bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 1/2 study of ARTS-021, a potent, oral administrated, selective CDK2 inhibitor, in advanced or metastatic solid tumors.
Authors: Wang Yan 
Published: June 2023

e17546 Background: ARTS-021 is an investigational, reversible, orally available CDK2 selective inhibitor that inhibits CDK2 at nanomolar potency and with over 600-fold selectivity against CDK1 (Liang J et al. AACR 2022). ARTS-021 has shown promising preclinical data, including strong single agent antitumor activity in CCNE1 amplified patient derived xenografts (PDX). Furthermore, consistent with the hypothesis that CDK2 activity may mediate resistance to CDK4/6 inhibitors, ARTS-021 significantly enhanced Palbociclib anti-tumor activity in an estrogen positive (ER+) breast cancer xenograft model. Taken together, these data support the clinical development of ARTS-021 as a monotherapy in CCNE1-amplified cancers and in combination with CDK4/6 inhibitors in ER+ breast cancer. Methods: A first in human, open label, multicenter phase1/2 dose escalation and dose expansion study will be conducted to evaluate the safety, tolerability, PK, pharmacodynamics (PD), and anti-tumor activity of ARTS-021 1) as a single agent in advanced or metastatic solid tumors harboring CCNE-1 gene amplification; 2) in combination with carboplatin to treat refractory/resistant CCNE-1 amplified ovarian cancer that has failed standard therapies; 3) in combination with endocrine therapy and CDK4/6 inhibitor to treat ER+/HER2- breast cancer patients have failed standard therapies. The phase 1 (dose-escalation) portion of the trial will have an accelerated dose escalation followed by a Bayesian Optimal Interval (BOIN) design. After the monotherapy recommended phase 2 dose (R2PD) is identified, the combination arms will be initiated at one dose level below the monotherapy R2PD. Phase1 primary endpoints are assessment of safety, tolerability, and pharmacokinetics (PK). The secondary endpoint is preliminary efficacy. Once the RP2D is defined for both monotherapy and in combination, the trial will be advanced into three Phase 2 expansion cohorts: monotherapy cohort (basket cohort), combination with carboplatin (ovarian cohort), and combination with endocrine therapy + CDK4/6 inhibitor (ER+ breast cancer cohort). The phase 2 primary end point is to estimate the anti-tumor efficacy in CCNE1 amplified cancer patients or CDK4/6 inhibitor resistant breast cancer patients. Objective tumor response rate will be measured per RECIST v1.1. The secondary endpoint of Phase 2 study will be safety/tolerability. Archival tumor and paired fresh tumor biopsy will be collected throughout the study for exploratory pharmacodynamics (PD) and biomarker evaluation. Results: ARTS-021 clinical study is ongoing. Conclusions: ARTS-021 shows potential anti-tumor activities.
Effect of multi-targeting bacterial gene therapy on tumour regression and survival in mouse models of ovarian and intraperitoneal cancer.
Authors: Samaranayake Haritha , Kurkipuro Jere , Smith Wesley , Mierau Igor , Kärkkäinen Hanna-Riikka , Tikkanen Mirka , Décory Laurent , Wirth Thomas , Yrjänheikki Juha 
Published: June 2023

e17550 Background: With a prevalence of more than 2 million cases, a 5-year survival below 20% in stage 3 and 4, and limited treatment options, ovarian cancer represents a significant unmet medical need. We assessed the efficacy of AUP-55, a genetically engineered Lactococcus cremoris for the treatment of ovarian cancer and peritoneal carcinomatosis. We evaluated the efficacy of two AUP-55 leads producing human therapeutic proteins in situ; namely interleukin 18 (IL-18), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-12 (IL-12) and interferon alpha (IFN-A) in syngeneic intraperitoneal ID8 ovarian cancer and B16F1 melanoma models in mice. Methods: ID8-Luc-mCherry-Puro ovarian cancer model was used for survival and tumor burden by bioluminescent imaging with post-mortem pathology for all animals, whereas the B16F1 melanoma model was used solely for survival. Animals were treated daily or every other day with i.p injections of the AUP-55 leads (1e8 CFU/dose for 12-22 times). Results: In the ID8 model treatment was started 14 days after tumor implantation. Most untreated mice were terminated due to the disease progress. Treatment with AUP-55 resulted in 91.3 % survival and lower tumor load during the study duration of 81 days compared to the 0 % survival and massively increased tumor load in untreated mice. When compared to the available data from the CRO, the survival advantage was superior to, for example anti-PD1 and cisplatin treatments in the same model. In the B16F1 model, treatment with AUP-55 led to 90 % survival in comparison to 10 % untreated mice. All AUP-55 treatments were well tolerated. In the pathology post-mortem, all untreated animals had typical findings for ovarian cancer, such as ascites and high number of tumor nodules present in abdominal cavity, liver, spleen, kidney and pancreas. In the group treated with AUP-55 there were no macroscopic tumor deposits detected. Conclusions: Cytokine armed Lactococcus cremoris AUP-55 enables multimodal action. Treatment with AUP-55 suggests anti-tumor activity as a single therapeutic entity for the treatment of ovarian cancer and peritoneal carcinomatosis.
