tbuckley/cabot-search huggingface dataset:
Correlation of plasma levels of free insulin-like growth factor 1 and clinical benefit of the IGF-IR inhibitor figitumumab (CP- 751, 871)
Authors: M. L. Hixon, A. Gualberto, L. Demers, L. G. Paz-Ares, S. Novello, L. J. Blakely, C. L. Langer, A. Lipton, M. Pollak, D. D. Karp
Journal: Journal of Clinical Oncology (2009)

3539 Background: Free IGF-1 (fIGF-1) represents the biologically active fraction of IGF-1, the main circulating ligand of the Insulin-like Growth Factor type I Receptor (IGF-IR). Signaling through the IGF-IR induces tumor survival and resistance to cancer therapy. Figitumumab (F) (CP-751,871) inhibits IGF-1-induced IGF-IR autophosphorylation with an IC50 of 0.42 nmol/L. Methods: Plasma levels of fIGF-1 were measured in a phase 1b/2 multi-center study of Paclitaxel (T) and Carboplatin (C) and F in patients (pts) with treatment-naïve NSCLC. Other serum markers of the IGF-IR pathway, including circulating soluble IGF-IR (sIGF-IR), IGFBP3 and ALS (acid-labile subunit), were also investigated. The Kaplan-Meier method was used to estimate median survival times. Results: A total of 536 blood samples from 159 pts were analyzed. Baseline median and range fIGF-1 were 0.53 and 0.07–1.99 ng/mL. fIGF-1 directly correlated with IGFBP3 and ALS, and inversely with sIGF-IR (Rho=-0.430, p=0.03). Treatment with F resulted in dose-dependent accumulation of fIGF-1 with a sustained &gt;10 fold increase in fIGF-1 plasma levels at the 20 mg/kg dose, suggesting complete systemic blockade of fIGF-1 binding to the IGF-IR. sIGF-IR decreased and IGFBP3 increased in response to F, but increases in IGBP3 were more modest than those of fIGF-1. Baseline plasma levels of fIGF-1 had a 96.6% negative predictive value for PFS status at 6 months (p=0.03). Median PFS were respectively 2.73 and 6.53 months for TC alone and TC with F (20 mg/kg) in the high fIGF-1 group (p=0.001) while no significant treatment effect of F was observed in the low (&lt;0.54 ng/mL) fIGF-1 group. Sixty three percent of pts with high fIGF-1 had tumors of adenocarcinoma histology. Conclusions: IGF-1 is a key element in the biology of NSCLC of adenocarcinoma histology and its determination may contribute to the identification of pts who benefit from figitumumab therapy. [Table: see text]
The Affordable Care Act: What's Next?
Authors: Mark McClellan, Mark Japinga
Journal: Annual Review of Medicine (2018)

The postelection efforts to repeal, replace, or modify the Affordable Care Act (ACA) suggest that the debate over healthcare coverage will remain contentious, particularly because of the high and rising cost of health care. Feasible, potentially bipartisan approaches to improving access to coverage should emphasize reforming health care to achieve higher quality at a lower cost. In the individual market, where many enrollees face limited options and rising premiums, a combination of high-risk pools, reinsurance, and risk adjustment could improve coverage options while encouraging innovations in care for the highest-risk patients. State Medicaid programs, which are increasingly important sources of coverage but are crowding out other important budget priorities that affect population health, could achieve better results through federal reforms that provide more flexibility for states alongside greater emphasis on achieving better outcomes. Accelerating payment reforms and other policy changes to encourage more innovative and efficient care delivery models, along with developing better evidence on successful models, can also improve the prospects for coverage reform.
The influence of childhood trauma on fatigue and depression in breast cancer patients during and after radiotherapy.
Authors: Tatiana Jihae Han, Anna Lee, Donna Mister, Andrew H. Miller, Mylin Ann Torres
Journal: Journal of Clinical Oncology (2014)

