bluuebunny/crossref_metadata_2025 huggingface dataset:
To conquer cervical and breast cancer in little charted waters: Synergistic and integrated approaches to identify early breast and cervical cancer in Cameroon.
Authors: Okwen Patrick Mbah , Mbangsi Maryanne Zithem , Okwen Kinlabel Tetamiyaka Tezok
Published: June 2022

e17510

Background: Across Africa, several governments have put in place policies to promote prevention of cervical and breast cancers. (Njunguna 2020, Njiru 2013, WHO 2017) These include routine screening at consultations, sensitization programs, HPV vaccination programs, and creation of cancer treatment centers. However there still exists a policy to practice gap and clinicians do not routinely screen for cancers and sensitization messages are not reaching those who need it most. Therefore, on the one hand the clinicians are not supplying these services and the women who need the services are not demanding for them. Methods: We used existing guidance for cervical and breast cancer screening and treatment including local policies and ASCO guidelines. We screened 64 women in the Ntasen and Ntanka communities of Cameroon. We then used the results to create sensitization and education programmes for community members using culturally relevant approach of storytelling. Results: We reported 11 out of 64 positive cervical conditions (VIA pos = 8; VILI pos = 10; both VIA/VILI pos = 7) making a 17.2% prevalence. The median age for VIA/VILI positive was 35.5 years (Range 21-60 years). 3 out of 11 (27.3%) were HIV positive. We reported 4 out of 64 positive breast conditions (BIRADS 2 (2); BIRADS 3 (1); BIRADS 4 (1)). We reported 12 out of 64 STIs (gonorrhea (4); Syphilis (2); HPV (6)). Treatment could not be initiated for breast and cervical conditions due to lack of health technologies needed. Patients were therefore referred for treatment. All participants with gonorrhea and syphilis were immediately initiated treatment. Conclusions: Considering the high burden of disease from cervical and breast cancer in Cameroon, Africa, and LMIC, exploring cost effective approaches for screening like VIA/VILI will be helpful in reducing disease burden. However, access to low-cost health technologies to provide treatment for positive cases, use of culturally relevant approaches to sensitize communities to uptake these health technologies, inclusion of patient representatives in decision making, and capacity building for clinicians and community health workers for diagnosis and treatment are needed to complete the recipe for conquering cancers in LMIC. A combined approach of routinely screening for breast, cervical, and STIs is useful for integrating a common cause for these conditions.
Whole exome sequencing facilitated diagnosis of patients with multiple mucinous neoplasms of the female genital tract.
Authors: Zhang Fang , Shi Min , Zhao Na , Guo Peng , Hou Jun , Liu Yang
Published: June 2022

e17513

Background: The differential diagnosis is challenging in clinical practice, especially among gastric-type AD of the cervix with ovarian metastases, multiple primary mucinous neoplasm in cervix and ovary, and synchronous mucinous metaplasia and neoplasia of the female genital tract (SMMN-FGT). Previous studies have revealed that next-generation sequencing might be a feasible tool in identifying the origin of tumor. Herein, whole exome sequencing (WES) was performed to distinguish patients with metastatic disease. Methods: WES analysis was performed on 28 tumors and 7 normal tissues derived from 8 patients. Each patient had one lesion of the cervix uteri. Most of them had lesions at other anatomical sites, including corpus uteri, ovary, oviduct, vermiform appendix and omentum. Mutations signatures and clonal evaluation inferred from single-nucleotide/copy number variants were explored. Results: Previous studies of multiple types of cancer have identified more than 40 single-base substitution (SBS) signatures. SBS3/6 referring to defective DNA mismatch repair and SBS10 reported in both uterus and colorectal AD were significantly enriched in this study. Next, we found no significant distribution of SBS3/6/10 among tumors at different anatomical sites. These findings indicate that primary cervical/ovarian AD with metastases other than multiple primary cancers was the predominant histology in 8 patients. The association of genomic alterations in POLE/ POLD1/HRR pathway with the distribution of SBS signatures was explored. SBS3 had a trend of significant distribution (p = 0.01) in four patients who had germline alterations in HRR pathway. Furthermore, SBS10 was significantly enriched (p = 0.009) in 2 patients with germline POLE/POLD1 alterations. Clonal evolution analyses revealed that 2 patients were identified as having SMMN-FGT, and other 6 patients had dominant clones in different tumors, which suggested a . Notably, besides the dominant clones and subclones, some tumors also exhibited extra independent clones, which might be the mixed histology of primary and metastatic tumor. In addition, we found the difference of overall survival in patients having gastric-type AD of the cervix with ovarian metastases and cervical AD patients with different FIGO stage disease based on SEER database data. Conclusions: Our study demonstrated that WES might be a feasible tool to distinguish patients having primary cervical AD with multiple metastases from those with multiple primary cancers of the female genital tract, which suggests that WES proved valuable in facilitating the diagnostic workup. A prospective, multi-center, large cohort study is needed to investigate the performance of WES in identifying the origin of tumors in patients with multiple tumors of the FGT.
Productivity losses under various second-line recurrent or metastatic cervical cancer treatment scenarios in the United States.
Authors: Ting Jie , Ayer Turgay , Dalgic Ozden Onur , Erdogan Melisa , Yaylali Emine , Chhatwal Jagpreet
Published: June 2022

