tbuckley/cabot-search huggingface dataset:
Population pharmacokinetic (popPK) model of pembrolizumab (pembro; MK-3475) in patients (pts) treated in KEYNOTE-001 and KEYNOTE-002.
Authors: Tara C. Gangadhar, Janice Mehnert, Amita Patnaik, Omid Hamid, Matteo S. Carlino, F. Stephen Hodi, Christian U. Blank, Antoni Ribas, Caroline Robert, Anna Georgieva Kondic, Malidi Ahamadi, Tomoko Freshwater, Rik de Greef, Marianne van Vugt, Gregory Lubiniecki, Scot Ebbinghaus, Soonmo Peter Kang, Adil Daud
Journal: Journal of Clinical Oncology (2015)

3058 Background: The anti–PD-1 antibody pembro has efficacy in advanced cancer pts. We characterized pembro PK properties and quantified the effect of clinical factors on exposure. Immunogenicity was also assessed. Methods: Pooled popPK analysis was performed to characterize pembro serum concentrations over time in pts with melanoma (n = 1077), non-small cell lung cancer (n = 46), and other advanced cancers (n = 16) treated in KEYNOTE-001 and KEYNOTE-002. Simulations were performed to evaluate the magnitude of the effects of several clinical covariates on exposure. To investigate the immunogenicity potential of pembro, the development of antidrug antibodies (ADA) was determined. Results: A 2-compartment model with linear clearance from the central compartment adequately describes the clinical pharmacokinetics of pembro over the 1-10 mg/kg dose range (Table). No significant differences in efficacy have been observed for pembro 2 and 10 mg/kg Q3W and 10 mg/kg Q2W and Q3W. The PK profile is similar to other monoclonal antibodies, with a low clearance (0.2 L/day), limited central volume of distribution (3.8 L), and low to moderate variability (22-41%). The effect of age, sex, geographic location, baseline ECOG PS, eGFR, AST, bilirubin, albumin, glucocorticoid coadministration, tumor type and burden, and prior ipilimumab on pembro exposure is limited, as alterations of 20% or less are predicted by the popPK model. Of 268 pts evaluable for ADA, 1 (<1%) developed confirmed treatment-emergent ADA with no impact on efficacy or safety. Conclusions: The pembro PK profile indicated a low clearance and limited volume of distribution, consistent with other monoclonal antibodies. There was no clinically meaningful effect of baseline clinical factors on pembro exposure. Pembro has limited potential to elicit the formation of ADA. Clinical trial information: NCT01295827 and NCT01704287.Median (90% prediction interval) PK parameters of pembro at steady state based on popPK model. PK Parameter Pembro Dose Regimen 2 mg/kg Q3W 10 mg/kg Q3W 10 mg/kg Q2W Cmax (μg/mL) 64.6 (43.9; 99.2) 318 (215; 488) 393 (261; 691) Ctrough (μg/mL) 22.3 (8.84; 50.1) 110 (40.8; 257) 185 (82; 395) AUCss, 6 wk (μg∙day/mL) 1398 (713; 2730) 6859(3403; 13712) 10353 (5308; 20137)
Endpiece: God, surgeon, medicine, patient
Authors: Jeremy Hugh Baron
Journal: BMJ (2005)

Hippocrates in his Aphorisms, as Galen writeth sure, Saieth, foure things are needfull to every kind of cure, The first, saith he, to God belongeth the chiefest part, The second to the Surgeon, who doth apply the art, The third unto the medicine, that is dame Natures friend The fourth unto the patient, with whom I heere will end.