e20567 Background: Women with a history of childhood abuse and/or neglect are at increased risk for psychological distress when confronted with new traumatic experiences including a diagnosis and treatment of breast cancer. The purpose of our study was to determine if patients with a history of childhood trauma are particularly susceptible to fatigue, depression and stress during whole breast radiotherapy (RT). Methods: 20 consecutive breast cancer patients were enrolled in a prospective, longitudinal study of fatigue, depression, and stress symptoms prior to RT, at week 6 of RT, and 6 weeks post-RT. All subjects received standard whole breast RT (50 Gy plus a 10 Gy boost) following breast conserving surgery. The Childhood Trauma Questionnaire (CTQ) was administered to determine history of abuse and/or neglect. Patients completed the Multidimensional Fatigue Inventory (MFI), Inventory of Depressive Symptomatology (IDS-SR), Perceived Stress Scale (PSS), and Short Form 36 Health Survey (SF-36) before, during, and after RT. Fatigue, depression, stress, and SF-36 scores were compared based on CTQ history. Results: 10 subjects (50%) were found to have a history of childhood trauma (CTQ+). CTQ+ women were less likely to have a graduate degree (p<.001) than CTQ- patients. There were no other significant differences in patient or treatment characteristics between the two groups. RT did not significantly increase fatigue, depression, or stress, or worsen QOL to a greater extent in CTQ+ patients. However, CTQ+ patients had significantly worse depression and stress scores before, during, and after RT than CTQ- patients (p<.05). Fatigue before and after RT was also significantly higher in CTQ+ patients (p<.01). CTQ+ patients also had worse SF-36 scores than CTQ- women after RT (p<.01). Conclusions: We found that a history of childhood trauma was relatively prevalent among our breast cancer patients. However, RT does not exacerbate fatigue, depression, and stress symptoms in CTQ+ women. Nevertheless, CTQ+ patients are generally more fatigued, depressed and stressed throughout RT. Efforts should be made to identify these patients early and provide them with medical services aimed at improving their symptoms.
Immune gene expression in primary melanomas to predict lower risk of recurrence and death.
Authors: Shanthi Sivendran, Rui R. Chang, Sara Harcharik, Lawrence Hall, Sebastian Bernardo, Marina Moskalenko, Robert Phelps, Meera Sivendran, Ariella Cohain, Analisa DiFeo, Michael Parides, Mark Lebwohl, Philip Friedlander, Jacques Banchereau, Nina Bhardwaj, William K. Oh, Steven J. Burakoff, Karolina Palucka, Miriam Merad, Yvonne M. Saenger
Journal: Journal of Clinical Oncology (2013)

3014 Background: Improved biomarkers are needed to define recurrence risk in patients with completely resected skin melanomas. Standard prognostic indicators used in staging, including depth, ulceration, and mitotic rate, while useful, often fail to accurately predict recurrence for individual patients. The immune system may prevent recurrence in this population, but no evidence-based immune biomarkers are in clinical use. Biomarker development has been hindered by clinical standards necessitating that the entire specimen be formalin fixed and paraffin embedded (FFPE) for morphology evaluation, a process damaging to RNA. Methods: To define a biomarker for melanoma recurrence, mRNA copy number of immune-related genes from FFPE melanoma was measured using NanoString, a hybridization assay suited for analysis of partially degraded RNA. Genes predictive of non-recurrence were defined using receiver operating characteristic (ROC) curves in a training cohort and then validated in an independent patient cohort. Results: A panel of 21 genes predictive of non-recurrence were defined using ROC curves in a training cohort (N=44). This result was validated in an independent patient cohort (N=37, AUC=0.794). Protein levels of the most differentially expressed gene, CD2, also associated with non-recurrence (p&lt;0.001). The immune gene panel and CD2 staining associated with prolonged survival (p&lt;0.001 and p=0.019, respectively). Conclusions: mRNA copy number of immune-related genes in primary FFPE melanomas predicts non-recurrence and prolonged survival. This data highlights the impact of immunosurveillance in primary human melanoma and the identified gene panel may be a useful tool for patient stratification for adjuvant immunotherapy studies.
LEFT ATRIAL VOLUME INDEX OVER LATE DIASTOLIC MITRAL ANNULAR VELOCITY: A NEW NON-INVASIVE PARAMETER FOR MEASUREMENT OF LEFT VENTRICULAR END DIASTOLIC PRESSURE
Authors: Rahul Vasudev, Upamanyu Rampal, Hiten Patel, Kunal Patel, Raja Pullatt, Mahesh Bikkina, Fayez Shamoon
Journal: Journal of the American College of Cardiology (2017)
Hermansky-Pudlak syndrome type 4 with interstitial pneumonia
Authors: Yoshihiko Sakata, Kodai Kawamura, Kazuya Ichikado, Moritaka Suga, Masakazu Yoshioka
Journal: European Respiratory Journal (2013)

