bluuebunny/crossref_metadata_2025 huggingface dataset:
Maintenance therapy for patients with recurrent or metastatic cervical cancer: A multicentre, cohort study.
Authors: Peng Chen , Guo Qiufen , Zhang Tingting , Chen Jinlong , Liu Naifu , Yan Peile , Lu Yuanyuan , Ma Anqun , Lv Pengzhong , Liu Jing , Xie Peng
Published: June 2023

e17518

Background: Maintenance therapy with alternative agents after chemotherapy was shown to improve the overall survival in some advanced cancers such as breast cancer, lung cancer, ovarian cancer and so on. However, maintenance therapy is not accepted as the standard treatment for recurrent/metastatic cervical cancer. Aim of this study is to elucidate the efficacy of maintenance therapy in cervical cancer and to explore the factors associated with the prognosis of recurrent or metastatic cervical cancer. Methods: In this multicenter cohort study, we retrospectively collected patients with a diagnosis of either recurrent or stage IVB cervical cancer to receive first-line chemotherapy with or without maintenance therapy. Patients did not have disease progression with chemotherapy and were divided into maintenance therapy group (Arm A) and conventional chemotherapy group (Arm B). Information on clinical characteristics, metastasis information, treatment outcome and survival of patients was collected using an electronic medical record system. The endpoints of the study were OS and PFS. Data were analyzed for general characteristics and survival using SPSS25.0 software, and the results were considered statistically significant at P < 0.05. Results: Between January 2019 and July 2021, a total of 270 patients were enrolled from 6 institutions in China. 26 patients were excluded because of short treatment cycles (less than 3 cycles). Finally, a total of 66 patients in Arm A and 178 patients in Arm B were analyzed for survival. The addition of maintenance significantly prolonged overall survival. Overall survival at 3 year was 50.1% in Arm A and 27.8% in Arm B (median overall survival, ≥36 months vs. 22 months; P < 0. 001). The median progression-free survival was 21 months in Arm A and 14 months in Arm B (P = 0.025). Univariate survival analysis showed that age, maintenance therapy, combined radiotherapy, and number of extra-pelvic metastases were associated with PFS. Further multifactorial analysis showed that maintenance therapy, combined radiotherapy, and number of extra-pelvic metastases were independent prognostic factors for patients with recurrent or metastatic cervical cancer. Conclusions: The addition of maintenance therapy significantly prolonged overall survival as well as progression-free survival in patients with recurrent or metastatic cervical cancer and did not increase the incidence of serious adverse events. It is time to consider maintenance therapy as the standard treatment after conventional chemotherapy for recurrent or metastatic cervical cancer, rather than waiting for disease progression.
The perception of cervical cancer screening and prevention among Saudi women.
Authors: Abusanad Atlal M. , Alharbi Lama , Alsalamah Seham , Almasary Manal , Alharthi Amnah , Al-hajeili Marwan R.
Published: June 2023

e17519

Background: Cervical cancer (CC) is the fourth cause of malignancy-related deaths among women globally. In Saudi Arabia, it is the 8th most prevalent cancer and the 7th cause of cancer mortality among women between the ages of 15–44. There is a limited national data on the awareness of CC, human papilloma virus (HPV), and knowledge of screening and prevention. We present the largest national study to date investigating knowledge of Saudi women toward CC, the HPV vaccine, Pap smear, and influencing factors of their application. Methods: A structured questionnaire of 22 questions included demographic data, CC awareness and associated risk factors, evaluation of Pap-smear and HPV vaccine knowledge and their application was constructed and validated. Participants were exclusively female. It was distributed across the country and scored according to a pre-defined scoring system. Influencing factors of CC, Pap-smear and HPV vaccine knowledge and awareness were examined. A regression model to predict the possibility of performing Pap-smear was generated. P-value of 0.05 and less indicated statistical significance in all tests. Results: 2539 female participants completed the questionnaire with (41%) aged 18 - 25 years old. A sizable portion were from the central region (30.4%) and a majority had a university degree (73.1%). 65% of the participants were sexually active. Two thirds of the participants have heard about Pap-smear and its role in detecting CC but only 20% took the test. Although one third knew that the HPV vaccine can prevent CC, only 2% received the vaccination. Poor knowledge on locating the Pap-smear and HPV vaccine were reported among participants. 12% reported that health campaigns were their source of information. Factors associated with adequate knowledge are listed in table. Age predicted the possibility of performing Pap-smear with participants of 18 - 25 years old are more likely to take the test (P=0.00). Conclusions: This large study evaluated the knowledge and awareness of CC, Pap-smear, and the HPV vaccine across the country. It demonstrated the need for better advocacy and for a nation-wide campaigning to further utilize early detection and preventive procedures. [Table: see text]
Ribosomal protein S26 (RPS26) expression of advanced cervical cancer (CC) to predict response to programmed death-1 inhibitor combination therapy: A secondary analysis of the CIBI308ALTER-C201 trial.
Authors: Liu Jing , Li Li , Chen Ying , Song Yanwen , Luo Lan , Zhu Shitao , Xu Qin
Published: June 2023

