tbuckley/cabot-search huggingface dataset:
SAT0480 How many patients do we really need to enroll in randomized clinical trials of biologic agents for the treatment of rheumatoid arthritis? An analysis of published trials
Authors: S. Celik, Y. Yazici
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Randomized controlled trials (RCT) are designed to answer specific questions using a certain number of patients, determined by sample size calculation. If the calculation is not done properly, more than the needed number of patients may be enrolled, leading to unnecessary exposure for those patients to potentially harmful drugs. In an ideal world, assumptions that go into the calculation of the sample size would be more certain. However in the real world it is not always possible to have ideal calculations and it would be expected that under and over enrolling would be seen in roguishly similar number of RCTs. <h3>Objectives</h3> To determine the actual numbers of patients needed to be enrolled in RA biologic RCT. <h3>Methods</h3> A Pubmed search was conducted, for RCT of abatacept, adalimumab, etanercept, infliximab, rituximab and tocilizumab, in rheumatoid arthritis (RA) patients (n=291). Only original initial studies where the primary outcome was efficacy were analyzed (n=42). Using the final results of the primary outcome, back calculation of the actually needed patients for the trials were calculated and compared to the actual enrollment numbers. <h3>Results</h3> 42 studies were analyzed (infliximab 10, etanercept 7, adalimumab 8, abatacept 7, tocilizumab 5, rituximab 5). Primer efficacy outcome was ACR 20 in 29 studies. ACR 50 in 3 studies, ACR N in 2 studies, DAS-28 in 5 studies, Paulus 20 in 2 studies and reduction of number of swollen/tender joints in 1 study. The mean number of patients enrolled in the treatment arms were 153 and the control arms were 114. After back calculation, the actual needed numbers for the treatment arm was 79 and control arm was 79. According to the recalculated sample size results, there were more patient than required to show differences between groups in 35 studies (83%) and less patients than required in 7 studies. In the 35 studies were more than necessary patients were enrolled had a median of 103 extra patients. <h3>Conclusions</h3> Over 80% of RCT of biologic agents in the treatment of RA had on average 103 patients unnecessarily enrolled. This was a trend seen regardless of agent or how many previous RCT had been done with the same agent. It is an ethical obligation to conduct a RCT with only the necessary number of patients to answer the scientific question that is being asked. Our data suggests that most RCT fall short of this standard. <h3>Disclosure of Interest</h3> S. Celik: None Declared, Y. Yazici Grant/Research support from: Abbott, BMS, Celgene, Genentech, Consultant for: Abbott, BMS, Centocor, Celgene, Pfizer, genentech, UCB, Takeda
Abstract P5-14-08: The Impact of Immediate Breast Reconstruction on Surgical Complications and the Delivery of Adjuvant Chemotherapy
Authors: R Chang, K Kirkpatrick, RH De Boer, GB. Mann
Journal: Cancer Research (2010)

Abstract Introduction: For women undergoing mastectomy immediate breast reconstruction (IBR) offers potential psychological benefits and increased quality of life. This study aimed to answer the question whether IBR might lead to higher complication rates and subsequently delay adjuvant chemotherapy (AdCT). Secondary aims included predictors for complications, and whether patients (pts) with worse tumour prognosis were less likely to undergo IBR. Materials and Methods: Retrospective analysis was performed on 220 pts who underwent mastectomy ± IBR and received AdCT. Results: Comparisons were made between the 107 pts who received IBR and 113 who had mastectomy alone (table 1). Women who were younger with less co-morbidity, lower BMI, and had better prognosis tumours were more likely to receive IBR. No statistically significant difference was found in the overall surgical wound complication rate between the groups. There was more return to surgery in the IBR group, resulting in a 9.8% (12/123) prosthesis loss rate. There was no significant difference in the average time to chemotherapy between the two groups. Conclusion: We found no evidence to suggest that IBR compromised the delivery of adjuvant chemotherapy, although there are significant risks of complications associated with reconstruction. Table 1: Comparison between women who underwent mastectomy alone (no IBR) and women who Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-14-08.
Tc-99m MAG3 Demonstration of Polycystic Kidneys in Tuberous Sclerosis
Authors: VICTOR J. MANSBERG, MONICA A. ROSSLEIGH, I. PROVAN C. MURRAY
Journal: Clinical Nuclear Medicine (1997)

