among the latter, a negative sentinel node was identified in 3 patients (Sensitivity 78.6% [95% CI: 57-100]; Specificity 100%; Accuracy 97% [95% CI: 94-100]; PPV 100%; NPV 96,6% [95% CI: 93-100]). Twenty-two (12.5%) intra- and 25 (14.2%) postoperative complications occurred (12 G1; 9 G2; 2 G3, 2 G4). Clinical trial information: EUCTR2019-001088-58 .
Levels of ANGPTL3 and characterization of other circulating cholesterol-related factors in high-grade serous ovarian cancers.
Authors: Wong Chong Emilie Yan Pin , Joncas France-Hélène , Douville Pierre , Bachvarov Dimcho , Bergeron Ann-Charlotte , Blais Jonatan , Seidah Nabil Georges , Calon Frédéric , Diorio Caroline , Gangloff Anne 
Published: June 2023

e17583 Background: Cancer cells require important amounts of cholesterol to sustain their growth. High-grade serous ovarian carcinomas (HGSOC), as an aggressive form of ovarian cancer, are no exception. Mechanisms allowing HGSOC to secure their lipid supplies are not yet fully elucidated. Recent years have highlighted ANGPTL3, PCSK9 and Apo CIII as key players in lipid metabolism. To date, impact of HGSOC on these key lipid-regulating factors is scantly documented. Herein, we compared ANGPTL3, PCSK9, Apo CIII and Lp(a) levels in women with HGSOC versus benign ovarian lesion (BOL) to better understand lipid metabolism in HGSOC. Methods: Plasma samples from 31 women with a HGSOC and 40 women with a BOL were assayed for ANGPTL3, PCSK9, and Apo CIII levels by ELISA. The lipid panel, Apo B and Lp(a) levels were measured on a Roche Modular analytical platform. Results: Higher levels of ANGPTL3 was observed in HGSOC (84 ng/ml, SD ±29 ng/ml, n = 31) vs. BOL (67 ng/ml, SD ±31 ng/ml, n = 40); HGSOC vs BOL p = 0.019. Receiver operating characteristic (ROC) curve analyses for ANGPTL3 combined with age indicated an area under curve of 67.7% (p = 0.005). Partial correlations indicated associations between the lipid panel and ANGPTL3, but only for BOL. Conclusions: In this cohort of 71 women, ANGPTL3 levels were higher in patients with HGSOC. This finding requires further validation in a larger cohort of HGSOC patients.
Role of BRCA1 promotor methylation (BRCA1meth) in homologous recombination deficiency (HRD) in high-grade epithelial ovarian cancer.
Authors: Zeimet Alain G , Schnaiter Simon , Reimer Daniel Uwe , Wimmer Katharina , Schamschula Esther , Leitner Katharina , Steger Katharina , Marth Christian , Fiegl Heidi 
Published: June 2023

e17592 Background: In TCGA data BRCA1meth was found to be inferior to BRCAmut regarding prognosis in high-grade ovarian cancer. This was explained by a probably lower sensitivity to platinum-based chemotherapy. Methods: In 151 high-grade epithelial ovarian cancers (HGOC) tested for BRCA status, BRCA DNA methylation was determined using MethyLight PCR. Additionally, genome-wide loss of heterozygosity (LOH) and Aneuploidy Normalized Telemetric imbalance (ANTI) by means of SNP-Array analysis (GSA-24 v 3.0/Ilumina) as surrogates for “genomic scaring” in BRCA-independent HRD. For both parameters a “clinical-threshold” was calculated on the basis of platinum-response determined at the first recurrence according to the platinum-free interval. Both variables were integrated in a common HRD-Score with a cut-off value of ≥ 10.3 for HRD positivity. Results: In the present cohort PFS of BRCA1meth HGOC (n = 15; 10%) was not revealed to be inferior to BRCAmut HGOC. Worst PFS was observed in the subgroup of BRCAwt-unmethylated HGOC (p = 0.013) as compared to HGOC with genetic and epigenetic BRCA alterations. In line, neither LOH nor ANTI and consecutively also HRD-Score did prove to be statistically different in BRCAmut - and BRCA1meth-HGOC. However, BRCAwt-unmethylated HGOC exhibited significantly lower HRD-, LOH- and ANTI-Scores when compared with BRCAmut (p < 0.001) and BRCA1meth-HGOC (p < 0.005). All but one of the HGOC classified as platinum-refractory or -resistant at first relapse (92%) were BRCAwt-unmethylated. None of the BRCA1meth cancers were rated platinum-refractory or -resistant at progression and only one of the BRCAmut cancers was associated with platinum-resistant first relapse. 