e17520

Background: PD-1 inhibitor combination therapy is widely used in cervical cancer, and improves prognosis. However, there is still a lack of effective predictive markers. The results of previous single-cell analysis of cervical cancer in our research group suggested that RPS26 is related to changes in the immune microenvironment. The purpose of this study is to evaluate whether RPS26 can be used as a prognostic marker for cervical cancer PD-1 inhibitor combination therapy. Methods: A total of 36 patients with CC were recruited. 18 patients were from CIBI308ALTER-C201 trail，and the other 18 were not. All patients underwent next-generation sequencing (NGS). Tumor RPS26 expression was assigned by immunohistochemistry as follows: 0, 1+, 2+, 3+. Significant difference was tested by Fisher's exact test. Kaplan-Meier analysis were applied for survival analysis. Results: The PFS of patients from CIBI308ALTER-C201 trail was significantly longer among patients with RPS26 expression for 2+/3+ than 0/1+ (not reached v 9.877 months, p= 0.0497). There were 11, 14, 9 and 2 patients with RPS26 expression of 0, 1+, 2+, and 3+, respectively. There were 12 and 24 for PIK3CA mutant patients and wild-type, respectively. There was no patient with RPS26 expression for 0 in the PIK3CA mutant group, and 9 patients with RPS26 expression for 0 in the PIK3CA wild group. The expression of RPS26 was significantly different between the two groups ( p= 0.0163). Conclusions: Our study suggested that RPS26 could be novel predictive biomarkers in patients with CC treated with PD-1 inhibitor combination therapy, and PIK3CA mutation enhances RPS26 expression in CC.
Tertiary lymphoid structure prevalence and prognostic value in cervical cancer.
Authors: Gorecki Grace , Coffman Lan Gardner , Taylor Sarah E. , Bruno Tullia C.
Published: June 2023

e17521

Background: Recurrent or progressive cervical cancer have limited second-line treatment options. Response rates are often poor to second-line therapy (average response rate of 15%). Identification of factors which predict response to immunotherapy and targets to enhance the immune response are critically needed in cervical cancer. Chronic inflammation can initiate an immune response in non-secondary lymphoid organs (SLO) and form a Tertiary Lymphoid Structure (TLS). TLS is composed of immune cells clustered and organized and responsible for immune cell chemotaxis, which impacts cancer therapeutic response. Chemokine ligand 13 (CXCL13) is related to B cell attraction and TLS formation. Recent work from our group demonstrated human papilloma virus (HPV) positive head and neck squamous cell carcinoma (HNSCC) exhibited greater tumor infiltrating B cells (TIL-Bs) and TLS vs HPV negative disease indicating a role for viral infection in immune infiltration. Most cervical cancer is caused by HPV infection, therefore we investigated prognostic significance of immune infiltration in cervix cancer. Methods: A cohort analysis was conducted on 43 patients diagnosed with early stage cervical cancer. The presence of B cells, CD8 T cells, and CXCL13 was analyzed using singleplex immunohistochemistry staining. We separated infiltration into high infiltration and low infiltration, defined by their median value. TLS was identified using a multiplex immunofluorescence for TLS maturity panel. Histological findings were associated with cohort data. Results: High intratumoral infiltration of CD8 T cells was associated with longer overall survival in cancer patients. Median survival was 45 months for low infiltration group, whereas it was not reached by higher T cell infiltration (p < 0.05). The prognostic value of T cell infiltration was stronger in adenocarcinoma, typically associated with worse outcomes, than in squamous cell carcinoma. In adenocarcinoma, median survival was 58 months for low T cell infiltration, it was not reached by high infiltration group. CXCL13 levels were prognostic for recurrence-free survival, with median survival of 53 months in low expression group and not reached in high CXCL13 presence group (p < 0.05). The presence of TLS compared to low B cell infiltration was associated to higher survival, with 0% of deaths in the TLS group vs 40% in low B cell infiltration. While there was no correlation between TIL-B and patient outcomes, the presence of B cells in the aggregation process and higher CXCL13 levels were associated with improved survival, with 9% deaths vs 36% in low B cell group, possibly due to the support of TLS formation by B cell aggregation surrounded by CXCL13. Conclusions: Our study suggests that the presence of TLS, whether forming or established, is linked to improved clinical outcomes in cervical cancer. Further research is necessary to investigate the response of this cancer type to immunotherapy.
Association between cervical immune markers and cervical high-risk HPV infections.
Authors: Adebamowo Sally Nneoma , Famooto Oluranti Ayotunde , Adebamowo Clement Adebayo ,   for the H3Africa ACCME Research Group
Published: June 2023

