tbuckley/cabot-search huggingface dataset:
The impact of androgen receptor (AR) expression on the prognosis of ductal carcinoma in situ (DCIS).
Authors: Choong Man Lee, Jisun Kim, Hwi Gyeong Jo, Hye Jin Park, Sae Byul Lee, Il Yong Chung, Jong Han Yu, Hee Jeong Kim, Beom Seok Ko, Jong Won Lee, Byung Ho Sohn, Sei-Hyun Ahn
Journal: Journal of Clinical Oncology (2019)

e14731 Background: Ductal carcinoma in situ (DCIS) display favorable outcome while little is known about the factors associated with invasive recurrence. To identify better prognostic biomarkers we performed gene expression analysis followed by immunohistochemistry (IHC) staining validation. Methods: Differential gene expression analysis of 29 pure DCIS patients was performed using nanostring platform. RNA was extracted from paraffin blocks from age/size matched 11 recurrence-free and 18 invasive-recurrence cases (disease free interval &gt; 5 years). Gene annotation enrichment analysis was done for differentially expressed genes (DEG) using DAVID. Eighty-two pure DCIS cases were selected for external validation by IHC staining. Allred score cutoff 1 was used for survival analysis. Results: Ninety-nine differentially expressed genes were found statistically significant (p-value &lt; 0.05). Androgen receptor (AR) gene, which encodes a transcription factor AR, has recently been highlighted as a favorable prognostic marker and a therapeutic target in invasive tumor (fold change = - 1.35, p &lt; 0.001). AR protein expression was externally validated by IHC staining of 82 pure DCIS cases (24 invasive-recurrence versus 58 recurrence-free). Similar to gene expression analysis result, patients with invasive recurrence showed lower AR staining score than recurrence-free patients (p = 0.007). Cox regression analysis showed lower AR level as an independent risk factor of long-term invasive recurrence (HR 7.43, 95%CI 1.50 – 36.62). Gene enrichment analysis revealed enrichment of kinase pathway and cell cycle pathway in recurred cases (Enrichment Score = 2.43, 2.41 respectively). Conclusions: DEG pattern was observed among pure DCIS cases. AR may serve as a prognostic biomarker and targeting kinase, cell proliferation may be effective for higher risk DCIS patients.
Association of forkhead box protein O1 and paired box gene 3 overexpression with prognosis in patients with cervical cancer.
Authors: Hanbyoul Cho, Gwan Hee Han, Doo Byung Chay, Jaehoon Kim
Journal: Journal of Clinical Oncology (2019)

e14519 Background: Transcriptional factor FOXO1and PAX3 has been reported to play an imported role in human cancer, but the role in cervical cancer has not yet been clarified. Here, we evaluated the functional role of FOXO1 with cervical cancer cells and the expression together with clinical significance of FOXO1 and PAX3 among cervical lesions was investigated. Methods: In vitro assessment of cell functions by cell viably assay, cell migration and invasion assay was evaluated using FOXO1 knockdown cervical cancer cell lines. Immuno-histochemical (IHC) staining analyses of FOXO1 and PAX3 were performed with tissue microarray (TMA) consisting of 209 cervical cancers, 366 high grade cervical intraepithelial neoplasias (CIN), 130 low grade CIN and 328 matched nonadjacent normal cervical epithelial tissues. The clinical significance was investigated by comparing the data with various clinicopathologic characteristics, including survival in cervical cancer. Results: In vitro result revealed that knockdown of FOXO1 was associated decreased cell viability ( p&lt; 0.001), migration ( p&lt; 0.001) and invasion ( p&lt; 0.05) supporting the oncogenic role of FOXO1 in cervical cancer. FOXO1 and PAX3 expression was significantly higher in CIN (both p&lt; 0.001) and cancer tissue (both p&lt; 0.001) than in normal tissue. FOXO1 expression showed significant correlation with PAX3 (Spearman’s rho = 0.377, p&lt; 0.001) in a cervical cancer. Multivariate analysis indicates that FOXO1 expression (hazard ratio = 4.01 [95% CI, 1.22–13.10], p= 0.021) and advanced FIGO stage (hazard ratio = 3.89 [95% CI, 1.35–11.19], p= 0.012) were independent prognostic factor on overall survival. Conclusions: This study reveals the association between FOXO1 and PAX3 expression with clinicopathologic variables, including survival of cervical cancer patients. Our results not only suggest the promising potential of FOXO1 as a prognostic and survival marker, but also warrant further studies on a possible link between the biological function of FOXO1 and the pathogenesis of cervical cancer.
Impact of adjuvant treatment according to gastric cancer molecular subtypes.
Authors: Tiago Biachi De Castria, Larissa Costa Amorim, Marcus Fernando Kodama Pertille Ramos, Marina Alessandra Pereira, Evandro Sobroza de Mello, Sheila Faraj, Jorge Sabbaga, Paulo Marcelo Hoff
Journal: Journal of Clinical Oncology (2019)

