tbuckley/cabot-search huggingface dataset:
A phase I study of sorafenib and RAD001 for metastatic clear cell renal cell carcinoma
Authors: A. L. Harzstark, J. E. Rosenberg, V. K. Weinberg, J. Sun, C. J. Ryan, A. M. Lin, L. Fong, D. R. Brocks, E. J. Small
Journal: Journal of Clinical Oncology (2009)

5104 Background: Both RAD001 and sorafenib have activity against advanced clear cell renal cell carcinoma (ccRCC). Inhibition of both mTOR and angiogenesis may improve outcomes; therefore, a phase I trial combining sorafenib and RAD001 was undertaken. Methods: Cohorts of 3 or 6 patients with ccRCC were treated with a 7 day run-in period of sorafenib 400 mg PO BID continuously followed by RAD001 (dose level I: 2.5 mg, dose level II: 5 mg) PO QD and sorafenib 400 mg PO BID continuously. Pharmacokinetic sampling of sorafenib was obtained on day -1, and of both RAD001 and sorafenib on day 15 of combination therapy. Dose-limiting toxicity (DLT) was defined as occurring within the first 28 days of therapy. Results: Fifteen patients with a median age of 65 (range 51–75) have been enrolled. Two patients were not evaluable for response or DLT evaluation. Five pts were treated with sunitinib previously. Zero of 6 pts on dose level 1 experienced a DLT. Two of 9 pts treated at dose level II have experienced protocol-defined DLTs (grade 4 uric acid and grade 3 lipase with grade 2 pancreatitis). Independently-reviewed best objective responses in 13 evaluable pts include 3 confirmed partial responses (10, 17+, and 23+ months), 6 stable disease (2+, 4+, 4.5, 6+, 13, and 23+ months), and 4 progressive disease. Steady state dosing of RAD001 demonstrated a steady state AUC0–24h of RAD001 of 193.3 (± 32.9) ng h/mL at a dosage of 5 mg QD, comparable to the single agent 5 mg QD steady state dosing AUC0–24h of 238 (± 77) ng h/mL, suggesting there is no pharmacokinetic interaction between RAD001 and sorafenib. Linear pharmacokinetics between the 2.5 and 5 mg QD dosages of RAD001 were observed. The AUC0–24h of sorafenib was not significantly changed by concomitant dosing with RAD001 with a steady state AUC0–24h of 134600 (±42072) ng h/mL pre-RAD001 and a post-sorafenib steady state AUC0–24h of 131451 (±53838) ng h/mL. Conclusions: Combination therapy with sorafenib and RAD001 is safe and feasible. No clinically relevant pharmacokinetic interaction was observed. Activity for the combination has been observed and a phase II study is planned at the 5 mg QD dosage of RAD001. No significant financial relationships to disclose.
Global Survey of Esophageal and Gastric Injury in Atrial Fibrillation Ablation
Authors: Chirag R. Barbhaiya, Saurabh Kumar, Roy M. John, Usha B. Tedrow, Bruce A. Koplan, Laurence M. Epstein, William G. Stevenson, Gregory F. Michaud
Journal: Journal of the American College of Cardiology (2015)
Complete, Circular Papovavirus Genomes in the Cells of Hamsters Exposed to a Horizontally Transmitted Lymphomagenic Agent&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: S S Leinbach, E Fowler, L S Heath, B Hyde, J H Coggin
Journal: JNCI Journal of the National Cancer Institute (1987)

Contagious lymphomas were produced in a colony of Syrian golden hamsters by an unknown agent that also caused fatal ulcerative bowel disease (UBD) lesions prior to lymphoma development. A low percentage of these animals developed epitheliomas of the skin independently of the UBD or lymphomas. Previous work has shown that the epitheliomas contain numerous hamster papovavirus (HaPV) particles, whereas lymphomas do not. Cells from both kinds of tumors do contain HaPV DNA sequences, however. In this study, Southern blot hybridization showed that complete, circular HaPV genomes were present in these cells. Complete, circular HaPV genomes also were found in the cells of animals with UBD. Electron microscopy revealed the presence of HaPV particles in UBD lesions. These results, together with previous data, indicate that in the hamster, lymphomas contain complete, circular papovavirus genomes in the absence of virus particles, whereas epitheliomas and UBD lesions contain these genomes in the presence of virus particles.
H1N1: The co-infection conundrum
Authors: Christopher Taylor, Sebastien Ellis, Matthew Harris, Suzanne Shuttleworth, Benjamin Marshall, Aye Aye Lwin
Journal: European Respiratory Journal (2011)