e17522

Background: Evidence suggests that human papillomavirus (HPV) infection of the cervix, alters local immune markers. The aim of this study was to comprehensively evaluate the types and concentration of cervical cytokines and chemokines in HPV-negative compared to HPV-positive women in sub-Saharan African. Methods: The study population was 275 women enrolled in the African Collaborative Center for Microbiome and Genomics (ACCME) HPV cohort study. The concentration of 27 chemokines, cytokines and growth factors was quantified from cervical samples, using multiplexed bead-based immunoassays. HPV types were characterized using SPF25/LiPA10. Regression models were used to estimate the association between each immune marker and HPV infection. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for fold-change in immune marker levels divided into quartiles, using the lowest quantile as a reference category. Results: The mean (±SD) age of the women was 41 (±8) years. Some, 49% (134/275) were HPV negative and 51% (141/275) were HPV positive. Of the HPV positive women, 39% (55/141) had low-risk HPV (lrHPV) types and 93% (131/141) had high-risk HPV (hrHPV) types. Compared to HPV negative women, lrHPV-positive women had significantly higher median concentration of IFN-g, IL-2, IL-4, IL-7, IL-10 and IL-13. While hrHPV-positive women had significantly lower median concentration of GMCSF, interleukin (IL)-1RA and MCP-1; and higher median concentration of interferon-g (IFN-g), IL-b, IL-6, IL-7, IL-8, IL-9, IL-10, IL-13, IL-15 and MCP-1b, compared to HPV negative women. Women had significantly higher odds of lrHPV infection if they were in the highest quartile for IL-2, IL-4, IL-5, IL-7, IL-10, IL-12p70 and IL-13. While women had significantly lower odds of hrHPV infection if they were in the highest quartile for IL-IRA (OR 0.16, 95% CI: 0.07, 0.34) or MCP-1 (OR 0.39, 95% CI: 0.18, 0.83), and significantly higher odds of hrHPV infections if they were in the highest quartile for eotaxin, IFN-g, IL-1b, IL-4, IL-5, IL-7, IL-8, IL-9, IL-10, IL-13, IL-15, MIP-1a, MIP-1b or TNFa. Conclusions: Consistent with findings from other populations, higher concentration of pro-inflammatory immune markers in the cervix were associated with higher odds of high-risk HPV infections among African women.
Trends in cervical cancer incidence rates among demographic groups: A SEER database analysis.
Authors: Thierheimer Marisa , Alkrekshi Akram , Al Zubaidi Anas , Al Armashi Abdul Rahman
Published: June 2023