A combination of niraparib plus anlotinib in patients with platinum-resistant ovarian clear cell carcinoma: Results of a single-arm phase II study (CC-ANNIE study).
Authors: Lin Shaodan , Gao Ming , Li Jing , Wang Lijuan , Lin Zhong-qiu , Zhang Bingzhong 
Published: June 2023

e17552 Background: Ovarian clear cell carcinoma (OCCC) is a histological subtype of epithelial ovarian cancer with distinct biological and molecular characteristics. Patients with platinum-resistant OCCC have a poor prognosis and their treatment represents a significant unmet medical need. Studies have suggested potential efficacy of targeting DNA damage response pathways and inhibition of angiogenesis in OCCC. We hypothesised that patients with platinum-resistant OCCC might benefit from a combination of the poly (ADP-ribose) polymerase (PARP) inhibitor niraparib and the anti-angiogenic agent anlotinib. Methods: This was a phase II, single-arm, two-stage study with a Simon’s two-stage optimal design. The trial could continue to stage 2 if ≥1 responses were observed in the first 6 patients. Eligible patients had histologically confirmed OCCC that was platinum resistant, defined as progression within 6 months after their most recent platinum-based chemotherapy. Use of prior bevacizumab was permitted but prior PARP inhibitor or tyrosine kinase inhibitor treatments were not. Patients received niraparib (300 mg/day or 200 mg/day [baseline body weight < 77 kg, platelet count < 150,000/μL], orally) plus anlotinib (10 mg/day, orally, 2 weeks on and 1 week off, every 3 weeks) until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) assessed by investigators according to the RECIST V.1.1. Secondary endpoints included disease control rate (DCR), time to response (TOR), duration of response (DOR), safety and investigator-assessed progression-free survival (PFS) and overall survival (OS). Results: Between January 2022 and August 2022, 6 eligible patients were enrolled and included in the analyses. The median duration of treatment was 9.8 (range, 6.5 to 19.0) weeks. Of the 6 patients, 0 patients (0%) achieved an objective response, resulting in a confirmed ORR of 0%. The DCR was 50% (0 complete response, 0 partial response, 3 stable disease). With a median follow-up time of 7.5 (range, 3.5 to 10.0) months, all patients experienced disease progression, with a median PFS of 12.0 (95% confidence interval [CI], 3.6 to 20.4) weeks. Frequent treatment-related adverse events (AEs) included hypertension (33.3%), thrombocytopenia (33.3%), and hand-foot syndrome (16.6%). Conclusions: The phase 2 CC-ANNIE study did not meet the primary efficacy endpoint. The combination of niraparib and anlotinib did not show activity in patients with platinum-resistant OCCC. Clinical trial information: NCT05130515 .
Impact of postoperative residual disease in patients with primary epithelial ovarian cancer in the era of maintenance therapies with targeted agents: A systematic review and meta-analysis.
