tbuckley/cabot-search huggingface dataset:
Can <sup>18</sup>F-alfatide micro-PET predict the radiotherapy response in Lewis lung carcinoma tumor-bearing C57BL/6 mice?
Authors: Yuchun Wei, Ning Liu, Yong Huang, Xudong Hu, Shuanghu Yuan
Journal: Journal of Clinical Oncology (2017)

e23011 Background: Integrin αvβ3 plays a major role in angiogenesis, tumor growth and progression. A new tracer, 18 F-AL-NOTA-PRGD2, denoted as 18 F-Alfatide, has been developed for positron emission tomography (PET) imaging of integrin αvβ3. This study aimed to explore the predictive role of integrin αvβ3 imaging with 18 F-Alfatide PET in non-small cell lung cancer (NSCLC) for radiation and also to assess changes in tumor uptake during the course of radiotherapy. Methods: A total of 40 mice with lewis lung carcinoma (LLC) xenografts were divided into 4 groups (Ⅰ, Ⅱ, Ⅲ and Ⅳ) randomly. The Ⅰ underwent 18 F-Alfatide Micro-PET scanning before and after radiotherapy, and so did the Ⅱ except for radiotherapy. The xenografts of Ⅲ were removed at the time before radiotherapy, while the Ⅳ’s were removed after radiotherapy. Tumor and muscle uptakes before and after radiotherapy of Ⅰ(SUV rad-1 , SUV rad-2 , SUV M-1 , SUV M-2 ) and Ⅱ(SUV blank-1 , SUV blank-2 , SUV m-1 , SUV m-2 ) depict 18 F-Alfatide Micro-PET uptake. The expression of integrin αvβ3 in Ⅲ and Ⅳ xenografts was analyzed by western blotting. Results: The changes of ΔSUV 1 ( SUV rad-2 /SUV M-2 ―SUV rad-1 /SUV M-1 ) was significantly lower than ΔSUV 2 (SUV blank-2 / SUV m-2 ―SUV blank-1 / SUV m-1 ) (2.65±1.72 versus 5.16±2.50, P = 0.019. Overall survival (OS) of Ⅰ(56.70±25.34 day) is significantly longer than Ⅱ(35.00±5.27 day), P = 0.002. Significant negative correlation was found between ΔSUV and OS (R = 0.640, P = 0.002). Significant higher αvβ3 was observed in Ⅲ(0.52±0.09) than Ⅳ(0.41±0.07), P = 0.007. Conclusions: Decrease of ΔSUV and integrin αvβ3 during the course of radiotherapy may predict improved response in LLC xenografts and affirm the predictive role of 18 F-Alfatide for radiation in NSCLC.
Bim and soluble PD-L1 (sPD-L1) as predictive biomarkers of response to anti-PD-1 therapy in patients with melanoma and lung carcinoma.
