bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-wide circulating tumor DNA monitoring for bladder cancer treatment management and organ preservation.
Authors: Nordentoft Iver , Christensen Emil , Birkenkamp-Demtröder Karin , Deochand Sunil , Maloney Dillon , Lauterman Tomer , Patel Kristofer , Bourzgui Imane , Ramaraj Nidhi , Viborg Lindskrog Sia , Agerbaek Mads , Jensen Jørgen Bjerggaard , Kandasamy Ravi , Tavassoly Iman , Oklander Boris , Zviran Asaf , Dyrskjøt Lars 
Published: June 2021

e16527 Background: Bladder cancer (BC) is the 9th most commonly diagnosed cancer worldwide and each year responsible for 165,000 deaths. Neoadjuvant combination chemotherapy, followed by radical cystectomy, is used for the management of localized muscle-invasive bladder cancer. One of the critical challenges in this therapeutic regimen is monitoring the tumor load to assess therapeutic efficacy – this is typically performed by assessing pathological downstaging in the cystectomy specimen. A high frequency of patients presents with T0N0 at cystectomy (no indication of residual disease), and consequently, it is vital to investigate organ preservation approaches to identify those patients who may qualify for bladder preservation. For precision oncology, we need to develop quantitative and non-invasive diagnostic methodologies to help the oncologist tailor the treatments to individual patients and monitor them for further clinical decision-making. Methods: Cell-free DNA (cfDNA) mutation detection has shown significant promise in its ability to monitor minimal residual disease and disease relapse by detection of cancer mutations in the peripheral blood. However, the combination of low tumor fraction and limited input material obtained from a typical plasma sample restricts the probability of detecting low metastatic burden in cfDNA through current deep targeted sequencing methods. Results: Here we present results from applying whole-genome sequencing (WGS) of cfDNA. We integrate a genome-wide mutation and copy number monitoring approach coupled with advanced signal processing and Artificial Intelligence (AI) for measuring the tumor load from low-input blood samples (̃1mL of plasma) with ultra-sensitive detection. The increased sensitivity allowed clinical detection of tumor fraction down to 8*10-5 and recurrence detection sensitivity achieving > 65% at the first two months post-surgery. The WGS cfDNA approach is being evaluated on a patient cohort of more than 50 bladder cancer patients with longitudinal plasma sampling during neoadjuvant chemotherapy (response measure), pre-cystectomy (complete response measure), and post-surgery (relapse monitoring). Conclusions: The results indicate the clinical potential of genome-wide mutation integration as an ultra-sensitive, non-invasive diagnostic method for bladder cancer clinical management and bladder organ preservation.
Plasma and urine free glycosaminoglycans as monitoring and predictive biomarkers in metastatic renal cell carcinoma: A prospective observational study.
Authors: Gatto Francesco , Bratulic Sinisa , Jonasch Eric , Limeta Angelo , Maccari Francesca , Galeotti Fabio , Volpi Nicola , Lundstam Sven , Nielsen Jens , Stierner Ulrika 
Published: June 2021

e16540 Background: No liquid biomarkers are approved in renal cell carcinoma (RCC). In metastatic RCC (mRCC), there is a need to predict and monitor response noninvasively to guide the choice of treatment. Urine and plasma glycosaminoglycan (GAGs) profiles – or GAGomes - are promising biomarkers reflective of RCC metabolism. Here, we explored if GAGomes could predict and monitor response noninvasively. Methods: A single-center prospective consecutive series of mRCC patients elected for first-line therapy was enrolled between June 2016 - April 2019 at Sahlgrenska University Hospital, Gothenburg, Sweden. Response was assessed by the investigator as progressive disease (PD) versus non-PD. Plasma and urine GAGomes were measured at treatment start, after 6 weeks, and every 3rd month in a blinded central laboratory. We conducted Bayesian estimation to correlate GAGomes to response and to design GAG scores to classify PD. So-trained GAG scores were validated to predict PD vs. non-PD at treatment start or after 6 weeks. Results: Fifty patients with treatment-naïve mRCC were enrolled (median age: 68.5 years, 33% female). All received tyrosine-kinase inhibitors (37 sunitinib, 4 pazopanib, 9 cabozantinib). The median follow-up time was 3.5 months, totaling 65 response evaluation visits - 23 PD and 42 non-PD. PD was compatible with alterations in 40% of the detectable GAGome features. These were used to design a plasma, urine, and combined GAG progression score to classify PD vs. non-PD at response evaluation. The area-under-the-curve (AUC) was 0.91 in plasma, 0.98 in urine, and 0.99 when combined. In validation, the AUC to predict PD at treatment start was 0.64 in plasma, 0.63 in urine, and 0.71 when combined (N = 50); and, after 6 weeks, 0.75 in plasma, 0.66 in urine, and 0.80 when combined (N = 47). The combined GAG progression score had 62% sensitivity and 86% specificity to PD at treatment start and 67% and 87% after 6 weeks. Conclusions: GAGomes correlated with treatment response in mRCC. GAG scores were validated for the early prediction of response. Their clinical utility remains to be ascertained. Clinical trial information: NCT02732665.
Real-world treatment patterns and overall survival in previously treated advanced renal cell carcinoma patients receiving nivolumab in the UK.
Authors: Waddell Tom , Fife Kate , Griffiths Richard , Sharma Anand , Dhokia Poonam , Gordon Jason , Groves Lara , Hurst Michael , Sugrue Daniel , Tsang Carmen , Mckenna Stephen , Houghton John , Carroll Robert 
Published: June 2021

