bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fully automated prostate cancer identification using multiplex fluorescence immunohistochemistry to assess prognosis markers on a single tissue section.
Authors: Blessin Niclas C. , Mandelkow Tim , Bady Elena , Mueller Jan H. , Simon Ronald , Lennartz Maximilian , Sauter Guido , Heinzer Hans , Graefen Markus , Steurer Stefan 
Published: June 2023

e17118 Background: Most prostate cancers diagnosed are low to intermediate risk and face the decision on whether active surveillance or active treatment represents the optimal treatment option. To incorporate a reproduceable parameter in treatment planning, prognostic marker assessment using multi-gene panels has been frequently proposed. However, the fluctuating tumor purity can reduce the predictive value of such tests. A more accurate prognostication would be the quantification of prognosis markers exclusively on cancer cells. Methods: To enable automated prognosis marker quantification, a framework for automated prostate cancer detection that comprises three different artificial intelligence analysis steps and an algorithm for cell-distance analysis have been developed and validated using 8 marker BLEACH&STAIN mfIHC (i.e., panCK, p63, PSA, PSMA, INSM1, AR, Ki-67, CD56) in a tissue microarray and prostate biopsy cohort of 10’234 prostate cancers. Results: The approach for automated prostate cancer detection mimics the way pathologists use for identification of cancer cells and identified epithelial cells (CKpan positive) that were non-adjacent to basal cells (p63 positive). Validation experiments revealed that the optimal distance between p63+ basal cells and benign panCK+ cells was 23 µm to exclude benign glands from the prognosis marker analysis. A distance of 23µm as threshold for automated cancer detection showed a 39% higher accuracy compared to the cutoff value 5 µm. To compare this automated mfIHC-based prognosis marker assessment with the frequently used bright field IHC-based QuPath software package, and the manual prostate identification by pathologists, a cohort of 30 biopsies from routine clinical practice was assessed. An excellent agreement between the mfIHC-based automated cancer detection and manual cancer identification by pathologists was found (intraclass correlation [ICC]: 0.94 [95% CI 0.87 – 0.97]), while the QuPath-based model showed a 20 % deviation from the gold standard (manual assessment by pathologists). Accordingly, the automated mfIHC-based approach was used to search for a prognosis marker panel for routine clinical practice. 5 out of 6 analyzed prognosis markers (PSA, PSMA, INSM1, AR, Ki-67) were significantly liked to biochemical recurrence in univariate analysis (p ≤ 0.021) and 2 of 6 parameters (AR, Ki-67) were independent in multivariate analysis (each p≤ 0.0078). Several prognosis scores of different marker combinations were found that showed strong prognostic relevance in univariate analysis (p < 0.001) and were independent from Gleason groups, pT, pN, serum PSA and R-Status (p = 0.001). Conclusions: Automated prostate cancer identification enables fully automated prognosis marker assessment in routine clinical practice using deep learning and mfIHC.
A cross-sectional study of 73,390 women without ovarian cancer and the effect of age and benign gynecological diseases on serum CA125 levels.
Authors: Zhu Chenchen , Jiang Shan , Yao Bei , Chen Liang , Liu Buyun , Liu Hanyuan , Qian Lili , Yan Qianqian , Liu Yi , Peng Cheng , Zhou Ying 
Published: June 2023

e17500 Background: As an important tumor marker for follow-up and prognosis of ovarian cancer, CA125 is not suitable as a screening indicator due to its frequent elevation in many physiological or pathological condition, thus women are often puzzled by unaccountably elevated levels of CA125. While we have known that the CA125 level is differed by age and benign gynecological diseases, the specific trend of CA125 level changes is still not clear. We hope that this study will contribute to a more accurate and individual interpretation of CA125 by evaluating the baseline levels of CA125 in healthy women of different ages and analysis the association between benign gynecological diseases and CA125 level. Methods: This was a cross-sectional study enrolled 73390 women without ovarian cancer from January 2016 to December 2021 in three health examination centers. We have assessed the distribution of CA125 levels in different age groups and analyzed the variation trend of CA125 