tbuckley/cabot-search huggingface dataset:
A phase I trial of TRU-016, an anti-CD37 small modular immunopharmaceutical (SMIP) in relapsed and refractory CLL
Authors: L. Andritsos, R. Furman, I. W. Flinn, A. Foreno-Torres, J. M. Flynn, S. C. Stromatt, J. C. Byrd
Journal: Journal of Clinical Oncology (2009)

3017 Background: CD37 is a tetraspan family member expressed predominantly on normal and transformed B-cells across a wide range of maturational stages. TRU-016 is a novel humanized anti-CD37 SMIP. Pre-clinical studies have demonstrated CD37 SMIP mediates significantly greater direct and NK-cell mediated killing of CLL cells as compared to other therapeutic antibodies used in CLL. A phase I study with TRU-016 was initiated based upon these data. Methods: Patients with relapsed/refractory CLL or SLL who had adequate organ function, platelets &gt; 30,000/mm 3 were eligible. Six doses and two different schedules (cohorts 1–8) have/or will be studied. The planned doses range from 0.03 mg/kg to 10 mg/kg IV once a week for 4 doses (cohort 1–6). The second schedule (cohort 7–8) will test 3.0 or 10.0 mg/kg on days 1, 3, and 5 the first week followed by 3 weekly doses. Dose escalation and de-escalation is based on CTC AE toxicity grades. Results: To date, 10 patients have been enrolled (cohort 1–5) and completed treatment; 1 patient (cohort 1–3: 0.03, 0.1, and 0.3 mg/kg); 3 patients at 1.0 mg/kg, and 4 patients at 3.0 mg/kg. Eight of the 10 have high risk genomic features [del(17p13.1), n=5 and del(11q22.3), n=3]. No dose limiting toxicities or serious adverse events have occurred. Mild (grade 1–2) infusion toxicity has been observed in 3 patients. Beginning with the 0.3 mg/kg dose, all eight patients demonstrated evidence of biological activity including patients with del(17p13.1). Two patients had partial clearing of leukemia cutis, and the other six had 27–94% reduction in peripheral lymphocyte count. One pt. had an increase in Hgb of 40% and a reduction in lymph nodes of 36%. Two patients had a significant increase in platelet count. Enrollment to cohort 6 is complete and further up-to-date data will be presented. Conclusions: To date, TRU-016 is a well tolerated treatment with minimal infusional toxicity and no observed dose limiting toxicity. Encouraging reduction in tumor lymphocyte blood counts, lymph node/spleen size and improvement in normal hematopoeitic function in patients with high risk genomic CLL have already been observed at low, non-saturating doses of CD37. Future single agent and combination studies of Tru16 in CLL are warranted. [Table: see text]
S51 Arterial oxygen content reflects haemoglobin more than oxygenation indices in 440 patients with pulmonary arteriovenous malformations
Authors: CL Shovlin, B Chamali, V Santhirapala, L Williams, JE Jackson, H Tighe
Journal: Thorax (2015)