Authors: Roxana Stefania Dronca, Aaron Scott Mansfield, Xin Liu, Susan Harrington, Elizabeth Ann Enninga, Lisa A. Kottschade, Chi Wan Koo, Robert R. McWilliams, Matthew Stephen Block, Wendy Kay Nevala, Svetomir Markovic, Haidong Dong
Journal: Journal of Clinical Oncology (2017)

11534 Background: To date, there are no validated blood-based biomarkers of predicting response to PD-1 blockade. We previously reported that Bim is a downstream signaling molecule of the PD-1 pathway, and that measurement of Bim levels in circulating T-cells may predict and monitor responses to anti–PD-1 therapy in melanoma. We have identified the existence of sPD-L1 in cancer patients and showed that the sPD-L1 is biologically active and capable of triggering apoptosis in activated T-cells. Here we evaluated T cell Bim and sPD-L1 in the peripheral blood (PB) as biomarkers of response in a cohort of patients with metastatic melanoma and lung cancer undergoing anti-PD1 therapy. Methods: 60 pts treated with anti-PD-1 had PB collected at baseline and at radiographic tumor evaluation. Frequencies of Bim + T cells and Bim median fluorescence intensity (MFI) were measured by flow cytometry in gated tumor-reactive CD11a high PD1 + CD8 + T cells. We also measured levels of sPD-L1 at baseline and serially during treatment with sPD-L1 ELISA. Baseline Bim and sPD-L1 levels and percent change in Bim levels in patients (pts) who had a radiographic response (CR/PR) were compared to those who had progressive disease (PD) at 12 wks. Results: Similarly to previously reported preliminary data, pts with objective response (CR/PR, 15/60) after 4 cycles of anti-PD1 therapy had higher frequency of Bim T cells at baseline compared to pts with PD (16/60) (mean 43% vs. 30%, P = 0.0484). The frequencies of Bim+ T cells decreased significantly after the first 3 months of treatment in responders compared with progressors (mean -16% vs. + 40% P = 0.0111). High baseline sPD-L1 were associated with progression on anti-PD1 therapy (mean 2.8 ng/mL vs. 0.7 ng/mL, p = 0.07, n = 13) and the levels increased by the first tumor assessment in patients resistant to anti-PD-1. Conclusions: Measurements of Bim and sPD-L1 levels may help to select patients who are likely to benefit from anti-PD1 monotherapy versus combinatorial strategies, and provide a new non-invasive way to monitor response to anti-PD-1 blockade. A larger validation study is underway.
Contribution of Adrenal Glands to Intratumor Androgens and Growth of Castration-Resistant Prostate Cancer
Authors: Elahe A. Mostaghel, Ailin Zhang, Susana Hernandez, Brett T. Marck, Xiaotun Zhang, Daniel Tamae, Heather E. Biehl, Maria Tretiakova, Jon Bartlett, John Burns, Ruth Dumpit, Lisa Ang, Alvin M. Matsumoto, Trevor M. Penning, Steven P. Balk, Colm Morrissey, Eva Corey, Lawrence D. True, Peter S. Nelson
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Tumor androgens in castration-resistant prostate cancer (CRPC) reflect de novo intratumoral synthesis or adrenal androgens. We used C.B.-17 SCID mice in which we observed adrenal CYP17A activity to isolate the impact of adrenal steroids on CRPC tumors in vivo. Experimental Design: We evaluated tumor growth and androgens in LuCaP35CR and LuCaP96CR xenografts in response to adrenalectomy (ADX). We assessed protein expression of key steroidogenic enzymes in 185 CRPC metastases from 42 patients. Results: Adrenal glands of intact and castrated mice expressed CYP17A. Serum DHEA, androstenedione (AED), and testosterone (T) in castrated mice became undetectable after ADX (all P &amp;lt; 0.05). ADX prolonged median survival (days) in both CRPC models (33 vs. 179; 25 vs. 301) and suppressed tumor steroids versus castration alone (T 0.64 pg/mg vs. 0.03 pg/mg; DHT 2.3 pg/mg vs. 0.23 pg/mg; and T 0.81 pg/mg vs. 0.03 pg/mg, DHT 1.3 pg/mg vs. 0.04 pg/mg; all P ≤ 0.001). A subset of tumors recurred with increased steroid levels, and/or induction of androgen receptor (AR), truncated AR variants, and glucocorticoid receptor (GR). Metastases from 19 of 35 patients with AR positive tumors concurrently expressed enzymes for adrenal androgen utilization and nine expressed enzymes for de novo steroidogenesis (HSD3B1, CYP17A, AKR1C3, and HSD17B3). Conclusions: Mice are appropriate for evaluating adrenal impact of steroidogenesis inhibitors. A subset of ADX-resistant CRPC tumors demonstrate de novo androgen synthesis. Tumor growth and androgens were suppressed more strongly by surgical ADX than prior studies using abiraterone, suggesting reduction in adrenally-derived androgens beyond that achieved by abiraterone may have clinical benefit. Proof-of-concept studies with agents capable of achieving true “nonsurgical ADX” are warranted.
A phase II study of early FDG-PET evaluation after one-cycle chemotherapy in patients with locally advanced esophageal squamous cell carcinoma treated with neoadjuvant chemoradiotherapy: Final report.