Clowes W. A profitable and necessarie booke of observations. London: 1596
Comparative Effectiveness of Treatment Strategies for Bladder Cancer With Clinical Evidence of Regional Lymph Node Involvement
Authors: Matthew D. Galsky, Kristian Stensland, John P. Sfakianos, Reza Mehrazin, Michael Diefenbach, Nihal Mohamed, Che-Kai Tsao, Paolo Boffetta, Peter Wiklund, William K. Oh, Madhu Mazumdar, Bart Ferket
Journal: Journal of Clinical Oncology (2016)

Purpose Patients with bladder cancer with clinical lymph node involvement (cN+) are at high risk for distant metastases, but are potentially curable. Such patients are excluded from neoadjuvant chemotherapy trials and pooled with patients with distant metastases in first-line chemotherapy trials not suited to define the role of combined-modality therapy. To address this evidence void, we performed a comparative effectiveness analysis. Methods We included cTanyN1-3M0 bladder cancer patients from the National Cancer Data Base (2003-2012) treated with chemotherapy and/or cystectomy. We used multistate survival analysis, allowing for delayed entry, to assess overall survival (OS) according to various treatment strategies. Effectiveness was estimated with multivariable adjustment for tumor-, patient-, and facility-level characteristics. Results Among 1,739 patients (cN1, 48%; cN2, 45%; cN3, 7%), 1,104 underwent cystectomy and 635 were treated with chemotherapy alone. Of the cystectomy patients, 363 received preoperative and 328 received adjuvant chemotherapy. The crude 5-year OS for chemotherapy alone, cystectomy alone, preoperative chemotherapy followed by cystectomy, and cystectomy followed by adjuvant chemotherapy was 14% (95% CI, 11% to 17%), 19% (95% CI, 15% to 24%), 31% (95% CI, 25% to 38%), and 26% (95% CI, 21% to 34%), respectively. Compared with cystectomy alone, preoperative chemotherapy was associated with a significant improvement in OS (hazard ratio, 0.80; 95% CI, 0.66 to 0.97). Adjuvant chemotherapy was also associated with a significant improvement in survival compared with cystectomy alone. The survival of patients treated with chemotherapy alone was worse than those treated with cystectomy alone. Conclusion A subset of patients with cN+ bladder cancer achieves long-term survival. Combined-modality therapy, with chemotherapy and cystectomy, is associated with the best outcomes.
Use of Cryoprecipitate
Authors: M J Inwood
Journal: New England Journal of Medicine (1976)

Additional findings concerning the evolution alpha fetoprotein (AFP) are reported in this letter. AFP levels of 440 amniotic fluids and 469 maternal sera were studied at different gestational ages. In addition, amniotic fluids and serum samples of 180 pregnant women were collected on the same day. Comparative study of amniotic fluid and maternal sera levels of AFP led to establishment of parallelism between these values from Week 17-20 of gestation. During this period, the ratio of amniotic fluid:maternal serum AFP was always between 100 and 250, whereas, it was less than 80 after Week 21 and greater than 400 before the 16th week. Fetal blood contamination of 2 samples resulted in high-for-date AFP levels, and subsequent amniocenteses were normal for AFP. In 2 twin pregnancies, the AFP value was normal in amniotic fluid and increased in maternal serum. The ratio was low for dates--about 1/2 normal. In cases with abnormalities the ratio was abnormal. High AFP levels in serum with normal amniotic values in 2 pregnant patients with renal disease were found: in these cases, the ratio was low for gestational age, but not as low as that observed in cases of intrauterine death. Ratios were too high for gestational age in cases of anencephaly and umbilical hernia.
THU0377 MIR-29C in Urinary Exosomes as Predictor of Early Renal Fibrosis in Lupus Nephritis
Authors: C. Solé-Marcé, J. Cortés-Hernández, M. Vidal, M.L. Felip, J. Ordi-Ros
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Despite overall improvement in prognosis, 10-30% of patients with lupus nephritis (LN) will develop End-Stage Renal Disease [1]. To date, renal biopsy is still the <i>gold standard</i> test used to predict renal outcome. However, due to its invasive nature, new non-invasive biomarkers are required. The anti-fibrotic effects of microRNA-29c may be result of its ability to inhibit TGF-β/Smad3-mediated deposition of extracellular matrix (ECM) [2]. Urinary exosomes, microvesicles released by every epithelial cell facing the urinary space, represent an ideal source of markers for renal dysfunction and injury. <h3>Objectives</h3> Here we sought to evaluate miR-29c expression levels in urinary exosomes as a novel biomarker of renal fibrosis in LN and study the relation between the expression of miR-29c and genes related with TGF-B pathway to investigate more about the mechanism of renal fibrosis in lupus nephritis. <h3>Methods</h3> Urinary exosomes were isolated from 28 patients with biopsy-proven LN and 20 healthy controls. Electronic microscopy and western blot were used to characterize the exosomes. Expression levels of miR-29c were detected by RT-PCR quantitative and correlated with clinical and histological parameters along with the expression levels of Smad2/3, TGF-β and MMP2/9. For comparison, miRNA expression was also evaluated in the urinary pellet. <h3>Results</h3> MiR-29c levels in urinary exosomes showed a negatively strong correlation with the histological chronicity index (r=-0.898, p=0.001) and glomerular sclerosis (r=-0.555, p=0.007). No correlation with eGFR and creatinine levels was found. MiR-29c expression levels could predict the degree of chronicity in patients with LN with an area under the curve (AUC) of 0.946 (p&lt;0.001) and with high sensitivity and specificity (94% and 82%). Smad3 and MMP2 expression in urinary exosomes correlated negatively with miR-29c expression (r=-0.737 and -0.856 respectively). In the urinary pellet, no miR-29c expression was detected; however, upregulation of Smad3 and MMP2 was observed (3.54 and 5.85 fold increase). <h3>Conclusions</h3> Overall, miR-29c correlated with the degree of renal chronicity but not with renal function, suggesting it could be used as a novel non-invasive marker of early progression to fibrosis in patients with LN. <h3>References</h3> Fiehn C. Early diagnosis and treatment in lupus nephritis: how we can influence the risk for terminal renal failure. J Rheumatol 2006; 33:1464–1466. Qin W. et al. TGF-/Smad3 signaling promotes renal fibrosis by inhibiting miR-29. J Am Soc Nephrol 2011; 22:1462-1474. <h3>Disclosure of Interest</h3> None declared
Racism and its impact on psychotherapy
Authors: T Brantley
Journal: American Journal of Psychiatry (1983)