99% of the recurrences from HGOC with genetically or epigenetically altered BRCA genes were platinum sensitive, from which 78% were classified as “high-sensitive”. In multivariate analysis, HRD-Score was found to be of independent prognostic significance regarding PFS (p = 0.022); this was mainly due to the prognostic power of ANTI-Score (multivariate: p = 0.014) but not to that of genome wide LOH (univariate: p = 0.771). Conclusions: HGOC without genetic or epigenetic BRCA alterations exhibit the most unfavorable PFS. This is related to impaired platinum sensitivity. From a clinical point of view BRCA1 promotor methylation seems to confer an equivalent detrimental effect on the homologous recombination DNA repair mechanism than do pathogenic mutations of the BRCA genes. This is corroborated by a nearly identical extent of genome-wide scaring in both cancer subgroups.
TABLET: Relative bioavailability and bioequivalence study of niraparib tablets and capsules in patients with advanced solid tumors.
Authors: Falchook Gerald Steven , Patnaik Amita , Sharma Manish , Harvey R. Donald , Hamilton Erika P. , Hafez Navid , Wise-Draper Trisha M. , Barve Minal A. , Patel Manish R. , Dowlati Afshin , Richardson Debra L. , Faltermeier Christina , Ewesuedo Reggie , Kneissl Michelle , Potocka Elizabeth 
Published: June 2023

e17603 Background: Niraparib is a poly (ADP-ribose) polymerase inhibitor, approved as a maintenance treatment (tx) for patients (pts) with advanced ovarian cancer and under investigation in solid tumors, available in 100 mg capsules (starting dose: 200 or 300 mg/day). Compared with capsules, tablets have improved stability in hot and humid conditions. This study assessed the relative bioavailability (BA; Stage 1 [S1]) and bioequivalence (BE; Stage 2 [S2]) between niraparib tablets and capsules. Methods: This was a US, open-label, multicenter, single-cohort, randomized-sequence study with an optional extension phase. Eligible pts were ≥18 years, had histologically/cytologically confirmed advanced solid tumors (metastatic or local), disease progression despite standard therapy (if available), and ECOG performance scores of 0–2. Pts were dosed 1x300 mg tablet or 3x100 mg capsules then crossed over to the other tx after full washout. Pharmacokinetic (PK) parameters were assessed up to 168 hours post-niraparib dose; safety was assessed throughout and for 30 days after last dose (90 days for serious adverse events). A comparison of the log-transformed PK parameters (maximum observed plasma concentration [Cmax], area under the plasma concentration–time curve from time 0 to time of the last quantifiable concentration [AUC0–t] and from time 0 extrapolated to infinity [AUC0–∞]) was carried out to evaluate the formulations using a linear mixed-effects model with fixed effects for sequence, period, and tx and random effect for pt nested within sequence. Results: Pts in both stages completed study drug and washout/PK periods and had sufficient PK samples to estimate PK parameters in both periods. In S1 (n=29), a comparable BA performance of both formulations was demonstrated; the 90% confidence intervals (CI) of the geometric least square means (LSM) for Cmax, AUC0–t, and AUC0–∞ for tablet/capsule were within prespecified 0.80–1.25 limits (intra-pt variability: 12.4–21.9%). An initial 7-day washout period between PK assessments was extended to 14 days in S2 due to significant carryover reported in 6 pts in S1. In S2 (n=108), niraparib PK characteristics were similar following dosing with tablet or capsule (Table); LSM ratios of the key parameters were close to unity and 90% CI for the ratio of Cmax, AUC0–t, and AUC0–∞ were within prespecified 0.80–1.25 limits required to demonstrate BE. No new safety signals were reported. Conclusions: Both niraparib formulations were bioequivalent and can be used interchangeably. Editorial support was provided by Fishawack Health, funded by GSK. Clinical trial information: NCT03329001 . [Table: see text]
Clinical predictors of survival in advanced epithelial ovarian cancer: Can we foresee the long-term survivors and develop a personalized treatment approach?
