tbuckley/cabot-search huggingface dataset:
Altered circadian rhythm in rest and activity (CircAct): Independent prognostic value for survival in patients (pts) with metastatic colorectal cancer (MCC)
Authors: P. F. Innominato, G. A. Bjarnason, C. Garufi, C. Focan, T. Moreau, T. Gorlia, J. Waterhouse, S. Giacchetti, F. A. Lévi
Journal: Journal of Clinical Oncology (2007)

14573 Background: Altered CircAct accelerated tumor growth in experimental models (JNCI 2002, 2005; Cancer Res 2004). CircAct was found to be related to survival in two studies (St) in MCC pts (St 1, Clin Cancer Res 2000; St 2, ASCO 2005 #3553). The current study attempted to provide an independent prognostic stratification criteria for survival according to baseline CircAct as a first step toward the development of a comprehensive prognostic model based on circadian physiology. Methods: CircAct was continuously and non- invasively assessed over 72h with a wrist accelerometer (Ambulatory Monitoring, USA), before chemotherapy in two independent datasets of 169 MCC pts (60% pretreated) at Paul Brousse Hospital (St 1) and 130 chemo-naïve MCC pts registered in the international EORTC 05963 trial (St 2). Activity distribution during rest and wakefulness was objectively quantified by I&lt;O (50=no rhythm; 100=marked rhythm). Kaplan-Meier survival curves with logrank tests and Cox regression models were used for analyses. Results: In both St, pts with I&lt;O = 92 (21% in St 1 and 22% in St 2) displayed a significantly poorer survival as compared to those pts with I&lt;O &gt; 92 (Table). The hazard ratios (HR) were 0.37 [95%CI: 0.25 to 0.55] (p&lt;0.0001) in St 1 and 0.56 [0.36 to 0.87] (p=0.01) in St 2. The prognostic value of altered CircAct persisted after adjusting for PS (HR=0.46 [0.30 to 0.69], p=0.0002 in St 1; HR=0.61 [0.38 to 0.97], p=0.04 in St 2). Conclusions: The independent stratification of MCC pts for survival according to baseline altered CircAct occurred using a threshold value of 92 for I&lt;O in both separate datasets. Subsequent studies will involve additional biomarkers of circadian physiology (cortisol, melatonin, clock genes) in order to further improve this prognostic stratification as a step toward tailored treatment of MCC pts. [Table: see text] No significant financial relationships to disclose.
Neurologic sequelae after treatment of severe hyponatremia
Authors: R H Sterns, J D Cappuccio, S M Silver, E P Cohen
Journal: Journal of the American Society of Nephrology (1994)

Severe, symptomatic hyponatremia is often treated urgently to increase the serum sodium to 120 to 130 mmol/L. Recently, this approach has been challenged by evidence linking "rapid correction" (> 12 mmol/L per day) to demyelinating brain lesions. However, the relative risks of persistent, severe hyponatremia and iatrogenic injury have not been well quantified. Data were sought on patients with serum sodium levels < or = 105 mmol/L from the membership of the American Society of Nephrology. Respondents were given a report form asking specific questions regarding the cause of hyponatremia, presenting symptoms, rate of correction, and neurologic sequelae. Data on 56 patients were analyzed. Fourteen developed posttherapeutic complications (10 permanent, 4 transient) after correction to a serum sodium > 120 mmol/L. Eleven of these 14 patients (including 3 with documented central pontine myelinolysis) had a biphasic course in which neurologic findings initially improved and then worsened on the second to sixth day. Posttherapeutic complications were not explained by age, sex, alcoholism, presenting symptoms, or hypoxic episodes. Increased chronicity of hyponatremia and a high rate of correction in the first 48 h of treatment were significantly associated with complications. No neurologic complications were observed among patients corrected by < 12 mmol/L per 24 h or by < 18 mmol/L per 48 h or in whom the average rate of correction to a serum sodium of 120 mmol/L was < or = 0.55 mmol/L per hour. It was concluded that patients with severe chronic hyponatremia are most likely to avoid neurologic complications when their electrolyte disturbance is corrected slowly.
Persistent hepatitis C viral replication despite priming of functional CD8+ T cells by combined therapy with a vaccine and a direct‐acting antiviral
Authors: Benoit Callendret, Heather B. Eccleston, William Satterfield, Stefania Capone, Antonella Folgori, Riccardo Cortese, Alfredo Nicosia, Christopher M. Walker
Journal: Hepatology (2015)

