bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma circulating tumor DNA in patients with cutaneous squamous cell carcinoma: Initial experience.
Authors: Fan Cong , Brito Karina , Geiger Jessica Lyn , Sussman Tamara A. , Campbell Shauna , Silver Natalie L. , McGrail Daniel , Ku Jamie , Lamarre Eric , Yilmaz Emrullah , Koyfman Shlomo A. 
Published: June 2024

e15034 Background: Circulating tumor DNA (ctDNA) has emerged as a potential noninvasive biomarker to assess tumor burden throughout cancer treatment and to aid in clinical decision-making. However, data on the use of ctDNA in cutaneous squamous cell carcinoma (cSCC) is currently lacking. In this study, we report our first experience with ctDNA in patients with cSCC. Methods: In this IRB-approved study at a tertiary care center, an initial cohort of patients with intermediate to high-risk cSCC had tissue and plasma sent for ctDNA analysis using Natera®’s proprietary bioinformatics pipeline. This cohort included 21 patients treated from 2023 to the present. Initial tissue samples were obtained through biopsy (i.e., excisional, punch, or shave), Mohs surgery, or surgical resection. Some patients had additional plasma sample(s) drawn later during or after the treatment course. Patients either received a “positive,” “positive below analytical range,” or “negative” result or had ‘insufficient sample’ to receive a result based on Natera®’s analysis. All patients were treated curatively with surgical resection with or without adjuvant radiation as per the standard of care. The assessment of gross disease was determined based on whether the patient had disease present on imaging or physical exam at the time of the plasma draw. A comparison of ctDNA results and the presence of gross disease was done using Fisher’s exact test. Results: Of the samples submitted for Natera® ctDNA analysis, 18/21 had sufficient tissue for analysis of tumor DNA. All 3 tumors with insufficient tissue were from biopsies (6/9 sufficient), while 12/12 of those from Mohs or surgical resection had sufficient tissue. The average tumor volume in these patients with insufficient samples for tumor analysis was relatively low (0.35 cm3) compared to those that resulted (17-30 cm3). 7/9 (78%) patients with gross disease had a positive ctDNA result, which was significantly greater than those with no gross disease (1/9 patients, 11%) (p = 0.004). Three patients in our cohort with an initially positive ctDNA result had multiple plasma draws, with all having a later draw demonstrating a negative ctDNA result after having surgery and/or radiation. Conclusions: Circulating tumor DNA is a reliable marker for patients with cSCC with a high tumor burden and is feasible in those with adequate tissue. However, in patients where it is only possible to obtain a small volume of tumor tissue and/or low tumor burden, ctDNA may be a less reliable biomarker. [Table: see text]
Flushing fluid of post-bronchoscopic biopsy as a novel liquid biopsy specimen for genome profiling in advanced lung cancer.
Authors: Xie Zhanhong , Wu YongQing , Xie Yingbo , Chen Yu , Li Junjun , Li Bing , Zhou Chengzhi , Liu Ming , Lin Xinqing , Xie Xiaohong 
Published: June 2024

e15038 Background: Tumour tissue is the primary substrate for molecular testing in advanced NSCLC. However, obtaining sufficient tissue samples from biopsy for molecular testing can often be challenging. Flushing fluid of post-bronchoscopic biopsy, which contains tumor-derived DNA, may serve as a supplement for genotyping. The aim of this study is to assess the efficacy and precision of detecting gene alterations in flushing fluid samples and evaluate their clinical potential. Methods: Flushing fluid, matched tissue (TIS), and whole blood were prospectively collected from 25 patients with stage III-IV NSCLC between June 2022 and December 2023. Ten milliliters of flushing fluid and whole blood were used to prepare flushing fluid supernatant (FFS) and plasma (PLA), respectively. Capture-based targeted sequencing of TIS, FFS and PLA samples was performed using a universal oncology panel. Results: In this cohort of 25 patients, there was a male predominance (22 out of 25) and the mean age was 60.2 years. The majority of patients were diagnosed with lung adenocarcinoma (23 out of 25), and smokers outnumbered non-smokers (16 out of 25). Furthermore, 18 out of 25 patients presented with metastatic disease at diagnosis. The performance of three sample types regarding key quality control indices was evaluated first. FFS exhibited a maximum allelic fraction similar to TIS, while PLA showed a significantly lower than TIS and FFS. Subsequently, we compared the positive detection rates, with TIS, FFS, and PLA achieving respective rates of 100%, 96%, and 80%. A total of 495 mutation events were detected from the three samples (FFP:209, FFS:196, PLA:90), Among these, 161 were concordant between TIS and FFS samples, and 72 were concordant between TIS and PLA samples. The sensitivity and positive predictive value (PPV) of detecting eight established driver alterations in NSCLC were compared using TIS as the gold standard with the two liquid biopsies. FFS demonstrated superior sensitivity and PPV compared to PLA (80.5% vs. 56.1%, 97% vs. 88.5%) and showed equivalent performance for EGFR mutation. Furthermore, estimates of tumor mutational burden (TMB) based on TIS and FFS were highly correlated (Pearson r= 0.97). Conclusions: Our study demonstrated that FFS performs comparably to matched TIS and superiorly to PLA for genotyping advanced NSCLC. FFS emerges as a valuable specimen source, especially in patients with insufficient tumor tissue.
