tbuckley/cabot-search huggingface dataset:
Prognostic impact and detection of minimal residual disease (MRD) in neuroblastoma patients.
Authors: Alexander Druy, Grigory Tsaur, Alexander Popov, Tatiana Verzhbitskaya, Egor Shorikov, Leonid Saveliev, Larisa Fechina
Journal: Journal of Clinical Oncology (2013)

10055 Background: Bone marrow (BM) involvement and MRD detection in neuroblastoma (NB) seems to be useful tool for patients’ prognosis, stratification and risk-adapted treatment. Real-time PCR (RQ-PCR) of tumor-specific gene transcripts and flow cytometry (FC) are commonly applied for this purpose. Aim. RQ-PCR MRD marker definition, its qualitative concordance with FC and prognostic impact in NB patients. Methods: We analyzed 331 BM samples from 57 NB patients and 26 ‘normal’ BM samples from 20 patients without malignancies for PHOX2B, TH, ELAVL4 and GD2 genes expression. BM samples were defined as positive either in case of positivity for PHOX2B or in case of NB cells presence in BM. 326 BM samples from 52 NB patients were analyzed by RQ-PCR and FC together. Results: PHOX2B and TH were not detecting in normal BM samples. Out of 224 negative BM samples TH was identified in 5 only, while ELAVL4 and GD2 expression was detected in the majority of normal and negative BM samples: 20 and 15 from 26 normal; 209 and 197 out of 224 negative samples correspondingly. TH, ELAVL4 and GD2 expression in positive BM samples was significantly higher comparing to negative and normal BM samples.Threshold levels of each gene expression were established by ROC-analysis and subsequently applied for overall correct prediction (OCP) calculation. OCP for PHOX2B and TH achieved 0.994 and 0.952, while OCP for ELAVL4 and GD2 were significantly lower: 0.828 and 0.767 respectively. Analytical sensitivity of RQ-PCR for PHOX2B achieved 1E-06, while sensitivity of FC ranged from 1E-03 to 1E-05. In 193(59.2%) out of 326 evaluated samples BM was negative by both methods. 38(11.7%) samples were negative by FC but positive by RQ-PCR for PHOX2B expression. 31(9.5%) samples were positive by FC but negative by RQ-PCR. 64(19.6%) samples were positive by both techniques. Thus qualitative concordance between RQ-PCR and FC achieved 78.8%. Conclusions: Patients with detectable PHOX2B expression have lower event-free survival comparing to patients with PHOX2B negative BM: 0.30±0.10 and 0.77±0.27 respectively, p=0.002 and overall survival is 0.51±0.11 and 0.79±0.07 correspondingly, p=0.083. Median of follow up in our NB patients series is 42 months, ranged from 1 to 156.
A DNA-repair prognostic signature for early-stage NSCLC patients, in IFCT-0002 trial of neoadjuvant chemotherapy.
Authors: Gerard Zalcman, Guenaelle Levallet, Pierre Fouret, Martine Antoine, Elisabeth Brambilla, Emmanuel Bergot, Francoise Galateau-Salle, Armelle Lavole, Elisabeth A. Quoix, Didier Debieuvre, Julien Mazieres, Denis Moro-Sibilot, Jean-Louis Pujol, Denis Braun, Michele Beau-Faller, Laurence Baudrin, Franck Morin, Virginie Westeel
Journal: Journal of Clinical Oncology (2013)