e17520

Background: Recent data showed that a substantial proportion of second-line (2L)-eligible recurrent or metastatic cervical cancer (r/mCC) patients do not receive therapy. Additionally, although higher direct medical costs has been demonstrated with increasing r/mCC disease severity, there is no data on the impact of 2L treatment choices on societal costs. This study aims to estimate productivity loss due to untreated r/mCC and reduction in productivity losses associated with various 2L therapy options in the United States. Methods: We simulated the natural history of r/mCC by developing a Markov model with three stages: progression-free (PF), progressive (P), and death (D) for the course of r/mCC patients (average age: 50 years) during 2L treatment. We considered four treatment scenarios for patients who progressed on 1L systemic therapy: no 2L therapy, chemotherapy, overall 2L treatments (including option of cytotoxic monotherapy, immunotherapy, or other combination therapies), and tisotumab vedotin (TV). The model was parameterized and calibrated to match the overall survival and progression-free survival reported in recent clinical studies. Productivity loss associated with each disease stage was estimated by time spent at each stage, activity performance rate, and annual market and non-market productivity. Model outcomes included cumulative time spent in each stage and per patient 1-year and 5-year productivity losses. Results: Within a 1-year period, patients spend an estimated 6.1 months in the P stage under the no 2L treatment scenario; 4.4 months in PF and 4.3 months in P under 2L chemotherapy; 4.4 months in PF and 4.8 months P under overall 2L treatments scenario; and 5.7 months in PF and 4.3 months in P under TV scenario. Per person 1-year productivity under no 2L therapy was between $11.7K-$16.8K. As compared with no 2L therapy, 1-year per-person productivity improved by $5K-$14.6K under chemotherapy, by $5.8K-$15.6K under overall 2L treatments, and by $7.3-$19.9K under TV. When extending to a 5-year horizon, the projected cumulative per patient productivity improvement relative to that of patients with no 2L therapy ranged by $9.2K-$20.7K under chemotherapy, by $12.9K-$25.3K under overall 2L treatments, and by $19K-$36.9K under TV. Conclusions: Societal costs of 2L r/mCC in terms of lost productivity is substantially less in patients receiving 2L treatment vs. no treatment, within a 1-year period of becoming eligible for 2L therapy. Among patients receiving treatment (chemotherapy only or overall 2L treatment), we projected that society still incurs potentially meaningful lost productivity, relative to being treated with TV. TV’s 2021 approval in 2L r/mCC offers additional treatment option for patients, and continued efforts should be directed toward providing more treatment options in this setting.
Patterns of care in Medicaid-enrollees with recurrent or metastatic cervical cancer.
Authors: Leath Charles A. , Nysenbaum Jessica , Fiori Anthony , Ting Jie , Zhang Jenny , Pauly Nathan
Published: June 2022

e17525

Background: Cervical cancer remains a disease with high unmet need, and a large proportion of patients are insured through Medicaid (̃30%). Previous real-world studies demonstrated significant variability in treatments for recurrent or metastatic cervical cancer (r/mCC) patients following doublet chemotherapy ± bevacizumab, despite the 2018 approval of pembrolizumab in PD-L1+ r/mCC. As r/mCC treatment landscape continues to evolve, there is a need to understand current real-world unmet need among Medicaid r/mCC patients. This study aims to evaluate treatment patterns and healthcare resource utilization (HCRU) among Medicaid-insured r/mCC patients. Methods: This is a retrospective analysis of nationwide Medicaid claims to assess patient characteristics, treatment patterns, and HCRU among r/mCC patients between 2016-2019 (most recent Medicaid data available). First line treatment (1L) for r/mCC was identified as the first administration of systemic therapy without concomitant radiation or surgery. Patient characteristics, treatment patterns, and HCRU were characterized by line of therapy. Results: A total of 2,741 adult females initiated systemic treatment for r/mCC between 2016–2019, mean age was 52.8 (SD = 12.8), and most patients were enrolled in comprehensive managed care plans (58%). Over 41% (N = 1,145) had evidence of second line treatment (2L), with over one third (N = 385) of those also having evidence of third line treatment (3L). Consistent with treatment guidelines, the majority (61%) of 1L regimens were doublet chemotherapy ± bevacizumab. In contrast, no clear standard of care was observed among patients receiving 2L or 3L therapy. Notably, immunotherapy accounted for 22% of treatment regimens in 2L/3L overall, with its use increasing significantly over time (< 6% in 2016 to 41% in 2019; p-value < 0.001); however, despite availability of immunotherapy, most patients did not remain on treatment for a prolonged duration (immunotherapy median duration 2.2 months vs. 2.5 months for non-immunotherapy, p-value = 0.9). Across all HCRU measures (inpatient admissions, outpatient visits, emergency visits, and pharmacy claims), 2L/3L patients had less utilization per patient, compared with 1L patients. Conclusions: There was no clear standard of care for 2L+ r/mCC patients enrolled in Medicaid treated between 2016-2019. Although immunotherapy use is increasing, there is still high medical unmet need based on short durations of treatment and poor historical outcomes. New therapies should provide meaningful clinical benefit without significant increase in HCRU.
Inhibition of the mToR pathway with everolimus can modulate heat shock genes and ERCC1 gene expression and improves outcomes on serous ovarian cancer in HIPEC in vitro model.
Authors: Andrade Warne Pedro , Gonçalves Bryan Ôrtero Perez , Silva Luciana Maria , Peixoto Iago Oliveira , Andrade Tatiana Torres Lisboa , Silva-Filho Agnaldo Lopes da
Published: June 2022