Effect of circulating tumor cells in clinically stable patients on the conundrum of recurrence with cellular residual disease.
Authors: Khandare Jayant , Ramesh Aarthi , Aland Gourishankar , Patil Prathamesh , Deshpande Tanvi , Khutale Ganesh , Jayant Sreeja , Joshi Ashish , Joshi Kshitij Chandrakant , Chugh Bhuvan , Choudhary Vaibhav , Raut Nirmal Vivek , Almel Sachin , Maniar Vashishth , Deshmane Vinay , Bharde Atul , Shafi Gowhar , Vasudevan Aravindan 
Published: June 2024

e15040 Background: Despite no evidence of disease by radiological imaging, up to 30% breast cancer cases are known to relapse after treatment with a curative intent. The presence of CTCs in stage I-II cancer patients signals the activation of extravasation and invasion process leading to micro-metastasis and may lead to poor outcome. CTCs in blood circulation at any stage of cancer indicate detectable Minimal Cellular Disease (MCD). Thus the longitudinal investigation of patients with such biomarker remains highly implicative to predict the recurrence, therapy escalations, and dose modifications. The expression of Program Death - Ligand 1 (PD-L1) on CTCs is a dynamic biomarker and they may escape the elimination by immune system, indicative of progression of metastatic signature. Methods: Retrospectively, ina cohort of 20 cancer patients (e.g. lung, colon-rectal, breast, stomach, etc.) who recently underwent treatment were investigated for the presence of CTCs using CDSCO approved OncoDiscover platform having multi-components conjugated with anti EpCam antibody on magnetic nanoparticles. All patients represented clinically stable disease from previous radiological findings. CTCs enumeration assay was performed using CD45, EpCAM+, and CK18 and over-expression of PD-L1 in1.5 ml of peripheral blood using automated motorized Zeiss fluorescence microscopy. Results: In spite of 'no radiological' findings with clinically stable disease, out of 20 selected patients, 75% (n=15) showed at least 1 CTC. While, 55% (n=11) patients were detected with 1 CTC, 5% patients (n=1) with 2 CTCs, and 15% patients (n=3) were identified with 3 CTCs. In addition, 50% (n=10) of patients demonstrated with PD-L1 expression on CTCs; 1 patient exhibited a CTC cluster. Conclusions: Patients showed CRD in spite of a stable disease, which is an indication of progression of localized disease transforming from primary to secondary. The longitudinal monitoring of patients for CTCs with PD-L1 expression may reveal ‘real time’ residual disease, progression, regression, and actual response to the treatment. CRD monitoring can improve the curative intent by improving PFS and OS in solid cancers.
Simultaneous detection of tumor-derived mutations in DNA and RNA extracted from a single circulating tumor cell based on droplet digital polymerase chain reaction.
