tbuckley/cabot-search huggingface dataset:
Tale of 2 Endothelin Receptor Antagonists in Eisenmenger Syndrome
Authors: Dunbar Ivy, Neil Wilson
Journal: Circulation (2018)

Antagonists in Eisenmenger SyndromeIt Was the Best of Times, It Was the Worst of Times Article, see p 51 I n 1897, Dr Victor Eisenmenger described a 32-year-old man with a history of cyanosis beginning as a child.After death from massive hemoptysis, his autopsy showed a large ventricular septal defect.In the 1950s, Wood 1 began to describe the hemodynamic effects of chronic volume and pressure overload leading to the reversal of a central shunt because of irreversible pulmonary vascular obstructive disease.Wood also recognized that Eisenmenger syndrome (ES) develops in patients with large unrestrictive shunt defects, such as a large ventricular septal defect, large patent ductus arteriosus, or atrioventricular septal defect.In the subsequent decades, conservative medical management has led to improved survival.The prevalence of ES is also decreasing because surveillance is more standard and surgical repair is more available.In a Nordic cohort, the incidence of ES decreased from 2.5/million inhabitants/year in 1977 to 0.2/million inhabitants/year in 2012. 2 Further, subclassification of congenital heart defects using the Nice World Symposium of Pulmonary Hypertension criteria has revealed disparate survival between congenital heart disease groups.In general, patients with ES live longer than those patients with fully repaired shunts and postoperative pulmonary arterial hypertension (PAH). 3However, patients with ES remain at risk for progressive disease and death.Treatment with targeted PAH therapy in ES was concerning for lowering systemic vascular resistance relative to pulmonary vascular resistance, leading to increased right to left shunting.One such target is the endothelin pathway.Endothelin is a potent vasoactive peptide discovered in 1988 by Yanagisawa et al. 4 The effects of endothelin are mediated by Endothelin A (ET A ) and Endothelin B (ET B ) receptors.ET A receptors are located on vascular smooth muscle cells and mediate vasoconstriction.ET B receptors are on both endothelial cells and vascular smooth muscle cells.ET B receptors on endothelial cells may lead to the clearance of endothelin and production of nitric oxide, whereas ET B receptors on smooth muscle cells also mediate vasoconstriction.Several targeted therapies have been developed toward the endothelin receptors.In 2001, bosentan, a dual endothelin receptor antagonist, was approved by the US Food and Drug Administration as a treatment for group 1 PAH.The BREATHE-5 study (Bosentan Randomized Trial of Endothelin Antagonist Therapy-5) was the first randomized, double-blind, placebo-controlled, multicenter study completed in patients with ES, with results reported in 2006. 5Fifty-four patients with ES were randomized 2:1 to bosentan or placebo for 16 weeks.Systemic pulse oximetry did not worsen with bosentan.Bosentan reduced pulmonary vascular resistance index and mean pulmonary arterial pressure, and improved exercise capacity.Subsequent observational research suggested that targeted PAH therapy improved survival in ES. 6
Disease-free survival for (neo-)adjuvant trastuzumab: A single-institution experience.