e17541

Background: Worldwide, epithelial ovarian cancer accounts for a significant percentage of malignancies and is the most lethal neoplasm of the gynecological system, mainly due to silent manifestation and late diagnosis. Predominantly, around 70% of newly diagnosed women with epithelial ovarian cancer have the locally advanced or metastatic stage (III/IV). The extensive peritoneal dissemination of epithelial ovarian cancer might occur at the time of primary tumor diagnosis or related to disease relapse after previous treatment. Therefore, understanding the dynamic of peritoneal dissemination is of utmost importance, as peritoneal carcinomatosis is frequently associated with disease morbidity and mortality. Methods: In this study, we cultivated ovarian cancer cells using the OV-90 cell line (high-grade serous) and assessed citoxicity using MTT assay. Initially, the ovarian cancer cells were treated with everolimus 18 nM (37˙C) for 24 hours for both experimental and control groups. Subsequently, two experimental groups were treated with cisplatin in normothermia (Group 1) and hyperthermia (Group 2) (37˙C and 41˙C, respectively) while the control group was treated with phosphate-buffered saline solution 1X at 37˙C (Group 3) and 41˙C (Group 4) for 24 hours. After the first treatment, we re-supplemented each group under the same beforementioned conditions and incubated it for three additional hours. Moreover, the RNA extracts of each sample set were submitted to RT-PCR for the obtention of the qRT-PCR material. Lastly, we compared the expression of the ERCC1 gene and heat shock genes amongst the different intervention groups. Results: There statistical difference concerning cytotoxicity between treatment with everolimus and heated cisplatin versus treatment with everolimus and cisplatin in normothermia. We observed that the ERCC1 and TRAP 1 genes were downregulated in OV-90 cell lines under heated conditions compared to the normothermia group. Conclusions: The use of everolimus in HIPEC in vitro model increases the cytotoxic response and suggest that inhibition of the mTOR pathway modulates the expression of heat shock genes e ERCC1 gene improving outcomes. Nevertheless, there is still a need for studies evaluating the effectiveness of everolimus in preclinical trials under hyperthermic conditions.
Anti-cancer effects of high-dose selenium via lipid peroxidation in ovarian cancer.
Authors: Choi Jung-A , Lee Elizabeth Hyeji , Kim Hyosun , Cho Hanbyoul , Kim Jae-Hoon
Published: June 2022

e17547

Background: Selenium is an essential trace element and act as a regulator in the oxidation-reduction system. Selenium deficiency is observed in various cancers. Therefore, we investigated the relevance of high-dose selenium with the anticancer effect of ovarian cancer. Methods: We evaluated cytotoxicity and cell death by MTT assay and Annexin V-FITC/PI-labeled flow cytometry and biological function by invasion assay, ROS assay, immunoblotting, and FACS analysis. Using SKOV3-bearing xenograft mouse models, we evaluated the anti-cancer effect of high-dose selenium. Selenium toxicity was evaluated by the amount of ALT, AST, BUN and creatinine in the serum of C57BL/6 mice. Results: We observed that high-dose selenium, which was exposed to ovarian cancer cells, significantly increases the generation of reactive-species oxygen (ROS), leading to more significant cell death and cytotoxicity compared to low doses. We found that high-dose selenium triggers lipid peroxidation-mediated cell deaths and causes a reduction of glutathione peroxidase (GPX) systems. As a result of examining the lethal dose of selenium to the C57BL/6 nude mouse, it occurred in the concentration range of 3000 μg/Kg or more. SKOV3-bearing mouse models revealed the high-dose selenium administration (2000 μg/Kg) significantly reduced the ovarian tumor growth (p < 0.05). Moreover, we confirmed that high-dose selenium inhibited the expression of increased GPX in SKOV3-bearing mice. Conclusions: Our results suggest that high-dose selenium induces an anticancer effect through lipid peroxidation regulation according to the GPX redox system. Furthermore, we can suggest that chemotherapy based on high-dose selenium may have the effect of maximizing therapeutic efficacy and reducing anticancer drug resistance in ovarian cancer.
BRCA1/2 genes mutations frequency in patients with various histological types of ovarian cancer (data for South of Russia).
Authors: Timoshkina Natalya N. , Petrusenko Natalia A. , Gvaldin Dmitry Yu. , Gappoeva Madina A. , Kavitskiy Sergey E. , Cherkes Maria A. , Verenikina Ekaterina V. , Kutilin Denis S.
Published: June 2022