Authors: Shachar Eliya , Raz Yael , Peleg-Hasson Shira , Laskov Ido , Mischan Nadav , Grisaru Dan , Wolf Ido , Safra Tamar 
Published: June 2023

e17605 Background: While women with recurrent disease have a poor prognosis, a subset of women are long term survivors (LTS). We aimed to characterize the demographic and clinical characteristics associated with long and short-term survival of patients with advanced epithelial OC (EOC). Methods: We conducted a retrospective descriptive analysis of 822 patients diagnosed with advanced EOC (FIGO stage III/IV) and treated at a single institution, between 2002-2020. Characteristics of short-term survivors (STS), women who survived less than 2 years, were compared to LTS, patients who lived beyond 7 and 10 years from diagnosis. Descriptive statistics of the clinical, oncologic, and treatment parameters were performed using t-test, chi-square. We assessed the contribution of age and stage, BRCA carrier status, interval or primary debulking, optimal debulking, platinum sensitivity, and treatment scheduling upon oncological outcomes. Results: Among 822 patients with advanced EOC, 112 women (13.6%) died withing 24 months from diagnosis, while 139 (16.9%), and 64 (7.8%) survived beyond 7 and 10 years, respectively. Histology, CA125 level at diagnosis, and interval or primary debulking approach, were not significant among the STS and LTS. LTS were younger at diagnosis, (median age of 57, and 56.5 among women who lived > 7 and 10 years, respectively vs. 70 in STS, p < 0.0001). The majority of LTS were diagnosed with stage III disease, (95%, and 97%, > 7 and > 10 years, respectively vs. 67% of STS), in contrast to a greater proportion of STS diagnosed with stage IV (33.0% of STS vs. 5.0%, 3.1% of LTS > 7 and > 10 years, respectively, p < 0.0001). BRCA mutation status was the strongest prognostic factor for LTS ( > 7 and 10 years, OR = 17.8, 21.2 respectively, p < 0.001). Almost half of LTS who were carriers of a deleterious BRCA mutation, (47.3%, 46.2% of LTS > 7 and 10 years, respectively, p < 0.0001), whereas most STS were not carriers of BRCA mutations (89.8%). LTS were predominantly platinum sensitive (99.3%, 98.4% > 7 and > 10 year, vs. 21.6% of STS, P < 0.0001). Optimal cytoreductive surgery was performed in a smaller number of STS compared to the LTS (41.9% of STS vs. 83.5% and 88.7% of LTS > 7 and 10 years, respectively, p < 0.0001). A greater proportion of LTS received weekly treatment scheduling of paclitaxel and carboplatin compared to STS (50.8% and 49.2% of LTS > 7 and 10 years, respectively vs. 31.6% of STS, p < 0.01). Conclusions: The long and short-term survivors of advanced EOC may be identified early in the clinical assessment, based on distinct patient characteristics associated with survivorship, which are critical in developing a personalized treatment approach. Our work demonstrated that LTS are a distinct group of women diagnosed at a younger age, lower stage, optimally debulked, platinum sensitive disease, and BRCA mutation carriers.
Targeting HE4 for treatment of endometrial cancer using a novel small molecule inhibitor.
Authors: Morell Alexandra , Miller John , Zhang Naixin , Snyder Cameron , Khazan Negar , Strawderman Myla S. , Singh Rakesh , Kim Kyu Kwang , Turner Rachael , Moore Richard G. 