7515 Background: IFCT-0002 trial compared two perioperative CT regimens, CDDP-Gemcitabine vs.CBDCA-Paclitaxel in 528 stage I-II NSCLC patients. Paraffin-embedded post-chemo specimens were collected in the 490 non-complete responder patients for tissue expression studies of DNA-repair proteins. Methods: Surgical specimens were processed for immunohistochemistry as previously published. Variables were studied as continuous variables. Cut-off values were validated by bootstrap. Multivariate backward Cox regressions were used to adjust for patients’ characteristics associated with the corresponding outcome at p&lt;0.20 in univariate analysis. Discrimination of the proposed Cox models was estimated using the c-indexes corrected for over-optimism by a resampling procedure. Median follow-up was 72.0 months, 95%CI [69.7-73.5]. Results: ERCC1, MSH2, XRCC5/Ku80 and BRCA1 immunostainings were available in 413, 356, 396 and 221 specimens. Expressed as a continuous variable, only MSH2 staining score correlated with overall survival. XRCC5 showed no influence on survival. When dichotomised, low BRCA1 (under median value) and ERCC1 (ERCC1=0), while high MSH2 protein expression (over median value), adversely affected overall survival with respective adj. HRs of 1.56, 95%CI [1.05-2.32], p=0.028 ; 1.37 95%CI [1.01-1.86], p=0.042 and 1.53, 95%CI [1.12-2.09], p=0.007. No interaction was found between the attributed treatment and any of the 4 markers. High MSH2 and low ERCC1 variables were tested in 200 bootstrap multivariate Cox models and correlated with OS in respectively 87% and 78.5% (c-index=0.570), whereas stage predicted survival in only 49% of those theoretical samples. A prognostic score led to the definition of three groups of high-, intermediate- and low-risk of death with respective HRs of 2.83, 1.60 and 1. Median OS were respectively 28.3 months, 71.5 and not reached, 5-y survival rates were 34.2%, 54.8% and 66.3% (Log-Rank p&lt;0.0001). Conclusions: With a 6-year median follow-up, a prognostic score derived from multivariate Cox regression, validated by bootstraping, accurately discriminates a sub-group with high risk of death according to tumor expression of MSH2 and ERCC1.
UCH-L1-mediated Down-regulation of Estrogen Receptor α Contributes to Insensitivity to Endocrine Therapy for Breast Cancer
Authors: Xi-Sha Chen, Kuan-Song Wang, Wei Guo, Lan-Ya Li, Pian Yu, Xin-Yuan Sun, Hai-Yan Wang, Yi-Di Guan, Yong-Guang Tao, Bo-Ni Ding, Ming-Zhu Yin, Xing-Cong Ren, Yi Zhang, Ce-Shi Chen, Yuan-Chao Ye, Jin-Ming Yang, Yan Cheng
Journal: Theranostics (2020)

Purpose: To determine the role of UCH-L1 in regulating ERα expression, and to evaluate whether therapeutic targeting of UCH-L1 can enhance the efficacy of anti-estrogen therapy against breast cancer with loss or reduction of ERα. Methods: Expressions of UCH-L1 and ERα were examined in breast cancer cells and patient specimens. The associations between UCH-L1 and ERα, therapeutic response and prognosis in breast cancer patients were analyzed using multiple databases. The molecular pathways by which UCH-L1 regulates ERα were analyzed using immunoblotting, qRT-PCR, immunoprecipitation, ubiquitination, luciferase and ChIP assays. The effects of UCH-L1 inhibition on the efficacy of tamoxifen in ERα (-) breast cancer cells were tested both in vivo and in vitro. Results: UCH-L1 expression was conversely correlated with ERα status in breast cancer, and the negative regulatory effect of UCH-L1 on ERα was mediated by the deubiquitinase-mediated stability of EGFR, which suppresses ERα transcription. High expression of UCH-L1 was associated with poor therapeutic response and prognosis in patients with breast cancer. Up-regulation of ERα caused by UCH-L1 inhibition could significantly enhance the efficacy of tamoxifen and fulvestrant in ERα (-) breast cancer both in vivo and in vitro. Conclusions: Our results reveal an important role of UCH-L1 in modulating ERα status and demonstrate the involvement of UCH-L1-EGFR signaling pathway, suggesting that UCH-L1 may serve as a novel adjuvant target for treatment of hormone therapy-insensitive breast cancers. Targeting UCH-L1 to sensitize ER negative breast cancer to anti-estrogen therapy might represent a new therapeutic strategy that warrants further exploration.
Abstract I02: Targeting Innate immunity in pancreatic carcinoma
Authors: George Miller
Journal: Cancer Research (2019)