Authors: Ta-Chen Huang, Chia-Chi Lin, Kai-Yuan Tzen, Yun-Chun Wu, Jason Chia-Hsien Cheng, Jang-Ming Lee, Hsiu-Po Wang, Pei-Ming Huang, Feng-Ming Hsu, Kun-Huei Yeh, Ann-Lii Cheng, Chih-Hung Hsu
Journal: Journal of Clinical Oncology (2017)

4042 Background: The optimal use of the metabolic tumor response measured by 18 fluorodeoxyglucose positron emission tomography (FDG-PET) in the treatment of esophageal cancer is currently unknown. We launched a phase II clinical trial to evaluate the early metabolic response to one-cycle chemotherapy in locally advanced esophageal squamous cell carcinoma (ESCC) patients, who subsequently received neoadjuvant chemoradiation (neo-CRT) followed by surgery. Methods: ESCC patients with stage T3 or N1M0 or M1a (AJCC, 6th edition) were enrolled to receive one-cycle chemotherapy, day 1 and 8 doses of paclitaxel, cisplatin, and 24-hour infusional 5-fluorouracil and leucovorin, followed by paclitaxel/cisplatin- based 40Gy neo-CRT and surgery. FDG-PET was performed at baseline and day 14 of the one-cycle chemotherapy. The primary endpoint is pathological complete response (pCR) to neo-CRT. We hypothesized that early PET responders, defined as &gt; 35% reduction of maximum standardized uptake value (SUV max ) from the baseline, would significantly improve pCR. Results: Between Feb 2008 and Mar 2012, 66 patients (M: F = 61: 5) were enrolled. Their clinical stages were: II or III, 56; IVA, 10. Forty seven received surgery. The pCR rate per surgical population was 34.0%. The median progression-free survival (PFS) and overall survival (OS) for the whole study group was 16 months (95% CI 9-27) and 22 months (95% CI 16-40), respectively. A total of53 patients were evaluable for PET response. The early PET response was not associated with high pCR rate or better survivals. However, in an exploratory analysis, the post-chemotherapy SUV max was an independent prognostic factor for pCR, PFS and OS. A predictive model for pCR composed of weight loss and the post-chemotherapy SUV max was established with an AUC of 0.84. Conclusions: Our study failed to validate the predictive value of predefined early PET response to one-cycle chemotherapy for pCR to neo-CRT in locally advanced ESCC patients. However, the FDG-PET SUV max after one-cycle chemotherapy may have prognostic and predictive significance, and may be explored in further studies. Clinical trial information: NCT01034332.
TCT-649 Impact of postdilatation on long-term outcome and valve durability in TAVR patients
Authors: Stephan Haussig, Felix Woitek, Norman Mangner, Constantin Pleissner, Florian Schlotter, Georg Stachel, Sergey Leontyev, Philipp Kiefer, Holger Thiele, Michael Borger, David Holzhey, Axel Linke
Journal: Journal of the American College of Cardiology (2018)
Association of comorbidity and polypharmacy with skeletal muscle measures in older adults with cancer.
