tbuckley/cabot-search huggingface dataset:
Concomitant and adjuvant androgen deprivation (ADT) with external beam irradiation (RT) for locally advanced prostate cancer: 6 months versus 3 years ADT—Results of the randomized EORTC Phase III trial 22961
Authors: M. Bolla, G. van Tienhoven, T. M. de Reijke, A. C. van den Bergh, A. P. van der Meijden, P. M. Poortmans, E. Gez, P. Kil, M. Piérart, L. Collette
Journal: Journal of Clinical Oncology (2007)

5014 Background: After EORTC trial 22863, 3 years of endocrine treatment has become standard adjuvant treatment to RT for locally advanced prostate cancer. EORTC 22961 tests if similar survival can be achieved in patients who underwent EBRT (to 70 Gy) and 6 months of combined ADT without further ADT (SADT arm) as in patients with 2.5 years of further treatment with luteinizing hormone-releasing hormone agonist monotherapy (LADT arm). Methods: Eligible patients had T1c-2b N1–2 or pN1–2, or T2c-4 N0–2 (UICC 1992) M0 prostate cancer with PSA &lt;150ng/ml. Non-inferior survival was defined as a morality hazard ratio (HR) = 1.35 for SADT vs LADT. Non inferiority at 80% power and 1-sided a=0.05 required 275 deaths. A stopping boundary was applied at 1-sided a=0.018. Results: 970 patients were randomized (483 SADT and 487 LADT). At 5.2 years median follow-up, 173 patients had died (100 vs 73). An Independent Data Monitoring Committee recommended disclosure of results based on an interim analysis showing futility. Patient characteristics were well balanced: median age 69 years, WHO PS 0 in 83.4%, most patients had T2c-T3 N0 disease. Progression (mostly biochemical and/or bone progression) occurred in 220 cases (159 on SADT vs 61 on LADT) and was treated by secondary hormonal manipulation. The 5-year overall survival rate was 85.3% on LADT and 80.6% on SADT (HR=1.43, 96.4% CI: 1.04–1.98), and failed to prove non-inferiority. The 5-year clinical progression-free survival rate was 81.8% on LADT versus 68.9% on SADT arm and the 5-year biochemical progression-free survival rate was 78.3% on LADT versus 58.9% on SADT, indicating inferiority of SADT with HR=1.93 and HR=2.29, respectively. Conclusions: The study was designed to demonstrate non-inferior survival with 6 months ADT compared to 3 years adjuvant ADT after irradiation for patients with locally advanced prostate cancer, but observed survival data indicate that non-inferiority cannot be confirmed. Progression-free survival was also shorter on SADT. No significant financial relationships to disclose.
The margins effect: Residual tumor after breast conserving surgery
Authors: A. Meirovitz, H. S. Rennert, T. Peretz, A. Salmon, G. Rennert
Journal: Journal of Clinical Oncology (2007)