Abstract Pancreatic carcinoma has proven largely resistant to immunotherapies as strategies directly targeting T cells or their receptors have failed in early clinical trials. Basic research has shown that effector T-cell infiltration and phenotype in pancreatic cancer is controlled by diverse innate immune elements including dendritic cells, macrophages and other myeloid cells, and subsets of innate-like T cells. However, the phenotype of macrophages and myeloid cells infiltrating pancreatic carcinoma is, for the most part, highly suppressive of effective adaptive antitumor immunity. Therefore, rather than directly targeting T cells in isolation, immunotherapeutic strategies addressing toleorogenic innate immune cell populations hold greater promise. New potential avenues for immunotherapy include activating or blockade of select innate immune receptors on tumor-associated macrophages to reprogram their suppressive phenotype, targeting the microbiome to modulate the intratumoral inflammatory environment toward a more favorable phenotype, or deleting select subsets of tolerogenic T cells such as delta1 cells. These type of approaches have the potential to enable efficacy for more traditional immunotherapies that target checkpoint or costimulatory receptors, and these strategies can also potentiate the effects of systemic chemotherapy or radiation therapy. Citation Format: George Miller. Targeting Innate immunity in pancreatic carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I02.
Editor's Note: Connective Tissue Growth Factor Confers Drug Resistance in Breast Cancer through Concomitant Up-regulation of Bcl-xL and cIAP1
Authors: Ming-Yang Wang, Pai-Sheng Chen, Ekambaranellore Prakash, Hsing-Chih Hsu, Hsin-Yi Huang, Ming-Tsan Lin, King-Jen Chang, Min-Liang Kuo
Journal: Cancer Research (2019)
Bronchial artery infusion of recombinant adenovirus-p53 and chemotherapeutic agents in treatment of bronchogenic carcinoma in advanced stage and failed to response to standard treatments.
Authors: Maoheng Zu, Qingqiao Zang, Ning Wei, Wei Xu Xu
Journal: Journal of Clinical Oncology (2012)

e13004 Background: Patients with advanced bronchogenic carcinoma (BC), who failed common standard treatments, poses a big challenge for clinicians. Here we report success cases of using bronchial artery infusion of recombinant adenovirus-p53 (rAd-p53) and chemotherapeutic agents in treatment of advanced BC failed to response to standard treatments. Methods: Sixteen patients with advanced unresectable BC, who failed standard chemo- and radio-therapy, were included in this study. There were 11 males and 5 Females with an average age of 59.4 years old. They received bronchial artery infusion of 2×10 12 rAd-p53 viral particles (VP), 40 mg of cisplatin (PPD), 20 mg of pirarubicin (THP), 0.5 g of 5-Fu, and 30 mg of endostatin. The infusion was given daily for 3 days. Response rate and overall survival were evaluated. Results: At 3 months follow-up after the last infusion, the partial response rate was 68.8% (11/16). Symptoms like cough and short of breath were significantly relieved in those patients responding to the treatment. Overall survival rate of one year was 81.3% and median survival time was 11.6 months. No significant adverse events were found in those patients. Conclusions: Bronchial artery infusion of rAd-p53 combined with chemotherapeutic agents is effective and safe treatment for patients with advanced BC, who failed common standard treatments.
A comparison of hematology/oncology clinic attendance between insured and under-insured patients at an urban academic hospital: Identifying barriers and ways to overcome them
Authors: J. A. Youssef, L. J. Lyckholm, T. J. Smith, L. M. Shickle, R. K. Matsuyama, G. L. Parker
Journal: Journal of Clinical Oncology (2006)

16015 Background: There are persistent disparities in cancer outcomes based on non-clinical factors such as race, socioeconomic status, and access to care. Successful treatment outcomes in oncology and symptom control depend heavily on patient compliance. To improve patient attendance at oncology appointments, the reasons why patients miss appointments must be understood, and then interventions must be enacted to rectify the problem. Methods: At the hematology/oncology clinics of Virginia Commonwealth University, the fellows’ clinic consists of patients that are primarily uninsured or underinsured, and the faculty clinic consists of patients that are primarily well-insured. On Mondays and Fridays from January 31–June 30, 2005, attendance of scheduled patients was recorded. Patients were then called and asked why they did not attend their appointments. Also, the patient’s sex, age, race, diagnosis, and insurance status were recorded. Results: Of the 1705 appointments scheduled in the predominantly under-insured fellows’ clinic, 223 (13.1%) of these were no shows. Of the 1614 appointments scheduled in the better-insured faculty clinic, 115 (7.1%) of these were no-shows (p &lt; .0001). Of African-American patients in both clinics, 30.9% did not attend their appointments as compared to 19.4% of Caucasian patients (p = .0003). The no-show rate among women was 22.4% as compared to 28.6% for men in both clinics (p = .025). Of all patients under age 50, 30.1% did not show up as compared with 22.4% of all patients aged 50 or higher (p = .009). Chi-square was used to test for significance. Among both clinics, the reasons for missing appointments included: the patient did not know of the appointment (35), patient illness (24), transportation difficulties (12), family emergency (7), forgot (7), and weather (2). Conclusions: In this study, appointment knowledge and patient illness affect oncology clinic attendance most. It is our goal to implement measures, such as appointment reminders and transportation assistance, and then reassess attendance rates. No significant financial relationships to disclose.
Treatment outcomes of pediatric oncology patients in Zambia.
Authors: Jeremy Slone, Catherine Chunda-Liyoka, Marta Perez, Nora Mutalima, Robert Newton, Chifumbe Chintu, Chipepo Kankasa, James Chipeta, Douglas C. Heimburger, Sten H. Vermund, Debra L. Friedman
Journal: Journal of Clinical Oncology (2012)