Authors: Kim Ji Hyun , Kim Se Ik , Park Eun Young , Ha Hyeong In , Kim Jae-Weon , Coleman Robert L. , Bristow Robert E. , Park Sang-Yoon , Fotopoulou Christina , Lim Myong Cheol 
Published: June 2023

e17555 Background: To investigate the impact of residual disease after cytoreductive surgery for epithelial ovarian cancer (EOC) on survival outcomes in the era of targeted maintenance approaches, including bevacizumab and poly (ADP-ribose) polymerase (PARP) inhibitor administration. Methods: We searched relevant literature from the MEDLINE, Embase, and Cochrane Library databases to identify randomized controlled trials and prospective clinical trials of primary EOC published between 1 January 2000 and 22 September 2022. To evaluate the impact of postoperative residual tumors on PFS and OS, we constructed a linear regression model for log-transformed median progression-free survival (PFS) and overall survival (OS). Patients with and without first-line maintenance therapy were examined. The protocol was registered in the PROSPERO (CRD42021265810). Results: In total, 97 trials with 41,799 patients were included: 2476 received PARP inhibitors, and 6920 received bevacizumab. The median rate of complete cytoreduction was 36.3% (range, 0–99.4%), regardless of the timing of surgery. Multivariable analysis of the linear regression model of all studies revealed that the median OS increased by 12.97% for every 10% increase in complete cytoreduction rates, independently of the use of systemic maintenance. In subgroup analysis of patients with maintenance therapies, the effect of complete tumor clearance was potentiated, with a median OS increased by 19.13% for every 10% increase in complete cytoreduction rates. The previously described significant effect of total macroscopic tumor clearance of PFS could not be retained when adjusting for maintenance treatment. Conclusions: Total macroscopic tumor clearance at the initial presentation of EOC significantly prolongs OS. Our results establish the importance of complete surgical cytoreduction in the era of novel targeted systemic agents.
Posterior reversible encephalopathy syndrome in malignancy: Hypercalcemic storm?
Authors: Dandwani Mehndi , Chennapragada Suma Sri , Sharma Shivani , Ramphul Kamleshun , Lohana Petras 
Published: June 2023

e17559 Background: Posterior reversible encephalopathy syndrome (PRES) is a clinical-radiological entity characterized by seizures, headaches, altered mental status and visual anomalies associated with vasogenic edema affecting the parietal-occipital lobes on brain magnetic resonance imaging. PRES is rarely described in hypercalcemia of malignancy although multiple mechanisms have been postulated in various case reports. Hence, we conducted this study to evaluate whether there is an increased risk of PRES with hypercalcemia of malignancy. Methods: We analyzed the 2016-2020 National Inpatient Sample (NIS) and extracted patient data with a diagnosis of ovarian cancer, lung cancer, multiple myeloma (MM), breast cancer, diffuse large B-cell lymphoma (DLBCL), and secondary bone cancer. Cases with a history of primary hyperparathyroidism, vitamin D intoxication and familial hypocalciuric hypercalcemia were excluded. The presence of hypercalcemia and PRES were estimated (per 10,000 cases), and their respective adjusted odds ratios (aOR) were calculated via multivariate regression analysis. Results: We identified 1,775 PRES cases in 3,781,899 cancer patients studied. Patients with breast cancers (26 per 10,000 hypercalcemia cases vs. 4 per 10,000 cases with no hypercalcemia, aOR 4.523, 95% CI 3.418-5.984, p < 0.01), ovarian cancers (41 per 10,000 hypercalcemia cases vs. 8 per 10,000 cases with no hypercalcemia, aOR 5.224, 95% CI 3.075-8.875, p < 0.010), and secondary bone neoplasms (14 per 10,000 hypercalcemia cases vs. 5 per 10,000 cases with no hypercalcemia, aOR 2.160, 95% CI 1.671-2.793, p < 0.01) exhibited a statistically significant increased outcome of PRES in association with hypercalcemia. The presence of hypercalcemia among lung cancer patients (aOR 0.755, 95% CI 0.451-1.263, p = 0.284), MM (aOR 1.005, 95% CI 0.751-1.346, p = 0.973), and DLBCL (aOR 1.393, 95% CI 0.806-2.408, p = 0.236) did not show a valid odds ratio for PRES. Conclusions: Our study found a higher association of PRES among hypercalcemia patients with ovarian cancer, breast cancer and secondary bone neoplasms. Prompt recognition of PRES and hypercalcemia-directed treatment can allay the morbidity related to PRES. While our study was limited in quantifying the cut-off values of hypercalcemia causing PRES, designated protocols entitled solely to determining serum calcium thresholds in these cancers warranting rigorous treatments are needed. PRES’s association with hypercalcemia in female-dominant cancers also paves way for further studies looking into the influences of sex hormones and hormonal therapies on the development of PRES with hypercalcemia.