11045 Background: Resection of breast cancer with good surgical margins is one of the fundamental aspects of breast conserving surgery. Most studies have shown that women with positive margins after breast conserving surgery (BCS) fared worse compared to those with negative margins, regardless of chemotherapy or radiation therapy. Nowadays, when partial breast irradiation is gaining popularity, understanding the natural history of positive or close margins is particularly important. We studied the surgical process in a large cohort of Israeli women with breast cancer to estimate the frequency of tumor margin involvement in the primary and subsequent surgical procedure. Methods: The National Israeli Breast Cancer Detection Programs has been monitoring the detection process of all new cases of breast cancer in Israel since 1996. Full data on tumor histology and surgical procedures, including indication of margins in the pathology report were available for 16,925 malignant breast tumors. Margins were classified as positive margins (PM), close (= 2mm) (CM) or negative margins (greater then 2mm)(NM). Results: BCS was identified in 14,815 women with invasive cancer and 2,110 with pure ductal carcinoma in situ (DCIS). Only 7,751 (52.3%) of the 14,815 women with invasive cancer had NM, while 2,868 (19.4%) had CM and 4,196 (28.3%) had PM. Among those with PM, 2,276 (54.6%) had a re-operation within 6 months from the index surgery and 1,265 (55.6%) of them were found to be malignant; 58% of them were invasive cancers and 42% DCIS. Among the invasives on re-operation, 24.4% still had PM and another 12.1% had CM while among the DCIS 14.4% had PM and 17.6% had CM. Of the 717 women with DCIS and positive margins at first surgery, 67.9% had a second operation. Of them, 59.8% had malignancy, 8.8% of them invasive. Overall 10.6% of all invasive cancers and 3.7% of all DCIS had PM on relumpectomy within 6 month regardless of initial margin status. Conclusions: A relatively high proportion of all women undergoing BCS were found to have positive or close margins, even after re-operations. If a failure to reach clean margins is a reflection of an aggressive tumor phenotype, special attention should be given to these patients and treatment should be adjusted accordingly. No significant financial relationships to disclose.
A7.08 Novel agents for blocking the interaction of immune complexes with the activatory FCγRIIIA receptor
Authors: EW Baxter, JI Robinson, DC Tomlinson, RJ Foster, RL Owen, SJ Win, JE Nettleship, C Tiede, J Kankanala, RJ Owens, CWG Fishwick, MJ McPherson, AW Morgan
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background and objectives</h3> Protein-protein interactions are essential for the control of cellular functions and critical for regulation of the immune system. One example is the binding of Fc regions of Immunoglobulin G to their receptors (Fcγ&nbsp;Receptors). High sequence identity (98%) between the genes encoding FcγRIIIa and FcγRIIIb has led to the lack of specific agents against this important therapeutic target. We aimed to develop a novel drug development pipeline using artificial binding proteins called Adhirons both for the identification of novel therapeutics and to guide drug discovery through the identification of novel hot spots/ druggable surfaces on the receptor. <h3>Materials and methods</h3> We cloned sequences encoding full-length FcγRIIa, FcγRIIIa and FcγRIIIb into expression vectors and created stably transfected HEK293 cells expressing each receptor. We also transiently transfected vectors encoding each ectodomain and the resulting proteins were purified. The FcγRIIIa ectodomain was used as a target for screening an Adhiron library using ‘phage display. High affinity binders were used in cellular and biophysical assays (including Surface Plasmon Resonance (SPR) and X-ray crystallography). <h3>Results</h3> Here we report the identification of FcγRIIIa-specific Adhirons. SPR experiments showed the selected Adhirons bind FcγRIIIa, but not FcγRIIa. We have demonstrated selective Adhiron blockade of IgG binding to FcγRIIIa, but not FcγRIIa or FcγRIIIb, by carrying out FACs assays in HEK293T cells ectopically expressing individual FcγRs. We also show blockade of effector functions downstream of FcγRIIIa signalling in THP-1-derived macrophage cells: these functions include immune complex-induced TNF release and phagocytosis. Co-crystal structures show one Adhiron binding directly to the Fc binding site whereas two others act as allosteric inhibitors. The structural basis for the specificity of the direct binder has been defined. <h3>Conclusions</h3> The results suggest that Adhirons can be developed to inhibit protein-protein interactions that were previously considered to be “undruggable”. Adhirons that inhibit the activatory FcγRIIIa (expressed on macrophages) but not FcγRIIIb (expressed on neutrophils), have been identified. This level of specificity has not been achieved using more conventional monoclonal antibody-based technology. Furthermore, the allosteric binders highlight a novel FcγRIIIa ‘hot spot’, which could be used in more conventional computational-based Medicinal Chemistry design tools. Topic: Novel Therapeutics
Lung exposure to lipopolysaccharide causes atherosclerotic plaque destabilisation
Authors: Jen Erh Jaw, Masashi Tsuruta, Yeni Oh, John Schipilow, Yuki Hirano, David A. Ngan, Koichi Suda, Yuexin Li, Jin Young Oh, Konosuke Moritani, Sheena Tam, Nancy Ford, Stephan van Eeden, Joanne L. Wright, S.F. Paul Man, Don D. Sin
Journal: European Respiratory Journal (2016)

Epidemiological studies have implicated lung inflammation as a risk factor for acute cardiovascular events, but the underlying mechanisms linking lung injury with cardiovascular events are largely unknown.Our objective was to develop a novel murine model of acute atheromatous plaque rupture related to lung inflammation and to investigate the role of neutrophils in this process.Lipopolysaccharide (LPS; 3 mg·kg(-1)) or saline (control) was instilled directly into the lungs of male apolipoprotein E-null C57BL/6J mice following 8 weeks of a Western-type diet. 24 h later, atheromas in the right brachiocephalic trunk were assessed for stability ex vivo using high-resolution optical projection tomography and histology. 68% of LPS-exposed mice developed vulnerable plaques, characterised by intraplaque haemorrhage and thrombus, versus 12% of saline-exposed mice (p=0.0004). Plaque instability was detectable as early as 8 h post-intratracheal LPS instillation, but not with intraperitoneal instillation. Depletion of circulating neutrophils attenuated plaque rupture.We have established a novel plaque rupture model related to lung injury induced by intratracheal exposure to LPS. In this model, neutrophils play an important role in both lung inflammation and plaque rupture. This model could be useful for screening therapeutic targets to prevent acute vascular events related to lung inflammation.
A phase I trial of nordihydroguareacetic acid (NDGA) in patients with non-metastatic prostate cancer and rising PSA
Authors: A. L. Harzstark, C. Ryan, M. Diamond, J. Jones, M. Zavodovskaya, B. Maddux, C. Claros, I. Goldfine, E. J. Small
Journal: Journal of Clinical Oncology (2007)