Hermansky–Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism, bleeding tendency, and lysosomal accumulation of ceroid-like material, with occasional development of interstitial pneumonia (IP). Nine genetically distinct subtypes of HPS are known in humans; IP develops primarily in types 1 and 4. Most reported cases of HPS with IP are type 1, and there are no published reports of type 4 in Japanese individuals. A 58-year-old man with congenital oculocutaneous albinism and progressive dyspnea for 1 month was admitted to our hospital. We administered high-dose corticosteroids on the basis of a diagnosis of acute exacerbation of interstitial pneumonia. Respiratory symptoms and the findings of high-resolution computed tomography (CT) showed improvement. He was diagnosed with HPS type 4 with interstitial pneumonia on the basis of gene analysis. He has been receiving pirfenidone for 1 year and his condition is stable. This is the first report on the use of pirfenidone for HPS with IP caused by a novel mutation in the HPS4 gene. We conclude that HPS should be suspected in patients with albinism and interstitial pneumonia. High-dose corticosteroid treatment may be useful in cases of acute exacerbation of interstitial pneumonia due to HPS-4, and pirfenidone may be useful and well tolerated in patients with HPS-4.
A phase Ib multicohort study of MK-3475 in patients with advanced solid tumors.
Authors: Rita Nanda, Elizabeth R. Plimack, Elizabeth Claire Dees, Shilpa Gupta, Raanan Berger, Aymen Elfiky, Lajos Pusztai, Laurence Buisseret, Ravit Geva, Sara I Pai, Kumudu Pathiraja, Robert Iannone, Christine Gause, Holly Brown, Jennifer Houp, Jonathan D. Cheng, Laura Quan Man Chow
Journal: Journal of Clinical Oncology (2014)

TPS3119 Background: Immune surveillance is one of the primary mechanisms to prevent neoplastic growth. The PD-1 receptor-ligand pathway can be used by tumors to evade immune surveillance. MK-3475 is a potent, highly selective, humanized IgG4/kappa isotype mAb designed to block PD-1 interaction with its ligands PD-L1 and PD-L2, and can reactivate the immune system to eradicate the host tumor. Methods: This is a multi-center, non-randomized, multi-cohort trial of single agent MK-3475 in over 130 patients diagnosed with locally recurrent and/or distant metastatic 1) triple negative breast cancer, 2) head and neck cancer (both HPV and non-HPV associated), 3) urinary tract cancer or 4) gastric cancer. All enrolled patients must express PD-L1 within their tumor microenvironment. MK-3475 is given intravenously at 10 mg/kg every 2 weeks. Primary objectives are to determine (1) safety and tolerability and (2) anti-tumor activity of MK-3475 in patients with PD-L1 positive, advanced solid tumors. Secondary objectives include progression-free survival, overall survival and response duration in treated patients. Radiographic imaging will be obtained every 8 weeks to assess clinical response defined by RECIST 1.1. Tumor biopsies will be available both pre-treatment and during treatment to allow investigation of candidate biomarkers which may predict clinical response to immune checkpoint blockade. Treatment continues for 24 months or until complete response, disease progression, unacceptable toxicity, physician decision, or patient’s withdrawal of study consent. Retreatment for patients who progress after a complete response is allowed. AEs will be monitored and graded according to guidelines in the NCI CTCAE v. 4.0. Summary statistics for safety endpoints and the incidence rate of immune-related AEs and of Grade 3-5 AEs will be calculated. Efficacy will be evaluated in each cohort, in patients with baseline and with either ≥1 post-baseline evaluation or who discontinue the trial due to progressive disease or a drug-related AE. Overall response rate assessed by independent radiology review will be used as the primary endpoint for efficacy. Clinical trial information: NCT01848834.
THE WAY TO A MAN'S HEART: THROUGH HIS QUADRICEPS
Authors: Eesha Khan, Safieh Golestaneh, Mit Patel, Ahmad Turk, Shakil Shaikh, Vikram Grewal, Fotis Katsikeris, Lincoln Tirpaeck, Jaime Hernandez-Montfort
Journal: Journal of the American College of Cardiology (2017)
Clonal, Exhausted and Activated Infiltrating T Lymphocytes in Langerhans Cell Histiocytosis Lesions
Authors: Rikhia Chakraborty, Amel G Sengal, Meryl Hahne, Amos S. Gaikwad, Brooks Scull, Harshal Abhyankar, Miriam Merad, Kenneth McClain, Carl E. Allen
Journal: Blood (2016)
Abstract MP095: Pregnancy as a Window to Racial Disparities in Hypertension
Authors: Claire E Margerison-Zilko, Janet M Catov, Claudia Holzman
Journal: Circulation (2017)