levels by age among women with normal ultrasonic results, as well as performed the correlation analysis between several benign gynecological diseases and CA125 levels. Results: 55422 women with normal ultrasonic results and CA125 level <200U/mL were included in the analysis of variations in CA125 depending on age. We observed CA125 levels were linearly associated with age (R2=0.0503, p<0.0001). Using the group <30 years as a baseline, average CA125 levels decreased by 3.4%, 10.1%, 42.6%, 40.5%, 31.8%, and 20.3% by every 10 years. With the increase of age, the downward trend of CA125 began to reverse at the age of 60, and it showed significantly difference between each adjacent subgroup (p<0.05). 8630 women were selected with abnormal ultrasonic results, we observed that CA125 was lower in women with uterine effusion, higher in endometrial hyperplasia, endometrial polyps, hydrosalpinx, ovarian cyst, adenomyosis and uterine fibroids. Age and all those diseases demonstrated possible associations (p<0.05) with CA125 levels ≥35U/ml in univariable logistic regressions. Multivariable analysis identified that ovarian cyst (p<0.001), adenomyosis (p<0.001) and uterine fibroids (p=0.018) were still significantly associated with abnormal CA125 level. Conclusions: With the increase of age, CA125 level generally showed a downward trend, but there is a slight increase in CA125 after age 60. Ovarian cyst, adenomyosis and uterine fibroids demonstrated significant associations with abnormal CA125 level. [Table: see text]
The combination of APR-246 and carboplatin in olaparib-resistant high grade serous ovarian cancer (HGSOC) and triple negative breast cancer (TNBC) cell lines.
Authors: Perez-Fidalgo Jose Alejandro , Martinez Pretel Juan Jose , Sanchez Serrano Paloma , Heredia Victoria , Mendiola Marta , Redondo Andres , Gonzalez Villena Lidia , Ruiz Linuesa Miriam , Pineda Begona 
Published: June 2023

e17504 Background: PARP inhibitors (PARPi), as Olaparib (OLA), have changed the therapeutic landscape in HGSOC and TNBC. However, most patients will develop resistance to PARPi. Although resistance mechanisms are poorly understood, it is suggested that BRCA mutations reversions or cell cycle alterations could be involved. APR-246 is a new targeted agent that restores p53 in TP53-mutated cells. The aim of our study was to assess the potential synergism of the combination of carboplatin (carbo) plus APR-246 in both OLA-sensitive and OLA-resistant HGSOC and TNBC cell lines. Methods: We selected two HGSOC (PEO1-S and Kuramochi-S) and one TNBC TP53 mutant cell lines (MDA-MB-231-S). Resistance to OLA was generated by pulse doses with IC75 OLA for 24 hours and recovered for two weeks during a period of 6 months (PEO1-R) and to increased concentrations of OLA for 72 hours during a period of 1 year (Kuramochi-R, MDA-MB-231-R). Next-generation sequencing was performed in order to assess mutations. IC50 of APR-246 and Carbo and the combination of both (combo) were calculated for Kura-S/R, PEO1-S/R and 231-S/R cell lines. Synergism between both drugs was assessed with Chou-Talalay method for combination index (CI) at Fa50. DNA damage was assessed by gamma-H2AX expression by western-blot (WB). Results: 231-S harboured a TP53 mutation (mut) (missense R280K) and BRCA wildtype (wt), in PEO1-S BRCA2 mut p.Y1655* and TP53 mut was detectable. Kuramochi-S was TP53 mut (missense D816Y) and BRCA2 mut. BRCA and p53 mutation remained unchanged in the resistant lines generated.The mutation profile of each line and the IC50 of APR-246, carbo and combo are shown in the table. IC50 of carboplatin is superior in all 3 resistant cell lines when compared to their sensitive parental line, suggesting a potential cross-resistance to platinum in OLA-resistance. The combination of carbo and APR-246 is synergistic even in OLA-resistant cell lines, in fact in those cross-resistant lines values of synergism by Chou-Talalay are improved by the combo suggesting a potential role of this combination in PARPi resistant cell lines. WB showed an increased DNA damage with the combo when compared to either single agent, with an increase in H2AX in all lines either sensitive or resistant. Conclusions: The combination of APR246 and carboplatin is synergistic in all 3 studied cell lines but also in the OLA resistant ones. The combo increased its synergistic effect suggesting a potential role of combo in OLA-resistant tumors. [Table: see text]
Predictive molecular markers of chemoradiation resistance in cervical cancer.