e17548

Background: About 10-15% of malignant ovarian tumors (OC) are associated with hereditary diseases, and about 65-85% of hereditary OC have a mutation in BRCA1/2 genes. The aim of the study was to analyze BRCA1/2 genes hereditary mutation spectrum in patients in the South of Russia diagnosed with OC. Methods: We used EDTA venous blood and FFPE-blocks of 324 patients with histologically verified epithelial OC (T1-3cNx-1Mx-1, stage I-IV). BRCA1 gene mutations (185delAG, 300T > C, 2080delA, 4153delA, 5382insC, 3819delGTAAA, 3875delGTCT) and BRCA2 gene mutations (6174delT) were determined by real-time PCR. Results: The most common types of OC were poorly differentiated serous carcinoma (high degree of malignancy) - 75.6%, well-differentiated serous carcinoma (low degree of malignancy) - 13%, mucinous tumors - 2.8%, endometrioid tumors - 4.3%, clear cell adenocarcinomas - 4.3%. BRCA1/2 genes mutations were found in 52 (16%) patients with OC. The frequency of detected BRCA1/2 genes mutations was: 5382insC - 53.8%, 4153 delA - 9.6%, 300T > G - 21.2%, 2080delA - 7.7%, 185delAG - 3.8%, 6174delT - 3.8%. 3819delGTAAA and 3875delGTCT mutations were not found in the BRCA1 gene. All carriers were confirmed to have the same mutations in the tumor. There were no cases of sporadic changes in BRCA1/2. BRCA1 mutation carriers prevailed in the group of high-grade serous carcinoma patients (11.1%), where all cases of BRCA2 gene mutations were identified. In the group of low-grade serous carcinoma patients, the mutation rate was 1.5%, in the endometrioid adenocarcinomas group - 0.6%, in the mixed epithelial tumors group - 2.8%. In the group of patients with mucinous tumors, mutations were not detected. Conclusions: Thus, frequency of BRCA1/2 gene mutations in OC patients living in the South of Russia was 16.0%. Distribution of mutation types in the BRCA1 gene, with a predominance of 5382insC (53.8%) and 300T > G (21.2%), corresponded to their occurrence ratio in the European populations. BRCA1/2 gene mutations were registered more often in the group of high-grade serous carcinoma patients.
On a possible mechanism of platinum resistance development in patients with advanced ovarian cancer.
Authors: Zhukova Galina V. , Ulianova Elena P. , Yakubova Darya Yu. , Sagakyants Aleksandr B. , Menshenina Anna P. , Moiseenko Tatiana I. , Verenikina Ekaterina V. , Zlatnik Elena Yu , Chalabova Tatiana G. , Pustovalova Alla V. , Kit Oleg I.
Published: June 2022

e17549

Background: The question of the mechanisms of platinum resistance development in advanced ovarian cancer (OC) remains open. The aim of the study was to reveal the relationship between the proliferative activity of OC cells, the disruption of apoptosis processes and the changes in the activity of transporter proteins that provide the efflux of chemotherapy drugs. Methods: Patients with advanced OC (T3-4N0-3M0-1) of postmenopausal age, sensitive (SPtPs, n = 23) and resistant to platinum drugs (RPtPs, n = 17), operated on after 3-6 cycles of neoadjuvant chemotherapy, were retrospectively studied. The parameters of proliferative activity (ki67), apoptosis disturbances (p53), as well as the expression of BCRP and Pgp transporter proteins were evaluated in OC tissue using immunohistochemistry methods. Statistical analysis was performed using the Mann-Whitney and Pearson tests (χ2), as well as the Spearman's rank correlation coefficient (SC). Results: In total, the dominance of the RPtPs over the SPtPs was noted in terms of intensity of the studied indicators (p < 0.05-0.003), the most significant for Pgp expression. At the same time, moderate and high values of these indicators were observed in SPtPs in 42-61% of cases, which reduced the predictive value of the revealed differences. It was of interest that statistically significant correlations between the indicators in SPtPs differed from those in RPtPs. Thus, the following values of the SC were observed in SPtPs: +0.848 (ki67-p53), -0.675 (ki67-BCRP), -0.575 (p53-BCR). In RPtPs, another intensity and/or direction of these relations were noted: +0.521 (ki 67-p53), +0.500 (ki 67-BCRP), +0.705 (p53-BCR). There were no statistically significant relationships between ki67-Pgp expression in SPtPs and RPtPs. The direction and intensity of the studied relationships could indicate changes in cell regulation in primary OC in SPtPs compared to RPtPs. Thus, in SPtPs, they reflected a significant contribution of apoptotic disturbances to the enhancement of OC cell proliferation, which was limited by the negative feedback mechanism via BCRP activity suppression indicated by the presence of an inverse correlation ki67-BCRP. In RPtPs, this mechanism was apparently already lost, which resulted in a change in the direction of the statistical relationship ki67-BCRP from reverse to direct one. Under these conditions, the positive contribution of apoptosis disruption to the proliferative activity of OC cells could obviously be supplemented by a synergistic increase in the activity of the BCRP transporter protein, which removes platinum drugs from OC cells. Conclusions: Patients with advanced OC may develop platinum resistance due to discoordination of proliferation, apoptosis, and regulation of the activity of the BCRP transporter protein.
Chemotherapy and radiofrequency hyperthermia in advanced ovarian cancer.
Authors: Deniz Gulhan Ipek , Can Ayten , Tansan Sualp
Published: June 2022

e17550

Background: Ovarian cancer (OC) is the the leading cause of cancer death in females. Most cases present at advanced stage. Standard treatment is cytoreductive surgery before or after paclitaxel and carboplatin chemotherapy (CT) followed by maintenance treatment. Weekly CT is at least as effective as three weekly CT in OC, and may overcome resistance in some patients. Hyperthermia has been used alone or in combination with radiotherapy and chemotherapy in the treatment of advanced cancer. Radiofrequency hyperthermia (Oncothermia-OT) is theoretically more effective and comfortable form of hyperthermia due to its selective effects on tumor cells. Since most advanced patients have disease limited to the abdominal cavity, OT can be applied with a single electrode to cover the whole abdomen. Immediately following CT, OT may result in aggregation of DNA repair ezymes secreted in response to CT in cancer cells. Methods: We used weekly CT with paclitaxel or nab-paclitaxel with carboplatin followed immediately by OT. (Oncotherm-EHY 3010) to the whole abdomen for one hour for eighteen weeks in 22 consecutive patients with advanced (III or IV) ovarian/primary peritoneal cancer between 2016 and 2021. 19 patients received bevacizumab every three weeks in addition to chemotherapy.All pts had ECOG PS 0-1. Maintenance treatment was bevacizumab (19 patients) or olaparib (3 patients) for one year. Patients were followed by periodic CT/MRI/PET-CT and CA-125 levels. Results: All patients completed eighteen weeks of planned treatment. No unexpected or grade III-IV toxicity was observed. Complete response was obtained in 21 patients and partial response in one patient. Median follow up is 30 months (range 8-73 months).18 patients are alive, with 12 patients in ongoing remission and 6 patients receiving palliative treatment. 4 patients have died of cancer. Conclusions: Although this is a single center retrospective observation, the combination of weekly paclitaxel/nab-paclitaxel and carboplatin CT in combination with immediate weekly OT appears tolerable and feasible. Despite all of the limitations of this observation, activity of CT and OT appears promising. These findings should be confirmed with prospective randomized trials.
Platinum vs non-platinum chemotherapy for platinum-resistant ovarian cancer: A meta-analysis.
Authors: Rumyantsev Alexey , Tyulyandina Alexandra , Fedyanin Mikhail , Pokataev Ilya , Glazkova Elena , Israelyan Edgar , Tjulandin Sergei
Published: June 2022