Authors: Choi Jaesung , Park Sehwan , Jeong Aejin , Kim Hanbyeol , Pak Sehyung , Song Min-Ji , Kim Jungwon , Lee Hai-Chon 
Published: June 2024

e15053 Background: Androgen receptor splice variant 7 (AR-V7) is a constitutively activated isoform of AR and has been associated with resistance to AR-targeted therapies and development of metastatic castration-resistant prostate cancer. Confirmation of AR-V7 expression is important step in prostate cancer diagnosis and determining the appropriate drug, however, the detection of AR-V7 with tissues has limitations, such as the clinical challenge to poorly accessible tumor tissues before and after therapy. In addition, KRAS mutations serve as a prognostic biomarker for the administration of appropriate anti-cancer drugs in patients with various cancers, including non-small cell lung cancer (NSCLC). Here, we developed the process for the simultaneous detection of AR-V7 and KRAS mutation in CTCs using isolation with CytoGen’s Smart Biopsy™ System with droplet digital polymerase chain reaction (ddPCR) with high sensitivity and specificity, overcoming the limitations of tissue biopsy. Methods: ddPCR assays were performed to detect the KRAS G12C mutation using CTC gDNA and to evaluate the absolute levels of AR-V7 using CTC mRNA. Analytical validation was performed using NSCLC NCI-H358 and prostate cancer 22Rv1 cells (10 and 5 cells each), which harbor KRAS G12C and AR-V7, respectively, spiked into 5 mL of healthy blood to mimic CTC. CTCs were isolated using CytoGen's Smart Biopsy™ System. Oligo-dT magnetic beads were used to isolate mRNA from CTCs, and gDNA was isolated from the mRNA-depleted CTC lysates using the AllPrep DNA/mRNA Nano Kit. PCR and droplet reading for each assay were performed on the QX200 AutoDG Droplet Digital PCR System. Results: As a result of CTC KRAS G12C detection using the ddPCR™ KRAS G12/G13 Screening Kit, the mutated KRAS gene was successfully detected in as few as 5 NCI-H358 cells. In the results of CTC AR-V7 detection using the custom TaqMan ddPCR assay, transcripts (AR-V7 and HPRT1) were successfully detected even with only 5 22Rv1 cells. These results suggest that CytoGen's Smart Biopsy™ System could be applied to the simultaneous detection of DNA/RNA mutated genes in clinical NSCLC and prostate cancer patients with detection technology requiring high sensitivity and specificity. Conclusions: Accurately detecting multiple genetic mutations in CTCs is a challenging because CTCs are very rare in the blood. In this study, we developed the process to simultaneously extract and detect DNA mutations and RNA splicing variants in CTCs using CytoGen's Smart Biopsy™ System. This process, along with the results from our ongoing clinical trials, could provide information for the diagnosis and appropriate treatment of patients with various cancers, including NSCLC and prostate cancer.
Multidimensional tumor profiling and its meaningful impact on personalized therapy outcomes: Insights from a real-world study.
Authors: Schaffrin-Nabe Dorthe , Crook Tim , Limaye Sewanti , Schuster Stefan , Josten-Nabe Anke , Reismann David , Patil Darshana , Datta Vineet , Heinze Adrian , Schaffrin Merle , Voigtmann Rudolf , Kurzrock Razelle 
Published: June 2024

e15064 Background: This real-world study underscores the transformative potential of multidimensional tumor profiling, including tissue and blood-based markers, in guiding personalized oncology treatments. We established a robust link between comprehensive diagnostics and improved clinical outcomes by correlating extensive profiling data with progression-free survival (PFS), the ratio of PFS2 to PFS1, and comparing these with treatment modalities. Methods: Over five years, 44 patients with advanced-stage solid tumors underwent comprehensive tumor profiling, including genetic markers from tissue and blood, mRNA expression, circulating tumor cells, pharmacogenomics, and immunohistochemistry, to tailor therapies. These multidimensional datasets were rigorously analyzed applying machine learning algorithms against responses to target, chemo, and combo therapies, using robust statistical frameworks to elucidate the impact of advanced diagnostics on therapy effectiveness. Results: Multidimensional tumor testing markedly extended progression-free survival, with median PFS1 and PFS2 at 22.5 and 30 weeks, respectively t(43) = 1.76, p = 0.043, and a significant median PFS2/1 ratio of 1.31. Targeted therapies achieved the highest median PFS2 at 61 weeks, surpassing chemo alone (10.5 weeks) and combination therapy (29.5 weeks) significantly. Patients treated based on gene expression, including mRNA profiling and immunohistochemistry/immunocytochemistry (n = 22), had a median PFS of 37.5 weeks, outperforming those treated based on NGS (n = 12) with 27.5 weeks significantly. Those not fully adhering to guideline treatments due to divergent findings had a median PFS2 of 16.5 weeks. Notably, 26 out of 44 patients with critical illness had a PFS2 over 6 months. Conclusions: A clear linkage was established between comprehensive profiling indicators, including genetic, molecular, and cellular markers, and the observed therapeutic outcomes. The study reaffirms the critical importance of multidimensional tumor profiling in the era of precision oncology. However, we proceed monitoring this growing group of patients to establish a clearer picture how to adapt complex diagnostic tools into modern oncological practice.