15500 Background: NDGA is a butanediol with effects on tumor cells, including inhibition of insulin growth factor receptor (IGF-1R) autophosphorylation. In vitro studies suggest that NDGA attenuates androgen-mediated prostate cancer growth without competitive androgen receptor blockade. Its effects on PSA in pts were studied. Methods: Eligible pts included men with recurrent prostate cancer following definitive local therapy with a rising PSA and no metastasis. Both androgen dependent prostate cancer (PSA rising with a normal tesosterone - ADPC) and androgen independent prostate cancer (PSA rising with castrate level of testosterone - AIPC) was allowed. Treatment consisted of continuous oral daily dosing of NDGA according to a planned dose escalation of 750, 1,250, 1,750, 2,250 and 2,500 mg. Pts were followed for safety and changes in PSA and PSA doubling time (PSADT). Results: 15 pts were enrolled: 11 pts with ADPC and 4 pts with AIPC. Median baseline serum PSA was 3.6 ng/mL in ADPC pts and 5.74 mg/mL in AIPC pts. Median age was 66 (range 48–81). Following a median of 5.5 cycles (range 1–13), transaminase elevations occurred in five pts (33%): 1 gr 1, 1 gr 2 and 3 gr 3- all occurring in month 3 or later. Transaminase elevations resolved after drug discontinuation but recurred with repeated dosing. Doses up to 2,500 mg/day were otherwise well- tolerated. The median baseline PSADT was 6.1 months for ADPC and 6.7 months for AIPC and was and 8.4 months on therapy (p=0.12) for ADPC and 4.2 months for AIPC. Of 11 ADPC pts, one (9%) had a decline in PSA by &gt;50% compared to baseline and one (9%) had a decline of 3 fold increase in PSADT while on therapy, one from 11 to 46 months (750 mg), one from 9.5 to 49.5 months (1,750 mg), and one from 5.9 to 46.2 months (2,500 mg). There were no PSA reductions in the AIPC pts, however one pt had a &gt;3 fold increase in PSADT (from 1.4 to 7.5 months). No significant effects on testosterone, adrenal androgen or estradiol levels were observed while on study. Conclusions: NDGA is well tolerated with the exception of transaminase elevations which occur after approximately 3 cycles in a minority of patients. Combined with preclinical data, the modest effects on PSA kinetics suggest that further study on androgen dependent tumors is justified. No significant financial relationships to disclose.
Adaptive immunity in the liver
Authors: Zongwen Shuai, Miranda WY Leung, Xiaosong He, Weici Zhang, Guoxiang Yang, Patrick SC Leung, M Eric Gershwin
Journal: Cellular and Molecular Immunology (2016)

The anatomical architecture of the human liver and the diversity of its immune components endow the liver with its physiological function of immune competence. Adaptive immunity is a major arm of the immune system that is organized in a highly specialized and systematic manner, thus providing long-lasting protection with immunological memory. Adaptive immunity consists of humoral immunity and cellular immunity. Cellular immunity is known to have a crucial role in controlling infection, cancer and autoimmune disorders in the liver. In this article, we will focus on hepatic virus infections, hepatocellular carcinoma and autoimmune disorders as examples to illustrate the current understanding of the contribution of T cells to cellular immunity in these maladies. Cellular immune suppression is primarily responsible for chronic viral infections and cancer. However, an uncontrolled auto-reactive immune response accounts for autoimmunity. Consequently, these immune abnormalities are ascribed to the quantitative and functional changes in adaptive immune cells and their subsets, innate immunocytes, chemokines, cytokines and various surface receptors on immune cells. A greater understanding of the complex orchestration of the hepatic adaptive immune regulators during homeostasis and immune competence are much needed to identify relevant targets for clinical intervention to treat immunological disorders in the liver.
Novel endoscopic management of a pancreatico-biliary limb obstruction by the creation of an entero-enterostomy following Roux-en-Y gastric bypass
Authors: Chin Lim, Sayeed Ikramuddin, Daniel Leslie, Mustafa Arain, Stuart Amateau
Journal: Endoscopy (2016)