e17551

Background: recurrent ovarian cancer (OC) patients with platinum-free interval (PFI) < 6 mo. are usually considered platinum-resistant and treated with non-platinum chemotherapy. However, this practice is not based on proper-conducted randomized trials. Methods: we queried the PubMed database for all full-text articles and abstracts on the treatment of patients with platinum-resistant ovarian cancer (PROC) in 01/01/2000-01/06/2019 timeframe. The PRISMA tool was used to ensure transparent reporting of the results. Inclusion criteria were: 1) histologically confirmed epithelial OC; 2) recurrent disease within 6 months after completion of platinum chemotherapy; 3) treatment with platinum- or non-platinum chemotherapy agents that are routinely used for OC; 4) no concomitant therapy with targeted or investigational agents; 5) defined response rate (RR) and assessment criteria. Proportion meta-analysis (random-effect model) and beta-regression were conducted to assess the impact of platinum agents on response rate as well as significance of other variables. In the beta-regression model response rate was a dependent variable, while platinum agents (yes or no), used non-platinum drugs and method of response assessment were independent variables. Statistical analysis was dose with meta and betareg packages of R software. Results: we identified 7156 articles and screened them for title and abstract, 157 studies for further analysis. Efficacy of non-platinum- and platinum-based therapy was assessed in 113 (n = 5272) and 44 (n = 1055) trials respectively. In meta-proportion random-effect model RR among patients treated with platinum-based and non-platinum chemotherapy RR was 36% (95% CI 30-41; I2 = 62%) and 16% (95% CI 14-19; I2= 70%) respectively. Multiple beta-regression model is presented in the Table below. For sensitivity analysis various regression models were made with different subsets of the trials and additional variables (including year of the trial, percentage of serous subtype of OC and median of prior therapy lines). Platinum was the strongest predictor of response in every developed model. Conclusions: this meta-analysis shows that patients with 'platinum-resistant' ovarian carcinoma may derive significant benefit from reintroduction of platinum agents. These results support recent ESMO-ESGO consensus on treatment of recurrent ovarian cancer and randomize trials are required to refine the role of platinum in early relapsed OC.[Table: see text]
Mechanisms of thrombosis pathogenesis and prevention vary in patients with ovarian and endometrial cancers.
Authors: Kaplieva Irina V. , Verenikina Ekaterina V. , Frantsiyants Elena M. , Myagkova Tatiana Yu. , Pogorelova Yulia A. , Surikova Ekaterina I. , Sheiko Elena A. , Trepitaki Lidia K. , Guskova Nailya K. , Zakharchenko Viktoria R. , Gusareva Marina A. , Atmachidi Dmitriy P. , Chernogorov Pavel V. , Moiseenko Tatiana I. , Kit Oleg I.
Published: June 2022

e17554

Background: Thrombosis in patients with gynecologic cancers worsens the outcome of antitumor treatment and is one of the leading causes of their death. The kallikrein-kinin system (KKS) is involved in both the regulation of thrombus formation and the development of cancer. The purpose of this study was to analyze characteristics of the KKS components in the blood in patients with endometrial cancer (EM) and ovarian cancer (OC) with and without secondary thrombosis (VTEC). Methods: The study included 39 patients, mean age 58.0±4.2 years: main groups – patients with OC T1c-3cN0M0 (n = 10) or EC T1a-2N0M0 (n = 9) with VTEC; comparison groups - patients with OC (n = 10) or EC (n = 10) without VTEC. EC was represented by adenocarcinomas (G1-G3), OC by serous carcinomas (90%) and clear cell adenocarcinomas (10%). The control group included healthy women of the corresponding age (n = 10). Blood levels of kallikrein 1 (K1), kallikrein 14 (K14), and kininogen (KG) were measured by ELISA after the surgery. Results: EC patients with VTEC showed 1.5 times (p < 0.05) higher blood levels of K1, compared to donors, while other indices were unchanged. EC patients without VTEC had 4 times lower KG levels, compared to donors and EC+VTEC. In OC, regardless of the presence or absence of VTEC, levels of K1 in the blood increased, as well as in women with EC+VTEC, by 1.5 times (p < 0.05) compared with donors, which was combined with a twofold increase in KG in OC+VTEC and a decrease in KG by 1.4 times in OC patients without VTEC. Blood levels of K14 increased only in OC patients without VTEC by an average of 1.9 times (p < 0.05) compared with donors and OC+VTEC. Conclusions: The revealed changes in some KKS components in the blood demonstrate the similarity (K1 increase) and differences (KG increase only in OC) in the pathogenesis of thrombosis associated with gynecologic cancers. The mechanisms of protection against VTEC in the early postoperative period also showed common (KG decrease) and specific features associated with the characteristics of cancer (K14increase only in OC). The development of therapy aimed at correcting the identified disorders will allow an antitumor treatment program for this category of patients with maximum efficiency improving their quality of life and survival.
Data independent acquisition mass spectrometry in relation to potential diagnostic and prognostic biomarkers for high-grade serous ovarian cancer.
Authors: Huh Sunghyun , Kim Se Ik , Park Jieun , Choi Kyerim , Jang Hyunjee , Lee Sang-Won , Hwang Daehee , Yu Myeong-Hee , Chung Hyun Hoon , Kang Un-Beom
Published: June 2022