Authors: Kumar Prashant , Chauhan Richa , George Irene A , Limaye Sewanti Atul , Sankaranarayanan Rengaswamy , Dhawale Ekta R , Kuriakose Moni , Venkataramanan R 
Published: June 2023

e17505 Background: Cisplatin based concurrent chemoradiation therapy (CCRT) has been recognized as the standard treatment for locally advanced cervical cancer. Although patients treated with CCRT have better chances of survival and prognosis, over 30–40% of patients do not achieve a complete response and may develop locoregional recurrence. Hence predictive biomarkers-based treatment selection of right cohort could be a strong approach for personalized treatment. Therapy resistance occur due to multifactorial events and targeting key molecules involved in treatment resistance could combat treatment resistance. Herein, we profiled both the global proteomic and phosphoproteomic landscape of the concurrent chemotherapy resistant cervical cancer to identify potential predictive biomarkers as well as therapeutic targets. Methods: We employed mass spectrometry based global proteomic and phosphoproteomic strategies to identify proteomic signature and dysregulated kinase involved in CCRT resistance. The biopsy tissue samples were collected before the start of the therapy and the protein was extracted, digested from each sample and labelled with 10 plex TMT (Tandem Mass Tags). The pooled peptides were fractionated by basic pH liquid chromatography analyzed on Orbitrap-Fusion-Tribrid mass spectrometer (ThermoFisher Scientific). For the phosphoproteomic experiment, the peptides were enriched using IMAC based phosphopeptide enrichment method. Liquid chromatography-mass spectrometry/ experiments together with thorough bioinformatics analysis were carried out to characterize the global proteome and phosphoproteome. Results: Analysis of protein expression and phosphorylation led to the identification of dysregulated protein expression and phosphorylation between treatment sensitive and resistant patient cohorts. Further analysis and validation experiment revealed the potential of differentially expressed protein syntaxin 3 (STX3) as a predictive biomarker for treatment resistance. Phosphoproteomic analysis revealed the enrichment of DNA repair pathway in treatment-resistant cohort and the phosphorylation of the proteins involved in DNA repair such as SMC1A, HMGN1, MGMT, DDB2, MSH6 are dysregulated between the cohort suggesting role of DNA repair pathway in the treatment resistance. Kinase-substrate enrichment analysis revealed the activation of kinases such as CSNK2A1, PRKDC, PLK1, NEK2 and ATM in non-responders. Conclusions: We have identified an accurate and reliable biomarker STX3 to predict CCRT resistance in cervical cancer. Further, the phosphoproteomic profiling revealed dysregulation of DNA repair pathways which may be involved in treatment resistance. Targeting the activated kinases such as CSNK2A1, PRKDC, PLK1, NEK2 and ATM could combat treatment resistance in cervical cancer patients.
Identifying small non-coding RNAs as biomarkers for cervical cancer.
Authors: Peitz Josephine , Stockett Arica , Chawla Kiranpreet , Carvajal Diana N. , Plotkin Amy , Staats Paul , Adebamowo Clement Adebayo , Adebamowo Sally Nneoma 
Published: June 2023

e17507 Background: Small non-coding RNAs (sncRNAs) that control post-transcriptional gene expression are attractive candidate molecular targets for cancer screening tests. We evaluated whether sncRNAs expression are markedly different in benign, precancerous, and cancerous cervical tissue. Methods: We examined the expression of six sncRNA species: circular RNAs (circRNAs) microRNAs (miRNAs), piwi-interacting RNA (piRNAs), small nuclear RNA (snRNAs), small nucleolar RNA (snoRNAs), and transfer RNA (tRNA), from archival formalin-fixed paraffin-embedded cervical specimen obtained from 172 women (74 benign, 58 high-grade squamous intraepithelial lesion (HSIL) and 40 invasive cervical cancer). We used DESeq2 to identify differentially expressed sncRNA molecules with adjusted p-value < 0.05 and at least 2-fold up- or down-regulation. Results: Comparing benign to HSIL samples, we foundseveral statistically significant, differentially expressed sncRNAs: 906 circRNAs (*circ_0066810, p=3.76x10-16), 87 miRNAs (*miR-149-5p, p=1.30x10-14), 11 piRNAs (*piR_016945, p=8.32x10-13), 32 snRNAs (*RNU1-17P, p=1.90x10-10), 5 snoRNAs (*SCARNA18, p=1.35x10-5), and 24 tRNA (*tRNA-Glu-TTC-8-1, p=6.45x10-17). Comparing benign to invasive cervical cancer samples, we also foundseveral statistically significant, differentially expressed sncRNAs: 3,192 circRNAs (*circ_0123115, p=7.46x10-50), 325 miRNAs (*miR-7-5p, p=6.72x10-36), 82 piRNAs (*piR-hsa-27513, p=1.44x10-15), 71 snRNAs (*RNU1-20P, p=1.37x10-45), 52 snoRNAs (*SNORD95, p=1.68x10-23), and 68 tRNA (*tRNA-Cys-GCA-9-3, p=1.01x10-21). * Indicates the sncRNA with the smallest p-value, for each specie. Conclusions: Our results identify sncRNAs with potential utility of as diagnostic and prognostic biomarkers, and therapeutic targets for cervical precancer and cancer.