Pancreatico-biliary or bilio-pancreatic limb obstruction is a rare but serious complication of Roux-en-Y gastric bypass (RYGB). This is characterized by an obstruction proximal to the jejuno-jejunostomy anastomosis resulting in back pressure of the pancreatico-biliary limb and remnant stomach with a potential for necrosis and perforation of the stomach, duodenum, and jejunum [1]. To our knowledge, the only reported treatment is surgical correction of the underlying cause.
Phase II Randomized Study Of Lenalidomide Or Lenalidomide and Rituximab As Maintenance Therapy Following Standard Chemotherapy For Patients With Intermediate-High/High Risk Diffuse Large B-Cell Lymphoma (DLBCL)
Authors: Nishitha M. Reddy, David S. Morgan, Steven I. Park, John P Greer, Kristy L. Richards
Journal: Blood (2013)
Abstract 9668: Comprehensive Analysis of Intravascular Ultrasonic and Angiographic Morphology of Culprit Lesions Between ST-Segment Elevation Myocardial Infarction and Non-ST-Segment Elevation Acute Coronary Syndrome
Authors: Naoko Takaoka, Kenichi Tsujita, Koichi Kaikita, Seiji Hokimoto, Michio Mizobe, Masahide Nagano, Naoki Nakayama, Eiji Horio, Koji Sato, Hiromi Yoshimura, Sunao Kojima, Shinji Tayama, Seigo Sugiyama, Sunao Nakamura, Hisao Ogawa
Journal: Circulation (2012)

Background: Rupture of vulnerable plaque is a major cause of acute coronary syndrome (ACS), with some clots being partially or totally occlusive. However, it is not clear why some plaque ruptures lead to ST-segment elevation myocardial infarction (STEMI), whereas others cause non-ST-segment elevation ACS (NSTEACS). Methods: A consecutive 158 ACS pts whose culprit lesions imaged by preintervention intravascular ultrasound (IVUS) were enrolled (STEMI=81; NSTEACS=77). IVUS and angiographic findings of culprit lesions, and clinical demographics were compared between the groups. Results: Pts’ characteristics were identical except lower rate of prior statin use in pts with STEMI (20% vs 44%, p=0.001). Angiographic complex Ambrose lesion and thrombus were more common in STEMI than in NSTEACS (83% vs 62%, p=0.002; 51% vs 5%, p&lt;0.0001, respectively). In contrast, SYNTAX score was lower in STEMI (9±5 vs 12±7, p=0.01). In pts with STEMI, culprit echogenicity on IVUS was more hypoechoic (63% vs 40%, p=0.01), and the incidence of plaque rupture, attenuation and “microcalcification (granular calcification with attenuation)” were higher (53% vs 18%, p&lt;0.0001; 86% vs 68%, p=0.01; 75% vs 61%, p=0.04, respectively). Further, the max area of ruptured cavity, echo lucent zone and arc of microcalcification were significantly greater in STEMI compared with NSTEACS (1.8±1.0mm 2 vs 1.1±0.9mm 2 , p=0.006; 1.5±0.7mm 2 vs 1.2±0.8mm 2 , p=0.004; 100±55° vs 77±51°, p=0.01, respectively). On quantitative and color-coded IVUS, vessel and plaque area were significantly larger at min lumen area (MLA) site in STEMI (16.6±5.4mm 2 vs 14.2±5.5mm 2 , p=0.003; 13.9±5.1mm 2 vs 11.6±5.2mm 2 , p=0.003, respectively) and at max vessel area site (20.2±5.4mm 2 vs 18.0±6.4mm 2 , p=0.007; 13.7±4.1mm 2 vs 12.2±5.6mm 2 , p=0.02, respectively), leading to larger necrotic (6.8±3.8mm 2 vs 4.8±3.9mm 2 , p=0.04) and lipidic (1.5±0.6mm 2 vs 1.1±0.6mm 2 , p=0.02) tissue area at MLA site in STEMI as well as fibrotic tissue (7.3±2.5mm 2 vs 5.7±2.2mm 2 , p=0.03). Conclusion: Morphological feature (outward vessel remodeling and IVUS vulnerability [e.g. greater ruptured cavity, larger necrotic and lipidic tissue, and microcalcification]) of culprit lesions might relate to clinical presentation of pts with ACS.
Diagnosis and Treatment of Chordoma
Authors: Brian J Williams, Daniel M S Raper, Erin Godbout, T David Bourne, Daniel M Prevedello, Amin B Kassam, Deric M Park
Journal: Journal of the National Comprehensive Cancer Network (2013)