Authors: Yoshihiko Kamada, Nobumitsu Tamaki, Kanou Uehara, Kentaro Tamaki
Journal: Journal of Clinical Oncology (2014)

e11568 Background: Trastuzumab has been approved in Japan for adjuvant use in operable breast cancer since 2008. We review our experience with (neo-) adjuvant trastuzumab use in HER2 over-expressing breast cancer (HER2-BC). Methods: We reviewed the medical records of primary breast cancer patients operated in our institute for disease free survival, who presented with HER2-BC as determined by the HercepTest or FISH. We divided them into patients presenting with no positive axillary nodes (group A), one to three positive nodes (group B), and 4 or more positive nodes (group C). These were further divided into patients who received (neo-) adjuvant chemotherapy without trastuzumab (groups A-1, B-1, C-1), patients who received (neo-) adjuvant chemotherapy with trastuzumab (groups A-2, B-2, C-2), and patients who received no (neo-) adjuvant chemotherapy (groups A-3, B-3, C-3). Results: From April 2004 to September 2013, there were 244 patients who presented with HER2-BC. The number of cases and average observation period for each of the above groups were group A-1:46 cases/120.4 months, group A-2:69 cases/63.6 mo., group A-3:40 cases/121.3 mo., group B-1:25 cases/104.4 mo., group B-2:25 cases/88.4 mo., group B-3:3 cases/49.2 mo., group C-1:23 cases/52.3 mo., group C-2:12 cases/57.5 mo., group C-3:0 cases. Disease free survival (DFS) was significantly longer for group A-2 versus A-1 (Logrank p<0.001), and for group A-2 versus A-3 (Logrank p<0.5). Also DFS was longer for A-3 versus A-1 (p<0.001). The DFS for group B-2 was longer than B-1, but this was not statistically significant (p=0.079). There was no difference of DFS between groups C-2 and C-1 (p=0.167). Conclusions: The beneficial effect of trastuzumab added to (neo-) adjuvant chemotherapy is clearly seen in early axillary node negative cases. It was seen that chemotherapy can be totally omitted in certain cases with good results. With longer follow up, the beneficial effect of trastuzumab will probably be shown in slightly advanced cases with one to three positive axillary nodes. Trastuzumab does not seem to benefit cases with advanced disease (i.e. cases presenting with 4 or more positive axillary nodes) in terms of DFS, and the incorporation of newer anti-HER2 agents seems necessary.
Correlation of intratumoral metabolic changes measured with 18F-FDG PET parametric response maps with concentrations of CC-223, a TORC 1/2 kinase inhibitor, in human glioblastoma.
Authors: Benjamin M. Ellingson, Timothy Francis Cloughesy, Pamela N. Munster, Kent C. Shih, Johanna C. Bendell, Angela James, Zeen Tong, Torsten Trowe, Rajesh Chopra, Kristen Hege
Journal: Journal of Clinical Oncology (2014)

2609 Background: CC-223 is a potent selective inhibitor of mTOR kinase. Through inhibition of TORC1, TOR kinase inhibitors may result in down regulation of genes involved in glucose metabolism. A decrement in 18F-FDG PET uptake might represent early response of mTOR kinase inhibition. PET parametric response maps (PRMs) are a new technique involving voxel-by-voxel quantification of changes in PET uptake before and after therapy. This study explored relationships between intratumoral metabolic changes with PET PRMs, intratumoral and plasma drug concentration in a Phase I, surgical dose-expansion study in GBM. Methods: Eight evaluable patients with recurrent GBM received CC-223 daily for 15±7days before planned salvage tumor resection. Tumor and plasma samples were obtained at surgery. MRI and 18F-FDG PET scans were obtained prior and after CC-223treatment. MRI and FDG standard uptake value (SUV) maps were aligned to baseline images. Voxel-wise percentage change and volume of changing FDG uptake in enhancing tumor was correlated with intratumoral and plasma measures of CC-223. Results: A positive linear correlation was found between tumor volume with decreasing FDG SUV and CC-223 concentration within resected tumor (R2=0.63, P=0.02), suggesting a higher penetration of CC-223 results in a larger decrease in FDG metabolism within tumor. The volume of tumor with increasing FDG SUV correlated with maximum CC-223 plasma concentration (R2=0.52, P=0.04), suggesting that lower plasma CC-223 concentration may result in a higher volume of growing tumor. There was a negative trend between the proportion of enhancing tumor with increasing FDG SUV and maximum CC-223 concentration in tumor (R2=0.39, P=0.1), suggesting more drug penetration results in a lower proportion of tumor with increasing metabolic activity. Results are preliminary based on a sparse sample size. Conclusions: The volume and proportion of tumor with changing FDG uptake may correlate with plasma and intratumoral CC-223 concentration, suggesting FDG PET PRMs may provide non-invasive insight into CC-223 brain penetration and changes in intratumoral metabolic activity.
Validation of patient-derived xenografts and histocultures as preclinical models of melanoma.
Authors: Samia Mourah, Mariana Varna, Aurelie Sadoux, Marie Pierre Podgorniak, Cécile Pagès, Geoffroy Leclert, Jean soULIER, Jean Paul Feugeas, Anne Janin, Celeste Lebbe
Journal: Journal of Clinical Oncology (2014)

e20013 Background: The goal of personalized medicine is to improve our understanding of the disease at the molecular level in order to optimize the therapeutic management. In addition, the biomarker response is evolving with developments in molecular pharmacodynamic. In this context, we have developed a preclinical strategy (in vivo and ex vivo) evaluating from human melanoma the efficacy of innovative drugs, with a comprehensive analysis of biomarkers of response. Methods: Human melanoma (n = 21) of different genotypes (mutated BRAF, NRAS, and amplified cKIT and
Development of hepatocellular carcinoma as a second primary cancer in hepatitis C virus-infected patients with a different primary malignancy.