Authors: Grant Richard Williams, Allison Mary Deal, Mackenzi Pergolotti, Hyman B. Muss, Hanna Kelly Sanoff, Jennifer Leigh Lund, Seul Ki Choi, Shlomit S. Shachar
Journal: Journal of Clinical Oncology (2018)

e22029 Background: Comorbidity and polypharmacy are common among older adults with cancer, yet their association with Computed Tomography (CT)-based skeletal muscle measures remains uncertain. The primary purpose of this study was to evaluate the association of comorbidity and polypharmacy with CT-based measures of skeletal muscle in older adults with cancer. Methods: Using the Carolina Senior Registry (NCT01137825), we identified patients with CT imaging within 60 days +/- baseline geriatric assessment (GA). Comorbidity was assessed using the Older Americans Resources and Services Physical Health subscale, and the number of daily prescription medications was assessed via patient-report. Skeletal muscle area (SMA) and density (SMD) were analyzed from CT scan L3 lumbar segments using radiological software [Chung et al. Medical Imaging 2009]. SMA and height (m2) were used to calculate skeletal muscle index (SMI). Differences were compared using Kruskal-Wallis tests and multivariable linear regression models controlling for age, gender, and BMI. Results: 143 patients had available CT imaging within 60 days of GA. Median age 73, 57% female, 85% white, 30% breast cancer, and 28% lung cancer. 90% of participants reported at least one comorbid condition. 40% of participants took between 5-8 daily medications, and 17.6% ≥9 medications. The presence of osteoporosis (19 [13%]) was associated with lower SMI (42.0 vs 37.0 cm2/m2, p < 0.05) and participants with arthritis (53 [37%]) and diabetes (25 [18%]) had lower SMD (27.8 vs 24.2 HU and 27.2 vs 23.0 HU, respectively, p < 0.05). In multivariable analyses, we found no association between the number of comorbid conditions and either SMI or SMD. Participants taking 5-8 or ≥9 daily medications had significantly lower SMD compared to those on 0-4 medications (25.4 and 21.9 vs. 29.1 HU, p < 0.05), and no differences on SMI. In multivariable analyses, an increasing number of prescription medications was associated with lower SMD, but not SMI. Conclusions: Although the overall number of comorbid conditions was not associated with worse muscle measures, we found that participants with osteoporosis had lower SMI, and those with arthritis, diabetes, or more medications had lower SMD.
Oxaliplatin plus fluorouracil/leucovorin or sorafneib as first-line treatments for advanced hepatocellular carcinoma: a cost-effectiveness analysis.
Authors: Pengfei Zhang, Feng Wen, Qiu Li
Journal: Journal of Clinical Oncology (2016)

e18270 Background: Both sorafenib and FOLFOX4 chemotherapy are recommended as the standard first-line treatment options for advanced hepatocellular carcinoma (HCC) according to Chinese Clinical Oncology Guidelines and National Health and Family Planning Commission. This study aimed to investigate the pharmaco-economic implications of FOLFOX4 and sorafenib for patients with advanced HCC in China. Methods: We performed a Markov model to simulate the process of advanced HCC treated with sorafenib and FOLFOX4. Clinical data were obtained from the ORIENTAL trial and the EACH trial. The prices of drugs were obtained according to the national drug prices. The unit cost of the laboratory and diagnostic tests were obtained from the West China Hospital, Sichuan University, China. Incremental cost-effectiveness ratio (ICER) was regarded as the primary outcome in the analysis. Cycle time was set at 1-month and monthly transition probabilities were calculated according to a formula previously described. Utilities for progression-free survival (PFS) state and progressive disease (PD)state were derived from previously published studies. One-way sensitivity analysis as well as probabilistic sensitivity analysis was performed to explore the impact of essential variables on the results of the analysis. Results: Treatment with sorafenib provided an effectiveness gain of 0.3935 quality-adjusted life year (QALY) at an average cost of $18,748.00, whereas chemotherapy of FOLFOX4 brought 0.3808 QALY at a cost of$6,876.02. The ICER of FOLFOX4 versus sorafenib was $934,801.57/QALY. One-way sensitivity analysis suggested that the results were sensitive to changes in duration of PFS state for sorafenib group, cost of PFS state for sorafenib group, cost of sorafenib and utility of PD state. In a probabilistic sensitivity analysis based on a Monte Carlo simulation of 1,000 items, the probabilities of FOLFOX4 and sorafenib being cost-effective were 100% and 0% using a willingness-to-pay (WTP) threshold of $20,301.00/QALY. Conclusions: FOLFOX4 chemotherapy is likely to be a cost-effective option compared with sorafenib in the treatment of advanced HCC in China.
Engineered t cells targeting E7 mediate regression of human papillomavirus cancers in a murine model.