A 17-month-old boy with recurrent seizures from tuberous sclerosis developed respiratory compromise due to compression resulting from rapidly enlarging kidneys. To assess the extent of nephrectomy required to assist respiratory excursion, a Tc-99m MAG3 study was performed. This identified the gross degree of polycystic involvement.
AB1198 IL-18 is a hallmark of juvenile dermatomyositis-associated interstitial pneumonia
Authors: S. Takezaki, Y. Yamazaki, Y. Okura, M. Yamada, I. Kobayashi, T. Ariga
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Dermatomyositis (DM) is an inflammatory disease characterized by weakness in the proximal muscles and pathognomonic skin rash. Although interstitial lung disease (ILD) is a common complication of DM [1] and makes poor prognosis, the etiology of ILD developing in DM (JDM) cases was still unknown. Recent report has demonstrated that serum interleukin (IL)-18 levels are significantly higher in adult patients with DM-associated ILD than those without ILD [2]. On the other hand, complication of ILD is rare and not well characterized in JDM. <h3>Objectives</h3> To evaluate the clinical significance of serum IL-18 levels and other JDM-associated markers in JDM cases with or without ILD. <h3>Methods</h3> 13 JDM patients, 5 with ILD (ILD+) and 8 without ILD (ILD-) followed-up at Hokkaido University Hospital from 1990 to 2008 were enrolled. Sex ratio and the age of onset were not significantly different between both groups. The samples were obtained at diagnosis and remission after treatment. Serum IL-18 levels were measured by Human IL-18 ELISA kit (BML, Nagoya, Japan). Serum neopterin, ferritin and soluble (s) IL-2 receptor (R) levels were also measured. Statistical analyses were performed by Mann-Whitney's U test and Pearson product-moment correlation coefficient. <h3>Results</h3> Serum IL-18 levels at diagnosis were significantly higher (p&lt;0.01) in ILD (+) cases than in ILD (-) cases. Serum levels of neopterin, ferritin and sIL-2R were not significantly different between both groups. No correlation among the tested makers was observed. All of the tested markers were significantly decreased at the inactive phase in both groups. <h3>Conclusions</h3> In JDM-ILD, serum IL-18 levels were significantly high in active phase and decreased with remission, suggesting involvement of innate immunity, particularly of macrophages, in the pathogenesis of ILD. On the other hand, serum levels of neopterin, ferritin and sIL-2R could be affected by the disease severity of JDM itself or other complication such as hemophagocytic syndrome. <h3>References</h3> Feldman BM, Rider LG, Reed AM, Pachman LM. Juvenile dermatomyositis and other idiopathic inflammatory myopathies of childhood. Lancet. 2008 Jun 28;371(9631):2201-12. Gono T, Kawaguchi Y, Sugiura T, Ichida H, Takagi K, Katsumata Y, Hanaoka M, Okamoto Y, Ota Y, Yamanaka H. Interleukin-18 is a key mediator in dermatomyositis: potential contribution to development of interstitial lung disease. Rheumatology (Oxford). 2010 Oct;49(10):1878-81. <h3>Disclosure of Interest</h3> None Declared
Abstract 5243: Gene expression analysis of CRC liver metastases with different growth patterns
Authors: Gert G. Van den Eynden, Michelangelo Fiorentino, Steven S. Van Laere, Dieter S. Peeters, Xuan Bich Trinh, Luc Y. Dirix, Peter B. Vermeulen
Journal: Cancer Research (2011)