9558 Background: Due to challenges in the delivery of pediatric oncology care in low-middle income countries (LMIC), diagnosis and treatment remains inadequate for the majority of patients. The University of Zambia School of Medicine/University Teaching Hospital (UTH) and Vanderbilt University School of Medicine/Vanderbilt Institute for Global Health established a partnership to investigate treatment outcomes at UTH, the only institution providing pediatric oncology care in Zambia, and assess risk factors associated with treatment abandonment. Methods: A retrospective study was conducted in a cohort of patients, presenting from July 2008 – June 2010, using an established database and medical record review. Results: Of the 230 children enrolled in the database, 162 met the inclusion criteria. The average age at diagnosis was 6.0 years; males comprised 55.6% of the cohort; 51.6% had a histopathological diagnosis and 10.5% of the cohort was HIV positive. The most common diagnoses were lymphoma (25.9%), Wilms tumor (22.8%), and retinoblastoma (17.9%). Leukemia and Kaposi sarcoma accounted for 7.4% each. Death (46.3%) and abandonment of treatment (45.7%) were the most common outcomes with only 8.0% having completed treatment or currently undergoing treatment, including palliative regimens, at the time of data acquisition. Residence in Lusaka or Central provinces, closest in proximity to UTH, was associated with a decreased risk for abandonment of treatment (Odds Ratio (OR) 0.41 (95% CI 0.21-0.81, p = 0.009) while maternal education less than secondary school (OR 2.73 95% CI 1.2-6.6, p = 0.03) was associated with an increased risk for abandonment of treatment. Conclusions: At the only pediatric cancer center in Zambia, treatment outcomes are dire with the majority of the cohort abandoning treatment or dying during therapy. Challenges include access to cancer chemotherapy, logistical facilitation, fiscal support of radiotherapy, and community engagement. Further investigation is required to inform effective intervention strategies to improve outcomes.
Amount and Intensity of Leisure-Time Physical Activity and Lower Cancer Risk
Authors: Charles E. Matthews, Steven C. Moore, Hannah Arem, Michael B. Cook, Britton Trabert, Niclas Håkansson, Susanna C. Larsson, Alicja Wolk, Susan M. Gapstur, Brigid M. Lynch, Roger L. Milne, Neal D. Freedman, Wen-Yi Huang, Amy Berrington de Gonzalez, Cari M. Kitahara, Martha S. Linet, Eric J. Shiroma, Sven Sandin, Alpa V. Patel, I-Min Lee
Journal: Journal of Clinical Oncology (2019)

To determine whether recommended amounts of leisure-time physical activity (ie, 7.5-15 metabolic equivalent task [MET] hours/week) are associated with lower cancer risk, describe the shape of the dose-response relationship, and explore associations with moderate- and vigorous-intensity physical activity.Data from 9 prospective cohorts with self-reported leisure-time physical activity and follow-up for cancer incidence were pooled. Multivariable Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% CIs of the relationships between physical activity with incidence of 15 types of cancer. Dose-response relationships were modeled with restricted cubic spline functions that compared 7.5, 15.0, 22.5, and 30.0 MET hours/week to no leisure-time physical activity, and statistically significant associations were determined using tests for trend (P < .05) and 95% CIs (< 1.0).A total of 755,459 participants (median age, 62 years [range, 32-91 years]; 53% female) were followed for 10.1 years, and 50,620 incident cancers accrued. Engagement in recommended amounts of activity (7.5-15 MET hours/week) was associated with a statistically significant lower risk of 7 of the 15 cancer types studied, including colon (8%-14% lower risk in men), breast (6%-10% lower risk), endometrial (10%-18% lower risk), kidney (11%-17% lower risk), myeloma (14%-19% lower risk), liver (18%-27% lower risk), and non-Hodgkin lymphoma (11%-18% lower risk in women). The dose response was linear in shape for half of the associations and nonlinear for the others. Results for moderate- and vigorous-intensity leisure-time physical activity were mixed. Adjustment for body mass index eliminated the association with endometrial cancer but had limited effect on other cancer types.Health care providers, fitness professionals, and public health practitioners should encourage adults to adopt and maintain physical activity at recommended levels to lower risks of multiple cancers.
Bioengineered Acellular Dermal Matrix Spacer Grafts for Lower Eyelid Retraction Repair
Authors: Jeremiah P. Tao, Vinay K. Aakalu, Edward J. Wladis, Rachel K. Sobel, Suzanne K. Freitag, Jill A. Foster, Michael T. Yen
Journal: Ophthalmology (2019)
Age-Dependent Definition of CKD
Authors: Howard Trachtman
Journal: Journal of the American Society of Nephrology (2019)