Safety and survival in adult women with platinum sensitive relapsed BRCA mutant ovarian cancer: A study of patients in Olaparib Turkey Early Access Program—LynTurk study.
Authors: Esin Ece , Ahmed Melin Aydan , Yıldırım Hasan Çağrı , Mandel Nil Molinas , Erdemoglu Engin , Sari Murat , Aydiner Adnan , Arik Zafer , Gumus Mahmut , Basaran Mert , Er Ozlem , Gokyer Ali , Kose Fatih , On Sercan , Ozet Ahmet , Özer Leyla , Paksoy Nail , sütcüoğlu Osman , Uzunoglu Sernaz , Paydas Semra 
Published: June 2023

e17509 Background: SOLO-2 trial results have proven the efficacy of Olaparib in BRCA-mutant platinum-sensitive relapsed ovarian cancer patients. LynTurk as an open label, multi-center study, designed to show the real world safety and efficacy results of Turkey Olaparib managed access program. Methods: Patients with BRCA mutated relapsed ovarian cancer who are in complete or partial response following platinum based chemotherapy were eligible for Olaparib maintenance in Turkish managed access program. The primary aim was safety. Progression free survival, overall survival were the secondary endpoints. Results: Between December 2014 and March 2021, 48 patients were accepted for program. Due to immaturity of data, in this report, a total of 26 patient results were analyzed. BRCA2 mutation was present in 5 patients, one patient have both BRCA1 and BRCA2 mutations; 20 cases were found to be BRCA1 mutated. The median age of patients was 51 (29-61) years. All patients have high grade serous adenocarcinoma of ovary or primary peritoneal carcinoma. The most common site of involvement are lymph nodes and peritoneal surfaces; in 11% of cases there are liver parenchyma metastasis. All of the patients received at least two lines of platinum-based chemotherapy; median 3 lines (2-4) of treatment were applied before Olaparib maintenance. Previous bevacizumab treatment was allowed in this program, 53.8% of cases were received at least 3 cycles, maintenance bevacizumab was given to 12 patients. Median treatment duration with Olaparib was 26,2 months (3-80m). In 30.7% of cases no adverse events were noted, at least one level dose reduction was needed for 50% of patients due to toxicity. Hematological adverse events were the mostly encountered followed by dyspepsia and fatigue. Anemia was the reason for permanent drug discontinuation in 2 patients (0.7%). No febrile neutropenia was reported. During the follow-up, no secondary malignancy and pneumonitis was noted. Median progression free survival from the end of last chemotherapy was 19.3 months. One-year PFS rate was 88.4% and 2-y PFS rate was 53.8%. One-year OS rate from the end of chemotherapy was 92.3% and 2-year was 61.5%. Conclusions: The real world data from Turkey managed access program has showed that Olaparib has a safety profile in paralel with clinical trials (SOLO). No new safety signals were reported. Although a heterogenous population including heavily pretreated patients, maintenance Olaparib was found effective. This report will be updated as the data of all intent to treat population will gather and will get mature.
Evaluation of the prevalence of HPV from environmentally unfavorable districts of the Republic of Karakalpakistan.