e17524

Background: Cervical cancer (CC) is the fourth most common cancer in women worldwide, with most cases caused by human papillomavirus (HPV) infection. The incidence of CC has decreased since the mid-1900s due to effective cytological screening, treatment of precancerous lesions, and vaccinations against HPV. Nonetheless, over ten thousand women in the US are diagnosed with CC yearly. Up-to-date data on the trends in cervical cancer incidence rates (IR) among different racial and age groups is lacking. Here we present an in-depth analysis of these IR trends between 1975-2018. Methods: The National Cancer Institute SEER 9 database was used to generate CC IR from 1975 to 2018 as they relate to age, race, histopathology, and county classification. Joinpoint modeling was used to incidence trends and annual percent changes (APC) with 95% confidence intervals (CI) using Monte Carlo permutation analysis to generate best-fit models with a 2-tailed t-test (p<0.05). Patients with CC were identified using ICD-O-3 primary site codes. Results: Overall, age-adjusted primary CC IR declined significantly between 1975 and 2018. Black individuals had the highest IR throughout the study period. When compared to the other racial groups, Black experienced a steeper decline in IR between 1975 and 2018. By 2018, the disparity in IR between Black individuals and White/Other individuals had nearly vanished. Of the two histopathologies studied, squamous cell carcinoma IR declined, while the IR of adenocarcinoma increased slightly. Among age groups, the IR among individuals aged 50-64 and 65+ decreased most dramatically over time. The two groups had the highest IR in 1975, but by 2018 the IR in both age groups had dropped below that of individuals aged 35-49 years. Patients in urban counties experienced similar IR decreases to those in urban and rural areas. Conclusions: Although screening and HPV vaccination initiatives have been successful at decreasing IR of CC, disparities in IR trends among racial and demographic groups persist. Examining age, racial, and community-specific CC IR trends at the population level will help prioritize resource allocation to reduce CC IR in all groups and minimize the existing gap. [Table: see text]
Risk factors for lymph node metastasis and clinical outcomes in cervical cancer patients following primary radical hysterectomy: A single-center analysis of 1495 patients.
Authors: Qian Lili , Yin Weiqi , Zhao Xingkun , Shen Zhen , Zhu Jing , Li Min , Zhang Tianjiao , Zhou Ying
Published: June 2023

e17525

Background: Histopathological information obtained from surgical specimen is important to identify patients at increased risk for disease relapse and mortality. Lymph node metastasis (LNM) carries the highest impact on decreased survival in suspected early-stage cervical cancer. To further identify risk factors for LNM and prognosis in early stage cervical cancer patients is definitely necessary owing to the findings from different centers are inconsistent. Methods: A total 1495 cervical cancer patients were diagnosed with stage IA2-IIA cervical cancer according to clinical stage and underwent radical hysterectomy between April 2009 and December 2020. The stage of all the patients were reclassified after surgery according to FIGO 2018. We analyzed their clinicopathologic data to identify the risk factors for LNM. Among all the patients, the progression-free survival (PFS) and overall survival (OS) of 1109 patients between 2015 and 2020 were collected and analyzed. Results: The incidence of LNM is 18.8% in all 1495 patients, which increases with depth of cervical stromal invasion, tumor size, lymphovascular space involvement (LVSI) and vaginal wall invasion in univariate analysis. Multivariable analysis shows only stromal invasion (OR, 3.0; 95% CI, 1.7–5.3; P < 0.001) and LVSI (OR, 4.9; 95% CI, 3.6-6.7; P<0.001) are to be independent risk factors for LNM. In addition, the clinical parameters age is a protective factor against LNM in both univariate and multivariable analysis(P<0.001). Among the 1109 patients, the median follow-up time is 49.7 months. Multivariate analyses using the Cox proportional hazards model show that LNM (HR, 8.5; 95% CI, 3.0-23.9; P<0.001), stromal invasion (HR, 3.4; 95% CI, 2.2-5.4;P<0.001) and special histologic type (HR, 3.2; 95% CI, 1.4-7.6; P=0.006) are independent prognostic factors for OS as well as PFS in early stage cervical cancer. Conclusions: The pattern of cervical stromal invasion and presence LVSI, but not the primary tumor size, predict risk of nodal metastasis. Cervical stromal invasion, LNM and special histologic type (non-squamous cell carcinoma; non-Adenocarcinoma) are independent prognostic factors for OS as well as PFS in early stage cervical cancer. [Table: see text]
Impact of hemoglobin on survival of young women with cervical cancer treated with concurrent chemoradiotherapy.
Authors: Castro-Mollo Melanie Wendy , Galvez-Nino Marco , Ruiz Rossana , Roque Katia , Coanqui Ofelia , Valdivieso Natalia , Olivera Hurtado de Mendoza Mivael , Mas Luis
Published: June 2023