e17564

Background: Ovarian cancer (OC) is one of the most common causes of cancer-related death among women worldwide. High-grade serous ovarian cancer (HGSOC) represents the major OC histological type, and challenges associated with its early detection and prediction of clinical outcomes significantly contribute to the high prevalence and poor prognosis of OC. Lack of reliable biomarkers further exacerbates the low survival rate of patients with HGSOC. Methods: In this study, we performed liquid chromatography data independent acquisition tandem-mass spectrometry (LC-DIA-MS/MS) experiments on depleted serum samples [26 HGSOC cases, 24 healthy controls (HCs)] to identify potential diagnostic and prognostic biomarkers for HGSOC. Results: A total of 1,148 proteins were identified in all samples combined, representing one of the largest quantifications in the serum proteome of OC to date. Among them, 122 proteins showed differential expressions between the serum proteome of HGSOC patients and HCs, including 109 up- and 14 down-regulated proteins in HGSOC. These potential diagnostic biomarkers were involved in the pathways related to immune response, TGF- β and IGF signaling, and lipid metabolism. Moreover, we performed Kaplan-Meier survival analysis on the HGSOC patients with and without recurrence, and identified several potential prognostic biomarkers highly associated with progression free survival (PFS). Using independent cohort samples, we validated the expression levels of HGSOC serum biomarker candidates using targeted proteomics approaches (MRM and PRM). In vitro functional assays revealed that some of these biomarkers may play an essential role in cancer cell migration and proliferation in HGSOC. Conclusions: In summary, our LC-DIA-MS/MS analysis of the HGSOC serum proteome successfully identified novel diagnostic and prognostic biomarkers for HGSOC, some of which were experimentally shown to have functional relevance to the pathophysiology of OC.
Brain metastases in ovarian cancer: Association of outcomes with timing of diagnosis.
Authors: Erfani Hadi , Mudgett Mudgett , Peterson Abigail , Seidman Benjamin , Nezhat Farr , Pejovic Tanja
Published: June 2022

e17565

Background: Brain metastases (BM) in ovarian cancer (OC) are rare and late events during the disease course. We report our data on patients with OC who developed BM and compared the outcomes with subjects with evidence of BM at the time of diagnosis from the Surveillance, Epidemiologic, and End Results (SEER) national database. Methods: Retrospective chart review of all patients with brain metastasis in the setting of previously diagnosed ovarian cancer was performed in single NCI designated comprehensive cancer institute. Inclusion criteria were: primary cancer documented as ovarian or tubal, evidence of BM, treatment and follow up information. For comparison and due to rare nature of ovarian cancer cases with BM we utilized the SEER database. SEER data base reports only on patients with OC who had BM at the time of diagnosis. Study groups were: 1- BM at diagnosis 2- BM during disease course. Primary outcomes were overall death, and overall survival (OS) months. Secondary outcome was survival months after diagnosis of BM. Variables are reported as median and interquartile range (IQR) or number (%). Mean survival was calculated using Kaplan Meier analysis and Mantel-Cox rank test. Cox regression analysis was performed to calculate adjusted hazard ratios (HR). Results: 106 and 24 subjects were included with evidence of BM at diagnosis (Group 1, 2010-2016, SEER database) and during the disease (Group2, 1992-2017, institutional data), respectively. Age at diagnosis of OC was significantly higher in group 1 (64 year vs. 55 year, p = 0.002). In group 2, BM were diagnosed at median interval of 33.5 months. The median OS month was 3 [1, 10] months and 58 [21, 122] in group 1 and 2, respectively (p < 0.001). Although overall mortality rate was not statistically significantly different between the study groups, survival months after diagnosis of BM in group 2 was significantly higher than group 1 (14 months [4, 32] versus 3 months [1, 10], p = 0.002). Cox-regression analysis revealed 58% decrease in the hazard of overall death when the BM is diagnosed during the disease course. (Adjusted HR = 0.42, 95% CI: 0.19-0.91, p = 0.03). Conclusions: Outcomes of OC with BM is poor with high mortality rate regardless of timing of diagnosis of BM. Our study revealed that patients with diagnosis of BM during the disease course have statistically significantly longer survival after diagnosis of BM compared to those with BM at the time of diagnosis. In order to understand the occurrence of BM in OC and these differences, it is necessary to gain knowledge in the genetic and immune mechanisms that drive and allow the development of BM in ovarian cancer. This will allow for development of effective therapeutic strategies to treat BM, which is of critical importance now as we are gaining better control of peripheral disease in women with ovarian cancer.
Evaluating the use of machine learning use in ovarian cancer: A systematic review.
Authors: Piedimonte Sabrina , Rosa Gabriela , Gerstl Brigitte , Sopocado Mars , Coronel Ana , Llenno Salvador , Vicus Danielle
Published: June 2022