Authors: Zakhirova Nargiza Nematovna , Tillyashaykhov Mirzagaleb , Nishanov Daniyar , Saydakhmedova Viloyat , Osmanova Elnara , Islamov Khurshid 
Published: June 2023

e17526 Background: Identification of HPV-positive women in the Aral regions of the Republic of Karakalpakstan and the city of Chirchik, Tashkent region. Methods: The study included 48,788 women aged 30-55 years.The project was approved by the Ministry of Health of the Republic, covering 10 districts, mainly near the Aral Sea: Khojeyli, Kanlykul, Shumanay, Chimbay, Karauzyak, Kungrad, Kegeili, Muynak, Buzatau, Nukus district. The Xpert HPV Assay is a qualitative in vitro diagnostic test for the detection of the E6/E7 region of high oncogenic risk human papillomavirus (HPV) genomic DNA in patient specimens. The analysis was performed on a Cepheid Gene Xpert system. The Xpert HPV test specifically identified HPV 16 and HPV 18/45 types in two separate detection channels and reported the presence of 11 other high risk virus types (31, 33, 35, 39, 51, 52, 56, 58, 59, 66 and 68) as a combined result. Results: Of these, HPV was detected in 3304 (6.8%) women, HPV-negative women were 45.484 (93.2%). Distribution by HPV types: among HPV-positive women HPV 16 - 28%; HPV 18.45-7.6%; HPV 31.33.35.52-23.9%; HPV 51-11.6%; HPV 39.56.66-18.4%; mixed forms - 10.2%. Erroneous tests were 2.9%. The age of HPV positive women was 35-45 years. Conclusions: In the studied regions, HPV types 16,31,33,35,52 were most often detected, which should be taken into account when developing the country's national screening program. Also, given the age-specific prevalence of HPV, may be considered for the target group of cervical cancer screening of women aged 35 and 45 years, which is more acceptable for a developing country.
Impact of hospital volume and margin status on survival following radical hysterectomy: An expanded NCDB study.
Authors: Jhaveri Vasanti , Tanner Jean Paul , Salemi Jason L. , Kamrava Mitchell , Rutherford Thomas , David John , Anderson Matthew L 
Published: June 2023

e17527 Background: Use of a minimally invasive surgical (MIS) approach to manage early-stage cervical cancer has been previously associated with an elevated risk of disease recurrence and death. However, the reasons why MIS would lead to worse clinical outcomes remains unclear. Here, we sought to determine whether hospital surgical volume and surgical margin status contribute to worse outcomes previously reported for minimally invasive radical hysterectomy (RH-MIS). Methods: Demographic and outcome data for women diagnosed with an invasive carcinoma of the cervix (SCCa) between 2010 and 2015 were abstracted from the National Cancer Database (NCDB). Differences by surgery type were examined using chi-square test for categorical variables and independent samples t-test test for continuous variables. Surgical margin status was reported as either positive or negative according to the presence of malignancy. Overall survival was evaluated using the Kaplan-Meier method and multivariable Cox proportional hazards regression. Analyses were stratified by hospital volume. Low volume facilities were defined as institutions performing <10 surgeries per year. Results: We identified a total of 5,090 women who underwent radical hysterectomy by either minimally invasive (n=2181) or open (n=2909) approach. Between 2010 and 2015, the proportion of radical hysterectomies performed by RH-MIS increased from 42.7% to 70.3% of all cases. In contrast to prior reports, 5-year survival among RH-MIS patients was significantly better compared to RH-open patients (92.5% vs. 90.8%, p=0.02). However, women who underwent RH-MIS were significant younger (45.6±12.3 v. 46.8±12.3 years, p<0.001), more educated (p<0.001), more likely to be White Non-Hispanic (p<0.001) and diagnosed with earlier stage disease (p<0.008). Women who underwent RH-MIS were also less likely to have positive surgical margins (2.2% v 3.5%, p=0.006). After accounting for these differences, there was no statistically significant difference in survival for women undergoing RH-MIS vs. RH-open (HR, 1.18; 95% CI: (0.96-1.45). Positive margin status was associated with worse survival only at low-volume hospitals (HR, 2.30; 95% CI: 1.09-11.31). However, no other association between hospital volume, surgical route, margin status and survival was observed. Curiously, survival for women diagnosed in 2012 (HR, 1.51; 95% CI, 1.05 – 2.17) and 2013 (HR, 1.49; 95% CI, 1.03-2.15) not other years was significantly worse when compared to 2015, regardless of surgical route. Conclusions: Positive surgical margins following radical hysterectomy appear to be most effectively addressed at high volume centers caring for women with cervical cancer. These observations underscore a national need for equitable access to radiation care for women being treated for early stage cervical cancer.