e17529

Background: Cervical cancer is a global public health problem, with higher impact in many low-income and middle income countries. In Peru, cervical cancer is the leading cause of cancer deaths among women. The aim of this study is to investigate the prognostic factors affecting long-term survival in locally advanced cervical cancer young patients treated with concurrent chemoradiotherapy. Methods: This is a retrospective study of young women with locally advanced cervical cancer who underwent radiotherapy with concurrent platinum-based chemotherapy at the national cancer peruvian institute (INEN), from 2008 to 2012. The clinicopathological factors of all patients were collected. To explore the relationship between factors and prognosis, survival rates were estimated by the Kaplan–Meier method. Results: A total of 192 patients under 35 years old . Among all patients, 167 were diagnosed with SCC, 19 with AC, and 5 with ASC. Most of the patients were IIB and IIIB FIGO stage, 69% and 22% respectively. 38 cases had no metastatic lymph nodes and 42 cases were diagnosed of lymph node metastases, of which 30 were positive for pelvic lymph nodes only, and 12 were positive for para-aortic lymph nodes. We obtained pretreatment hemoglobin levels for all patients and found a median of 111 g/L, also we calculated the Prognostic nutritional index (PNI) with a median of 41.87 that correlates with a moderate to severe malnutrition in patients prior treatment. Response to chemoradiotherapy was not available in 13 patients, 136 achieved complete response, 30 patients with persistent disease and 12 with disease progression. Estimated median OS of all patients was 114.1 months [101.8-126.4] and median DFS was 112.3 months [98.9-125.7]. Exploratory analysis was performed to determine potential prognostic factors, only hemoglobin ≤ 100 g/L was statistically significant (p = 0.007). Conclusions: In young patients undergoing chemoradiation for cervical carcinoma, the hemoglobin prior treatment is prognostically significant.
A phase I dose-finding trial of hyperthermic intraperitoneal docetaxel combined with cisplatin in patients with advanced-stage ovarian cancer.
Authors: Li Jing , You Zhi-yao , Wu Miao-fang , Lin Zhong-qiu , Chen Qing
Published: June 2023

e17532

Background: To identify the maximum tolerated dose (MTD) of docetaxel combined with a fixed dose of cisplatin (75 mg/m2) delivered as hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with ovarian cancer. Methods: In this single-center Phase I trial, time-to-event Bayesian Optimal Interval Design (TITE-BOIN) was used. The starting dose for docetaxel was 60 mg/m2, with escalation in 5 mg/m2 increments until the MTD was determined or the maximum dose level of 75 mg/m2 was reached. The target dose-limiting toxicity (DLT) rate was 25%, and the total sample size was 30 patients. HIPEC was delivered immediately following the debulking surgery using the closed technique with a target temperature of 43 ℃ for 90 minutes. Results: A total of 30 patients were enrolled from August 2022 to November 2022. Among patients who received a docetaxel dose level ≤ 65 mg/m2, no DLT was reported. DLTs were observed in one patient at 70mg/m2 docetaxel (grade 3 anemia) and three patients at 75mg/m2 docetaxel (one grade 3 anemia, one grade 3 hepatic impairment and one grade 4 thrombocytopenia). When patients were treated with docetaxel at a dose of 75 mg/m2 in combination with 75 mg/m2 cisplatin, the estimated DLT rate was 25% which was closest to the target DLT rate and therefore selected as the MTD. Conclusions: For ovarian cancer patients who receive HIPEC following debulking surgery, docetaxel, in combination with a fixed dose of cisplatin (75 mg/m2), can be safely used at intraperitoneal doses of 75 mg/m2(ClinicalTrials.gov identifier, NCT05410483).
Single cell multiomic profiling of high-grade serous carcinoma.
Authors: Assad Maia Sandoval Leticia , Dumbrava Mihai , Mohammed Ismail Wazim , Mazzone Amelia , Hou Xiaonan , Weroha Saravut John , Gaspar-Maia Alexandre
Published: June 2023