Exhaustion of antiviral CD8 + T cells contributes to persistence of hepatitis C viral (HCV) infection. This immune response has proved difficult to restore by therapeutic vaccination, even when HCV replication is suppressed using antiviral regimens containing type I interferon. Because immunomodulatory effects of type I interferon may be a factor in poor T‐cell priming, we undertook therapeutic vaccination in two chronically infected chimpanzees during treatment with a direct‐acting antiviral (DAA) targeting the HCV NS5b polymerase protein. Immunization with genetic vaccines encoding the HCV NS3‐NS5b nonstructural proteins during DAA treatment resulted in a multifunctional CD8 + T‐cell response. However, these antiviral CD8 + T cells did not prevent persistent replication of DAA‐resistant HCV variants that emerged during treatment. Most vaccine‐induced CD8 + T cells targeted class I epitopes that were not conserved in the circulating virus. Exhausted intrahepatic CD8 + T‐cell targeting‐conserved epitopes did not expand after vaccination, with a notable exception. A sustained, multifunctional CD8 + T‐cell response against at least one intact class I epitope was detected in blood after vaccination. Persistence of HCV was not due to mutational escape of this epitope. Instead, failure to control HCV replication was likely caused by localized exhaustion in the liver, where CD8 + T‐cell expression of the inhibitory receptor programmed cell death 1 increased 25‐fold compared with those in circulation. Conclusion: Treatment with a DAA during therapeutic vaccination provided transient control of HCV replication and a multifunctional T‐cell response, primarily against nonconserved class I epitopes; exhaustion of liver‐infiltrating CD8 + T cells that target conserved epitopes may not be averted when DAA therapy fails prematurely due to emergence of resistant HCV variants. (H epatology 2016;63:1442‐1454)
Association Between Asthma Symptom Scores and Increased Perceived Stress and Trait Anxiety in Asthmatic Adolescents
Authors: Cathryn J. Luria, Alexandra R. Sitarik, Suzanne Havstad, Ganesa R. Wegienka, Haejin Kim, Edward M. Zoratti, Christine L.M. Joseph, Andrea Cassidy-Bushrow
Journal: Journal of Allergy and Clinical Immunology (2016)
Abstract 16074: Triple Antiplatelet Therapy (Aspirin, Clopidogrel, Cilostazol) Loading Followed by Maintenance Reduces Greater Serum Level of Scd40l and Tnf-a Than Dual Antiplatelet Therapy in Patients With Acute Myocardial Infarction Undergoing Pci: Two-Center, Prospective, Open Label, Randomized, Pilot Study
Authors: Mahn Won Park, Sung-Ho Her, Jung-sun Cho, Chan Joon Kim, Gyung-Min Park, Kiyuk Chang, Ki-Bae Seung, Eun-Ho Choo, Jin-Jin Kim, Jae-Kyung Kim, Sang-Hyeon Yim, Suk-Min Seo, Byung-Hee Hwang, Pum-Jun Kim, Wook-Sung Chung
Journal: Circulation (2013)
Phase II study of the mTOR inhibitor sirolimus for nonprogressive NF1-associated plexiform neurofibromas: A Neurofibromatosis Consortium study.
Authors: B. C. Widemann, M. J. Fisher, E. Dombi, A. Cantor, S. Vinks, B. Korf, E. Schorry, D. Gutmann, R. Packer, B. D. Weiss
Journal: Journal of Clinical Oncology (2010)

e13601 Background: Plexiform neurofibromas (PN) are a common and potentially debilitating complication of neurofibromatosis type 1 (NF1). These benign nerve sheath tumors cause significant morbidity through disfigurement and compression of vital structures. Surgery is the only standard treatment for PN, but complete resection is often not feasible. The NF1 gene regulates mTOR pathway activation. In in vitro and in vivo NF1 models Nf1 loss results in Ras- and PI3K-dependent mTOR pathway activation, which could be inhibited with sirolimus. We performed a multicenter, Department of Defense funded phase II trial to determine if sirolimus can induce objective radiographic response (PN volume decrease ≥20%) of PN. Methods: Subjects with NF1 and ≥ 1 inoperable PN with the potential to cause significant morbidity but without radiographic progression within one year prior to trial entry were eligible. Sirolimus (0.8 mg/m2/dose) was given orally q12h on a continuous dosing schedule (one course=28 days), and trough sirolimus levels were maintained between 10-15 ng/ml. Subjects received a maximum of 6 courses of sirolimus unless there was evidence of response, in which case treatment could be continued for up to 60 total courses. Volumetric MRI analysis was performed at baseline and after every 3 courses. Subjects with progressive disease or unacceptable toxicity were removed from sirolimus treatment. Using a two-stage Simon Optimal design (target response rate 20%, rule out 5%), enrollment would be expanded if ≥1 of the initial 12 enrolled subjects had a response. In the absence of response in the first 12 subjects, the stratum would close. Results: Seven females and 5 males with median age of 11 years (range, 3-35 yrs) and a median PN volume of 847 mL (range, 23-2,476 mL) were enrolled. All subjects were removed from sirolimus after 6 courses: one for PN progression, 11 for lack of response. Conclusions: Sirolimus was well tolerated, but not effective in shrinking nonprogressive NF1 PN. Evaluation of whether sirolimus can prolong the time to progression in subjects with NF1 and progressive PN at trial entry is ongoing in another stratum of this trial. No significant financial relationships to disclose.
The assessment of cost and other barriers to patient clinical trial participation in the community setting.
Authors: D. Weckstein, C. Thomas, I. F. Emery, B. F. Shea, A. Fleury, M. White, E. Chase, S. Frazier, C. Robinson, C. Pilar
Journal: Journal of Clinical Oncology (2010)