Quality of life (QoL) in patients with recurrent ovarian clear cell carcinoma (rOCCC) receiving durvalumab (D) versus physician’s choice chemotherapy (PCC) in the randomized phase II MOCCA/APGOT-OV2/GCGS-OV3 trial.
Authors: Ngoi Natalie YL , Sun Haoyang , Choi Chel Hun , Heong Valerie , Ow Samuel Guan Wei , Chay Wen Yee , Kim Hee Seung , Goss Geraldine , Goh Jeffrey C. , Lin Meiqi , Lim Diana , Kim Jae-Weon , Friedlander Michael , Tai Bee Choo , Kim Kidong , Tan David Shao Peng 
Published: June 2023

e17564 Background: In the phase II MOCCA/ APGOT-OV2/ GCGS-OV3 trial, D was not superior to PCC in prolonging progression-free survival in patients with rOCCC. Fewer all-grade and high-grade adverse events were observed for patients treated with D compared with PCC. We analysed health-related QoL by treatment arm. Methods: In this multicentre, open-label, randomised phase II trial, eligible patients were randomly assigned (2:1), using dynamic block randomization with block size of 6, and stratification by Eastern Cooperative Oncology Group performance status, to receive D (1500mg on day 1, in 28-day cycles) or PCC until disease progression, intolerable toxicity or withdrawal of consent. Patients treated with PCC were able to receive any agent deemed appropriate by the Investigator, however the addition of anti-angiogenic drugs was prohibited. Patients with disease progression on PCC were allowed to crossover to D. Patients completed European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-OV28 QoL questionnaires at baseline and every 4 weeks until end of study treatment. The minimal important difference for clinically relevant change was fixed at 10 points. Linear mixed-effects models were used to estimate the treatment effect on QoL outcomes, accounting for the intra-subject correlation in QoL scores at repeated visits from treatment cycles 2 to 6, while adjusting for baseline QoL scores (cycle 1 day 1) and time of visit. We included all patients whose QoL scores were available at both baseline and at least one visit from cycles 2 to 6. Results: 47 patients were randomly assigned to treatment with D (31 patients) or PCC (16 patients). Compliance to QoL questionnaires was 81.6 % (D) and 87.5% (PCC) at baseline. QoL data was available for 22.6-81.6% (D) and 31.3-87.5% (PCC) of patients over time. Longitudinal analysis of QoL data by domain revealed no significant differences in global health status, functional scales or most of the symptom scales based on EORTC QLQ-C30 or QLQ-OV28 between patients treated with D compared with PCC, except for the Constipation symptom scale on QLQ-C30 which showed an estimated mean difference of -20.8 points (95% confidence interval (CI), -31.5 to -10.2; p = 0.001) and the Hair loss symptom scale on QLQ-OV28 which showed an estimated mean difference of -19.6 points (95% CI -36.6 to -2.6; p = 0.025). Conclusions: D and PCC did not lead to significant differences in patient-reported global health status or functional scales. However, PCC was associated with increased patient-reported constipation and hair loss compared with D in rOCCC. Clinical trial information: NCT03405454 .
The landscape of BRCA1 and BRCA2 alterations in Chinese ovarian cancer patients.