e17535

Background: High-grade serous ovarian carcinoma (HGSOC) is the most frequent and deadliest type of ovarian cancer (OC). With the recent advances in transcriptomic and epigenomic profiling of cancer at single cell resolution, it has become clear that intra-tumor heterogeneity driven by genetic and epigenetic factors may be the basis of drug resistance. Current treatments are not homogeneously effective against all the cancer cell subpopulations, thus enabling resistance. With single cell sequencing technology, characterization of cell signatures and regulatory mechanisms may translate to prognostic markers and novel drug targets. Methods: The transcriptomic and epigenomic landscape of HGSOC was mapped for five tumor samples from debulking surgeries and one tissue patient-derived xenograft (PDX) using the 10X genomics sequencing platform. This strategy permits the combination of single cell ATAC-seq and single cell RNA-seq within the same nucleus (Multiome). Isolation of nuclei, library preparation and sequencing were performed following 10X genomics protocols. Sample quality and library quality were assessed by nuclear morphology and fragment size analysis, respectively. Sequenced reads were mapped to the human genome and downstream analysis including copy number variant prediction, pathway enrichment, motif enrichment and gene regulatory network analysis were performed. The sampled patients continue to be followed for clinical outcomes, such as response to therapy. Clinical data including patient age, grade, and stage of cancer, debulking status, CA-125 levels, and neoadjuvant status, were used in conjunction with the genomics data to characterize patient specific molecular regulatory signatures. Results: Cells from the six samples (total N= 26,421) were projected via UMAP. Immune and stromal cells were shown to cluster by cell-type while cancer cells clustered by patient. Cancer cells were identified as cycling cells, ciliated cells, cells with enrichment of the JAK-STAT signaling pathway, and cells exhibiting cancer stemness signatures. Transcription factor motifs and binding-site enrichment in open chromatin regions reveal transcription regulation-based subpopulations. Using the combined gene expression and open chromatin information from these cells, there is potential to uncover the genetic regulatory network(s) that drives treatment resistance. Conclusions: With single cell technology, specific clusters of cancer and tumor microenvironment cells can be classified. Beyond characterizing patient specific signatures, multiome enables the discovery of genomic, transcriptomic and epigenomic signatures that provide insight in tumor progression and treatment resistance.
Different disease progression patterns based on RECIST and CA-125 criteria and the impact on prognosis in patients with ovarian cancer treated with PARP inhibitors.
Authors: Song Kun , Ma Yana , Bu Hualei , Zhang Yawen
Published: June 2023

e17536

Background: We aimed to assess the clinical features of disease progression (PD) based on Response Evaluation Criteria in Solid Tumors (RECIST) and CA-125 criteria, and analyse the impact on prognosis in ovarian cancer patients treated with poly (ADP-ribose) polymerase (PARP) inhibitors. Methods: All epithelial ovarian cancer patients included in this retrospective analysis were admitted to the Department of Obstetrics and Gynecology, Qilu Hospital of Shandong University between January 2011 and July 2021. All enrolled patients were treated with PARP inhibitor monotherapy or combination therapy with antiangiogenic agents and regularly assessed with RECIST and CA-125 criteria until disease progression confirmed by RECIST criteria. Patients were divided to RECIST PD group and CA-125 PD group based on regular assessment: RECIST PD group comprised patients who were first confirmed with RECIST-assessed PD and did not achieve PD according to CA-125 criteria during the subsequent 28 days; CA-125 PD group comprised as follows: (i) patients who were first diagnosed with RECIST-assessed PD and defined as consistent if CA-125 PD occurred within the following 28 days; (ii) patients who had doubled CA-125 levels for the first time, confirmed after at least 1 week, and defined as consistent if subsequent RECIST progression occurred within 28 days of the initial doubling of CA-125; (iii) patients in whom the first occurrence of CA-125 was doubled and confirmed after at least 1 week, defined as priority PD of CA-125 provided there was no progression in RECIST assessment during the subsequent 28 days. Results: A total of 124 patients were included, with 64 (51.6%) in RECIST PD group and 60 (48.4%) in CA-125 PD group. Forty-three patients (34.7%) had disease progression consistent with RECIST and CA-125 criteria, 64 patients (51.6%) had priority PD with RECIST criteria, and 17 patients (13.7%) had priority PD with CA-125 criteria. The median interval between disease progression as determined by priority CA-125 criteria and subsequent RECIST criteria was 55 days (range 29–192 days). Patients in CA-125 PD group had a higher proportion of lymph node progression (40.0% vs. 17.2%, p = 0.005), multi-site disease progression (41.7% vs. 21.9%, p=0.018), and a worse prognosis with a median overall survival (OS) of 70.5 vs. 87.2 months (hazard ratio (HR)=2.01, p=0.015). In multivariate analysis, residual lesions after primary surgery (no vs. yes, HR=0.493, p=0.015), duration of PARP inhibitor treatment (≤ 6 vs. > 6 months, HR=2.262, p=0.006), priority criteria for PD (RECIST vs. CA-125, HR=0.441, p=0.006), and BRCA1/2 mutation status (wild-type vs. mutation, HR=2.150, p=0.028) were significantly associated with OS. Conclusions: Priority disease progression based on CA-125 criteria in ovarian cancer patients treated with PARP inhibitors might suggest a poor prognosis.
Comparison of bevacizumab plus doublet chemotherapy regimens in patients with metastatic or recurrent ovarian cancer.
Authors: Khanmammadov Nijat , Dogan Izzet , Saip Pinar , Aydiner Adnan
Published: June 2023