It is necessary to deal with racial material in therapy as well as in the real world outside of therapy. When this is not done, patients terminate their treatment feeling that the therapist did not understand them as patients and individuals. Black therapists have heard this often from their black patients who have previously seen nonblack therapists. The author does not propose that all therapy of black patients be done by black therapists but that a definite concern for racial issues should prevail in any therapeutic encounter to which a black patient brings problems related to racial prejudice and/or discrimination.
PTU-007 Needle knife mucosal incision to obtain deep biopsies of submucosal lesions along the gi tract – efficacy and safety
Authors: S Chandrapalan, R Sringeri, B Polewiczowska, K Kalyanasundaram, R Glass, J Green, S Hebbar
Journal: Gut (2015)

<h3>Introduction</h3> Submucosal lesions in the GI (gastro-intestinal) tract are difficult to diagnose. The diagnostic yield from mucosal biopsies using standard endoscopic forceps (bite-on-bite technique) and from EUS guided FNA is limited. Endoscopic submucosal dissection and surgery are high risk methods of tissue acquisition as the majority of these lesions are benign. Early diagnosis of a benign lesion will reduce the need for regular surveillance. In some instances, the diagnosis will also help in the endoscopic treatment of symptomatic benign lesions. We therefore evaluated the diagnostic yield achieved from mucosal incision-assisted biopsies of various submucosal lesions in a series of 10 patients. <h3>Method</h3> A 20 month retrospective study of all patients who had mucosal incision-assisted biopsy of submucosal GI lesions. In case of upper GI lesions, EUS assessment preceded the needle knife mucosal incision. In lesions with a higher risk of bleeding, the defect was closed with clips. For all patients, we recorded the size, site and histopathological findings of the lesions and any procedure-related complications. <h3>Results</h3> 10 submucosal lesions (size varying from 10–30 mm) were biopsied using prior mucosal incision between May 2013 and Dec 2014. Two were colonic, 3 duodenal, 2 in the stomach and 3 in the oesophagus. Adequate tissue for diagnosis was obtained in all except one small oesophageal lesion. Histological diagnosis and site is shown in the Table 1. One patient had delayed bleeding which settled following endoscopic treatment. There were no other complications, immediate or late. <h3>Conclusion</h3> Mucosal incision-assisted biopsy is effective in the diagnosis of submucosal GI lesions with a high yield. It also appears safe. Although significant bleeding and perforation are possible complications, only one case of delayed bleeding, endoscopically treated, occurred in this series. Patients with asymptomatic benign lesions can be therefore be reassured with no need for further surveillance whilst appropriate treatment (endoscopic or surgical) can be rapidly arranged for malignant or symptomatic benign lesions. <h3>Disclosure of interest</h3> None Declared.
Central Retinal Artery Occlusion Successfully Treated with Plasmin
Authors: Sydney P. Hecker
Journal: JAMA (1961)