Abstract Introduction: Liver metastases of colorectal cancer (CRC) grow according to different growth patterns (GPs) with different angiogenic properties. The aim of this study was to characterize these GPs on a molecular level using genome-wide gene expression analysis. Materials and Methods: On 18 CRC liver metastases of which genome-wide gene expression data were available from a previous study (publicly available at GSE 10961), we assessed the GP using a haematoxylin-eosin and Gordon Sweet's reticulin stain. 7 metastases had a desmoplastic GP, 6 had a pushing GP and 3 had a replacement GP. Of 2 metastases the GP could not be assessed due to lack of sufficient material and these were excluded for further analysis. We used (hierarchical) cluster analysis, principal component analysis, significance/prediction analysis of microarrays and gene set enrichment analysis to study differences in gene expression between the different GPs. Results: Principal component analysis and hierarchical cluster analysis showed significant gene expression differences between metastases with a desmoplastic and pushing GP (p=2.2e−16) and between metastases with a desmoplastic and replacement GP (p=2.2e−16). Gene set enrichment analysis demonstrated increased expression of biological processes, molecular functions, cellular components and KEGG pathways related to immune response, antigen processing, leucocyte activation and cell adhesion molecules in the metastases with a desmoplastic GP. Similar differences were found when metastases with a pushing GP were compared to metastases with a replacement GP and when the 3 groups were compared. Conclusion: These results confirm on a molecular level that liver metastases of patients with CRC have a heterogeneous biology. Metastases with a desmoplastic GP appear to have upregulation of immunological processes, compared to metastases with a pushing or replacement GP. Further elucidation of these differences might lead to better understanding of host-tumour interactions in metastatic biology and new therapeutic strategies for patients with metastatic CRC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5243. doi:10.1158/1538-7445.AM2011-5243
Homeostasis without Reserve — The Risk of Health System Collapse
Authors: Lewis G Sandy
Journal: New England Journal of Medicine (2002)

In this Sounding Board article, the author describes the changes in public policy and in the marketplace that have placed stress on the U.S. health care system over the past decade. The system has showed considerable homeostasis, and its structure has not changed dramatically. The author contends, however, that we have not addressed the underlying problems and that the turbulence of the past 10 years has left our health care system with little reserve and vulnerable to collapse.
Stone Dissolution in Vivo and Control of Cystinuria with D-Penicillamine
Authors: Joseph E. McDonald, Philip H. Henneman
Journal: New England Journal of Medicine (1965)

CYSTINURIA is a hereditary defect in the renal tubular reabsorption of cystine, ornithine, arginine and lysine.1 Because of the relative insolubility of cystine precipitation occurs and stone formation results. Limited therapeutic success has been reported with increased fluid intake,2 alkalinization of the urine3 and dietary restriction of methionine.4 Crawhall et al.5 , 6 recently reported a marked decrease in twenty-four-hour urinary cystine excretion in several patients with cystinuria during brief treatment with penicillamine.§ This report describes the effects of penicillamine therapy in 3 patients with cystinuria, including 1 patient with a large cystine stone.Case ReportsCase 1. P.A.'s 1st renal symptoms . . .
MS-04 * A NOVEL MINIMALLY INVASIVE APPROACH FOR THE RESECTION OF INTRAVENTRICULAR TUMORS
Authors: J. Alzate, R. Young, R. Rovin
Journal: Neuro-Oncology (2014)

The endoscopic management of intraventricular pathology is effective and safe. However, there are limitations to this method including: the size and type of lesion that can be treated, hemostasis and visualization in a fluid medium, and, in particular, the lack of bimanual dexterity. Recently, a minimally invasive integrated systems approach to the subcortical space has been developed that addresses these issues. With this technique, termed Six Pillar, a 15 mm outer diameter cylindrical retractor is inserted through a sulcus to the target along a trajectory specifically planned to minimize disruption of white matter fiber tracts. The authors operated on six intraventricular tumors using this method: two colloid cysts, two subependymomas, one grade two astrocytoma, and one metastatic tumor with intraventricular extension. A gross total resection was achieved for the colloid cysts, the astrocytoma, and one subependymoma. For the metastatic tumor, the intraventricular portion was completely resected. No patient experienced a new postoperative deficit. Historically, approaches to intraventricular abnormalities were transcortical or transcallosal. The endoscope offered less invasive ventricular access but with documented limitations in the published literature such as hemostasis, and management of fibrous and larger lesions. Most importantly, though, is the inability to operate with both hands. The Six Pillar approach does not have these limitations. The operation is conducted through an air medium, improving hemostasis and visualization. Because the inner diameter of the cylindrical retractor is 13 mm, standard bimanual microneurosurgical technique is employed. This means a larger variety of intraventricular pathologies are amenable to surgical resection, not just biopsy. Because advances in imaging permit identification of white matter fiber tracts, safe surgical corridors to the entire ventricular system can be created. The authors conclude that the Six Pillar approach to intraventricular tumors is an important addition to the neurosurgical armamentarium.
A Blinking Knee
Authors: Jeffrey D Lazar, Lucy K Willis
Journal: New England Journal of Medicine (2014)