e15513 Background: The four subtypes of gastric adenocarcinoma (GC) identified by the Cancer Genome Atlas project (TCGA) have different molecular signatures and prognosis. Several centers have tried to classify GC using immunohistochemistry (IHC) and in situ hybridization (ISH), examining the tumors according to Epstein–Barr virus (EBV) status, microsatellite instability (MSI), aberrant E-cadherin expression and TP53 status. Here we aim to verify the impact of adjuvant/perioperative chemotherapy (ACT/PCT) or adjuvant chemoradiation (CRT) according to the molecular subtypes profile. Methods: We retrospectively reviewed all GC patients who underwent gastrectomy and D2-lymphadenectomy at our institution from a prospective collected medical database. Deficient DNA mismatch repair (dMMR), E-cadherin and p53 were evaluated by IHC for determining the MSI, genomically stable (GS) and chromosomal instability (CIN, with and without p53 aberrant) subtypes, respectively. EBV positivity was detected by ISH. Results: Among the 178 stage II/III patients included, 67 had surgery alone, 47 received ACT/PCT and 64 CRT. 16 had aberrant E-cadherin (GS, 9%), 33 dMMR (MSI, 18.5%), 74 aberrant p53 expression (CIN p53-aberrant, 41.6%), 104 normal p53 expression (CIN p53-normal, 58.4%) and 18 EBV-positivity (EBV, 10.1%). Two or more altered status were present in GC of 16 patients. When analyzed independently, Kaplan-Meier survival analysis showed that EBV, dMMR, CIN p53-normal and GS subtypes did not obtain any benefit of ACT/PCT or CRT in disease free survival (DFS) (p = 0.71; p = 0.33; p = 0.41; p = 0.21, respectively). Meantime, those treatments impact positively in DFS for EBV-negative, proficient MMR and non-GS (p = 0.01; p = 0.007; p = 0.01). CIN subtype with p53 aberrant obtained most benefit for ACT/PCT or CRT (p &lt; 0.001). Conclusions: In accordance with other studies we achieved no benefit for adjuvant chemotherapy in patients with EBV, dMMR and GS GC subtypes. Patients with p53 aberrant expression had greater benefit for ACT/PCT or CRT. This simple method of classification can potentially help to tailor adjuvant treatment.
3-Year Outcomes After Valve-in-Valve Transcatheter Aortic Valve Replacement for Degenerated Bioprostheses
Authors: John G. Webb, Dale J. Murdoch, Maria C. Alu, Anson Cheung, Aaron Crowley, Danny Dvir, Howard C. Herrmann, Susheel K. Kodali, Jonathon Leipsic, D. Craig Miller, Philippe Pibarot, Rakesh M. Suri, David Wood, Martin B. Leon, Michael J. Mack
Journal: Journal of the American College of Cardiology (2019)
Abstract 16592: A Next-Generation Artificial Intelligence-Based Integrated Genetic-Epigenetic Prediction of 5-Year Risk for Coronary Heart Disease
Authors: Meeshanthini V Dogan, Ronald L Simons, Steven Beach, Amaury Lendasse, Robert A Philibert
Journal: Circulation (2018)