Background:  Bacterial co-infection is known to increase the severity of H1N1 influenza. Past pandemics have been associated with  Staphylococcus aureus  which can lead to severe infection. Increasingly co-infection with  Streptococcus pneumoniae  has been recognised with H1N1 influenza.   Aims:  To evaluate the causative organism9s associated with co-infection; in association with the H1N1 winter outbreak of 2010-2011, and the impact on clinical course.   Method:  A patient cohort with proven H1N1 influenza admitted between December 2010 and January 2011 were retrospectively studied, using electronic patient records and paper medical notes. Bacterial co-infection was identified by positive result from blood, respiratory secretion or pneumococcal urinary antigen test.   Results:  Out of a total 76 H1N1 positive cases blood, respiratory sample and urinary antigen testing was performed in 53 patients. Co-infection was detected in 12 of 53.  Of 12 co-infection cases: 5 (42%) were  Streptococcus pneumoniae , 2  Pseudomonas aeruginosa , 1  Streptococcus sanguis , 1  Coliform/Proteus , 1  Stenotrophomonas , 1  Escheria coli  and 1 Coagulase negative  Staphylococcus .  9 of those with co-infection required escalation to the intensive care unit (ICU), (19/76 in total were admitted to ICU). 4 had  Streptococcus pneumoniae , 1  Pseudomonas aeruginosa , 1  Coliform/Proteus , 1 Coagulase negative  Staphylococcus , 1  Stenotrophomonas  and 1  Escheria coli .  Of the 9 admitted to ICU with H1N1 and co-infection, 6 were    Conclusion:  Our study highlights that co-infection with H1N1 is likely to increase the severity of disease course; including young adults and those without co-morbidity. This illustrates the importance of investigating H1N1 cases for concomitant infection in all groups.
Phase I study of stereotactic radiotherapy for unresectable hepatobiliary cancer and liver metastases
Authors: L. A. Dawson, R. Tse, J. Kim, R. Dinniwell, G. Lockwood, M. Sherman, J. J. Knox, S. Gallinger
Journal: Journal of Clinical Oncology (2007)

4590 Background: Safety of stereotactic radiotherapy (SRT) for unresectable hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CC) and liver metastases (LM) has not been well established. Results from a phase I study of 6 fraction SRT are reported. Methods: Eligible patients had unresectable or medically inoperable HCC, CC or LM, liver enzymes &lt; 6 fold higher than normal, platelets &gt; 80,000 bil/L, Child score A, &gt; 800 cc uninvolved liver, KPS = 60 and unsuitability for standard therapies. Patients were treated with breath hold and image guided 6 fraction SRT. Dose was individualized to maintain the same risk of liver toxicity at three risk levels (I-5%, II-10%, III-20%). Escalation to level II and III occurred once at least 3 patients had been followed for &gt;3 months without dose limiting toxicity (grade 4/5 &lt; 1 month or grade 4/5 liver &lt; 3 months) for each stratum. Stratification was based on diagnosis and liver volume irradiated (low &lt;20%, mid 20–50%, high 50–80%). Results: From Aug. 2003 to Dec. 2006, 82 patients initiated SRT. Two patients discontinued SRT after 1 fraction for progressive disease (LM) and a variceal bleed (HCC). 80 patients completed SRT (38 LM, 32 HCC, 10 CC). Median age was 64 years (38–92 years). Median tumor volume was 293 cc (3–3088 cc). 24 patients (30%) had extra-hepatic disease. 17 HCC patients had portal vein thrombosis (53%), 14 HBV, 12 HCV and 4 alcoholic cirrhosis. The median prescribed dose was 40 Gy (24 Gy - 60 Gy) in 6 fractions. Within 3 months post SRT, no dose-limiting grade 4/5 toxicity or classic radiation liver toxicity was observed. Grade 3 liver enzymes (2 new, 9 pre-existing), thrombocytopenia (3), nausea (3) and fatigue (1) was observed. Child score declined in 8 patients (5 HCC, 2 CC, 1 LM), 6 with progressive disease. Late toxicity included 1 tumor-duodenal fistula, 1 bowel obstruction and 2 GI bleeds. The in-field response rate was 60% (LM 57%, CC 50%, HCC 67%): CR 14%, PR 46%, SD 23%, PD 17%. Actuarial 12 month local control was 78% (95% CI: 58- 90%). The median survival for LM, CC and HCC was 16.6 months (7.9–25.6), 13.1 months (6.0–28.4) and 11.0 months (8.6–20.8) respectively. Conclusions: Individualized SRT is a safe, promising treatment for unresectable liver cancer. No significant financial relationships to disclose.
Insulin-mediated signaling promotes proliferation and survival of glioblastoma through Akt activation
Authors: Yuanying Gong, Yufang Ma, Maksim Sinyuk, Sudan Loganathan, Reid C. Thompson, Jann N. Sarkaria, Wenbiao Chen, Justin D. Lathia, Bret C. Mobley, Stephen W. Clark, Jialiang Wang
Journal: Neuro-Oncology (2015)