e16561 Background: CheckMate 025 demonstrated favorable efficacy and safety results for nivolumab monotherapy in previously treated advanced or metastatic renal cell carcinoma (aRCC). However, real-world evidence on treatment patterns and clinical outcomes is limited. Methods: This multi-centre, retrospective cohort study examined treatment patterns and overall survival (OS) in aRCC patients treated with nivolumab monotherapy. Eligible patients who initiated nivolumab at second-line (2L) or beyond (index) between 01 March 2016 and 30 June 2018 were sampled from four UK centers. Data were extracted using an electronic case report form from index to earliest of: most recent visit; death; end of follow up (31 May 2019). Results: Overall , 151 patients were included in analyses (mean age at index 66.9 years, 72.2% male, median follow-up from index 15.2 months), with 109 (72.2%) and 42 (27.8%) receiving nivolumab at 2L and ≥ third-line (3L+), respectively. Key clinical characteristics are outlined in Table 1. All 2L nivolumab patients had received first-line (1L) tyrosine kinase inhibitors (TKI), pazopanib (57.8%), sunitinib (30.3%), or both in sequence (10.1%). After 2L nivolumab, 3L cabozantinib (36/52, 69.2%) was most common. Most 3L nivolumab patients received 2L TKI (31/36, 86.1%) - commonly axitinib (70.9%). After 3L nivolumab, most patients received fourth-line cabozantinib (8/12, 66.7%). Median time on line of therapy (LOT) decreased with LOT progression: from 7.8 months at 1L to 4.6 months at fifth-line (5L). The proportion of patients who discontinued treatment due to adverse events decreased by LOT, (28.6%, 22.7%, 16.0% and 0%, and 34.7%, 28.1%, 0% and 0% from 2L to 5L, overall and for nivolumab treatment, respectively). Overall, median OS from nivolumab initiation was 19.2 months [95% CI, 16.9-27.0]. Patients who received 2L nivolumab had longest median OS (23.0 months [95% CI, 17.2, not reached]), comparable to CheckMate 025 (25.8 months [95% CI, 22.2-29.8]). Median OS for 3L+ nivolumab patients was 12.4 months [95% CI, 8.8, 23.2]. Among 2L nivolumab patients, 73.9%, 46.2%, and 33.6% survived 12, 24, and 36 months, respectively. For the same respective timeframes, 52.4%, 24.7%, and 18.6% of 3L+ nivolumab patients survived. Conclusions: This study provides real-world evidence on the characteristics, treatment patterns and effectiveness of 2L or ≥ 3L nivolumab monotherapy in previously treated aRCC patients. OS results from UK routine clinical care were comparable to those found in CheckMate 025.[Table: see text]
First-line therapy in patients with metastatic renal cell carcinoma (mRCC): Results from consecutive patients over 25 years in a single institution.
Authors: Fristrup Niels , Donskov Frede 
Published: June 2021