6030 Background: Although cancer clinical trials are perceived by patients and providers as an essential component of cancer care, less than 10% of patients with cancer participate in trials. Few studies have addressed the role of cost in influencing a patient's decision to participate in a trial. Methods: Four community oncology practices in northern New England issued written surveys to consecutive cohorts of patients with solid tumor or hematologic malignancy from October 2008 through November 2009. Patients were assessed for eligibility for clinical trials at their practice site. Trial-eligible patients were asked if they discussed trial participation with their providers. If they considered trial participation, but declined enrollment, they were asked to select from a list of reasons influencing their decision. The survey listed concern about cost, feeling overwhelmed, concern about side effects, concern about additional time required, discomfort with randomization, and other as options to select. Data were analyzed to determine the percentage of patients declining trial participation for the above reasons. The number of trial eligible patients not recalling a discussion with their provider about trials was tabulated. Results: Surveys were issued to 1,243 patients between October 2008 and November 2009. The surveys were returned by 61% of patients. Of those patients who returned surveys, 165 were clinical trial eligible, but did not participate in a trial. Sixty-nine (69) of these 165 patients did not recall hearing about clinical trials from their provider. Ninety-five (95) of 96 who were trial eligible and discussed trials offered reasons why they declined participation. Conclusions: Concerns about side effects and randomization were the most common reasons cited by patients declining clinical trial participation. Cost considerations were also important to a significant proportion of these patients. Many patients eligible for a trial were not informed by their provider about the availability of clinical trials. Reason declining trial % listing as a reason % listing as most important Possible side effects 52 20 Randomization 46 16 Time 34 12 Cost 31 13 Overwhelmed 28 12 Other 9 8 MD did not recommend 5 5 No significant financial relationships to disclose.
Bispecific Antibody Conjugated Manganese-Based Magnetic Engineered Iron Oxide for Imaging of HER2/neu- and EGFR-Expressing Tumors
Authors: Shou-Cheng Wu, Yu-Jen Chen, Hsiang-Ching Wang, Min-Yuan Chou, Teng-Yuan Chang, Shyng-Shiou Yuan, Chiao-Yun Chen, Ming-Feng Hou, John Tsu-An Hsu, Yun-Ming Wang
Journal: Theranostics (2015)

The overexpression of HER2/neu and EGFR receptors plays important roles in tumorigenesis and tumor progression.Targeting these two receptors simultaneously can have a more widespread application in early diagnosis of cancers.In this study, a new multifunctional nanoparticles (MnMEIO-CyTE777-(Bis)-mPEG NPs) comprising a manganese-doped iron oxide nanoparticle core (MnMEIO), a silane-amino functionalized poly(ethylene glycol) copolymer shell, a near infrared fluorescence dye (CyTE777), and a covalently conjugated anti-HER2/neu and anti-EGFR receptors bispecific antibody (Bis) were successfully developed.In vitro T 2 -weighted MR imaging studies in SKBR-3 and A431 tumor cells incubated with MnMEIO-CyTE777-(Bis)-mPEG NPs showed -94.8 ± 3.8 and -84.1 ± 2.8% negative contrast enhancement, respectively.Pharmacokinetics study showed that MnMEIO-CyTE777-(Bis)-mPEG NPs were eliminated from serum with the half-life of 21.3 mins.In vivo MR imaging showed that MnMEIO-CyTE777-(Bis)-mPEG NPs could specifically and effectively target to HER2/neu-and EGFR-expressing tumors in mice; the relative contrast enhancements were 11.8 (at 2 hrs post-injection) and 61.5 (at 24 hrs post-injection) fold higher in SKBR-3 tumors as compared to Colo-205 tumors.T 2 -weighted MR and optical imaging studies revealed that the new contrast agent (MnMEIO-CyTE777-(Bis)-mPEG NPs) could specifically and effectively target to HER2/neu-and/or EGFR-expressing tumors.Our results demonstrate that MnMEIO-CyTE777-(Bis)-mPEG NPs are able to recognize the tumors expressing both HER2/neu and/or EGFR, and may provide a novel molecular imaging tool for early diagnosis of cancers expressing HER2/neu and/or EGFR.
Vemurafenib Treatment of<i>BRAF</i>V600E-Mutated Malignant Peripheral Nerve Sheath Tumor
Authors: Henry G. Kaplan
Journal: Journal of the National Comprehensive Cancer Network (2013)