Authors: Parag Mahale, Ahmed Omar Kaseb, Manal Hassan, Boris Blechacz, Andreas Kyvernitakis, Harrys A. Torres
Journal: Journal of Clinical Oncology (2014)

e15092 Background: Hepatitis C virus (HCV)-infected patients (pts) are at increased risk of developing hepatocellular carcinoma (HCC). Approximately 7% of HCV-infected pts with non-liver primary malignancy developed HCC as second primary cancer (SPC). However, predictors for development of HCC as SPC in HCV-infected pts with a different primary malignancy have not been studied. Methods: Records of cancer pts seen at MD Anderson Cancer Center, Houston, between 2008 - 2011 were reviewed. Controls (HCV-infected cancer pts with non-liver primary who did not develop HCC as SPC) were matched 1:1 to cases (HCV-infected cancer pts who developed HCC as SPC) on cirrhosis status and age. HCV therapy did not include new antivirals. Results: Thirty two pts developed HCC as SPC; most were men (75%), whites (63%), with solid first primary malignancies (81%), and genotype 1 infection (77%). All pts had cirrhosis. HCC as SPC was found incidentally in most (75%) pts. Surgery (69%) and chemotherapy (34%) were main treatment modalities for first primary malignancies. Most common chemotherapeutic agents administered were targeted therapies (55%). Twenty four (75%) pts received HCV treatment; only 2 pts achieved sustained virologic response (SVR), regarded as cure. Seventeen matched case-control pairs were analyzed. Compared to controls, more cases had underlying primary solid tumors (82% vs 47%; P=0.07), but fewer cases received chemotherapy (29% vs 76%; P=0.01) and achieved SVR (29% vs 65%; P=0.05). There were no significant differences between groups with respect to race, hepatitis B co-infection, family history of HCC, steatohepatitis, diabetes mellitus, alcohol abuse, obesity, or baseline Child-Pugh score. Conclusions: HCC can develop as SPC in HCV-infected patients with a different primary malignancy, especially in patients who have primary solid tumors or failed antiviral therapy. Therefore, surveillance for HCC in such patients should be continued as recommended in other HCV-infected patients. Treatment with newer and more efficacious antivirals may reduce the risk of HCC development as SPC.
SAT0485 What is the effect of cyclophosphamide iv pulse therapy in patients with diffuse cutaneous systemic sclerosis on skin involvement: an observational study
Authors: B. Kersten, N. den Broeder, F. van den Hoogen, E. van den Ende, M. Vonk
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Patients with systemic sclerosis who have proximal skin involvement are classified as diffuse cutaneous systemic sclerosis (DcSSc). Patients with progressive skin involvement have worse prognosis due to internal organ involvement. Treatment options of these patients consist among others of cyclophosphamide iv pulse therapy (iv CYC).<sup>1</sup> Recent studies show significant improvement of skin thickening in patients treated with CYC orally,<sup>2</sup> but the effect of iv CYC on skin involvement remains unclear. <h3>Objectives</h3> To examine the extent of skin involvement during 12 monthly iv CYC (750 mg/m<sup>2</sup>) in DcSSc and to identify factors that predict response to therapy. <h3>Methods</h3> Patients with DcSSc receiving iv CYC between 2004 and 2016 were included if they received at least 6 pulses. Skin involvement was accessed with the modified Rodnan Skinscore (mRSS) at baseline, month 6, 12, 24 and 36 by the same trained rheumatologist as part of routine care. Data of patients with the baseline measurement and at least one follow up measurement were included in the study. Missing mRSS data were imputed using multiple imputation by chained equation. Patients were classified as responders if the mRSS decreased at least 5 points and 25% from baseline at month 12. A prediction model for response at 12 months was created using backwards logistic regression considering baseline variables and response at 6 months as possible predictors. <h3>Results</h3> A total of 99 patients were included. The mean improvement of mRSS over time was −4.05 (95% CI −5.53 to −2.55) (figure 1). 