Coronary heart disease (CHD) is a leading cause of death in the US. CHD associated morbidity and mortality can be reduced if those at risk can be identified well in advance, to put in place prevention interventions prior to an acute coronary event. Limitations of current approaches call for additional efforts to improve risk predictions. We recently developed a Precision Medicine tool capable of predicting 5-year risk, that can also guide personalized prevention interventions and monitor changes in risk over time. It was developed using an application of AI, machine learning, in the Framingham Heart Study to mine integrated genetic-epigenetic biosignatures that capture the complex interplay between our genome and the environment in conferring risk for CHD. The training and test sets consisted of 1180 (19/695 females and 23/485 males developed symptomatic CHD within 5-years) and 524 (8/293 females and 12/231 males developed symptomatic CHD within 5-years) individuals, respectively, of Northern European ancestry. Non-linear data mining and modeling techniques were employed on the training set to identify prediction signatures from genome-wide SNP and DNA methylation (DNAm) data. We identified 14 DNAm and 10 SNPs from the training set (training bootstrap average sensitivity and specificity of 0.61 and 0.71, respectively) that predicted the 5-year risk in the test set with a sensitivity and specificity of 0.60 and 0.69, respectively. Performance was compared to that of the Framingham Risk Score (FRS) and the ASCVD Risk Estimator. The sensitivity and specificity in the test set were 0.05 and 0.99 for FRS, and 0.38 and 0.85 for ASCVD. Even with a small number of incident cases, our tool performed with superior sensitivity, which is vital because, while a false positive would result in additional testing, a false negative can be detrimental. Unlike genetics, because DNAm is dynamic, it can be mapped to actionable risk factors to guide personalized interventions and over time, re-assess risk and continuously monitor heart health. We demonstrate translational feasibility of this tool via next-gen digital PCR assays. Additional efforts are ongoing to optimize, validate and extend our tool to further improve performance in larger, more ethnically diverse cohorts.
Assessing adherence to hormone therapy (HT) in breast cancer (BC) patients receiving care at BC unit in a Uruguayan university of Hospital de Clínicas.
Authors: Cecilia Castillo, Natalia Camejo, Nora Artagaveytia, Ana laura Hernandez, Patricia Apud, Florencia Melo, Lucia Beatriz Delgado
Journal: Journal of Clinical Oncology (2019)

e12026 Background: Adjuvant HT in Hormone Receptors (HR) + BC increases overall survival (OS). Adherence to therapy is a complex and multifaceted issue that can alter outcomes; however, not much of it is known abouth this in routine clinical practice. Methods: This was a retrospective study that enrolled patients treated with HT because of HR+ BC (stages I-III) at the BC unit in the 2002-2012 period. Methods: The proportion remaining on endocrine therapy was analysed by Kaplan-Meier curve. Univariate analysis (log rank test) was used to identify the factors that might independently impact on such discontinuation. The study was approved by the Ethics Committee of the Hospital de Clínicas. Results: 139 (73.1%) of the 190 patients enrolled were postmenopausal; their median age being 61 years. Most patients were single or divorced or widowed (121, 63.7%) and resided in the capital (125, 65.7%). Most tumors (166, 87.3%) were ductal carcinomas and most presented at a low histological grade: HG 2-3: 112 (58.9%). The distribution by stage was: SI: 63 (33.1%); SII: 82 (43.1%); SIII 39 (20.5%); S0 6 (3.1%). At the end of their first, second, third, fourth and fifth years of treatment; 95.3%, 87.9%, 80.6%, 76.4% and 69.5% of the patients still adhered, respectively. Adherence was not associated with either age (p = 0.687), menopausal status (p = 0.449), marital status (p = 0.221), origin (p = 0.5640), or stage (p = 0.168). The patients who received combined HT (tamoxifen followed by AI) adhered better than those who received one drug alone (p = 0.017). Conclusions: we assessed the adherence to HT in real life and found that it was reduced by 30.5% in 5 years, despite patients were well informed about the well-known benefit in terms of OS, of being a well-tolerated treatment and of being provided for free. These results are similar to or even better than those reported in several international studies. Further investigation is needed to understand why patients interrupt HT. We need to work harder to increase compliance, given the potential impact this may have on the patients’ OS.
Electrostatic human leukocyte antigen-neoantigen interactions and durable benefit in non-small cell lung cancer patients treated with immunotherapy.
Authors: Amy Lauren Cummings, Jaklin Gukasyan, Henry Lu, Benji Bachrach, John Madrigal, James M. Carroll, Wisdom O Akingbemi, Zorawar Singh Noor, Aaron Elliott Lisberg, Edward B. Garon
Journal: Journal of Clinical Oncology (2019)