Authors: Benjamin Y Jin, Tracy E Campbell, Lindsey Draper, Sanja Stevanovic, Bianca Weissbrich, Zhiya Yu, Nicholas P. Restifo, Steven A. Rosenberg, Cornelia Trimble, Christian S. Hinrichs
Journal: Journal of Clinical Oncology (2018)

e15048 Background: T-cell receptor (TCR) gene-engineered T cell therapy is a promising cancer treatment strategy. Its successful development for epithelial cancers may depend on the identification of high-avidity TCRs directed against tumor-restricted target antigens. The human papillomavirus (HPV) E7 antigen is constitutively expressed by HPV+ cancers but not by healthy tissues. Here, we report the discovery and preclinical testing of a TCR that targets HPV-16 E7. Methods: Cervix-infiltrating T-cells from women with cervical intraepithelial neoplasia were screened for reactivity against HPV-16 E6 and E7. A T cell with HLA-A*02:01-restricted specificity for E711-19 was identified, and the TCR sequence was determined. Expression of the this TCR was optimized by TCR constant region modifications. Gene-engineered T cells expressing the E7 TCR (E7 T cells) were characterized for tumor cell targeting, functional avidity, cytokine production, cytolytic function, and cross reactivity. In vivo anti-tumor activity was assessed in a murine model of established, subcutaneous human cancer xenografts. Results: E7 T cells demonstrated recognition of cervical cancer and oropharyngeal cancer tumor cell lines in cytokine production and cytolysis assays. E7 T cells displayed recognition of cognate peptide at concentrations as low as 10 picomoles, which indicated high-avidity. Consistent with this finding, the E7 TCR showed function in CD4 T cells, which lack a CD8 coreceptor. Alanine scanning of the target peptide revealed positions 4, 5, 6, and 7 to provide the major contribution to recognition by E7 T cells. Cross-reactivity assays did not detect E7 T cell targeting of human peptides with potential HLA-A*02:01 anchor resides that shared residues at positions 4, 5, 6, and 7 with E711-19. Finally, E7 T cells mediated regression of established human xenograft cervical cancer tumors in an immunodeficient mouse model. Anti-tumor activity was increased in some conditions by the concomitant administration of systemic interleukin-2. Conclusions: These preclinical findings support a clinical trial of E7 T cells for the treatment of patients with metastatic HPV-16+ cancers that is now active (NCT02858310).
The Placebo Effect in Pain Therapies
Authors: Luana Colloca
Journal: The Annual Review of Pharmacology and Toxicology (2018)

Pharmacological strategies for pain management have primarily focused on dampening ascending neurotransmission and on opioid receptor-mediated therapies. Little is known about the contribution of endogenous descending modulatory systems to clinical pain outcomes and why some patients are mildly affected while others suffer debilitating pain-induced dysfunctions. Placebo effects that arise from patients' positive expectancies and the underlying endogenous modulatory mechanisms may in part account for the variability in pain experience and severity, adherence to treatment, distinct coping strategies, and chronicity. Expectancy-induced analgesia and placebo effects in general have emerged as useful models to assess individual endogenous pain modulatory systems. Different systems and mechanisms trigger placebo effects that highly impact pain processing, clinical outcomes, and sense of well-being. This review illustrates critical elements of placebo mechanisms that inform the methodology of clinical trials, the discovery of new therapeutic targets, and the advancement of personalized pain management.
Environmental health sciences education--a tool for achieving environmental equity and protecting children.
Authors: L Claudio, T Torres, E Sanjurjo, L R Sherman, P J Landrigan
Journal: Environmental Health Perspectives (1998)

Children are highly susceptible to deleterious effects of environmental toxins. Those who live in underserved communities may be particularly at risk because environmental pollution has been found to be disproportionately distributed among communities. Mounting evidence suggests that asthma rates are rising and that this disease can be caused or aggravated by air pollution. Although ambient air quality has generally improved, these improvements have not reached minority communities in equal proportions. This and other data has fueled the concept of environmental justice or environmental equity, which has led to community activism and government actions. One possible example of environmental inequity and its consequences is the Hunt's Point community, in the South Bronx, New York. This community experiences a high pollution burden with the siting of facilities that emit hazardous wastes into the air. Our approach to this problem has been the formation of mechanisms for bidirectional communication between community residents, government entities, and academic institutions such as Mount Sinai Medical Center. As a result of this experience, we believe that the key to achieving environmental health, especially in communities of color where many children are at risk, is to empower residents to take charge of their environment by providing relevant educational opportunities. Strategies for environmental health education include multitiered training approaches that include community residents, parent education, direct children education, and community education through professional counselors and train-the-trainer approaches. We propose that academic researchers must use community residents not just as subjects of our studies, but to increase our mutual understanding of environmental health, resulting in active participation of community members in research design, data collection, analysis, and dissemination of results in order to make intervention strategies more effective.