Metabolic complications such as obesity, hyperglycemia, and type 2 diabetes are associated with poor outcomes in patients with glioblastoma. To control peritumoral edema, use of chronic high-dose steroids in glioblastoma patients is common, which can result in de novo diabetic symptoms. These metabolic complications may affect tumors via profound mechanisms, including activation of insulin receptor (InsR) and the related insulin-like growth factor 1 receptor (IGF1R) in malignant cells. In the present study, we assessed expression of InsR in glioblastoma surgical specimens and glioblastoma response to insulin at physiologically relevant concentrations. We further determined whether genetic or pharmacological targeting of InsR affected oncogenic functions of glioblastoma in vitro and in vivo. We showed that InsR was commonly expressed in glioblastoma surgical specimens and xenograft tumor lines, with mitogenic isoform-A predominating. Insulin at physiologically relevant concentrations promoted glioblastoma cell growth and survival, potentially via Akt activation. Depletion of InsR impaired cellular functions and repressed orthotopic tumor growth. The absence of InsR compromised downstream Akt activity, but yet stimulated IGF1R expression. Targeting both InsR and IGF1R with dual kinase inhibitors resulted in effective blockade of downstream signaling, loss of cell viability, and repression of xenograft tumor growth. Taken together, our work suggests that glioblastoma is sensitive to the mitogenic functions of insulin, thus significant insulin exposure imposes risks to glioblastoma patients. Additionally, dual inhibition of InsR and IGF1R exhibits promise for treating glioblastoma.
Synergistic Action of Flt3 and gp130 Signalings in Human Hematopoiesis
Authors: Yasuhiro Ebihara, Kohichiro Tsuji, Stewart D. Lyman, Xingwei Sui, Makoto Yoshida, Kenji Muraoka, Kaoru Yamada, Ryuhei Tanaka, Tatsutoshi Nakahata
Journal: Blood (1997)
Erlotinib-induced papulopustular rash: Need for new management approach?
Authors: S. Wong, H. Nguyen, V. Green, T. E. Byun, E. P. Grahn, T. Lindgren
Journal: Journal of Clinical Oncology (2010)