2635 Background: Human leukocyte antigen (HLA) binding relies on energy from the interaction of B-pocket residues with anchor amino acids (AA). Among HLA class I supertypes, only HLA-B has distinct electrostatic B-pocket specificities, and of 7 HLA-B supertypes, B08, B27, and B44 feature binding pockets with preferences for charged AAs (Lund Immunogen). Whether electrostatic interactions in HLA-neoepitope binding would identify superior neoantigens and associate with survival in NSCLC patients treated with immunotherapy was unknown. Methods: Forty patients with advanced NSCLC treated with single agent pembrolizumab on a clinical trial with at least 5 years follow-up underwent paired tumor-normal whole-exome sequencing (WES) with Illumina HiSeq 2000/3000. HLA typing used normal (germline) WES from peripheral blood mononuclear cells analyzed with BWA-ALN and Athlates software (Liu Nuc Acids Res); supertype was determined by 2008 criteria (Sidney BMC Immunol). Tumor nonsynonymous coding mutations were identified with GATK v3.8, annotated with Ensembl-VEP, and passed through pVAC-Seq using a NetMHC 4.0 algorithm to identify potential neoepitopes 9 AAs in length (Hundal Genome Med). Neoepitopes were characterized based on mutant AA charge (D/E negative, H/K/R positive) and position. High affinity neoepitopes (HAN) were defined as those an with IC50 &lt; 50 nM with wildtype IC50 &gt; 50 nM (Ghorani Annals Oncol) and a mutation to a known B-pocket supermotif (K in position 3 or 5 for B08, R in position 2 for B27, E in position 2 for B44) (Lund Immunogen). Progression-free survival (PFS) was compared with logrank tests and proportional hazards (JMPv14, Cary, NC). Results: Of the 40 patients, 29 (72.5%) had at least one B08, B27, or B44 allele. One or more supertype-matched HAN were found in 10 of the 29 (34.5%), including 6/7 with PFS &gt; 2 years, 3 of whom continue on therapy beyond 5 years. Median PFS in those with HAN was 26.7 months (m) vs 4.3 m in those without (HR 0.34, 95% CI 0.11-0.88, p = 0.024). Conclusions: Electrostatic charge may serve as a mechanism for enhanced binding affinity in HLA-B supertypes with a preference for charged AA in their B-pockets. Identification of favorable HLA-matched neoepitopes may identify distinct prognostic groups and potentially durable responders to immunotherapy in NSCLC.
Association between radiotherapy and obstructive sleep apnea in cancer patients: A systematic review and meta-analysis.
Authors: Gehad Mohamed Tawfik, Abdulmueti Alshareef, Esraa Mahmoud Mostafa, Samar Khaled, AlMotsim Ben Hmeda, Khloud Amr Abdelwahed, Ahmed Esmail Amer, Hesham Agage, Nehad Samy Emara, Saleh Adel Mahran, Amr Ebied, Nguyen Tien Huy
Journal: Journal of Clinical Oncology (2019)

e17576 Background: With the increase in survival of cancer patients, consequently, increasing their quality of life is mandatory as well. Sleep disturbances, particularly Obstructive Sleep Apnea (OSA), is one of the main complaints of cancer patients in which patients face frequent episodes of upper airway closure during sleep. Possible causes for OSA include either the specific cancer or its treatment whether sedatives, narcotics, radiotherapy, or chemotherapy, but the primary cause is still hard to prove. Our aim was to investigate the association between the occurrence of OSA and radiotherapy in cancer patients. Methods: On the 9th of September, 2018, we have searched comprehensively 12 electronic databases to retrieve relevant studies. All eligible studies that assess the association between OSA and radiotherapy in cancer patients were included in our meta-analysis. Quality assessment of included studies was done using the NIH tool for cohort and cross-sectional studies. Results: Fourteen studies met our selection criteria, eight studies were eligible for our meta-analysis. There was a positive association between the occurrence of OSA and radiotherapy in cancer patients (OR 1.16, 95% CI [0.52–2.56]; P = 0.718). OSA was noted in 103 of 181 cancer patients who received radiotherapy, yielding a remarkable overall prevalence of 63% (95% CI [0.36–0.85]; P = 0.343). A positive risk ratio for the development of OSA in cancer patients treated with radiotherapy was detected (RRs 1.27, 95% CI [0.81–2.00]; P = 0.297). The overall mean of apnea hypopnea index (AHI) for patients with OSA in six studies was 22.45. Conclusions: These findings point to a striking association between OSA risk and radiotherapy in cancer patients. Since the early recognition and management of OSA in such patients may play an important role in improving their quality of life, we recommend screening all cancer patients treated with radiation for early signs of OSA to further improve their survival.
Direct oral factor Xa inhibitors for the treatment of acute cancer-associated venous thromboembolism: A systematic review and network meta-analysis.
Authors: Harry E Fuentes, Robert McBane, Waldemar Wysokinski, Alfonso Javier Tafur, Charles L. Loprinzi, M. Hassan Murad, Irbaz Bin Riaz
Journal: Journal of Clinical Oncology (2019)