Published: June 2023

e17616 Background: HE4 expression is upregulated in endometrial cancer and has been shown to have prognostic significance in endometrial cancer patients. High-throughput screening and lead optimization led us to discover UR-238, a novel small molecule inhibitor of HE4. The purpose of this study was to investigate the in vitro and in vivo effects of UR-238 in treatment of endometrial cancer. Methods: UR-238 was identified by focused medicinal chemistry. Six endometrial cancer cell lines (ECC1, AN3CA, HEC1A, MFE296, MFE280, and KLE) were grown in cell culture and treated with 8 concentrations of UR-238 (125 nM, 250 nM, 375 nM, 500 nM, 625 nM, 750 nM, 875 nM, and 1000 nM) or DMSO (control). Cell proliferation was assessed using SRB assays at 24 and 48 hours. Effects of UR-238 on the cell cycle were assessed by flow cytometry and related cell-cycle proteins were targeted via Western blots. An ELISA was performed to evaluate UR-238 treatment effect on HE4 expression. An AN3CA xenograft mouse model was used to assess in vivo effects of UR-238. Mice were treated with vehicle control or UR-238 (5 mg/kg, IP, 3 days/week) for 20 days (N=5/group). Tumor volume and weight were evaluated over time using a repeated measures ANOVA. Results: UR-238 resulted in decreased cell proliferation in a dose-dependent manner in all 6 endometrial cancer cell lines. UR-238 increased expression of p21 and p27 and induced M/G2 cell cycle arrest. UR-238 also downregulated HE4 expression. In vivo treatment with UR-238 of AN3CA expressing xenograft mice caused a significant reduction (p=0.02) in mean tumor volume compared with vehicle control after 20 days (control mean 1068.13 mm3, SE 239.76; UR-238 mean 265.62 mm3, SE 68.82). Conclusions: UR-238 inhibits cell proliferation in endometrial cancer cell lines and exhibits antitumorigenic effects in xenograft mouse models. Future studies are warranted as UR-238 may be a promising therapeutic agent for treatment of endometrial cancer.
Lynch screening and genetic testing in endometrial cancer in a diverse population.
Authors: Kim Kee-Hwan Michael , Hayek Judy , Acker Cheyenne , An Anjile , Zhang Peilin , Gorelick Constantine , Kanis Margaux Jenna 
Published: June 2023

e17619 Background: Lynch syndrome (LS) accounts for most of the inherited endometrial cancers. Universal screening of endometrial tumors for defects in DNA mismatch repair (MMR) is recommended using immunohistochemistry (IHC) to identify which patients qualify for genetic counseling and testing. We report Lynch screening and genetic testing rates at a New York City tertiary care center with a large minority population, while investigating any potential disparities. Methods: This is a retrospective cohort study of patients with newly diagnosed endometrial cancer between January 2014 and June 2022. Data were obtained from pathology and chemotherapy databases at the NewYork-Presbyterian Brooklyn Methodist Hospital. Variables including age, race, ethnicity, BMI, insurance, language, family history of cancer, date of diagnosis, stage, MMR IHC, and genetic counseling/testing status were manually extracted. Descriptive statistics were used. Chi-square/Fisher’s exact tests were used to examine the association between genetic counseling/testing and categorical variables. Wilcoxon rank-sum/t-tests were used for continuous factors. The Mann-Kendall trend test was used to determine the significance of time trends. Results: 373 patients were identified. 45% identified as white, 42% black, 1.3% Asian, 12% other/unknown; 8.3% were of Hispanic ethnicity and 18% were non-English speaking. Mean age at diagnosis was 66 years (SD:10). 207 (55%) patients were screened using MMR IHC. 82 (40%) of these patients had MMR deficiencies on IHC. Of these, 63 (77%) received genetic counseling. 62 (98%) of those counseled subsequently underwent genetic testing, and ultimately 7 (11%) were diagnosed with LS. The overall rate of LS detected was 1.9% in the study population. The rate of MMR IHC testing has been increasing, reaching 95% in 2021 and 100% in 2022. It was associated with significant differences in mean age at diagnosis (p < 0.01) and insurance type (p = 0.04). 45% of patients that received MMR IHC had private insurance, compared to 34% of patients that did not. The rate was not influenced by race, language, BMI, family history of cancer, or stage. The proportion of patients that received genetic counseling and testing for endometrial cancer also showed a significant upwards trend over time (p < 0.01). Genetic counseling and testing rates were significantly different by ethnicity (p = 0.03), with only 3.0% of patients receiving genetic counseling/testing identifying as Hispanic. 98% of genetic counseling was performed by a gynecologic oncologist, as opposed to a genetic counselor. Conclusions: There were no disparities in access to initial IHC screening in this diverse patient population, however more work must be done to reach all ethnicities for genetic counseling and testing. The rate of LS detected was less than the known prevalence in endometrial cancer, possibly indicating demographic differences or gaps in screening.