A 30-year-old woman with no notable medical history presented with a 1-day history of spreading redness, swelling, and blistering of her left leg, possibly due to insect bites during sleep. A video shows Quincke's sign in an area of exuberant dermatitis due to insect bites to the knee.
Abstract 4305: Invasion of primary glioma- and cell line-derived spheroids implanted into corticostriatal slice cultures
Authors: Charlotte Aaberg-Jessen, Annette Norregaard, Karina Garnier Christensen, Stine Skov Jensen, Claus Andersen, Bjarne Winther Kristensen
Journal: Cancer Research (2011)

Abstract Gliomas are known for being highly invasive and therefore incurable by surgery explaining a recurrence rate close to 100%. The aim of the present study was to develop and evaluate an in vivo-like in vitro model preserving the invasive features of glioma cells in order to facilitate research using more true models. This study was performed by implantation of glioma spheroids into organotypic corticostriatal slice cultures. The spheroids chosen for implantation were primary glioma spheroids as well as spheroids derived from the U87 glioblastoma cell line. Primary glioma spheroids are cultured small glioma fragments obtained from freshly removed tumor tissue. In contrast to cell line-derived spheroids, primary glioma spheroids preserve the tumor tissue components and structures such as cell-to-cell interactions, blood vessels and macrophages. In the present study, primary glioma spheroids from one anaplastic astrocytoma (WHO grade III) and two glioblastomas (WHO grade IV) were included in addition to U87 spheroids. The spheroids were labelled with the fluorescent dye DiI and implanted into 400 µm thick corticostriatal slice cultures prepared from newborn rat pups. The tumor cell invasion was followed by confocal microscopy. Hereafter the co-cultures were prepared for anti-human vimentin immunohistochemical staining identifying invasive tumor cells. The results showed that the primary glioma spheroid area was constant after implantation, but there was a clear increase in number of invading cells with time. In contrast, the U87 spheroid area increased after implantation, but there was only relatively few invading cells entering the brain tissue. Anti-human vimentin stained paraffin sections of co-cultures confirmed the tumor cell invasion recorded by confocal microscopy. The present study suggests implantation of primary glioma spheroids into corticostriatal slice cultures as an excellent in-vivo like in-vitro model suitable for studies of invasion. Similar to earlier results obtained in vivo, the U87 cell line, when used in vitro as well, appears to have lost the invasive feature of gliomas, preventing the use of this cell line in studies of invasion. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4305. doi:10.1158/1538-7445.AM2011-4305
Multimodal Somatostatin Receptor Theranostics Using [<sup>64</sup>Cu]Cu-/[<sup>177</sup>Lu]Lu-DOTA-(Tyr<sup>3</sup>)octreotate and AN-238 in a Mouse Pheochromocytoma Model
Authors: Martin Ullrich, Ralf Bergmann, Mirko Peitzsch, Erik F Zenker, Marc Cartellieri, Michael Bachmann, Monika Ehrhart-Bornstein, Norman L Block, Andrew V Schally, Graeme Eisenhofer, Stefan R Bornstein, Jens Pietzsch, Christian G Ziegler
Journal: Theranostics (2016)

Pheochromocytomas and extra-adrenal paragangliomas (PHEO/PGLs) are rare catecholamineproducing chromaffin cell tumors.For metastatic disease, no effective therapy is available.Overexpression of somatostatin type 2 receptors (SSTR2) in PHEO/PGLs promotes interest in applying therapies using somatostatin analogs linked to radionuclides and/or cytotoxic compounds, such as [ 177 Lu]Lu-DOTA-(Tyr 3 )octreotate (DOTATATE) and AN-238.Systematic evaluation of such therapies for the treatment of PHEO/PGLs requires sophisticated animal models.In this study, the mouse pheochromocytoma (MPC)-mCherry allograft model showed high tumor densities of murine SSTR2 (mSSTR2) and high tumor uptake of [ 64 Cu]Cu-DOTATATE.Using tumor sections, we assessed mSSTR2-specific binding of DOTATATE, AN-238, and somatostatin-14.Therapeutic studies showed substantial reduction of tumor growth and tumor-related renal monoamine excretion in tumor-bearing mice after treatment with [ 177 Lu]Lu-DOTATATE compared to AN-238 and doxorubicin.Analyses did not show agonist-dependent receptor downregulation after single mSSTR2-targeting therapies.This study demonstrates that the MPC-mCherry model is a uniquely powerful tool for the preclinical evaluation of SSTR2-targeting theranostic applications in vivo.Our findings highlight the therapeutic potential of somatostatin analogs, especially of [ 177 Lu]Lu-DOTATATE, for the treatment of metastatic PHEO/PGLs.Repeated treatment cycles, fractionated combinations of SSTR2-targeting radionuclide and cytotoxic therapies, and other adjuvant compounds addressing additional mechanisms may further enhance therapeutic outcome.
P5-06-06: The RNA Binding Protein FUS Is a Potential Marker for Breast Cancer Progression and Therapy Response.
Authors: GN Brooke, CL Bevan, B Rudraraju, C Palmieri
Journal: Cancer Research (2011)