<h3>Introduction and objectives</h3> Our goal was to use a long term model of human hypoxaemia to evaluate factors that reduce arterial oxygen content (CaO<sub>2</sub>) and therefore demand higher cardiac outputs to maintain tissue oxygen delivery. This is important for clinical practice; for clinical trials that use cardiac index as a primary outcome measure; and particularly relevant for patients with pulmonary and systemic arteriovenous malformations (AVMs) due to hereditary haemorrhagic telangiectasia (HHT). <h3>Methods</h3> Presentation data were evaluated on 497 consecutive patients with pulmonary AVMs due to HHT, reviewed between 1999 and 2013. SaO<sub>2</sub> was measured by pulse oximetry in the supine and erect postures, and the mean SaO<sub>2</sub> calculated after 7, 8, 9 and 10 min standing. Same-day haemoglobin was measured in venous blood samples in 440 patients. Presentation CaO<sub>2</sub> was calculated by the equation <i>oxygen saturation (SaO<sub>2</sub>, </i>%<i>) x haemoglobin</i><i>(gram/dL) x 1.34/100.</i> <h3>Results</h3> There was a four-fold difference in CaO<sub>2</sub> across the 440 patients (range 7.6–27.5, median 17.6) mls of oxygen per decilitre (dL) of arterial blood. SaO<sub>2</sub> ranged from 59–100% (median 94.8%), but CaO<sub>2</sub> did not change appreciably across the SaO<sub>2</sub> quartiles (median CaO<sub>2</sub> 17.1; 18.1; 17.7; 17.8 mls/dL; p = 0.34, Figure 1A). In contrast, CaO<sub>2</sub> was primarily determined by haemoglobin which ranged from 5.9–21.8 g/dL (median 14.1 g/dL). The median CaO<sub>2 </sub>across quartiles of haemoglobin were 14.1; 16.7, 18.5; and 20.5 mls/dL (p &lt; 0.0001, Figure 1B). For each 1 g/dL rise in haemoglobin, there was a 10% increase in mls of oxygen per unit blood volume. <h3>Conclusions</h3> Currently, in long term conditions, more attention is paid to modest differences in SaO<sub>2</sub> than to haemoglobin.<sup>1</sup> It has been shown that patients with PAVMs maintain CaO<sub>2</sub>, and deliver the same amount of oxygen per heart beat (oxygen pulse) before and after correction of hypoxaemia by PAVM embolisation.<sup>2,3</sup> For patients where higher cardiac outputs may be detrimental, further attention should be given to minor incremental falls in haemoglobin that substantially reduce arterial oxygen content. <h3>References</h3> 1 Hardinge M, Annandale J, Bourne S, <i>et al</i>. BTS guidelines for home oxygen use in adults. <i>Thorax</i> 2015:<b>70</b>:i1–i43 2 Santhirapala V, Williams LC, Tighe HC, <i>et al</i>. Arterial oxygen content is precisely maintained by graded erythrocytotic responses in settings of high/normal serum iron levels, and predicts exercise capacity: an observational study of hypoxaemic patients with pulmonary arteriovenous malformations. <i>PLoS One</i> 2014;<b>9</b>(3):e90777 3 Howard L, Santhirapala V, Murphy K, <i>et al</i>.<i> Chest</i> 2014;<b>146</b>(3):709–18
NAIP proteins are required for cytosolic detection of specific bacterial ligands in vivo
Authors: Isabella Rauch, Jeannette L. Tenthorey, Randilea D. Nichols, Khatoun Al Moussawi, James J. Kang, Chulho Kang, Barbara I. Kazmierczak, Russell E. Vance
Journal: The Journal of Experimental Medicine (2016)

NLRs (nucleotide-binding domain [NBD] leucine-rich repeat [LRR]–containing proteins) exhibit diverse functions in innate and adaptive immunity. NAIPs (NLR family, apoptosis inhibitory proteins) are NLRs that appear to function as cytosolic immunoreceptors for specific bacterial proteins, including flagellin and the inner rod and needle proteins of bacterial type III secretion systems (T3SSs). Despite strong biochemical evidence implicating NAIPs in specific detection of bacterial ligands, genetic evidence has been lacking. Here we report the use of CRISPR/Cas9 to generate Naip1−/− and Naip2−/− mice, as well as Naip1-6Δ/Δ mice lacking all functional Naip genes. By challenging Naip1−/− or Naip2−/− mice with specific bacterial ligands in vivo, we demonstrate that Naip1 is uniquely required to detect T3SS needle protein and Naip2 is uniquely required to detect T3SS inner rod protein, but neither Naip1 nor Naip2 is required for detection of flagellin. Previously generated Naip5−/− mice retain some residual responsiveness to flagellin in vivo, whereas Naip1-6Δ/Δ mice fail to respond to cytosolic flagellin, consistent with previous biochemical data implicating NAIP6 in flagellin detection. Our results provide genetic evidence that specific NAIP proteins function to detect specific bacterial proteins in vivo.
The Where, the When, and the How of Immune Monitoring for Cancer Immunotherapies in the Era of Checkpoint Inhibition
Authors: Priti S. Hegde, Vaios Karanikas, Stefan Evers
Journal: Clinical Cancer Research (2016)

Abstract Clinical trials with immune checkpoint inhibitors have provided important insights into the mode of action of anticancer immune therapies and potential mechanisms of immune escape. Development of the next wave of rational clinical combination strategies will require a deep understanding of the mechanisms by which combination partners influence the battle between the immune system's capabilities to fight cancer and the immune-suppressive processes that promote tumor growth. This review focuses on our current understanding of tumor and circulating pharmacodynamic correlates of immune modulation and elaborates on lessons learned from human translational research with checkpoint inhibitors. Actionable tumor markers of immune activation including CD8+ T cells, PD-L1 IHC as a pharmacodynamic marker of T-cell function, T-cell clonality, and challenges with conduct of trials that ask scientific questions from serial biopsies are addressed. Proposals for clinical trial design, as well as future applications of peripheral pharmacodynamic endpoints as potential surrogates of early clinical activity, are discussed. On the basis of emerging mechanisms of response and immune escape, we propose the concept of the tumor immunity continuum as a framework for developing rational combination strategies. Clin Cancer Res; 22(8); 1865–74. ©2016 AACR. See all articles in this CCR Focus section, “Opportunities and Challenges in Cancer Immunotherapy.”
PAZONET: A phase II trial of pazopanib in patients with metastatic neuroendocrine tumors (NETs) who may have previously received antiangiogenic or mTOR treatment.
Authors: J. Capdevila, A. Teule, D. E. Castellano, J. Sastre, R. Garcia-Carbonero, I. Sevilla, I. Duran, P. Escudero, J. Fuster, E. Grande Pulido
Journal: Journal of Clinical Oncology (2011)