43% of patients had a response according to the response criteria. In univariate prediction models, baseline mRSS (OR 1.06, p=0.024), response at 6 months (OR: 37.45, p&lt;0.001) and completed treatment (yes/no) (OR: 4.108, p=0.033), were significant predictors of response at 12 months. For the last variable it should be mentioned that some patients who did not achieve a response at month 6 did not continue iv CYC for that reason. <h3>Conclusions</h3> This study shows that only 43% of the treated DcSSc patients experienced clinical important improvement of skin involvement following iv CYC. Response at month 6 is the best predictor for response on month 12. This could imply that at this time point, counselling about other available treatment options, should be considered in those patients. <h3>References</h3> [1] Kowal-Bielecka O, et al. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Annals of the rheumatic diseases2009;68(5):620–8. [2] Namas R, et al. Efficacy of mycophenolate mofetil and oral cyclophosphamide on skin thickness: Post-hoc analyses from the Scleroderma Lung Study I and II. Arthritis care &amp; research2017. <h3>Disclosure of Interest</h3> None declared
Abstract 21087: Coronary Reperfusion Ameliorates the Deleterious Effect of Mechanical Unloading on Infarct Size and Interstitial Fibrosis After Acute Myocardial Infarction
Authors: Sean O Bello, Charanjit Singh, Prakash Punjabi, Filippo Perbellini, Cesare Terracciano
Journal: Circulation (2017)

Background: Contemporary studies show that myocardial fibrosis worsens after mechanical unloading with left ventricular assist devices (LVADs). The exact mechanism underlying this phenomenon remains unknown. Mechanical unloading has however been associated with a reduction in microvascular lumenal diameter in the failing heart, suggesting a link with negative auto-regulatory effects on the collateral circulation. We hypothesise that coronary reperfusion after myocardial infarction ameliorates the deleterious effect of mechanical unloading on infarct size and interstitial fibrosis. Methods: Syngeneic male Lewis rats weighing 200 to 300g were studied. Myocardial infarction – acute (AMI) and chronic (CMI) - was induced by LAD ligation. Two groups were generated: a permanent ligation group (AMI and CMI) and a reperfusion - coronary circulation restored after 90 minutes - group (AMI/R and CMI/R). In each group hearts were either loaded (L) or unloaded (U). In the loaded subgroup, rats were recovered after coronary ligation. In the unloaded subgroup, the infarcted hearts were explanted after 90 minutes and transplanted into the abdomen of healthy recipients via heterotopic abdominal heart transplantation. Hearts were explanted on day 2, day 7, and 16wks. The recipient’s heart acted as control. Histological analysis and western blotting for αSMA and TGF-β1 (markers of fibrosis) were completed. Results: Ninety rats were studied. There was a significant increase in infarct ratio (IR) - infarct size/area at risk-, and interstitial fibrosis (IF) after mechanical unloading in the permanent ligation group at day 2 (AMI-L vs AMI-U p = 0.0073 (IR) and p = 0.0012 (IF)) and day 7 (AMI-L vs AMI-U p = 0.0166 (IR) and p = 0.0363 (IF)). After coronary reperfusion, there was no increase in IR or IF with mechanical unloading. At 16wks however, this protective effect of reperfusion was lost (CMI/R-L vs CMI/R-U p = 0.004 (IR) and p = 0.0024 (IF)). The expression profiles of αSMA and TGF-β1 correlated with the results above. Conclusion: These data suggest an association between the revascularisation of a less auto-regulated vessel and amelioration of the deleterious effect of mechanical unloading on the extracellular matrix with implications for LVAD induced recovery.