e16574 Background: Immune checkpoint inhibitors (ICI) have demonstrated improved activity in metastatic renal cell carcinoma (mRCC). Real-world data comparing the effectiveness of ICI with interleukin-2 (IL-2) is limited. Methods: We retrospectively assessed consecutive patients with biopsy-proven mRCC at our institution between 1994 and 2020. Patients were classified into four groups based on first-line therapy: vascular endothelial growth factor (VEGF) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, IL-2, or ICI. The primary endpoint was overall survival (OS). Kaplan-Meier method was used to compare OS between treatment groups. We used Cox proportional hazards models to adjust for prognostic covariates. Results: A total of 1424 patients were treated with first line therapy; 51% received VEGF, 3% received mTOR, 40% received IL-2, and 6% received ICI. Median follow-up was 97.6 months. Except for the mTOR group, baseline characteristics were largely balanced between the treatment groups. Median OS in the ICI group compared with IL-2, mTOR and VEGF was 40.1, 17.6, 6.3 and 14.7 months (p < 0.001), respectively, and the 5-year survival rate was 36%, 20%, 9% and 14%, respectively. After adjusting for IMDC and MSKCC individual risk factors, histology, age, gender, year of treatment initiation, low sodium, and location of metastases (lung, liver, bone, lymph node), the hazard ratio (HR) (95%CI) for OS with VEGF as reference was 0.50 (0.33-0.74, p = 0.001) for ICI, 0.81 (0.70-0.92, p = 0.002) for IL2, and 1.09 (0.79-1.52, p = 0.6) for mTOR. Conclusions: In this largest single institution cohort to date, patients with mRCC who received CPI achieved longer OS.[Table: see text]
Combination of immunotherapy and tyrosine kinase inhibitor in first-line metastatic renal cell carcinoma: A real-world Indian experience.
Authors: Rauthan Amit , Patil Poonam , Murthy Nitin Yashas , Somashekhar SP , Zaveri Shabber , Aswath Rajashri , V Prathyush 
Published: June 2021

e16576 Background: Immuno-oncology (IO) agents in combination with oral tyrosine kinase inhibitors (TKIs) has become a standard first line therapy in metastatic renal cell carcinoma (mRCC) patients. Various combinations such as pembrolizumab + axitinib, avelumab + axitinib, nivolumab + cabozantinib and pembrolizumab + lenvatinib have all shown better results than sunitinib. There is very limited data about this from India. Methods: This is a single center, retrospective study of mRCC patients, who received first line treatment was nivolumab or pembrolizumab with axitinib or lenvatinib. The endpoints were objective response rate (ORR), progression free survival (PFS), overall survival (OS) and adverse events (AE). Results: Between Jan 2019 to Jan 2021, 22 patients were treated with IO + TKI combination. 12 patients received axitinib, and 10 lenvatinib. Age range was 35 to 78 years with 18 males and 4 females. IMDC risk stratification showed 3 favorable (13.6%), 13 intermediate (59%) and 6 poor risk (27.2%) patients. 2 patients (9%) achieved complete response(CR), 13 (59%) partial response (PR), 4 (18.2%) had stable disease and 3 (13.6%) progressed. The ORR was 68%. Median PFS was 22 months (1 month- 24 months). OS at 1 year was 92%, and median OS was not reached. Grade 3/4 immune related adverse events (AEs) were seen in 3 (14.2%) patients (1 colitis,1 pneumonitis,1 encephalitis), for whom the IO was discontinued. TKI related grade 3/4 AEs were seen in 8 patients (38%), and were managed with dose reductions. Conclusions: Combination IO + TKI is a very effective first line therapy in mRCC. An ORR of 68%, median PFS of 22 months and 1 year OS of 92% is the best we have seen in our patients. The efficacy of this combination is seen in all IMDC subgroups. The combination is well tolerated, and the TKI AEs are comfortably managed with dose reduction. IO combinations should be preferred over single agent TKIs (sunitinib or pazopanib) as first line therapy.
Features of genes copy number in normal, primary tumor, and lymph nodes metastases cells in patients with cervical cancer.
Authors: Kecheryukova Madina M. , Snezhko Aleksandr V. , Verenikina Ekaterina V. , Menshenina Anna P. , Adamyan Meri L. , Ardzha Anna Yu. , Kit Oleg I. , Kutilin Denis S. 
Published: June 2021