Role of artificial intelligence in ocular tumors: A systematic review.
Authors: Farabi Maleki Shadi , Yousefi Milad , Hajiesmailpoor Zanyar , Jafarizadeh Ali , Pedrammehr Siamak , Alizadehsani Roohallah , Gorriz Saez Juan Manuel 
Published: June 2024

e15070 Background: Integrating oncology and artificial intelligence (AI) shows significant potential in improving treatments and early detection of ocular tumors. This systematic review aims to strengthen existing evidence regarding the application of AI in diagnosing and treating ocular tumors. Methods: We systematically searched PubMed, Embase, Web of Science, Scopus, and Google Scholar until January 15, 2024. Inclusion criteria comprised original peer-reviewed human studies (retrospective or prospective) investigating AI approaches in patients with ocular tumors such as retinoblastoma, uveal melanoma, conjunctival melanoma, and choroidal melanoma. The quality of the literature was assessed using JBI checklists. The eligibility criteria involved assessing studies that explored the application of AI in ocular tumor detection, classification, and treatment planning. We employed a rigorous screening process, and subsequent data extraction focused on key characteristics, including tumor types, sample sizes, AI input data specifications, and study aims. Exclusion criteria encompassed studies not meeting the inclusion criteria, lacking relevant outcome measures, exhibiting insufficient methodological quality, or inadequate reporting. Results: The initial database search yielded 903 records, of which 37 studies (retrospective = 24 and prospective = 13) were included. Most studies selected the retinoblastoma (n = 12) and uveal melanoma (n = 14). Other studies utilized other types of ocular tumors, including ocular metastasis (n = 2), ocular surface squamous neoplasia (n = 2), and ocular lymphoma (n = 2). The conjunctival melanoma, choroidal melanoma, intraocular melanoma, cavernous hemangioma, and schwannoma patients were utilized once. The AI-based models were employed for the classification (n = 22), prognosis prediction (n = 6), lesion segmentation (n = 5), and predicting the gene expression (n = 4) tasks. The data types used Included magnetic resonance imaging (MRI), computed tomography (CT), whole-slide imaging (WSI), clinical data, and fundus images. A meta-analysis was precluded because of the significant heterogeneity observed across the included studies in terms of demographics, study design, interventions, and outcome measures. Conclusions: Although imaging and patient presentation have played a crucial role in ocular tumor diagnostics, AI presents promising results in prediction, prognosis, and disease management. Meanwhile, AI's primary role has been in classification, demonstrating significant success. Additionally, continued exploration of less-discussed eye tumors is essential for enhancing AI's predictive and therapeutic capabilities. The absence of reported evaluation criteria and low evaluation parameter rates in certain studies underscores the importance of standardized reporting practices for robust assessments in future ocular oncology research.
Unraveling the role of ubiquitin C-terminal hydrolase L1 in high grade serous ovarian cancer pathogenesis.
Authors: Jansen Corinne , McAdams Julia , Woodman Morgan , De La Cruz Payton , Grive Kathryn , James Nicole 
Published: June 2024

e15078 Background: High grade serous ovarian cancer (HGSOC) is the most lethal of all gynecologic malignancies, due to the fact that the majority of patients are diagnosed at an advanced stage and eventually develop chemoresistant disease 12-18 months following completion of frontline therapy. Therefore, novel targeted therapies are urgently needed to combat chemoresistance and improve patient clinical outcomes. Ubiquitin C-terminal hydrolase L1 (UCHL1) is a deubiquitinating enzyme that plays a vital role in protein homeostasis and is highly overexpressed in HGSOC. It was previously uncovered that targeting UCHL1 with small molecule inhibition reduced cell viability in a chemoresistant ovarian cancer cell line. Methods: Comparative-label free proteomic analysis was used to uncover significant changes in HGSOC cell line OVCAR8WT following treatment with UCHL1 small molecule inhibitor, LDN-5744 or corresponding DMSO control. Significant pathway changes were determined by KEGG analysis. Matched chemosensitive and resistant HGSOC cells PEA1 