Background: Black women in the United States have 50% higher rates of hypertension (HTN) than white women. This disparity persists after accounting for many known HTN risk factors. Evidence indicates that pregnancy complications may reveal increased risks for later HTN, and some complications, such as preterm delivery, are more common in black vs. white women. Hypotheses: 1) Adjustment for multiple HTN risk factors measured at mid-life will explain some, but not all, of the black-white disparity in mid-life HTN among women. 2) Markers of pregnancy health will help explain the remaining black-white disparity in mid-life HTN. Methods: Data came from a Michigan-based cohort study of women enrolled during pregnancy and followed-up at mid-life (n=678, mean age = 37, range 25-58). We included women without pre-pregnancy hypertension (n=652) categorized as African American (AA) (n=242) and white (n=373). We categorized women as hypertensive (systolic BP ≥140, diastolic BP ≥90, or self-reported use of antihypertensive medications, n=126), pre-hypertensive (systolic BP 120-139 or diastolic BP 80-89, n=149), and normotensive (n=340). Mid-life risk factors for HTN were grouped into 4 domains: socioeconomic status ([SES], based on education, occupation, marital status, insurance, and wealth), psychosocial (depression, hostility, job strain), behavioral (current smoking, diet quality score, sedentary hours/day, global sleep score), and physiological (body mass index [BMI], lipids, c-reactive protein [CRP]). We used generalized logit models to assess the degree to which each individual factor attenuated the AA (vs. white) odds ratio (OR) for HTN at mid-life and then sequentially added variables to a multivariable model. We then added indicators of pregnancy health (preterm delivery, pre-pregnancy BMI, and CRP, depressive symptoms, hypertensive disorders, and lipids during pregnancy). Results: AA women had 3.28(95% CI:1.96,5.51) times the odds of HTN compared to white women after adjusting for age. Adjustment for SES attenuated the OR to 2.52(95% CI:1.46,4.36). Further adjustment for psychosocial factors and behaviors attenuated the OR to 2.30(95% CI:1.29,4.11), and BMI and CRP attenuated it to 2.13(95%CI:1.15,3.93). Adjustment for preterm delivery, pre-pregnancy BMI, and CRP and depressive symptoms during pregnancy reduced the OR to 1.88(95%CI:0.97,3.64), with BMI, CRP, and depressive symptoms playing a larger role than preterm delivery. Adjustment for hypertensive disorders and lipids during pregnancy did not further reduce the race disparity. Conclusions: SES, psychosocial factors, behaviors, and biomarkers measured at mid-life explained some, but not all, of the race disparity in mid-life HTN. Indicators of pregnancy health, particularly pre-pregnancy BMI, inflammation (CRP), and depressive symptoms contributed substantially to the race disparity in HTN at mid-life.
Beneficial effect of ustekinumab in familial pityriasis rubra pilaris with a new missense mutation in <i>CARD14</i>
Authors: S.M. Lwin, C-K. Hsu, L. Liu, H-Y. Huang, N.J. Levell, J.A. McGrath
Journal: British Journal of Dermatology (2017)