e17537

Background: Ovarian cancer is the most common cause of death due to gynecological malignancies. Although the primary treatment is surgery, there are different chemotherapy regimens that can be used in metastatic disease. In this study, it was aimed to compare doublet chemotherapy regimens in combination with bevacizumab in patients with metastatic ovarian cancer. Methods: Our study was designed as a retrospective observational study. The clinical, pathological, radiological, and treatment characteristics of the patients were recorded. Survival analyzes were performed using the Kaplan-Meier method, and multivariate analysis using cox regression analysis. Results: 198 patients were included in the study. Median follow-up period after bevacizumab was 18.7 months. The most common pathological subtype was serous carcinoma (%85.9). Before bevacizumab treatment, 96% of patients received perioperative chemotherapy. The most common sites of metastasis were the peritoneum (94.5%), liver (43.9%), lung (18.7%), bone (4.5%), and brain (3%). In combination with bevacizumab, 92 (46.4%) patients used gemcitabine + carboplatin, 76 (38.4%) patients used paclitaxel + carboplatin, and 30 (15.2%) patients used gemcitabine + cisplatin. In the whole patient group, the rate of complete response was 18.7%, partial response 56.1%, stable disease 6.6%, and progressive disease 18.7%. The patients received a median of 9 cycles of bevacizumab and a median of 7 cycles of doublet chemotherapy. Median progression-free survival was 11.9 (95% CI, 9.2-14.5) months, and median overall survival was 24.7 (95% CI, 19.9-29.4) months. History of surgery before bevacizumab (p=0.006) and type of doublet chemotherapy (p=0.024) were found to be statistically significant factors affecting overall survival. The presence of brain metastases (p=0.062) had borderline significance. Conclusions: Doublet chemotherapy regimens with bevacizumab have been found to be effective and safe in the treatment of metastatic ovarian cancer in terms of survival. The combination of bevacizumab with gemcitabine + carboplatin was superior to other doublet chemotherapy regimens in terms of overall survival.
Molecular profile of SWI/SNF complex in Chinese patients with ovarian cancer.
Authors: Li Jianmin , Han Tiantian , Guo Didi , Kong Rongrong , Chen Siqi , Wang Mengjuan , Dong Yuwei , Ding Ran , Deng Wanglong , Bu Fanfeng , Chen Yang
Published: June 2023