No effective systemic treatment exists for malignant peripheral nerve sheath tumors (MPNSTs). These tumors have been reported to show increased activity in the mitogen-activated protein kinase pathway from the loss of neurofibromatosis-1 regulation and occasionally from BRAF V600E mutation. A patient with sporadic metastatic MPNST and the BRAF V600E mutation was treated with standard doses of sorafenib and later vemurafenib and followed for response. The patient showed a rapid but modest and transient response to sorafenib and a very dramatic response to vemurafenib. This case represents the first report of successful systemic treatment of MPNST with an inhibitor of the BRAF V600E mutation. It will be important to define the general utility of this approach and related therapies in this disease.
Carbonyl reductase 1 polymorphisms: Influence of diplotype structures on doxorubicin disposition in Asian breast cancer patients
Authors: S. Lal, E. Sandanaraj, X. Q. Xiang, Z. W. Wong, C. S. Ang Peter, N. S. Wong, E. J. Lee, B. Chowbay
Journal: Journal of Clinical Oncology (2008)

14572 Background: Carbonyl reductases are ubiquitously expressed monomeric NADPH dependent cytosolic enzymes which catalyze reduction of chemically diverse substrates. The study aimed to identify polymorphisms in the gene encoding carbonyl reductase 1 (CBR1) and investigate their influence on doxorubicin disposition. Methods: Patients (N=62) with histologically confirmed invasive breast cancer (Stage I-III) receiving adjuvant chemotherapy were recruited. Doxorubicin (60 mg/m2) and cyclophosphamide (600 mg/m2) were administered every 3 weeks for 4–6 cycles. Genomic DNA was isolated from peripheral blood for direct sequencing. Doxorubicin pharmacokinetic parameters were estimated using noncompartmental analysis (WinNonlin) and Mann-Whitney U test was used to assess genotypic-phenotypic correlations. Results: Four CBR1 polymorphisms (-48G>A, c.219G>C, c.627C>T, +967G>A) were identified. Moderate degree of linkage between the c.219G>C, c.627C>T and +967G>A polymorphisms [ID’I>0.7 in all groups] were observed. Major CBR1 haplotypes (>5%) [G-C-G,C-T-A,C-T-G] had a cumulative frequency of 83%. Sequence clustering using complete linkage algorithm identified 2 major groups (D1 and D2) among the 12 CBR1 diplotypes. Patients in the D1 diplotype group had significantly higher clearance [CL/BSA(Lh-1m-2), median: 25.09; range:16.44–55.66] and significantly lower exposure levels of doxorubicin [AUC0-∞/dose/BSA (hm-5):median:15.08;range:6.18–38.03] compared to patients belonging to the D2 diplotype group [CL/BSA(Lh-1m-2), median:20.88;range:8.68–31.79,(P=0.014) and AUC0-∞/dose/BSA(hm-5):median: 21.35; range:9.82–67.17,(P=0.007), respectively]. Patients harboring the D1 diplotype family had lower exposure levels of doxorubicinol [AUC0-∞/dose/BSA (hm- 5): median:8.99; range:3.68–20.63] when compared to patients belonging to the D2 [AUC0- ∞/dose/BSA(hm-5):median:11.28;range:6.25–18.71,P=0.057] diplotype family. Conclusion: The CBR1 D2 diplotypes correlate with significantly higher exposure levels of doxorubicin suggesting lowered intracellular conversion to doxorubicinol in these patients which may predispose them to greater toxicity. No significant financial relationships to disclose.
An artificial network model improves diagnostic ability of nuclear matrix protein 22 in the screening for bladder urothelial carcinoma: a prospective analysis of 800 consecutive cases
Authors: T. Kobayashi, Y. Matsui, K. Nishizawa, K. Mitsumori, K. Ogura
Journal: Journal of Clinical Oncology (2004)