Authors: Hou Minmin , Sun Li , Yu Xiuzhang , Du Pengyao , Liu Chuang , Meng Fanfan , Zhang Yaxuan , Li Ling 
Published: June 2023

e17565 Background: BRCA1 and BRCA2 are tumour suppressor genes, involved in the homologous repair of double-stranded DNA breaks, located at 17q21.31 and 13q13.1, respectively. Germline BRCA1/2 mutations are identified in 13-15% of ovarian cancers (OC), while an additional 5-7% of ovarian cancers harbor somatic BRCA1/2 mutations among foreign populations. To determine the landscape of germline and somatic pathogenic BRCA1 and BRCA2 alterations in Chinese patients with ovarian cancer tested by next‐generation sequencing (NGS), with the aim of defining the best strategy to be implemented in future routine testing. Methods: 472 normal-paired samples from Chinese patients with ovarian cancers were analyzed using hybridization capture-based next generation sequencing. Somatic and germline mutations were identified including 500 genes associated with tumor development. Sequencing data were analyzed to call tumor specific single nucleotide variants (SNV), small insertions and deletions (InDels), copy number alterations (CNA) and gene fusions and rearrangements. Results: Overall, 472 ovarian cancer patients underwent somatic and/or germline NGS analysis, the BRCA1 and BRCA2 genes sequenced in this study covers all targeted coding exons and exon-intron boundaries. Among these patients, 54/472 (11.4%) patients carried BRCA( BRCA1/2) mutations. Inside, there were 43/472 (9.1%) patients occurred somatic BRCA mutations, 62.8% (27/43) of variants were in BRCA1 and 37.2% (16/43) were in BRCA2. Furthermore, 3 cases carried BRCA1 and BRCA2 somatic co-mutation, of which only 1 showed BRCA1/ BRCA2 copy number losses. In 54 OC patients who carried BRCA mutations, 10 patients occured copy number alterations, of which 6 patients showed BRCA1 copy number losses, 4 patients showed BRCA2 copy number losses, and 1 patient showed BRCA2 copy number gains. Germline BRCA variant was detected in 18/472 (3.8%) patients, 66.7% (12/18) of variants were in BRCA1 and 33.3% (6/18) were in BRCA2. Of the 12 BRCA1 germline mutations, 11 were pathogenic heterozygous mutations (c.2679_2682del; c.2101_2102del; c.5085_5086insT; c.1660G > T; c.4810C > T; c.1504_1508del; c.1465G > T; c.1480C > T; c.2110_2111del; c.4185+1G > A; c.81-2A > G), one was likely pathogenic heterozygous mutation (c.5216A > G). Of the 6 BRCA 2 germline mutations, four were pathogenic heterozygous mutations (c.5722_5723del; c.5291C > G; c.5164_5165del; c.3109C > T), one was likely pathogenic heterozygous mutation (c.869_870del), and one was uncertain significance heterozygous mutation (c.7976+3A > G). Conclusions: This study revealed the molecular features of BRCA1 and BRCA2 in Chinese ovarian cancer patients, which could help to identify therapeutic targets and personalize therapy management, leading to improved patient outcomes as predictive biomarkers or platinum-based therapy.
A web-based prediction model for overall survival of elderly patients with epithelial ovarian cancer: A population-based study.
Authors: Tang Lingliya , Song Kun , Chu Ran , Chen Zhongshao , Zhao Yong , Wang Shuaixin 
Published: June 2023

e17570 Background: Epithelial ovarian cancer (EOC) has been extensively studied. However, no prediction model has been carried out on the prognosis of elderly patients. Our study aims to explore survival patterns in elderly EOC patients. Methods: Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Patients over 65 with EOC between 2004 and 2014 were included for model training and validation, while 2015 for external validation. COX proportional-hazards regression model was used to identify risk factors and applied them to the prediction model. We then evaluated performance of our model through receiver operating characteristic (ROC) curve, calibration curve and decision curve analysis (DCA). Risk stratification system was used to reflect the survival. To facilitate daily use, we developed an online application. Results: A total of 6141 patients were included. COX regression models indicated 10 independent risk factors. Our model was proved to have good performance with AUC of ROC curve: 0.768(95CI:0.749-0.788), 0.748 (95CI:0.733-0.763), 0.766 (95CI:0.750-0.781) for 1-, 3-, 5-year OS in the training cohort and 0.776 (95CI:0.757-0.796), 0.760 (95CI:0.745-0.775), 0.784 (95CI:0.769-0.799) for CSS. In the validation cohort, 0.800 (95CI:0.773-0.827), 0.770 (95CI:0.748-0.793), 0.787 (95CI:0.765-0.810) for OS and 0.808 (95CI:0.780-0.836), 0.780 (95CI:0.758-0.803), 0.801 (95CI:0.779-0.824) for CSS. In the risk stratification system, the low-risk group had the highest survival rate. Almost all patients in the low- and intermediate-risk groups underwent surgery, about 1/3 patients in the high-risk group did not receive surgery. Their survival rates were not optimistic, and patients over 85 were more likely to be classified as high-risk. Conclusions: A predictive model was constructed to evaluate survival for elderly EOC patients and demonstrated good predictive value that we can apply to help physicians make clinical decisions and plan treatment. [Table: see text]