e13647 Background: Papulopustular rash associated with epidermal growth factor inhibitor (EGFRI) monoclonal antibodies (Mabs) showed a “wax and wane” pattern until cessation of therapy. A pharmacokinetic study suggested that rash caused by erlotinib, an EGFR tyrosine kinase inhibitor (TKI), regresses despite continuation of therapy at same dose (defined as “spontaneous regression”). To date, description of spontaneous regression of erlotinib-induced rash remains absence in the literature. The objective of this study is to document the clinical manifestations of erlotinib-induced skin rash to determine if characteristic differences occur between different classes of EGFRIs. Methods: Retrospective single-center chart reviews were conducted in patients (pts) who received erlotinib 150 mg daily for treatment of non-small cell lung cancer (NSCLC). Exclusion criteria included: medical records not available, insufficient documentation, rash at start of erlotinib or rash that appeared within three days after starting erlotinib, and non-papulopustular rash. The demographics of the patients, EGFRI treatment information, and dermatologic intervention management were examined. Results: Forteen eligible pts identifed out of 152 pts screened. Nine pts were not evaluable because erlotinib dose was modified or inadequate follow-up period. The median age for the 5 evaluable pts was 62 years, 3 females, 1 current and 4 former smokers, and ethnicity distribution included 3 Caucasian, 1 Hispanic, and 1 Asian. Four pts received monotherapy erlotinib. The documented rash regression occurred at a median time of 32 days (range = 12-35 days) with up to 24 months follow-up duration. None of the five pts received antimicrobial therapy and 4 received topical treatment for the management of skin rash. Conclusions: This review confirmed the occurrence of spontaneous regression of erlotinib-induced papulopustular rash. More data are warranted to better understand the EGFR TKI-induced skin rash and to improve rash management. Practitioners should note the potential difference between EGFRI Mabs and TKIs-induced skin rash to determine if different management approaches should be considered to avoid premature dose modifications of the EGFR TKI therapy. No significant financial relationships to disclose.
Combination drug shows promise for treating agitation in patients with Alzheimer’s disease
Authors: Jacqui Wise
Journal: BMJ (2015)

A combination drug treatment can reduce agitation in patients with probable Alzheimer’s disease and is generally well tolerated, preliminary research published in JAMA has shown.1

The phase II double blind randomised clinical trial showed that patients who received the combination dextromethorphan hydrobromide and quinidine sulphate had lower occurrence and severity of agitation than patients who received placebo. This combination is approved in the United States and the European Union for treating pseudobulbar affect, a neurological disorder characterised by uncontrollable episodes of crying.

Agitation and aggression are common in dementia patients, which can be distressing for the patient and can put carers …
CEA-targeted engineered IL2: Clinical confirmation of tumor targeting and evidence of intra-tumoral immune activation.
Authors: Jan H. M. Schellens, Josep Tabernero, Ulrik Niels Lassen, Ignacio Melero, Krisztian Homicsko, Guillem Argilés, Jose Luis Perez Gracia, Morten Sorensen, George Coukos, ERIC ANGEVIN, Heikki Joensuu, Emilie Van Brummelen, Catharina Wilhelmina Menke, Tapan K. Nayak, Solange Romagnoli, Bernhard Reis, Sophia Soehrman Brossard, Stefan Evers, Jose M. Saro Suarez, Henk M.W. Verheul
Journal: Journal of Clinical Oncology (2015)

3016 Background: CEA-IL2v (RG7813) is an engineered IL-2 variant (IL-2v) with abolished IL-2Rα (CD25) binding fused to an antibody targeting Carcinoembryonic Antigen (CEA). The molecule was designed to improve the pharmacological and safety profile of IL-2 and enable tumor targeting. Methods: In an ongoing Phase I trial of CEA-IL2v (ranges 0.1 – 40 mg flat dose IV; schedule q1W and q2W) in patients (pts) with advanced and/or metastatic solid CEA+ tumors, extensive pharmacodynamic monitoring in peripheral blood as well as immunohistochemical (IHC) and flow cytometric (FC) analysis of pre- and on-treatment biopsy specimens (day + 4) were performed, including tests for effector (CD8+) and helper T cell (CD4+) percentage and density. In a sub-study, biodistribution was analyzed using PET imaging of 89Zr-CEA-IL2v at doses of 6 and 30 mg. Results: Of the 11 pts treated at 30 mg, 4 had sequential tumor biopsies evaluable both by IHC and FC. An increase in the median density (IHC) of CD8+ T cells from 62.5 (7 - 90) [median (range)] to 104.2 (7 - 255) cells/ mm2 was observed in 3/4 subjects after the 1st dose. No relevant change in the density of CD4+ T cells was detected. FC analysis confirmed the increase in CD8:CD4 ratio in the same 3/4 patients: from 0.88 (0.57 - 1.24) to 4.54 (0.36 - 7.47). Effects in peripheral blood included strong lymphocyte expansion that was mostly driven by Natural Killer (NK) and CD8+ T cells. Medians and ranges for the 11 pts before and 4 days after dosing were: NK: 168 (range: 52 - 337) vs. 655 (206 - 1569) cells/µl; CD8+: 340 (19 - 464) vs. 831 (78 – 3754) cells/µl. While there was no clear evidence of CEA-mediated tumor accumulation at 6 mg in the first 6 pts, intra-tumoral accumulation of 89Zr-CEA-IL2v was observed in 2/2 pts at 30 mg. Additional studies are ongoing. Conclusions: Collectively, these data support the concept that reduced affinity of CEA-IL2v for IL2R-alpha together with high-affinity binding to CEA enables tumor targeting. These findings suggest that CEA-IL2v is the first tumor-targeted cytokine, which increases immune infiltration and activates NK and T cells both in the periphery and within tumors. Clinical trial information: NCT02004106.
Effectiveness of cycle helmets
Authors: P. Priest
Journal: BMJ (1994)