4581 Background: Although urine nuclear matrix protein 22 (NMP22) is one of useful molecular markers for the diagnosis of urothelial cancer, sole use of NMP22 would not be superior to urine cytology. It is mainly because NMP22 is affected by leukocyturia, erythrocyturia, and urinary tract instrumentation. We established an artificial neural network model to improve the diagnostic ability of NMP22.. Methods: We prospectively assessed urinalysis, urine cytology, and NMP22 in 800 consecutive patients (men; 48%, mean age ± standard deviation; 61.5 ± 14.8 years) who had no history of urological malignancy. Microscopic hematuria (57.5%) was the major reason for reference. Definitive diagnosis of urothelial tumor was obtained by cystoscopy, ultrasonography, excretory urography, and contrast enhanced computerized tomography. Receiver operating characteristic (ROC) analysis was performed for NMP22, urine cytology, and output of the neural network model incorporating patient age, gender, microscopic count of erythrocyte, leukocyte, and epithelial cell, and proteinuria grade on dipstick test. Results: There were 41 patients diagnosed to have urothelial carcinoma including 32 bladder cancers and 9 upper urinary tract cancers. ROC analysis failed to show a significant difference in areas under curve (AUC) for sole use of NMP22 (AUC; 0.862) and cytology (AUC; 0.827, p = 0.472). AUC for the neural network was 0.945 which is significantly superior to sole use of NMP22 (p = 0.005) and cytology (p = 0.007). Positive and negative predictive values (PPV and NPV) for our model were superior to sole NMP22 and cytology (see table). Conclusions: Our neural network model enables to create a screening test superior to conventional modalities by combining NMP22 with urinalysis results in patients without history of urothelial cancer. No significant financial relationships to disclose.
Abstract P382: Visceral Adiposity is a Stronger Correlate of Plasma C-Reactive Protein Levels than Liver Fat in the INSPIRE ME IAA Study.
Authors: Jessica D Smith, Julie-Anne Nazare, Anne-Laure Borel, Steven M Haffner, Beverley Balkau, Robert Ross, Christine Massien, Natalie Alméras, Jean-Pierre Després
Journal: Circulation (2012)

Although it is well established than plasma C-reactive protein (CRP) levels predicts cardiovascular events beyond traditional risk factors, the main drivers of elevated CRP in the population are still under investigation. Among those, obesity and body fat distribution have been suggested to be important correlates of circulating CRP concentrations. The present analysis explored the correlates of CRP in the INSPIRE ME IAA cohort, a large CT imaging cardiometabolic risk study involving 2262 men and 2093 women for whom complete CT imaging and cardiometabolic, as well as CRP data, were available. CRP&gt;10mg/l were excluded (N= 327). Both visceral adiposity (Men r=0.41 p&lt;0.0001; Women r=0.50 p&lt;0.0001) and liver attenuation, inversely related to liver fat, (Men r=-0.24 p&lt;0.0001; Women r=-0.27 p&lt;0.0001) were significantly correlated with plasma CRP levels. When both liver fat and visceral adiposity were placed in a multivariate model including age, region and physician’s specialty, we found that visceral adiposity (Men: partial R2=17.4 p&lt;0.0001; Women: partial R2=24.1 p&lt;0.0001) was more strongly related to CRP level than liver attenuation (Men: partial R2=0.3 p&lt;0.0001; Women: partial R2=2.0 p&lt;0.0001). Further adjustment for BMI, smoking status and statin use yielded similar results. We then divided patients into six groups according to tertiles of visceral fat (VAT) and the median of liver fat (LF): 1) lowVAT-lowLF, 2) lowVAT-highLF, 3) midVAT-lowLF, 4) midVAT-highLF, 5) highVAT-lowLF, 6) highVAT-highLF. In both men and women, CRP levels were higher in the midVAT and highVAT groups compared to the lowVAT group; yet, there was no difference between low and high LF within each respective VAT tertile after adjustment for age, BMI, region and specialty. This pattern was similar when statin use, smoking status, and the presence/absence of type 2 diabetes or cardiovascular disease (CVD) or metabolic syndrome were included. Our results show that CRP is strongly related to visceral adiposity, independent of several other covariates including liver fat. Due to the role of CRP in the prediction and prognosis of CVD, the assessment/management of visceral adiposity, by its surrogate marker waist circumference, will provide clinicians and patients with valuable information regarding an important correlate of this key inflammation marker.