Mite and Pet Allergen Levels in Homes of Children Born to Allergic and Nonallergic Parents: The PIAMA Study. (Children's Health: Articles)
Authors: Rob T. van Strien, Laurens P. Koopman, Marjan Kerkhof, Jack Spithoven, Johan C. de Jongste, Jorrit Gerritsen, Herman J. Neijens, Rob C. Aalberse, Henriette A. Smit, Bert Brunekreef
Journal: Environmental Health Perspectives (2002)
Survival by age in children and adolescents with Hodgkin lymphoma: A pooled analysis of Children’s Oncology Group (COG) trials.
Authors: Justine M. Kahn, Kara M. Kelly, Qinglin Pei, Debra L. Friedman, Frank G. Keller, Rizvan Bush, Smita Bhatia, Tara O. Henderson, Cindy L. Schwartz, Sharon M. Castellino
Journal: Journal of Clinical Oncology (2018)

7543 Background: The National Cancer Institute defines adolescent/young adult as 15-39y. Guidelines from ASCO and Friends of Cancer Research call for including children ≥12y on late phase trials spanning children and adults. We examined whether, in children and adolescents receiving response-based therapy for Hodgkin lymphoma (HL), age ≥12y would define a group with inferior outcomes compared to younger patients. Methods: This was a pooled analysis of individual patient-level data from three COG Phase 3 trials for intermediate, low, high-risk HL (AHOD0031, AHOD0431, AHOD0831). 5-yr event free survival (EFS) and overall survival (OS) by age were estimated via Kaplan Meier method. Cox regression models examined the influence of age on EFS and OS, adjusted for race/ethnicity, sex, insurance, histology, Ann Arbor stage, B symptoms, bulk, study, and radiation therapy (RT). Results: We included 2071 of 2155 patients, 1-21y enrolled from 2002 -2012. Mean age at diagnosis was 14.6y (±3.5) with 54% ≥15y (N = 1121) and 81% ≥12y (N = 1684). At median follow-up of 6.9 years, patients < 15y had statistically significantly better EFS ( < 15y: 85% vs. ≥15y: 80%, p = 0.02). A difference in EFS was noted in those < 12y vs. ≥12y (87% vs. 81%, p = 0.0503). OS was significantly better in patients < 15y vs. ≥15y (98% vs. 95%, p = 0.006), but did not differ in < 12y vs. ≥12y (99% vs. 97%, p = 0.136). Cumulative incidence of second malignant neoplasm did not differ by age category. In multivariable models, older age was an independent predictor of treatment failure in both age categories (Table). Conclusions: With contemporary, response-based therapy on COG trials, adolescents ≥12 and ≥15y had worse EFS than younger groups. This suggests that children ≥12y may benefit from therapy escalation and inclusion in late phase trials of novel agents incorporating antibody drug conjugates or checkpoint inhibitors. Multivariable cox model of 5-yr EFS and OS by age group. 5-yr EFS 5-yr OS HR 95% CI p-value HR 95% CI p-value < 12 years (R: ≥12) 0.71 (0.51, 0.98) 0.04 0.51 (0.2, 1.34) 0.17 < 15 years (R: ≥15) 0.74 (0.59, 0.93) 0.01 0.39 (0.2, 0.76) 0.006 HR: hazard ratio; 95%CI: 95% confidence interval; R: reference group