e17570

Background: Ovarian cancer(OC) is the leading cause of death from gynecologic malignancy. Current challenges include lack of diagnostic tools, predictive biomarkers, and identifying appropriate surgical candidates. Machine learning(ML) is an emerging field that can make accurate projections by making inferences on data and may play a crucial role in OC.The objective of the current study was to review the literature on application of ML in OC and report the most commonly used algorithms and their performance in comparison to existing prediction tools and traditional regression models. Methods: This is a systematic review of published literature from January 1985 to March 2021 on the use of ML in OC. An extensive search of electronic library databases was conducted. Four independent reviewers screened the articles initially by title then full text. Quality was assessed using the MINORS criteria. P-values were generated using the Pearson’s Chi-squared(x2) test to compare performance of ML models with traditional statistics. No p-values were reported if only one study was available. Results: Among 4,295 articles screened, 88 studies on ML in OC were included. The mean age of OC patients was 54.7 years(11-90) and the most common stages at diagnosis were:Stage III (39.9%) and IV (34%). Applications of ML were in clinical datasets(33%, n = 29), preoperative diagnostics(30.7%, n = 27), serum biomarkers (21.6%, n = 19), genomics (12.5%, n = 11), and prediction of cytoreductive outcomes (2.3%, n = 2). The most commonly applied algorithms were Support Vector Machine [SVM](28%, n = 33)and Neural Networks[NN] (25.28%). Over the past decades, the number of publications on ML in OC increased three-fold from 20(1994-2010) to 67 (2011–2021). Only 9 (10%) studies compared ML techniques with existing prediction tools, or traditional regression models. Among 29 clinical dataset studies, 4 compared ML with traditional logistic regression(LR). Two studies reported better performance with ML compared to LR but not significant(accuracy: 0.88 vs 0.84, p = 0.15), one study performed comparably(accuracy: 0.1 vs 0.1) while one study performed worse(accuracy: 0.1 vs 0.97). Only one preoperative diagnostic study compared ML techniques with LR. SVM classifiers outperformed LR in classifying ovarian masses as benign or malignant(sensitivity: 0.88 vs. 0.70). One serum biomarker study compared LR with ML algorithms; LR performed better using two biomarkers for predicting OC(accuracy: 0.97 vs. 0.94). Among five studies reporting overall survival outcomes, only one study compared survival ML techniques using NN with LR and showed that NN classifiers outperformed LR in predicting overall survival(AUC: 0.72 vs. 0.62). Conclusions: This is the first systematic review exploring the literature on ML algorithms in OC. Most ML models outperformed traditional models. However, larger datasets would be required to validate findings.
Assessing homologous recombination deficiency (HRD) in ovarian cancer: Optimizing concordance of the regulatory-approved companion diagnostic and a next-generation sequencing (NGS) assay kit.
Authors: Weichert Wilko , Qiu Ping , Lunceford Jared , Wehn Amy , Yarunin Alexander , Cristescu Razvan , Liu Li , Roessler Kyria , Timms Kirsten , Marton Matthew John
Published: June 2022

e17571

Background: Olaparib + bevacizumab is approved as first-line maintenance treatment of ovarian cancer that is HRD positive, defined as the presence of a deleterious/suspected deleterious BRCA mutation (BRCAm) and/or genomic instability. HRD genomic instability score (GIS) has been assessed in clinical trials using a regulatory-approved companion diagnostic, Myriad myChoice® CDx. We evaluated the performance of an in-development NGS assay kit that identifies BRCA variants based on genomic content from Illumina’s TruSight™ Oncology 500 research assay, and, with additional genomic content, measures HRD GIS in tumor tissue (Illumina test) in parallel. Analytic concordance of the Illumina test versus the Myriad myChoice® PLUS assay (Myriad test) under improved algorithms for calculating GIS scores is reported. Methods: Ovarian cancer tissue samples were analyzed with the Illumina (40 ng DNA; N = 227) and Myriad (200 ng DNA; N = 254) tests. Agreement rates for BRCA analysis, HRD GIS, and overall HRD status (includes BRCAm and HRD GIS [cutoff, 42]) were analyzed. For the overall and the non-BRCAm analysis cohorts, Pearson correlation between the continuous HRD GIS of the Illumina and Myriad tests was determined. Analytic sensitivity and specificity of the Illumina-derived HRD GIS to classify HRD GIS (cutoff, 42) were evaluated using AUROC. After initial concordance calculations, modifications were made to increase the quality of the Illumina preprocessing data (ie, reducing allele dosage noise and allele bias) upstream of the GIS calling algorithm. Reprocessing of the existing raw data led to further improvement in the point estimates of positive and negative percent agreement. Results: Prevalence using the Illumina and Myriad tests was 51.2% and 49.2% (overall HRD positive) and 27.6% and 25.5% (BRCAm), respectively. Agreement rates are reported in the Table. Correlation of the Illumina HRD GIS with Myriad HRD GIS was 0.980 (all samples) and 0.976 (non-BRCAm cohort); AUROCs were 0.995 and 0.992, respectively. Conclusions: Comparison between the Illumina and Myriad tests showed that overall HRD status, BRCA analysis, and HRD GIS detection results were > 90% concordant; HRD GIS was highly correlated (r > 0.98); and prevalence estimates were similar. These data suggest that a distributable kit solution, such as the Illumina test under development, will approach the performance of the Myriad myChoice HRD assay.[Table: see text]
The influence of carrying BRCA pathogenic mutations in ovarian cancer and its platinum-sensitivity: 5-year experience of a tertiary center.
Authors: Jiménez Labaig Pablo , Lombardero Lara , Rivero Maria Pilar , Mohamed Lamin Failah , Ortega Berezi , Miñambres Nagore , Fuente Natalia , Marrodan Ines , Iza Estibaliz , Carrera Sergio , Iruarrizaga Eluska , Sancho Aintzane , Rubio Itziar , Mañe Joan Manel
Published: June 2022