TPS171 Background: NETs are characterized by profuse vasculature, VEGF and VEGFR-2 are overexpressed in 60-84% of the carcinoids and pancreatic islet cells tumors. Other pro-angiogenic factors like PDGFR have been also involved in NETs development and progression. Pazopanib is an oral tyrosine kinase inhibitor of VEGFR, PDGFR and KIT with both antiangiogenic and anti-tumoral activity. Previous activity of pazopanib in advanced gastroenteropancreatic NETs has been reported (Phan et al. ASCO 2010). No data is available of the activity of pazopanib after tumor progression to prior anti-VEGF or mTOR treatment. Methods: Patients with locally advanced or metastatic NETs derived either from the digestive tract, bronchial, thymic or pancreatic islet cell origin will receive pazopanib 800 mg/day until disease progression or intolerance. Patients could have previously received treatment with somatostatin analogues, chemotherapy, anti-VEGF, or m-TOR inhibitors. The primary endpoint is overall clinical benefit rate (ORR + SD) at 6 months according to RECIST criteria. Secondary endpoints include PFS, safety, duration of response, time to tumor response and biomarker studies. Circulating VEGF, and soluble VEGFR-2 plasma levels will be correlated with clinical outcome as well as circulating tumor cells (CTCs), circulating endothelial cells (CECs), and circulating endothelial progenitor cells (CEPCs). Results: 44 patients are expected to be enrolled. In November 2010 the study protocol received institutional review board approval and in January 2011 the trial commenced enrolment. Recruitment is expected to be completed in September 2011, with the last patient visit estimated in August 2012. Study results are anticipated in 2012. Conclusions: There is a high unmet medical need for patients with advanced NETs resistant to either sunitinib or everolimus. This study will investigate the antiproliferative potential of pazopanib in patients with metastatic NETs already treated with other novel agents. In addition this trial will provide evidence for the role of CTCs, CECs, and CEPCs as feasible biomarkers in NETs. On behalf of the GETNE group (NCT01280201).
Surgical Treatment of Lung Cancer Found on X-Ray Survey
Authors: Richard H. Overholt, James A. Bougas, Francis M. Woods
Journal: New England Journal of Medicine (1955)

A SYMPTOMATIC lung cancer, discoverable only by x-ray examination, has a higher rate of resectability and a greater potential curability than symptomatic cancer. Pessimism should not deter the search for silent cancer in mass chest surveys and individual chest screening. An effective use of x-ray examination by the medical profession combined with the intelligent co-operation of the public will uncover more lung cancers at the most favorable time for cure.ExperienceIn support of this contention, we present the experience of the Overholt Thoracic Clinic with 46 cases of silent lung cancer seen between December, 1947, and August, 1953. (This . . .
PTU-021 The use of a novel endoscopically placed radiofrequency probe for the management of malignant bile duct obstruction
Authors: A Steel, A Postgate, P Vlavianos, S Khorsandi, N Habib, D Westaby
Journal: Gut (2010)