e23156 Background: A direct meta-analysis was performed to explore the efficacy and safety of direct oral factor Xa inhibitors with dalteparin in patients with cancer associated acute venous thromboembolism (VTE). Also, the comparative efficacy and safety of apixaban, rivaroxaban, and edoxaban was assessed with a network meta-analysis. Methods: MEDLINE, CENTRAL, and EMBASE were searched for trials comparing direct oral anticoagulants (DOACs) to dalteparin for the management of cancer associated acute VTE. A network meta-analysis using both frequentist and Bayesian methods was performed to analyze VTE recurrence, major and clinically relevant non-major bleeding (CRNMB). Results: Three randomized control trials, at low risk of bias, enrolled 1,739 patients with cancer associated VTE. Direct comparison showed a lower rate of VTE recurrence in DOAC compared to dalteparin groups (odds Ratio [OR]:0.48, 95% Confidence interval [CI]:0.24-0.96; I2:46%). Indirect comparison suggested that apixaban had greater reduction in VTE recurrence compared to dalteparin (OR: 0.10; 95% CI: 0.01–0.82), but not rivaroxaban or edoxaban. Apixaban also had the highest probability of being ranked most effective. By direct comparisons, there was an increased likelihood of major bleeding in the DOAC group compared to dalteparin (OR: 1.70; 95% CI: 1.04–2.78). CRNMB did not differ. Indirect estimates were imprecise. Subgroup analyses in gastrointestinal cancers suggested that dalteparin may have the lowest risk of bleeding whereas estimates in urothelial cancer were imprecise. Conclusions: DOACs appear to lower the risk of VTE recurrence compared to daltaparin while increasing major bleeding. Apixaban may be associated with the lowest risk of VTE recurrence compared to the other DOACs.
A multicenter, single-armed, prospective phase II study of apatinib combined with chemotherapy neoadjuvant for locally advanced gastric cancer.
Authors: JianXian Lin, Changming Huang
Journal: Journal of Clinical Oncology (2019)

e15508 Background: Molecular targeted therapy has made great progress in the treatment of gastric cancer. In some previous studies, apatinib, an oral small molecular of VEGFR-2 tyrosine kinase inhibitor, had been confirmed can improve OS and PFS with an acceptable safety profile in patients with advanced gastric cancer refractory to two or more lines of prior chemotherapy. However, there is limited evidence about the safety and feasibility of apatinib combined with SOX regimen as neoadjuvant therapy for locally advanced gastric cancer (LADG). Methods: This is a multicenter, single-armed, prospective study. Patients with LAGC (cT 2-4 N + M 0 ) without prior anti-cancer strategies were included. Patients were received 3 to 5 cycles (21 days a cycle) of neoadjuvant therapy using S-1 (po, 40-60 mg bid, day1-day14), oxaliplatin (iv, 130 mg/m 2 , day1), and apatinib (po, 500 mg qd). Apatinib was prohibited in the last cycle. The operation should be performed 2 to 4 weeks later of the neoadjuvant therapy. The primary outcome was safety of the neoadjuvant therapy. The secondary outcomes included R0 resection rate, objective response rate (ORR), and disease control rate (DCR). Results: A total of 30 patients from 7 centers in China were recruited between Sep. 1, 2017 and Aug. 31, 2018. There were 21 males and 9 females. The median age was 66 years (range 41-75 years). There were 25 patients with tumor response evaluation, 18 patients had partial response (PR), 6 patients had stable disease (SD), and 1 patient had progressive disease (PD). The ORR and DCR were 72.0% (18/25) and 96.0% (24/25), respectively. 10 patients discontinued the study (withdrew consent 8 patients, physical deterioration in performance status 1 patient, and Disease progression 1 patient). 20 patients received gastric surgery, the R0 resection rate was 100%, 3 patients had postoperative complication: one had intestinal obstruction and two had pneumonia (all Clavien-Dindo classification less than grade II). All patients were included for safety analysis. The incidence of adverse events (AEs) and grade 3/4 AEs were 56.7% (17/30) and 6.7% (2/30), respectively. The most common AEs were leucopenia (33.3%), liver function damage (6.7%), up-GI hemorrhage (6.7%), and hypertension (6.7%). Conclusions: This prospective study shows that neoadjuvant therapy using apatinib plus SOX brings clinical benefit to LAGC with a high disease control rate and tolerable adverse reactions. This study is registered at ClinicalTrials.gov and carries the following ID number: NCT 03192735. Clinical trial information: NCT 03192735.