e17572

Background: Platinum-based chemotherapy still remains as the backbone treatment in ovarian cancer (OC) and its homologous tumors (primary peritoneal PP and fallopian tube FT cancer). BRCA mutational status is a sensitivity predictor to platinum chemotherapy. The aim of this study is to quantify the benefit of carrying a BRCA mutation along the subsequent platinum treatments and beyond. Methods: A descriptive, retrospective, single center study was developed in a tertiary hospital. OC, PP and FT neoplasms in stage III/IV, treated between 01/2015 and 12/2020 were included. Demographic characteristics, BRCA and HRD pathogenic mutational status, platinum-sensitive survival (PSS), platinum-resistant survival (PRS) and overall survival were analyzed. A p-value of < 0.05 was considered statistically significant. Results: 116 patients were recruited (96 OC, 9 PP, 7 FT). 100 were non-BRCA mutated (including 2 germline BRIP, 1 RAD51C), 16 were BRCA-mutated (8 germline BRCA1, 7 germline BRCA2, 1 somatic BRCA2). 83 (71.6%) were stage III at diagnosis and 33 (28.4%) stage IV. Histologically, 90 cases were serous subtype (77.6%), 40.5% were grade 3. Mean age was 62.1 years. 90 (77.6%) received oncological surgery (debulking or interval procedure). A table is annexed with demographic characteristics without unbalanced distribution.Between BRCA-mutated group and non-mutated, the mean of platinum-based treatments was 2.63 (range 1-7) vs 2.49 (1-8), median PSS 42,8 months (9.7-80.1) vs 24.5 (2-78.9) HR 0.27 (95% IC 0.07-0.88. Log rank p-value 0.019), median PRS 20.3 (16-24.9) vs 9 (1.3-67.4) HR 1.1 p-value 0.715, and overall survival of 43.4 (11.3-81.4) vs 29 (0.7-78.9) HR 0.8 p-value 0.083. In contrast, histology factors, tumor markers, type of performed surgery, maintenance treatments and nonplatinum treatments didn’t result in a significant benefit as being carrier of BRCA mutation showed. Conclusions: Our analysis confirms that the platinum sensitive survival is deeply depend on the BRCA mutational status, remaining the most beneficial prognostic and predictive factor in the operated III/IV stages.[Table: see text]
Burden of cremophor-related paclitaxel therapy on patients with ovarian cancer: A patient focused study from the United Kingdom, Germany, and Spain.
Authors: Brixner Diana , Holtorf Anke-Peggy , Bhatia Ayesha , Oak Bhagyashree , Dehipawala Sumudu , Whitcher Clive , McKinley Kate , Martin Kyle , Hadker Nandini
Published: June 2022

e17576

Background: Cremophor EL (CrEL) is a solubilizer used in paclitaxel and is associated with side effects (i.e., hypersensitivity reactions, peripheral neuropathy). Current CrEL-containing therapies require long infusion times (2-4 hours) and pre-medication with steroids to manage these side-effects. However, the holistic burden of CrEL on patients is not well studied. This study aimed to characterize the burden associated with CrEL-paclitaxel treatment on patients with ovarian cancer, including clinical, safety, and quality of life (QoL) implications. Methods: This quantitative, Institutional Review Board (IRB) approved, cross-sectional survey of patients (≥18 years) who received ≥3 cycles of CrEL-containing paclitaxel within the prior 6 months was conducted in UK, Germany, and Spain in 2021. Data were collected via a web-enabled instrument including a screener, questionnaire, and validated Functional Assessment of Cancer Therapy (FACT)-Taxane scale. Results are reported overall for the 3 countries. Results: Of the 90 patients surveyed, the mean age was 38.8 years. Most patients reported improvement of QoL (77%), treatment effectiveness (77%), less need for pre-medications (74%), and manageable/less disruptive infusion times and schedules (71%) as extremely desirable treatment attributes. Prior to or during chemotherapy, 41% of patients reported receiving steroids. Most patients (71%) experienced 3-6 side effects related to ovarian cancer treatment. Of the patients that experienced neuropathy (27%), the side effect lasted for up to 1 week for 54% of patients, and over multiple cycles of treatment (> 3 weeks) for 13% of patients. Of the 82% of patients eligible to complete the FACT-Taxane scale, 62% were somewhat to very much bothered by the side effects of paclitaxel. Half of these patients reported tingling/numbness in their hands/feet, moderately or very often. Patients reported an average of 4.8 hours as the time taken for their travels to/from the infusion center and receive their medication. Additionally, 91% of patients needed caregiver support for an average of 16 hours per week. 51% of patients reduced their work hours due to treatment and 58% reported a substantial impact on work productivity. To cover treatment costs, 63% purchased supplemental insurance. Conclusions: The patient-reported burden of treatment associated with CrEL-containing paclitaxel is significant and complex. Multiple treatment side effects occur in most patients which are burdensome and can recur and/or persist with future treatment cycles. There is an unmet need for an effective therapy that reduces treatment burden for patients and improves tolerability through fewer side effects, a reduced need for premedication, and shorter infusion time.