EDITOR,--In their analytical epidemiological study of the effectiveness of cycle helmets, Steven Thomas and colleagues' discussion of biases was incomplete and possibly misleading.1 In the second paragraph of the discussion they describe some sources of bias that would cause their data to underestimate the strength of the association between wearing a helmet and reduced risk of injury to the upper head. They then state: “Similarly, reduction in the estimated risk of upper head injury would have been greater if …
Bevacizumab (BEV) plus chemotherapy (CT) continued beyond first progression in patients with metastatic colorectal cancer (mCRC) previously treated with BEV plus CT: Results of a randomized phase III intergroup study (TML study).
Authors: Dirk Arnold, Thierry Andre, Jaafar Bennouna, Javier Sastre, Pia J. Osterlund, Richard Greil, Eric Van Cutsem, Roger Von Moos, Irmarie Reyes-Rivera, Belguendouz Bendahmane, Stefan Kubicka
Journal: Journal of Clinical Oncology (2012)

CRA3503 The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Sunday, June 3, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
The Luminal P2Y Receptor in the Isolated Perfused Mouse Cortical Collecting Duct
Authors: PHILIPP DEETJEN, JO[Combining Diaeresis]RG THOMAS, HEIKO LEHRMANN, SUNG JOON KIM, JENS LEIPZIGER
Journal: Journal of the American Society of Nephrology (2000)

Abstract. Extracellular nucleotides regulate renal ion transport. With the use of in vitro perfusion and [Ca 2+ ] i imaging, this study investigated whether mouse and rabbit cortical collecting ducts (CCD) respond to luminal nucleotides. In mouse CCD, luminal ATP (EC 50 : 10 μM) and UTP (EC 50 : 9.7 μM) increased [Ca 2+ ] i with an initial peak and a plateau. To make certain that basolateral P2 receptors were not activated by luminal nucleotides via leak diffusion, luminal trypsin (1 μM), a known agonist for basolateral proteinase-activated receptors, was perfused. Mouse CCD that were responsive to luminal ATP were nonresponsive to luminal trypsin but always showed [Ca 2+ ] i elevations by basolateral trypsin (10 or 100 nM). Luminal α,β- and β,γ-methylene ATP, 2-methyl-S-ATP, ADP, UDP, and 2′,3′-O-4-benzoylbenzoyl ATP had no effect (100 μM, n = 9). Without external Ca 2+ , luminal ATP still stimulated a [Ca 2+ ] i increase. Mouse CCD also responded to basolateral ATP (EC 50 : 23 μM) and UTP (EC 50 : 23 μM) with smaller [Ca 2+ ] i elevations. Confocal microscopy of perfused CCD showed that luminal ATP (100 μM) rapidly increased [Ca 2+ ] i in nearly all cells ( n = 6) and the same cells that responded to luminal ATP responded to basolateral ATP (100 μM). In contrast, rabbit CCD did not respond to luminal ATP/UTP ( n = 8) despite ATP's known effect from the basolateral side (EC 50 : 34 μM). These data indicate the expression of luminal P2Y receptors (probably P2Y 2 ) in principal cells of mouse CCD but not in rabbit CCD.
Persistence and reactivation of human adenoviruses in the gastrointestinal tract
Authors: K Kosulin, E Geiger, A Vécsei, W-D Huber, M Rauch, E Brenner, F Wrba, K Hammer, A Innerhofer, U Pötschger, A Lawitschka, S Matthes-Leodolter, G Fritsch, T Lion
Journal: Clinical Microbiology and Infection (2015)
Minneapolis Hip Prosthesis in Severe Destructive Lesions of the Femur
Authors: J M Kumar, K Norcross
Journal: Journal of the Royal Society of Medicine (1985)