Chordoma is a primary bone cancer arising on the midline from the skull base to the sacrum. Diagnosis is often delayed because of insidious onset and nonspecific symptoms. Chordomas appear histologically low-grade but are highly invasive and often recur locally. Management centers primarily on radical en bloc surgical resection when possible. Radiation therapy using protons and/or photons is often necessary because complete resection is seldom possible due to critical location and invasion of the cancer cells into surrounding structures. No approved medical therapy exists. The high rate of recurrence is reflected by a median survival of 6 to 7 years. This article reviews the clinical management of chordoma and discusses ongoing research in the field.
Infection and Transformation of Dog Cells With a Modified Sarcoma Virus
Authors: A. L. Chapman, Peter J. Fischinger, Timothy E. O'connor
Journal: JNCI Journal of the National Cancer Institute (1970)

Dog-embryo cell cultures were infected with a mixture of feline leukemia virus (FeILV) and a modified murine (Moloney) sarcoma virus MSV(FelLV). Morphological alteration of the cells was observed 3 days post infection. Virus progeny from the infected cultures increased 50-to 100-fold in foci of cellular alteration on dog cell cultures pretreated with diethylaminoethyl-dextran, but only twofold on cat embryo cultures similarly treated. The numbers of foci produced corresponded to a dual infection with the MSV(FelLV) and endogenous FelLV and could be increased by simultaneous infection with exogenous FelLV. After five serial passages in dog cell cultures, the virus mixture still had a superior focus-inducing capacity on cat cells as compared with dog cells. Electron microscopic examination of infected dog cultures showed typical C-type virions. FelLV alone propagated in dog cell cultures without inducing morphological alteration, and progeny virus, capable of promoting focus formation by MSV(FeILV), could be detected 48 hours post infection.
Abstract 361: Time Interval From Collapse to Return of Spontaneous Circulation and Neurologically Intact Survival for Out-of-Hospital Shockable (Ventricular Fibrillation or Pulseless Ventricular Tachycardia) Cardiac Arrest
Authors: Ken Nagao, Eizo Tachibana, Tukasa Yagi, Naohiro Yonemoto, Morimasa Takayama, Sigemasa Tani, Hiroshi Nonogi, Shinichi Shirai, Takeshi Kimura
Journal: Circulation (2013)

Background: Early achievement of return of spontaneous circulation (ROSC) after cardiac arrest is critical to neurologically intact survival, but few data are available concerning this interval for shockable cardiac arrest (ventricular fibrillation or pulseless ventricular tachycardia). Methods: From the All-Japan Utstein Registry, a prospective, nationwide, population-based registry of out-of-hospital cardiac arrest (OHCA) between 2005 and 2011, we included adult patients who received resuscitation care after witnessed OHCA due to shockable arrest, whose ROSC was achieved before hospital arrival and who received post cardiac arrest care after hospital arrival. We evaluated the relationship between the collapse-to-ROSC interval and favorable neurological outcome 30 days after cardiac arrest. Results: Of the 31,845 patients who achieved ROSC after witnessed OHCA, 11,621 (36.5%) achieved ROSC after shockable cardiac arrest. Of these, 54.5% (6,187/11,621) had a 30-day favorable neurological outcome. The favorable group had a significantly shorter collapse-to-ROSC interval compared to the unfavorable group (13.5±8.2 vs. 19.2±10.7 minutes, p&lt;0.0001). After adjustment for resuscitation, the likelihood of favorable neurological outcome decreased for every 1 minute increment in the collapse-to-ROSC interval (adjusted OR; 0.94, 95% CI, 0.93 to 0.94). Non-linear regression analysis showed that frequency of favorable neurological outcome decreased from 76.4% to 0% for every minute that passed between collapse and ROSC. For favorable neurological outcome, a collapse-to-ROSC interval of 57.5 minute had a sensitivity of 100% with a negative predictive value of 99.8%. Furthermore, a collapse-to-ROSC interval with a sensitivity of 100% for favorable neurological outcome was 55.5 minutes in patients receiving bystander CPR, and 58.5 minutes in patients not receiving bystander CPR. Conclusion: Resuscitation efforts to achieve ROSC, contributing to neurologically intact survival, are needed for about 60 minutes for patients with witnessed out-of-hospital shockable cardiac arrest irrespective of bystander CPR attempt.