Pityriasis rubra pilaris (PRP) represents a group of rare chronic inflammatory skin disorders in which around one in 20 affected individuals show autosomal dominant inheritance. In such cases there may be gain-of-function mutations in CARD14, encoding caspase recruitment domain-containing protein 14 (CARD14), which activates the noncanonical nuclear factor (NF)-κB pathway, thereby promoting cutaneous inflammation. Here we report a mother and son with PRP due to a new missense mutation in CARD14 and describe the beneficial clinical effects of ustekinumab, a monoclonal antibody against interleukins 12 and 23, in both patients. A 49-year-old woman and her 20-year-old son had lifelong, generalized, patchy erythematous scale with a few islands of sparing, as well as minor nail ridging and mild palmoplantar keratoderma, features consistent with generalized PRP. Topical steroids, phototherapy and oral retinoids proved ineffective. Following informed consent, Sanger sequencing of CARD14 in both individuals revealed a new heterozygous single-nucleotide transversion in exon 4, c.356T>G, resulting in the missense mutation p.Met119Arg. Ustekinumab, at a dose of 45 mg every 12 weeks, brought about a significant physical and emotional improvement in both the mother and son within a few days of the initial dose, which was sustained on maintenance dosing. This report highlights the therapeutic potential of biologics that downregulate NF-κB signalling in familial PRP with mutations in CARD14.
Regulatory T cells promote myelin regeneration in the central nervous system
Authors: Yvonne Dombrowski, Thomas O'Hagan, Marie Dittmer, Rosana Penalva, Sonia R Mayoral, Peter Bankhead, Samara Fleville, George Eleftheriadis, Chao Zhao, Michelle Naughton, Rachel Hassan, Jill Moffat, John Falconer, Amanda Boyd, Peter Hamilton, Ingrid V Allen, Adrien Kissenpfennig, Paul N Moynagh, Emma Evergren, Bernard Perbal, Anna C Williams, Rebecca J Ingram, Jonah R Chan, Robin J M Franklin, Denise C Fitzgerald
Journal: Nature Neuroscience (2017)
The Nationwide Study of Erdheim-Chester Disease in Japan
Authors: Mizuki Ogura, Takashi Toya, Akihide Yoshimi, Aya Shinozaki Ushiku, Akira Honda, Toyama Kazuhiro, Kenjiro Honda, Yasuhito Nannya, Yusuke Shinoda, Akiko M. Saito, Takashi Ogura, Ichiro Katayama, Kiyoshi Miyagawa, Masaomi Nangaku, Masashi Fukayama, Mineo Kurokawa
Journal: Blood (2016)
ASSOCIATION BETWEEN ATRIAL FIBRILLATION AND SUDDEN CARDIAC DEATH: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Pattara Rattanawong, Tanawan Riangwiwat, Veeravich Jaruvongvanich, Sikarin Upala, Anawin Sanguankeo, Wasawat Vutthikraivit, Eugene Chung
Journal: Journal of the American College of Cardiology (2017)
Evaluation of cardiac dose reduction with deep inspiration breath hold in patients with left-sided breast cancer receiving adjuvant radiotherapy.
Authors: Rosanna Yeung, Karen Long, Daphne Walrath, Wendy Smith, Alana Hudson, Tien Phan
Journal: Journal of Clinical Oncology (2014)

1096 Background: Studies have suggested increased cardiac morbidity from radiation exposure to the heart and left anterior descending artery (LAD) in breast cancer patients receiving adjuvant radiotherapy (RT). Deep inspiration breath hold (DIBH) techniques have demonstrated reduction to heart, LAD and lung dose in left-sided breast cancers. There is, however, limited data on which patients derive most benefit from DIBH technique. Objective: To compare reduction in cardiac and LAD doses using a DIBH technique in left-sided breast cancer patients treated with adjuvant RT to the breast alone versus those also receiving regional nodal RT Methods: Twenty consecutive patients with left-sided breast cancer underwent CT simulation in free breathing (FB) and DIBH. Patients were grouped into two cohorts: those receiving whole breast RT alone +/- boost (WBRT) versus whole breast/chest wall RT with regional nodal irradiation (WBRT + RNI). 3D conformal plans were devised, and dosimetric comparisons were made between the two techniques for each cohort. Results: Eleven patients received WBRT while nine patients received WBRT + RNI. All patients had comparable CTV coverage on both DIBH and FB treatment plans. Mean heart and LAD doses were lower in all DIBH versus FB plans in both groups, but the benefit was larger in the group receiving RNI compared to those receiving WBRT alone (average relative reduction in mean heart and LAD dose: 55.9% and 71.9% vs 34.2% and 45.1%, respectively). All patients met a mean heart dose of <4Gy on DIBH. On FB, only one patient in the WBRT group did not meet this constraint, compared to five patients in the WBRT +RNI group. Conclusions: Patients receiving WBRT+RNI had a greater reduction in heart and LAD dose from DIBH than patients receiving WBRT alone. The majority of patients receiving WBRT met a mean heart dose of <4Gy on FB planning, while less than half of patients receiving WBRT + RNI were able to meet this constraint. These findings suggest a greater benefit from DIBH treatment in patients receiving RNI, while patients receiving WBRT alone may be safely treated with a FB technique. Ongoing prospective cohorts are being evaluated to ensure validity of these findings.