The use of the Minneapolis prosthesis was abandoned about 1955 by its originators, who had used it without acrylic for uncomplicated fractures of the femoral neck. This is the first report of its use with ‘cement’ fixation. It has been found to be very useful and reliable for arthroplasty of the hip in 57 patients with carcinomatous or other severe destructive lesions in the trochanteric region of the femur, being more convenient and easier to use than alternative prostheses and especially valuable in metastatic disease. Technical points relating to operative techniques are described, and postoperative Hamilton-Russell traction is recommended.
Identification of a Systemic Lupus Erythematosus Risk Locus Spanning <i>ATG16L2, FCHSD2</i>, and <i>P2RY2</i> in Koreans
Authors: Christopher J. Lessard, Satria Sajuthi, Jian Zhao, Kwangwoo Kim, John A. Ice, He Li, Hannah Ainsworth, Astrid Rasmussen, Jennifer A. Kelly, Miranda Marion, So‐Young Bang, Young Bin Joo, Jeongim Choi, Hye‐Soon Lee, Young Mo Kang, Chang‐Hee Suh, Won Tae Chung, Soo‐Kon Lee, Jung‐Yoon Choe, Seung Cheol Shim, Ji Hee Oh, Young Jin Kim, Bok‐Ghee Han, Nan Shen, Hwee Siew Howe, Edward K. Wakeland, Quan‐Zhen Li, Yeong Wook Song, Patrick M. Gaffney, Marta E. Alarcón‐Riquelme, Lindsey A. Criswell, Chaim O. Jacob, Robert P. Kimberly, Timothy J. Vyse, John B. Harley, Kathy L. Sivils, Sang‐Cheol Bae, Carl D. Langefeld, Betty P. Tsao
Journal: Arthritis & Rheumatology (2015)

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder whose etiology is incompletely understood, but likely involves environmental triggers in genetically susceptible individuals. Using an unbiased genome-wide association (GWA) scan and replication analysis, we sought to identify the genetic loci associated with SLE in a Korean population.
Automated external defibrillators in public places: position statement from the Faculty of Sport and Exercise Medicine UK
Authors: Zafar Iqbal, John Somauroo
Journal: British Journal of Sports Medicine (2015)

Position statements published by the Faculty of Sport and Exercise Medicine UK are quick reference or information documents and include up to 10 short points of clinical relevance for the Sport and Exercise Medicine community as well as for general practitioners and health professionals. The Faculty of Sport and Exercise Medicine (FSEM) UK has published a statement to create greater awareness that the survival rate from Sudden Cardiac Arrest could improve with prompt access to an automated external defibrillator (AED).
Rendezvous computed tomography-assisted endoscopic needle-knife stricturotomy for sealed outlet of diverted large bowel
Authors: Custon Nyabanga, Joseph Veniero, Bo Shen
Journal: Endoscopy (2015)

The patient was a 27-year-old woman, with a past medical history notable for 15 years of recalcitrant Crohn's disease with severe perianal fistulas and strictures, and anemia, psoriasis, and osteoporosis. Throughout, she had been treated with glucocorticoids for flare-ups and with antibiotics, surgical drainage, and seton placement for her perianal disease. Periodic remission was maintained with immunomodulators and antitumor necrosis factor (anti-TNF) biologic therapies throughout the disease course.