I read the online article by Delanaye et al.1 calling for age-dependent definitions of CKD and the two accompanying editorials2,3 with great interest. As a pediatric nephrologist, I do not have a stake in the details of the adult argument. However, as a nephrologist, I also recognize the importance of clinically relevant definitions of CKD stages and I was struck by one of the arguments advanced by Chertow and Beddhu2 who advise caution before tampering with the current scheme. They take exception to the claim by Delanaye et al. that overdiagnosis of CKD in the elderly could lead to inappropriate care, including diagnostic evaluation and treatment of nonexistent kidney disease. Chertow and Beddhu assert that the elderly are less likely to get clinically indicated care for cardiac disease and other conditions that require contrast-enhanced imaging. In fact, this well documented observation reinforces the call for change by Delanaye et al. because inappropriate care is bidirectional—overzealous evaluation of patients who are healthy and insufficient testing of patients who are presumed sick, in this case with CKD. Rethinking the threshold GFR to define CKD may have the potential to be helpful, not only in the geriatric population but across the life span if that includes the older end of the pediatric spectrum. Disclosures None. Funding Dr. Trachtman is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (grant DK100307).
Genetics of height and risk of atrial fibrillation: A Mendelian randomization study
Authors: Michael G. Levin, Renae Judy, Dipender Gill, Marijana Vujkovic, Shefali S. Verma, Yuki Bradford, Marylyn D. Ritchie, Matthew C. Hyman, Saman Nazarian, Daniel J. Rader, Benjamin F. Voight, Scott M. Damrauer
Journal: PLoS Medicine (2020)

Background Observational studies have identified height as a strong risk factor for atrial fibrillation, but this finding may be limited by residual confounding. We aimed to examine genetic variation in height within the Mendelian randomization (MR) framework to determine whether height has a causal effect on risk of atrial fibrillation. Methods and findings In summary-level analyses, MR was performed using summary statistics from genome-wide association studies of height (GIANT/UK Biobank; 693,529 individuals) and atrial fibrillation (AFGen; 65,446 cases and 522,744 controls), finding that each 1-SD increase in genetically predicted height increased the odds of atrial fibrillation (odds ratio [OR] 1.34; 95% CI 1.29 to 1.40; p = 5 × 10−42). This result remained consistent in sensitivity analyses with MR methods that make different assumptions about the presence of pleiotropy, and when accounting for the effects of traditional cardiovascular risk factors on atrial fibrillation. Individual-level phenome-wide association studies of height and a height genetic risk score were performed among 6,567 European-ancestry participants of the Penn Medicine Biobank (median age at enrollment 63 years, interquartile range 55–72; 38% female; recruitment 2008–2015), confirming prior observational associations between height and atrial fibrillation. Individual-level MR confirmed that each 1-SD increase in height increased the odds of atrial fibrillation, including adjustment for clinical and echocardiographic confounders (OR 1.89; 95% CI 1.50 to 2.40; p = 0.007). The main limitations of this study include potential bias from pleiotropic effects of genetic variants, and lack of generalizability of individual-level findings to non-European populations. Conclusions In this study, we observed evidence that height is likely a positive causal risk factor for atrial fibrillation. Further study is needed to determine whether risk prediction tools including height or anthropometric risk factors can be used to improve screening and primary prevention of atrial fibrillation, and whether biological pathways involved in height may offer new targets for treatment of atrial fibrillation.