<h3>Introduction</h3> In un-resectable malignant bile duct obstruction the use of self expanding metal stents (SEMS) is the standard technique to ensure continued biliary drainage in patients with life expectancy beyond 3 months. Up to 50% of patients with SEMS will re-present with stent occlusion within the first 6- 8 months, this often leading to significant morbidity and mortality as well as delays in chemotherapy regimes. This study reports the first use in humans of an endoscopically applied radiofrequency treatment prior to insertion of SEMS. The Habib EndoHPB (EMcision UK) catheter is a bipolar radiofrequency ablation (RFA) probe that is 8Fr, 1.8 m long and compatible with standard (3.2 mm working channel) side viewing endoscopes. 2 ring electrodes 8 mm apart at the tip provide local coagulative necrosis over a 2.5-cm length. This study aimed to demonstrate the safety and efficacy of RFA applied within the bile duct by the Habib EndoHPB catheter in patients with malignant biliary obstruction. <h3>Methods</h3> Patients with un-resectable pancreatic or bile duct cancer were recruited to this pilot study. At ERCP prior to deployment of SEMS the wire guided Habib EndoHPB catheter was placed under fluoroscopy within the biliary stricture. Based upon prior animal studies ablation was carried out using an RFA generator set at 7–10 W for a time period of 2 min. Depending on the length of the stricture sequential applications were applied to ensure RFA treatment to the entire stricture. After RFA treatment SEMS were deployed as per standard protocols. Immediate and 30-day complications and stent patency were recorded. <h3>Results</h3> 15 patients (9 women, mean 70.8 years, 11 pancreatic cancer, 4 cholangiocarcinoma) were recruited between January and October 2009. Deployment of the Habib EndoHPB catheter was successful in all but 1 patient in whom there had been proximal migration of a previously placed plastic stent. Mean procedure time was 44 min, using a median of two RFA applications. SEMS placement was achieved in all cases of successful EndoHPB deployment. Mild pancreatitis developed post-ERCP in one patient. One patient developed a tumour related gallbladder collection, not procedure related, and required cholecystostomy. 30-day patency was maintained in all patients. One patient died with a patent stent within 30 days due to progressive disease. <h3>Conclusion</h3> This phase 1 study of endobiliary RFA treatment of malignant biliary obstruction with the Habib EndoHPB catheter demonstrates immediate and 30-day safety and efficacy. Studies to determine the effect of endoscopically applied RFA therapy on long-term biliary stent patency are warranted.
Recurrent Hematuria in Childhood
Authors: Don B. Singer, L. Leighton Hill, Harvey S. Rosenberg, Joyce Marshall, Richard Swenson
Journal: New England Journal of Medicine (1968)

Recurrent hematuria, unaccompanied by obvious renal disease or urinary-tract lesions, was associated with microscopic glomerular disease in 21 of 31 patients. On bright-field microscopy, segmental glomerulitis was the most common lesion. In 11 cases electron-dense deposits in the basement membrane of glomerular capillaries were similar to those in resolving acute glomerulonephritis. Some of the clinical data, including glomerulonephritis in family members and a preponderance of males, also suggested a relation between recurrent hematuria and glomerulonephritis. None of the patients had abnormal renal function within seven years of the onset of hematuria. It is possible that these patients are in a latent phase preceding chronic glomerulonephritis.
Long-Term Safety and Efficacy of Reslizumab in Children and Adolescents with Eosinophilic Esophagitis: A Review of 477 Doses in 12 Children over 7 Years
Authors: Jonathan E. Markowitz, Laura Jobe, Michelle Miller, Carrie Frost, Ransome Eke
Journal: Journal of Allergy and Clinical Immunology (2016)
Campaign Contributions from the American Medical Political Action Committee to Members of Congress -- For or Against the Public Health?
Authors: Joshua M. Sharfstein, Steven S. Sharfstein
Journal: New England Journal of Medicine (1994)

The American Medical Political Action Committee (AMPAC), the political arm of the American Medical Association (AMA), contributed $2.4 million to candidates for Congress during the 1989-1990 campaign and $2.9 million during the 1991-1992 campaign. It is not known whether these funds preferentially benefited representatives who supported the AMA's positions on public health issues.
Coronary-Artery Rupture Treated with a Polytetrafluoroethylene-Coated Stent
Authors: Thuraia Nageh, Martyn R. Thomas
Journal: New England Journal of Medicine (2000)

To the Editor: Coronary-artery rupture is a rare but well-recognized complication during percutaneous revascularization1 that usually requires urgent surgical intervention and often has a poor or fatal outcome. The management of coronary-artery rupture is becoming an increasingly important issue in interventional cardiology as high-pressure balloon inflation is advocated to ensure maximal expansion and optimal deployment of a coronary stent, thereby minimizing the risk of subsequent tissue proliferation within the stent and restenosis.2 There are few reports of percutaneous techniques that have been used successfully to treat this complication. These techniques include vessel occlusion by microcoil and spring embolization and the . . .
Action of 1,25-Dihydroxycholecalciferol, a Potent, Kidney-Produced Metabolite of Vitamin D<sub>3</sub>, in Uremic Man
Authors: Arnold S. Brickman, Jack W. Coburn, Anthony W. Norman
Journal: New England Journal of Medicine (1972)