Chronic inflammation deteriorates structure and function of collagen fibril in rat temporomandibular joint disc
Authors: Sheng-Jie Cui, Yu Fu, Yan Liu, Xiao-Xing Kou, Jie-Ni Zhang, Ye-Hua Gan, Yan-Heng Zhou, Xue-Dong Wang
Journal: International Journal of Oral Science (2019)

Collagen is the building component of temporomandibular joint (TMJ) discs and is often affected by inflammation in temporomandibular disorders. The macromechanical properties of collagen are deteriorated by chronic inflammation. However, the mechanism by which inflammation influences disc function remains unknown. The relationship between the ultrastructure and nanomechanical properties of collagen in inflamed discs should be clarified. Seven-week-old female Sprague–Dawley rats were randomly divided into two groups. Chronic TMJ inflammation was induced by intra-articular injection of complete Freund's adjuvant, and samples were harvested after 5 weeks. Picrosirius staining revealed multiple colours under polarized light, which represented alternative collagen bundles in inflamed discs. Using atomic force microscopy scanning, the magnitude of Young's modulus was reduced significantly accompanied with disordered collagen fibril arrangement with porous architecture of inflamed discs. Transmission electron microscopy scanning revealed a non-uniform distribution of collagen fibres, and oversized collagen fibrils were observed in inflamed discs. Fourier transform infrared microspectroscopy revealed a decrease in 1 338 cm−1/amide II area ratio of collagen in different regions. The peak positions of amide I and amide II bands were altered in inflamed discs, indicating collagen unfolding. Our results suggest that sustained inflammation deteriorates collagen structures, resulting in the deterioration of the ultrastructure and nanomechanical properties of rat TMJ discs. Chronic inflammation damages the collagen disk that cushions the temporomandibular joint (TMJ) of the jaw, contributing to jaw disorders. Although chronic inflammation is known to harm collagen, its effects on TMJ disks were unclear. Xue-Dong Wang and Yan-Heng Zhou and coworkers at the Peking University School and Hospital of Stomatology in Beijing used advanced imaging technologies to investigate how inflammation affects TMJ collagen in rats. In TMJ disks, collagen is composed of long, intertwined threads called fibrils. Inflammation damaged the collagen's chemical structure, preventing correct winding, and resulting in oversized and unevenly arranged fibrils. The TMJ disks were overly porous, with poor elasticity. The researchers hypothesize that these changes thicken and deform TMJ disks, leading to disk displacement and jaw disorders. Further studies are needed to determine whether anti-inflammatory treatments can protect TMJ collagen.
Development and validation of a gene expression signature to distinguish malignant melanoma from benign nevi.
Authors: Colleen Rock, Loren E Clarke, M. Bryan Warf, Darl D Flake, Anne-Renee Hartman, Steven Tahan, Christopher R Shea, Pedram Gerami, Jane Messina, Richard J. Wenstrup, Kristen Rushton, Kirstin M Roundy, Benjamin Roa, Kathryn A Kolquist, Alexander Gutin, Steven D Billings, Sancy Ann Leachman
Journal: Journal of Clinical Oncology (2014)

9021 Background: Histopathologic distinction between benign and malignant melanocytic tumors can be unreliable and may lead to misdiagnosis. Measurement of biomarker gene expression has been proposed as an adjunctive diagnostic method in the evaluation of ambiguous melanocytic lesions with uncertain malignant potential. This study aimed to develop and validate a gene signature capable of accurately differentiating malignant melanoma and benign nevi. Methods: Seventy-nine candidate genes were identified based on expression changes previously observed in melanoma or other cancer types. RNA expression in five 5-μm recut sections from FFPE skin biopsy specimens was measured by qRT-PCR. The panel was refined to 40 genes based on the ability of each gene to differentiate benign from malignant lesions (AUC >70%). Expression of this refined panel was measured in 464 melanocytic lesions and forward selection in a logistic regression model was used to finalize the signature. By applying a weighting algorithm and threshold value to the expression data, the signature was translated into a numeric score capable of classifying melanocytic lesions as benign or malignant. Performance of the assay was clinically validated in a second cohort of 437 melanocytic lesions representing a spectrum of histopathologic types. Results: Using the 464 case cohort, a final signature of 23 genes was identified, consisting of 13 genes involved in immune signaling and cell differentiation and 9 housekeeping genes. In the second cohort of 437 lesions, the signature was validated to differentiate benign nevi from malignant melanoma with a sensitivity of 90% and a specificity of 91%. Conclusions: The predominance of genes that regulate melanocyte differentiation and immune response in the final signature indicates that these pathways represent critical differences between benign and malignant melanocytic lesions. The performance, objectivity, reliability, and minimal tissue requirements of this diagnostic test make it well-suited for clinical use as an adjunct to histopathology. Integration of this assay into current practice has the potential to enhance patient care through more definitive diagnoses of melanocytic lesions.