e17538

Background: The SWI/SNF chromatin remodeling complexes are involved in cancer initiation and progression. ARID1A, ARID1B, and SMARCA4, the essential ATPase subunit of the SWI/SNF chromatin remodeling complex, play important roles in altering chromatin structure for various cellular functions, including transcription, DNA synthesis, and repair. In ovarian cancer (OC), mutations in several SWI/SNF complexes were found, but the molecular and clinical characteristics of SWI/SNF complexes in Chinese ovarian cancer patients have never been reported. Herein, we explored the profiles of SWI/SNF mutation in the Chinese population. Methods: Genetic mutations were reviewed in OC patients who underwent hybridization capture-based next-generation sequencing (NGS). SWI/SNF mutant tumors (MT) were compared to wild-type (WT), and other co-mutations were also evaluated. The pathogenicity of germline mutations was categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Among 461 OC patients, mutation in at least one evaluated SWI/SNF gene was identified in 23% of cases. The higher frequency of SWI/SNF alterations were ARID1A (41.03%), ARID1B (13.33%), SMARCA4 (11.28%). The co-mutated genes mainly were TP53, PIK3CA, PTEN. In addition, the MT group tended to have more BRCA1/2 somatic mutations (16.34% vs. 7.84%, χ2＝5.42, p < 0.05) and less BRCA1/2 germline pathogenic mutations (8.7% vs. 17.2%, χ2＝4.40, p < 0.05) compared to WT group. There was a significant statistical difference in TMB value that the MT group was higher than the WT group (11.1 vs. 2.7, p < 0.001). In the MT group, the TMB of patients co-mutated with TP53, PIK3CA, or PTEN mutations were 10.2, 17.3, and 32.3, respectively. The proportion of SWI/SNF alterations in MSI-H tumors was higher than those without mutations (10.0% vs. 0.8%, χ2＝19.29, p < 0.001). Conclusions: SWI/SNF mutant tumors tended to be associated with higher TMB (11.1 vs. 2.7), a higher proportion of MSI-H (10% vs. 0.8%), and more BRCA1/2 somatic mutations ( 16.34% vs. 7.84%) in OC patients. Patients with SWI/SNF alterations combined with PTEN mutation have extremely high TMB (TMB=32.3), indicating they may benefit more from immunotherapy.
Effects of the baseline prognostic factors on efficacy of the p62/SQSTM1-encoding plasmid combined with gemcitabine in patients with recurrent platinum-resistant ovarian cancer.
Authors: Shneider Alexander , Polyakov Sergey , Baranau Yauheni , Gabai Vlad , Zharkova Ekaterina , Streltsova Olga , Filimonava Aliona , Siarheyeva Volha , Kazlouskaya Sviatlana , Khorau Anton , Pothuri Bhavana , Krasny Sergei
Published: June 2023

e17540

Background: We recently reported on the efficacy of the p62/SQTM1-encoding plasmid in patients with advanced, recurrent platinum-resistant ovarian cancer (PROC) receiving gemcitabine chemotherapy. Here we analyze the effects of baseline prognostic factors on efficacy. Methods: A prospective multicenter randomized study took place between 01/2020 and 08/2023. Cohort A (n=20) consisted of Gemcitabine 1000 mg/m2 days 1,8 every 3 weeks and Cohort B (n=20) consisted of Gemcitabine (Gem) 1000 mg/m2 days 1,8 every 3 weeks plus p62-plasmid 2.5 mg i.m. weekly. We stratified the patients into subgroups according to their baseline CA-125 level (normal vs high), number of lines of chemo (1 vs 2-3) received by a platinum-sensitive ovarian cancer (PSOC) patient before they became PROC, platinum-free interval (PFI) (up to 3 mo vs more than 3 mo), and presence or absence of peritoneal effusion. Cox proportional hazards regression analysis was utilized to determine effect of progression free survival (PFS). Results: The median follow-up was 13.8 months (mos). The median PFS was 2.8 mos in Gem (Arm A) and 7.2 mos in Gem + Plasmid (Arm B) respectively (p = 0.03). The overall response rate (ORR) by RESIST 1.1 was higher in the Gem +Plasmid arm: partial response (PR) - 5.0% and 20.0%, stable disease (SD) - 40.0% and 60.0%, and disease control rate 41.2 and 80% in Chemo and Plasmid arms respectively). In cohort A, all patients have progressed, whereas in Cohort B (Gem +Plasmid) 9 patients (45%) remained progression-free with the longest duration of response being 30 mo. Overall survival cannot be assessed yet. Analyzing prognostic factors with Cox Proportional Hazards Regression Analysis identified that the following factors increase p62 sensitivity: initial high CA-125 level PFS 2.5 and 6.5 (p = 0.01) in Arm A vs B, 1 line chemo vs 2 or 3 lines for PSOC, PFS 2.3 and 7.1 (p = 0.008) in Arm A vs B, and presence of peritoneal effusion PFS 2.4 and 7.6 (p = 0.008) in Arm A vs B (Table ). Conclusions: We observed maximal effect on PFS when combining the p62-encoding plasmid with Gem in the patients with the most dismal prognosis PROC: rapid progression (relapse as PROC after the first line of treatment and/or short PFI), in patients with an initial high level of CA-125, and/or pleural effusion. [Table: see text]
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.