and PEA2 were treated in combination with LDN-5744 and carboplatin, with cell viability was determined by an MTS assay. Furthermore, western blot analysis was employed to compare common cell growth pathway changes as a result of UCHL1 inhibition in HGSOC cells. Results: Proteomic analysis revealed a significant (p<0.05) upregulation in methyl phosphate capping enzyme (MEPCE) (4.9-fold), asparagine synthetase (ASNS) (2.5-fold), Phosphoserine aminotransferase 1 (PSAT1) (1.7-fold), and downregulation in centrosomal protein 55 (CEP55) (-7.2-fold), These identified proteomic changes were confirmed by western blot. KEGG pathways analysis using all significantly (p<0.05) differentially expressed proteins showcased significant (p<0.05) enrichment in amino acid biosynthesis, and metabolism, and chemical carcinogenesis-reactive oxygen species. Chemoresistant PEA2 cells treated in combination with LDN-5744 and carboplatin demonstrated a 59% reduction in cell viability, significantly (p<0.001) lower than the 13% and 22%, that was observed from UCHL1 and carboplatin treatment alone, respectively. Conversely, PEA1, the chemosensitive counterpart to PEA2 demonstrated a significant (p<0.001) 37% increase in cell viability upon combinatorial treatment compared with carboplatin alone, indicating that UCHL1 inhibition rescues the cells from chemotherapy induced cell death. Finally, LDN-5744 treatment in PEA2 led to a reduction in levels of phospho-(p-)AKT, p-STAT3, and p-ERK, while conversely in PEA1 cells levels of these proteins were increase or unchanged. Conclusions: Our findings demonstrate that targeting UCHL1 results in prominent metabolic changes in HGSOC cells and that the efficacy of UCHL1 inhibition is heavily dependent upon platinum status. Overall, this study highlights UCHL1’s novel therapeutic role in the recurrent HGSOC.
Results of a first-in-human, dose-escalation phase 1 study of the ERK1/2 inhibitor ATG-017 in patients with advanced solid tumors.
Authors: Wahlroos Sara , Teng Christina , Tran Ben , Voskoboynik Mark , Gan Hui Kong , Spencer Andrew , Kudva Anupa , Song Ming , Lynch Kevin , Yu Zhinuan , Desai Jayesh , Lemech Charlotte Rose 
Published: June 2024

e15114 Background: This open-label, first-in-human, phase 1 study evaluates the safety, pharmacokinetics, and maximum tolerated dose (MTD) of ATG-017, an oral, potent, and highly selective inhibitor of ERK1/2, in patients with refractory advanced solid tumors. Methods: Twenty-one patients with solid tumors harboring activating alterations in the RAS-MAPK pathway were enrolled in the 3+3 design dose-escalation phase for continuous dosing: 5 mg QD (n=1), 5 mg BID (3), 10 mg BID (3), 20 mg BID (7), 30 mg BID (4), and 40 mg BID (3). Results: Safety: All patients reported at least 1 treatment-emergent adverse event (TEAE). Fourteen patients (66.7%) experienced serious adverse events. At 40mg BID, 2 of 3 patients experienced a dose-limiting toxicity (DLT) (grade 3 diarrhea and grade 3 retinopathy). At 30mg BID, 2 of 4 patients experienced a DLT (grade 3 acneiform dermatitis and grade 2 blurred vision). All DLTs resolved with drug interruption. At 20mg BID, a potentially biologically active dose, 7 patients were treated with no DLTs observed. At all dose levels, the most commonly observed TEAEs were consistent with previously reported toxicities with other ERK pathway inhibitors (gastrointestinal, skin, and ocular adverse events). Pharmacokinetics: Between 5mg BID and 30mg BID, exposure increased proportionally. At doses 20mg BID or higher, the concentration in the whole dosing interval (≥ 328ng/mL, geometric mean) was higher than the target concentration (231 ng/mL) for effective ERK inhibition derived from preclinical PK/PD models. Efficacy: Of the 21 treated patients, one patient (4.8%) with mesonephric-like ovarian adenocarcinoma (KRAS G12V mutation) in the 30 mg BID cohort achieved a best response of partial response (sustained for six cycles of treatment), and 8 (38%) patients were assessed as having stable disease (sustained over an average of five cycles), based on RECIST v1.1. Conclusions: In patients with solid tumors, 20mg BID continuous dosing of ATG-017 was identified as the MTD and delivers exposure that is likely to be active in inhibiting ERK. This dose is currently being explored in a dose expansion phase. A combination regimen with nivolumab is also being investigated. Clinical trial information: NCT04305249 .