Central retinal artery thrombosis usually results in severe visual loss despite all therapeutic efforts. The thrombolytic effect of plasmin may reopen a thrombosed retinal artery and thereby improve retinal function. A diabetic man with incomplete retinal artery occlusion and visual acuity reduced to the ability to count fingers at a distance of 1 ft. failed to improve when treated with other methods. Prompt improvement of vision began within one hour after the beginning of an infusion of plasmin. Retinal blood flow was rapidly restored. Visual acuity was 20/40 six weeks later.
CONTINUOUS SLEEP TREATMENT
Authors: JOHN S. CLAPP, EARL A. LOOMIS
Journal: American Journal of Psychiatry (1950)

Experience with 70 applications of prolonged narcosis in psychotic and psychoneurotic disorders is presented. One fatality occurred in the series as a result of pulmonary emboli. Special attention was given to the study of bronchopneumonia, an outstanding complication of prolonged narcosis therapy, and a suggested technique is presented that effectively reduces this and other hazards. Psychotic excitements, both manic and schizophrenic, respond to narcosis therapy. Of 7 cases of dementia præcox less than one year in duration, 6 responded well to treatment. Experience with psychoneurotic patients is not sufficient to warrant conclusions; therapeutic results, however, were sufficient to suggest the possibility that this procedure might be of value in various psychoneuroses, particularly severe anxiety states with prominent phobic features. The outstanding disadvantage of narcosis is the necessity of constant nursing attention during treatment.
Case 39-1972
Authors: Richard C. Cabot, Benjamin Castleman, Robert E. Scully, Betty U. McNeely, James C. Melby, Richard B. Cohen
Journal: New England Journal of Medicine (1972)