e17503 Background: Early stages of cervical cancer (CC) can be treated with surgery or radiation therapy, metastatic CC is incurable, and therefore new diagnostic approaches based on highly effective molecular markers are required. As such markers, the Copy Number Variation (CNV) is of great interest. Purpose of the study: to analyze the peculiarities of genes CNV in normal cells, primary tumor and lymph nodes tumor metastases cells in patients with CC. Methods: Tissue sections from FFPE-blocks of 300 patients with CC were used for the study. Primary tumor, tumor metastatic and normal cells were isolated using non-contact laser microdissection (Palm MicroBeam, Carl Zeiss). DNA was extracted from the cells using the phenol-chloroform method. Determination of 14 genes CNV (LAMP3, PRKAA1, TORC2, FOXO3, HDAC5, MEF2C, MLXIPL, EP300, HNF4A, TP53, SREBF1, SREBF2, PPARGC1A, and CCND1) was performed by Real-Time qPCR method. Statistical analysis was performed using the Mann-Whitney test; Bonferroni's correction was applied to correct multiple comparisons. Results: An increase in the CNV of LAMP3 and TORC2 genes by 2.5 and 3.2 times (p < 0.05), respectively, and a decrease in the CNV of TP53 and FOXO3 genes by 2.3 and 2.0 times (p < 0.05), respectively, were found in the primary tumor cells relative to normal cells. The effect of the simultaneous change in the CNV of LAMP3, TORC2, TP53 and FOXO3 genes was observed in 60% of the sample, and LAMP3 and TP53 genes - in 80%. In cells of lymph nodes tumor metastases an increase in the CNV of CCND1 and TORC2 genes by 2.0 and 3.5 times (p < 0.05), respectively, was found, as well as a decrease in the CNV of PPARGC1A gene by 2.1 times (p < 0.05) relative to normal cells. A simultaneous change in the CNV of CCND1, TORC2, and PPARGC1A was observed in 70% of the sample, and CNV of CCND1 and TORC2 genes - in 85%. Primary tumor and metastases cells differed in the CNV of CCND1 (2.5 times higher in metastatic cells), LAMP3 (3.0 times lower in metastatic cells) and FOXO3 genes (2.0 times higher in metastatic cells). Conclusions: Thus, the primary tumor and lymph nodes metastases cells differ in the level of genes CNV from normal cervix cells. Accordingly, the CNV of LAMP3, TORC2, TP53 and FOXO3 genes may have the potential for diagnosing a primary cervical tumor, and the CNV of CCND1, TORC2 and PPARGC1A genes for diagnosing its metastases to regional lymph nodes.
Association of alterations in DNA damage repair and Notch pathways with high tumor mutational burden in patients with cervical cancer.
Authors: Zou Dongling , Li Zirong , Liu Jing , Gao Yunong , Zheng Hong , Yuan Mingming , Wang Haixia , Yuan Li , Wang Dong , Liu Jingshu , Chen Rongrong , Xia Xuefeng , Zhou Qi 
Published: June 2021

e17511 Background: The outstanding efficacy of pembrolizumab reported in study KEYNOTE-158 led to FDA approval of pembrolizumab in the treatment of patients (pts) with positive PD-L1 expression (CPS ≥1) cervical cancer (CC) and tumor mutational burden-high [TMB-H, ≥10 mutations/megabase (mut/Mb)] solid tumors including CC. This study aims to investigate the immunotherapy-related molecular characteristics in pts with CC. Methods: The study recruited pts with CC whose tissues were send to perform parallel hybridization-based next-generation sequencing and/or immunohistochemistry of PD-L1 with 22C3 assay. KEGG pathway enrichment analysis was conducted to explore whether the differentiated mutated genes (DMGs) that were more frequently mutated in the TMB-H cohort were enriched in certain pathways. In addition, pair-wise comparison of TMB and PD-L1 was analyzed to identify the proportion of pts who might benefit from immunotherapy. Results: Among 249 pts with TMB evaluated, median TMB was 5 muts/Mb (range: 0 - 58.56 muts/Mb). The prevalence of microsatellite instability was 1.2% (3/255). The threshold of TMB was defined as 10 muts/Mb according to KEYNOTE-158. Consequently, 47 pts were considered as TMB-H and 202 pts were TMB-L. Regardless that TERC amplification was only found in the TMB-L group (9.5%, 19/202), Fisher’s exact test identified 98 genes with significantly higher alteration frequency in the TMB-H group compared with TMB-L group, including MLL2/3, TERT, PIK3CA, LRP1B, EP300 and ARID1A. Pathway enrichment analysis suggested that these DMGs were mainly enriched in mismatch repair, Notch, homologous recombination and Fanconi anemia pathways. There was no evident correlation between TMB and MSI (spearman r=0.2401, p=0.0101). The positivity rate of TMB or PD-L1 was 71.9%. Conclusions: Mutations in DNA damage repair and Notch pathways may explain TMB-H in pts with CC who might may serve as surrogate markers for TMB in CC.
Amount of cancer stem cells in tumors of patients with ovarian cancer with different responses to platinum-containing chemotherapy.
Authors: Sagakyants Aleksandr B. , Bondarenko Elena S. , Yakubova Darya Yu. , Ulianova Elena P. , Zhukova Galina V. , Menshenina Anna P. , Novikova Inna A. , Verenikina Ekaterina V. , Adamyan Meri L. , Cherkasova Anna A. 
Published: June 2021