Treatment with lenvatinib plus pembrolizumab in recurrent or advanced endometrial cancer: A systematic review and meta-analysis.
Authors: Moraes Francisco Cezar A , Vilbert Maysa , B Carnevalli Sarah Vitoria , Almeida Gustavo de Oliveira , Feio Danielle , Stecca Carlos , Da Costa Alexandre Andre B. A. 
Published: June 2023

e17630 Background: Endometrial cancer (EC) is the second most prevalent gynecological cancer. After failure to first-line platinum-based chemotherapy, treatment options are sparse, but recent studies have investigated new approaches with promising results. We conducted a systematic review and meta-analysis to evaluate the efficacy and safety of Lenvatinib plus Pembrolizumab in patients with advanced or recurrent EC. Methods: PubMed, Web of Science, Cochrane, Scopus, and LILACS databases, Central Register of Clinical Trials, and congresses publication websites were searched for studies using Lenvatinib plus Pembrolizumab in advanced or recurrent EC with progression after platinum-based chemotherapy. Outcomes of interest were best overall response rate (BORR) and disease control rate (DCR), on intention-to-treat (ITT) and per-protocol analyses, and according to mismatch repair status. Progression free-survival (PFS) and overall survival (OS) were also assessed. Heterogeneity was examined with the Cochran Q test and I2 statistics. We use a DerSimonian and Laird random-effects model. Results: Four studies, with 637 patients, were included: two clinical trials and two retrospective observational cohorts. Endometrioid EC was the predominant histology (53%), and most patients had mismatch repair-proficient tumors (pMMR, 86.5%). In a pooled analysis, with a medium follow-up of 12.2 months, BORR was 31% (95%CI 26, 37), and DCR was 74% (95%CI 65, 83) on ITT. CR, PR, and SD were documented in 37 (5.8%),168 (26.3%) and 284 (44.5%) patients, respectively. BORR was 48% in microsatellite unstable tumors compared to 31% in stable microsatellite disease (p = 0.07), while DCR was similar in both groups (p = 0.33). Median progression-free survival was 7.2 months (95%CI 3.2, 7.4), and median overall survival was 18.3 months (95%CI 8.6, 18.3) in patients receiving Lenvatinib and Pembrolizumab. The most common treatment-related adverse events (AE) included diarrhea 277/514 (53.8%), nausea 244/514 (47.4%), hypothyroidism 288/562 (39.1%), hypertension 338/632 (36.9%), fatigue 213/632 (31.0%), and vomiting 178/514 (34.6%). Grades 3 or 4 AE was reported in 436/514 (79.6%) patients. Overall, dose reductions, treatment interruptions, and discontinuation due to toxicities were required in 61%, 63%, and 27% of patients, respectively. Conclusions: This systematic review and meta-analysis reinforce the antitumor activity of the combination of Pembrolizumab and Lenvatinib in patients with advanced or recurrent EC, regardless of MMR status. Despite high rates of serious adverse events related to treatment, most were manageable.