Presentation of CaseA 51-year-old woman was admitted to the hospital because of hypertension.There was a history of severe toxemia during her second pregnancy 18 years previously and of edema with her third pregnancy. Ten years before admission fixed hypertension was found. Multiple attempts at treatment were abandoned because of intolerance of phenobarbital, thiazide compounds, guanethidine, methyldopa and reserpine, as well as multiple analgesic agents and several antibiotics. For many years she had experienced severe, persistent fatigue and right-sided headaches that generally began on awakening and were sometimes preceded by an aura of flashing lights on the previous day. . . .
Lenalidomide with Low-Dose Dexamethasone (Rd) Continuously Versus Rd Induction, Tandem MEL140 with Autologous Transplantation and Lenalidomide Maintenance: Planned Interim Analysis of a Prospective Randomized Trial in Patients 60-75 Years of Age with Multiple Myeloma
Authors: Christian Straka, Kerstin Schaefer-Eckart, Florian Bassermann, Hansen Timon, Bernd Hertenstein, Christian Langer, Hans Salwender, Stefan Knop, Monika Engelhardt, Martin Kropff, Wolf Roesler, Thomas Decker, Holger Hebart, Norbert Frickhofen, Albrecht Reichle, Christian Gerecke, Bernd Metzner, Else Heidemann, Tim H Brummendorf, Juliane Ababei, Wolfram E Jung, Martin Gramatzki, Marcus Hentrich, Peter Bojko, Ivana von Metzler, Martin Kaufmann, Ralph Naumann, Thomas Kubin, Burkhard Schmidt, Jochem Walther, Tobias Dechow, Hannes Wandt, Brigitte Schnabel, Axel Hinke, Hermann Einsele
Journal: Blood (2014)
AB1192 Decreasing Trend of Total Joint Arthroplasties for Rheumatoid Patients Compared to Osteoarthritis Patients in Our Institutes in Last Decade
Authors: Y. Takakubo, K. Sasaki, Y. Naganuma, H. Oki, Y. Tamaki, T. Hirayama, M. Takagi
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> Elderly people over 65 year-old have increased year by year in many countries<sup>1</sup>. Because their rate was from 19.5% at 2005 to 25.1% at 2014 in Japan, the numbers of total joint arthroplasties have increased too. On the other hand, modern treatments for rheumatoid arthritis (RA) have drastically changed in the last decade. The rate of orthopaedic surgery, especially total joint arthroplasty, may reflect trends in disease severity of RA, management and health outcomes<sup>2,3</sup>. <h3>Objectives</h3> The aim of this study was to analyze the trend of total joint arthroplasties for RA patients and osteoarthritis (OA) patients in our institutes in the last decade. <h3>Methods</h3> We surveyed the number and rate of orthopaedic surgeries and total joint arthroplasties in our three institutes from 2004 to 2013. <h3>Results</h3> We had 19,833 cases of orthopaedic surgeries, including 6,962 total joint arthroplasties in the last decade. They have increased year by year (r=0.9, p&lt;0.05). They have been suffered by OA (82%, 5,697 cases); trauma (6%, 393 cases); RA (5%; 358 cases), loosening of implants (4%), osteonecrosis (2%), infection (0.7%), dislocation of total joint arthroplasty (0.3%) (Fig. 1). The rate of OA (r=0.9), osteonecrosis (r=0.8) and infection (r=0.8) were related to total numbers of orthopaedic surgeries.They contained 3,165 cases of total hip arthroplasties (45%), 2561 total knee arthroplasty (37%), 453 bipolar hip prosthesis (7%), 317 unilateral knee arthroplasty (0.3%), 340 revision of total hip arthroplasties (5%), 41 revision of total knee arthroplasties (0.6%), 22 bipolar shoulder prosthesis (0.3%), 21 total ankle arthroplasties (0.3%), 3 swanson arthroplasty for fingers and 2 total shoulder arthroplasties. The rate of total hip arthroplasties (r=0.9), total knee arthroplasties (r=0.9), unilateral knee arthroplasties (r=0.9) and revision of total knee arthroplasties (r=0.8) were related to total numbers of orthopaedic surgeries. <h3>Conclusions</h3> The rate of total joint arthroplasties were increased year by year, and related to total numbers of orthopaedic surgeries. Trend of total joint arthroplasties for RA patients compared to OA patients has decreased in our institutes in the last decade because of increasing of elderly people and improving of the treatment for RA<sup>4</sup>. <h3>References</h3> Ethgen O and Reginster JY. Ann Rheum Dis, 2004. Gillam MH, Osteoarthritis Cartilage, 2012. Ravi B, Arthritis Rheum, 2012. Momohara S, J Rheumatol, 2014. <h3>Disclosure of Interest</h3> None declared
Synchronous pancreatic and gastric metastasis from an ovarian adenocarcinoma diagnosed by endoscopic ultrasound-guided fine-needle aspiration
Authors: Kentaro Yamao, Masayuki Kitano, Masatoshi Kudo, Osamu Maenishi
Journal: Endoscopy (2015)

Metastasis of ovarian carcinoma to the stomach [1] [2] [3] [4] [5] or pancreas [6] [7] is uncommon. Furthermore, synchronous metastasis of ovarian adenocarcinoma to the stomach and pancreas has never been reported. We report here the detection of synchronous metastasis to both the stomach and pancreas from a resected ovarian papillary serous cystadenocarcinoma.
Megaloblastic Anemia
Authors: Victor Herbert
Journal: New England Journal of Medicine (1963)