Abstract Background The RNA binding protein FUS is a multifunctional protein that has recently been demonstrated to be directed to target genes via non-coding RNA, where it represses transcription via disruption of the transcriptional complex. We have shown that FUS is an important regulator of prostate cancer cell growth; FUS over-expression causes G1 arrest, promotes apoptosis and blocks proliferation in vitro and in vivo, whereas knock-down increases proliferation. This regulation appears to be, at least in part, via direct regulation of cyclin D1. Further, analysis of patient samples demonstrated that FUS levels are inversely correlated with Gleason grade and directly correlated with survival and the presence of bone metastases. We hypothesised that FUS is a predictive and/or prognostic marker for hormone-dependent cancers. Materials and Methods: FUS expression in breast cancer was analysed in silico and using Western blotting and immunohistochemistry on a tumour microarray. FUS levels were knocked down by siRNA in MCF-7 cells and chemosensitivity analysed using caspase 3/7 assays. Results: Analysis of the Finak dataset (2008) demonstrated that FUS expression is significantly lower in breast cancer compared to normal breast. Immunohistochemistry revealed that FUS expression is also inversely correlated with grade. Importantly, FUS expression was also correlated with survival (Kaplan-Meier Plotter); significantly longer relapse free survival was seen in patients whose tumours had high levels of FUS. FUS expression also appears to correlate with therapy response since analysis of the Chang dataset (2003) revealed that FUS levels are significantly lower in patients resistant to Docetaxel and we found FUS levels to be lower in the tamoxifen resistant MCF-7 cell line (MCF-7 TAMR) compared to the parental line. We therefore hypothesised that loss of FUS expression may be driving therapy failure. In support of this, reducing FUS expression in the parental MCF7 line resulted in a significant reduction in docetaxel-induced Caspase 3/7 activity, suggesting that FUS is a regulator of chemosensitivity. Discussion: FUS may be an important regulator of breast cancer progression since its levels are inversely correlated with grade and directly correlated with relapse free survival. Further, lower FUS expression is also correlated with reduced hormone therapy and chemo-sensitivity. Since knock-down of FUS reduced MCF-7 chemosensitivity, we believe that the observed changes in FUS expression are, in part, driving therapy failure and hence propose that FUS is a novel target and biomarker for breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-06-06.
Warfarin Sodium versus Low-Dose Heparin in the Long-Term Treatment of Venous Thrombosis
Authors: Russell Hull, Terry Delmore, Edward Genton, Jack Hirsh, Michael Gent, David Sackett, Dermot McLoughlin, Peter Armstrong
Journal: New England Journal of Medicine (1979)

Acute deep-vein thrombosis is usually treated with intravenous heparin for a number of days, then with oral anticoagulants for weeks to months. We have compared adjusted-dose warfarin sodium with fixed low-dose subcutaneous heparin in the prevention of recurrent deep-vein thrombosis. Sixty-eight patients with acute deep-vein thrombosis confirmed by venography were treated with intravenous heparin and then randomized to secondary prophylaxis. Nine of 35 patients receiving subcutaneous heparin, but none of 33 receiving warfarin sodium, had new episodes of objectively documented venous thromboembolism (P = 0.001). Seven patients on warfarin sodium experienced bleeding complications (of which four were major), as compared with no patients receiving subcutaneous heparin (P less than 0.005). Thus, adjusted-dose warfarin sodium is more effective than low-dose subcutaneous heparin in preventing recurrent venous thromboembolism, but its use is accompanied by a significant risk of bleeding.