Only the kidney is capable of producing 1,25-dihydroxycholecalciferol (1,25diOHC), the probable active form of vitamin D. The possibility that parenchymal damage in chronic renal disease impairs production of 1,25diOHC and accounts for "vitamin-D-resistant" uremia prompted our evaluation of its effect in uremic man. Three patients with advanced renal failure showed significant responses to daily treatment with only 100 U (2.7 μg) of 1,25diOHC for six to 10 days: serum calcium and phosphorus rose; intestinal radioactive calcium (47Ca) absorption increased by 30 to 220 per cent; and fecal calcium decreased by 25 to 71 per cent in those undergoing balance studies. In contrast, 40,000 U (1 mg) of vitamin D3 caused no change in serum calcium and phosphorus and had negligible effects on 47Ca absorption. Thus, 1,25diOHC is highly active in uremic man, and its impaired production may account for certain abnormalities of calcium homeostasis in uremia. The agent may hold future promise in management of disordered calcium metabolism in uremia.
Combination of pegylated-liposomal doxorubicin (PLD) and bevacizumab (B) (PLD-B) in sarcoma (SAR)
Authors: K. M. Skubitz, P. A. Haddad
Journal: Journal of Clinical Oncology (2007)

20506 Background: Vascular endothelial growth factor (VEGF) plays an important role in many tumors including SAR. Because of the known efficacy of PLD in SAR and the presumed importance of VEGF in SAR, we have treated SAR patients with PLD-B. It is possible that the addition of B to PLD might alter the toxicity profile. The toxicities of this combination are not well described. Methods: To better define the toxicity of the combination of PLD-B in SAR, we reviewed our experience with PLD-B in patients treated between 2004 and 2006. Results: We identified 20 patients with SAR treated with PLD-B at our institution. There were 9 men and 11 women, with a median age of 47.5 years (range 23–77). Ten patients initiated therapy with PLD q28 days at a median dose of 45 mg/m 2 (range 45–50), and 10 q14 days at a median dose of 21.2 mg/m 2 (range 20–25), in combination with B at 5 mg/kg q14 days. A median of 5 cycles was given (range 1–15). Dose delay was required in 3 patients for the second cycle, and dose reduction was required in 9 patients by cycle 3. Of the 10 patients starting with monthly PLD, 7 were changed to q14 day PLD by cycle 4. Mucositis and skin toxicity were the dose limiting toxicities (DLT) in 14/20 patients, and myelosuppression was the DLT in 1/20 patients. Nine patients were felt to have clinical benefit; 3 had a PR and 6 had SD. Notably, 2/4 recurrent Ewing sarcoma patients had symptomatic improvement and at least SD for 10 and 11 months, respectively, with minor toxicity allowing a good quality of life. Conclusions: This report describes the toxicity profile of PLD-B in 20 patients with SAR. The toxicities observed were similar to those seen with PLD alone, however, these toxicities appeared more pronounced with the addition of B. Since VEGF is important for wound healing, the known effects of B on this process may contribute to more skin and mucosal toxicity of PLD at a given dose. Future studies of PLD-B should consider the potential of increased mucosal and skin toxicity. The use of q14 day PLD to allow more control over toxicity is suggested; a maximal starting dose of 20 mg/m 2 is reasonable, although dose reduction will be common due to skin or mucosal toxicity. This combination can be given with limited toxicity, and meaningful responses were observed in recurrent sarcomas, including 2/4 Ewing sarcomas. No significant financial relationships to disclose.
Expanded Opportunities for Methods and Clinical Development
Authors: Roland W Herzog
Journal: Molecular Therapy (2016)

Now well into its third year, Molecular Therapy — Methods & Clinical Development (MTM) is firmly established as one of our Society's successful open-access journals. Its first special issue has just been published, providing in-depth coverage of recent advances in manufacturing of gene therapy vectors. At the core of the issue, which was edited by two leading experts in the manufacturing of gene therapy products, are six comprehensive reviews on the methodology of the production, purification, formulation, and quality control of major gene transfer vectors, with emphasis on process development for their clinical use.
Smoking and Impaired Endothelium-Dependent Dilatation
Authors: Rino Migliacci, Paolo Gresele
Journal: New England Journal of Medicine (1996)

To the Editor: Celermajer et al. (Jan. 18 issue)1 reported that passive smoking is associated with a dose-related impairment of flow-mediated, endothelium-dependent arterial dilatation in healthy young subjects. Previous studies have shown that active cigarette smoking induces a reduction of flow-mediated arterial dilatation that is partially reversible on smoking cessation.2 However, it is not known whether the endothelial dysfunction induced by smoking is the consequence of chronic damage to the endothelium or whether some components of cigarette smoke acutely affect endothelial function. We assessed the short-term effects of cigarette smoking on flow-mediated arterial dilatation in healthy young adults who were . . .