Therapeutic TrialsThis very important way to make a definitive differential diagnosis of vitamin B12 or folate deficiency should be used properly, but generally is not. The principles of therapeutic trial were laid down in a classic paper by Minot and Castle.11 In the words of that paper, these principles include the following:1. A control period of a few days [seven to ten days if feasible] is desirable in order to establish the constancy of the reticulocyte level. 2. Elimination of other sources of active material than the substance under test. . . The diet. . . should . . .
Signaling and Immune Regulation in Melanoma Development and Responses to Therapy
Authors: William M. Lin, David E. Fisher
Journal: Annual Review of Pathology Mechanisms of Disease (2016)

Melanoma is a complex and genomically diverse malignancy, and new genes and signaling pathways involved in pathogenesis continue to be discovered. Mechanistic insights into gene and immune regulation in melanoma have led to the development of numerous successful and innovative pharmacologic agents over recent years. Multiple targeted therapies and immunotherapies have already entered the clinic, becoming new standards of care and transforming the prognosis for many patients with malignant melanoma. In this review, we provide an overview of the current understanding of signaling and immune regulation in melanoma and implications for responses to treatment, organized in the framework of hallmark characteristics in cancer.
PTH-066 Activation of the bile acid receptor, farnesoid-x receptor, maintains gut epithelial cell morphology, possibly via inhibition of myosin light chain kinase expression
Authors: RA Speight, T Davey, K White, JA Kirby, JC Mansfield
Journal: Gut (2015)

<h3>Introduction</h3> By inducing epithelial barrier dysfunction, IBD associated inflammatory cytokines increase the leakiness of the gut mucosa, driving chronic inflammation.<sup>1</sup>Epithelial permeability increases, in part, due to cell-cell junction re-arrangement, mediated by myosin light chain kinase (MLCK).<sup>2</sup>FXR agonism has been shown to maintain the epithelial barrier in a mouse model of colitis.<sup>3</sup>The aim of this study was to assay the effect of FXR agonism on epithelial cell morphology in a human, gut-derived epithelial model of barrier dysfunction. <h3>Method</h3> Fully differentiated Caco-2 cells were cultured as a polarised monolayer and treated with TNFα, IFNγ or IL-6 with or without an FXR agonist. At 48 h, transmission electron microscopy was performed to assess for morphological re-arrangement of the cell-cell junction. Two independent researchers, blinded as to intervention, counted the number of morphological re-arrangements in 20 samples, chosen at random. RNA was isolated from IL-6 treated monolayers and the expression of MLCK was measured by RT-PCR (ΔΔCt method). Unpaired <i>t-</i>tests were calculated using Prism version 6.0e. All P values were 2-tailed, and a P value of 0.05 or less was considered significant. <h3>Results</h3> FXR agonism reduced the number of epithelial cell-cell junction fissures for monolayers stressed with IFNγ (mean 62.5% to 30%) and IL-6 (mean 69.5% to 42.5%). This was significant in the IFNγ group (p = 0.03), but failed to reach significance in the IL-6 group (p = 0.08). There were no, or few, morphological re-arrangements in control, FXR agonist only or TNFα treated monolayers. Cells stressed with IL-6 demonstrated a significant increase in the relative expression of MLCK (fold increase 435.4). The IL-6 induced upregulation of MLCK was completely abolished by co-treatment with FXR agonist. <h3>Conclusion</h3> Evidence is presented to demonstrate that FXR acts to maintain human, gut-derived epithelial cell morphology after stress with IFNγ and IL-6, probably via a mechanism involving the regulation of MLCK expression. FXR agonists are potential therapeutic compounds in the management of IBD. <h3>References</h3> Capaldo CT <i><i>et al</i></i>. <i>Bioch. Bioph. Acta</i>2009;1788:864–871 Cunningham KE <i><i>et al</i></i>. <i>Ann. N. Y. Acad. Sci</i>. 2012;2058:34–42 Gadaleta RM <i>et al</i>. Gut 2011;60:463–472 <h3>Disclosure of interest</h3> None Declared.