e17527 Background: Resistance to chemotherapy is a complex problem in the treatment of patients with ovarian cancer (OC), and this phenomenon is associated, among other things, with the presence of cancer stem cells (CSCs). The purpose of the study was to determine the amount of CSCs in tumors of OC patients with different responses to chemotherapy they receive. Methods: Samples of ovarian tumors were obtained from 100 patients (aged 29-79 years) with advanced ovarian cancer stage IIIC-IV with/without ascites. All patients recruited in 2016-2020 received standard combination treatment with surgery and platinum-containing polychemotherapy (Pt CT). Based on the results of neoadjuvant Pt CT, patients were divided into groups: patients with stabilization or progression–group 1 “without effect”; patients with complete/partial regression–group 2 with positive effect. All patients gave their informed consent for the study. Cell suspension obtained from the tumor fragments was processed using monoclonal antibodies labeled with various fluorochromes: CD45-APC-Cy7, CD44-FITС, CD133–РЕ according to the manufacturer's instructions (BD, USA). The percentage of CSCs was determined using the FACS Canto II flow cytometer (BD, USA). The amount of cells with CSC markers (CD44+, CD133+, CD44+CD133+) was calculated as a percentage from the total amount of CD45--cells. Statistics: STATISTICA 13 (StatSoftInc., USA). Results were presented as Me (LQ; UQ). The significance of differences was assessed using the Mann-Whitney test (the differences were considered significant at p<0.05). Results: The amount of CD45- _cells, as well as CD45-CD44+ cells, in OC tumors did not differ between patients of groups 1 and 2: 79.0 (72.1; 85.9) vs. 82.8 (76.7; 89.0), and 6.2 (3.3; 9.1) vs. 6.6 (3.5; 9.8), respectively. The percentage of cancer cells with the CD45-CD133+ phenotype in group 2 was significantly lower than in group 1: by 52% (p≤0.05), 3.2 (2.4; 3.9) vs. 6.7 (3.8; 9.6), respectively. The amount of CD45-CD44+CD133- CSCs in tumors in group 1 was lower than in group 2: by 82% (p≤0.05), 0.6 (0.3; 0.7) vs. 3.3 (1.8; 4.7), respectively. Conclusions: The results demonstrated certain differences in the distribution of CSCs in tumors of OC patients with different sensitivity to chemotherapy, which may be one of the factors determining the treatment outcomes.
Impact on survival of surgical therapeutic strategy in the initial management of advanced ovarian cancer: A study from the Cote d’Or gynaecological cancer registry from 1998 to 2015.
Authors: Amet Alix , Costaz Hélène , Fumet Jean-David , Arnould Laurent , Favier Laure , Beltjens Françoise , Bengrine Leila , Dabakuyo Tienhan Sandrine , Coutant Charles 
Published: June 2021

e17537 Background: The management of ovarian cancer is based on a combination of surgery and chemotherapy. The aim of surgery is to achieve zero residual tumour at the end of the procedure. In advanced stage ovarian cancer, two therapeutic approaches are possible: primary debulking surgery, or primary chemotherapy followed by interval debulking surgery. The primary objective of this study was to describe overall survival (OS) in FIGO stage III and IV ovarian cancers according to the therapeutic sequence (i.e. primary surgery or interval surgery). Methods: We performed a retrospective, observational study using data from the gynecological cancer registry of the Cote d’Or, for patients diagnosed with FIGO stage III or IV ovarian cancer between 1998 and 2015. We recorded FIGO stage, histological type, treatment and completeness of cytoreduction. Results: In total, 460 patients were included. OS at 5 years was 47% in patients with primary surgery, versus 38% in patients with interval surgery (p = 0.06). Five-year OS was 45% in patients with complete cytoreduction, versus 30% in those with incomplete cytoreduction (p < 0.001). The rate of complete cytoreduction was 43% in patients with primary surgery, versus 55% in those with interval surgery. Conclusions: OS appears to be slightly better in patients receiving primary surgery, and when cytoreduction is complete. Every effort should be made during surgery to achieve complete cytoreduction, by an experienced team. Primary surgery should be preferred in these patients.