tbuckley/cabot-search huggingface dataset:
External validation of a sunitinib prognostic nomogram in patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Changhong Yu, Michael W. Kattan, Thomas E. Hutson, Gary R. Hudes, Jinyu Yuan, Olga Valota, Robert John Motzer
Journal: Journal of Clinical Oncology (2012)

e15070 Background: A nomogram was previously developed from pretreatment clinical features to predict the probability of achieving 12-month progression-free survival (PFS) with sunitinib in treatment (Tx)-naïve mRCC pts from a randomized, phase 3 trial (Cancer 2008;113:1552). Here, validation and update of this nomogram using pts from a phase 2 sunitinib mRCC study (Renal EFFECT Trial) is reported, as is evaluation of its usefulness for clinical decision making. Methods: The Tx-naïve mRCC pts included in the current analysis were randomized 1:1 to sunitinib 50 mg/d on a 4-weeks-on-2-weeks-off schedule (Schedule 4/2; n=146) or 37.5 mg/d on a continuous daily dosing (CDD) schedule (n=146). The variables included in the prior nomogram and used here for validation purposes were corrected serum calcium, number of metastatic sites, hemoglobin, prior nephrectomy, presence of lung and liver metastases, ECOG performance status, thrombocytosis, time from diagnosis to treatment, alkaline phosphatase, and lactate dehydrogenase. The nomogram was updated by removing prior nephrectomy as a variable, including baseline neutrophils and presence of bone metastases, and replacing thrombocytosis with baseline platelets. Validation of the existing and updated nomograms consisted of quantification of the discrimination with the concordance index. A decision curve analysis was used to examine whether this prediction model is useful for medical decision making. Results: With comparable pt characteristics and no significant difference in PFS (8.5 vs. 7.0 months; P=0.070) between the Schedule 4/2 and CDD arms of the phase 2 trial, the combined pt population (N=292) was used to validate the existing nomogram. The overall concordance index was 0.615. Based on the decision curve analysis, the existing nomogram has clinical utility when the probability of 12-month PFS exceeds 60%. Using Schedule 4/2 pts only, the concordance index was 0.594 for the updated nomogram; however, its utility showed more variability. Conclusions: The sunitinib nomogram has been validated in a similar pt cohort; however, its clinical utility may be limited and more research is needed to refine the tool further.
Clinical significance of mutational status in gastrointestinal stromal tumors (GIST).
Authors: Peter Arkhiri, Ivan S. Stilidi, I. Poddubnaya, Maxim P. Nikulin, Natalia Tsymzhitova, Natalia N. Mazurenko
Journal: Journal of Clinical Oncology (2012)

e20501 Background: Mutational status of GIST patients plays an important role in clinical practice. In most cases, mutations are localized in KIT exon 11. KIT exon 9 mutations are less common and are associated with poor prognosis. The study aims to analyze the prognostic role of mutational status and type of mutation in GIST patients. Methods: Analysis of the mutational status of 52 GIST patients with localized disease was conducted between January 1, 2001 and November 1, 2007. KIT/PDGFRA tyrosine kinase inhibitors were used in the treatment of GIST patients with diseases progression only. Results: 89.6% of KIT mutations were associated with spindle cell stromal tumors while 85.7% of PDGFRA - with gastric epithelioid GISTs. KIT mutations were discovered in 40 patients (76.9%), of which 34 cases (65.5%) exhibited 11 exon, 5 (9.6%) – 9 exon and 1(1.9%) case - 13 exon. PDGFRA mutations have been detected in 7 (13.5%) patients and all of them involved 18 exon. Deletions were detected in 17 cases: 10 in patients with gastric and 7 with small intestinal GISTs. Less frequent were substitutions, in 14 patients and duplications, in 3 patients. All 5 cases with KIT 9 exon mutations were duplications in small intestine stromal tumors. Duplications and substitutions in 11 exon KIT were associated with better clinical outcome (5-year survival rate of 100.0% and 75.0 ± 21.7%) when compared with deletions and duplications in 9 exon (5-year survival rate of 48.4 ± 14.1% and 25.0 ± 21.7%). Survival analyses with deletions KIT 11 exon showed no significant difference, with 5 year survival rate in patients with gastric stromal tumors of 47.6 ± 17.1%, compared with 53.3 ± 17.3% in intestinal tumors (g = 0.6496). Conclusions: The better prognosis was observed for patients with duplications and substitutions in 11 exon KIT and worse outcome—in patients with deletions in 11 and duplications in 9 exon KIT. No prognostic difference has been detected in patients with gastric and small intestinal stromal tumors with similar mutations (deletions in KIT exon 11). The poor prognosis in small intestinal stromal tumors patients is probably due to duplications in KIT exon 9.
BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease
Authors: Nour M. Moussa‐Pacha, Shifaa M. Abdin, Hany A. Omar, Hasan Alniss, Taleb H. Al‐Tel
Journal: Medicinal Research Reviews (2019)

Abstract Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no current cure. One of the important therapeutic approaches of AD is the inhibition of β‐site APP cleaving enzyme‐1 (BACE1), which is involved in the rate‐limiting step of the cleavage process of the amyloid precursor protein (APP) leading to the generation of the neurotoxic amyloid β (Aβ) protein after the γ‐secretase completes its function. The produced insoluble Aβ aggregates lead to plaques deposition and neurodegeneration. BACE1 is, therefore, one of the attractive targets for the treatment of AD. This approach led to the development of potent BACE1 inhibitors, many of which were advanced to late stages in clinical trials. Nonetheless, the high failure rate of lead drug candidates targeting BACE1 brought to the forefront the need for finding new targets to uncover the mystery behind AD. In this review, we aim to discuss the most promising classes of BACE1 inhibitors with a description and analysis of their pharmacodynamic and pharmacokinetic parameters, with more focus on the lead drug candidates that reached late stages of clinical trials, such as MK8931, AZD‐3293, JNJ‐54861911, E2609, and CNP520. In addition, the manuscript discusses the safety concerns and insignificant physiological effects, which were highlighted for the most successful BACE1 inhibitors. Furthermore, the review demonstrates with increasing evidence that despite tremendous efforts and promising results conceived with BACE1 inhibitors, the latest studies suggest that their clinical use for treating Alzheimer's disease should be reconsidered. Finally, the review sheds light on alternative therapeutic options for targeting AD.
Catherine Helen Roberts
Authors: Bethany Davies
Journal: BMJ (2019)

Catherine Helen Roberts (“Cathy”) studied preclinical medicine at St Catherine’s College, Oxford, in 1996-99. She gained an MA Hons (Oxon) in physiological sciences before transferring to University College London Medical School for her clinical studies. After junior doctor posts in central London and a post in Thailand, she pursued her interest in infections and gained a specialty training number in infectious diseases and medical microbiology. She enjoyed the challenge of the tropical diseases she encountered while working at the Hospital for Tropical Diseases and the rare and imported pathogens laboratory at Porton Down before taking an out-of-programme period for research (OOPR) in this area. She was awarded a Wellcome tropical academic fellowship …
Phase I safety, pharmacokinetic (PK), and pharmacodynamic (PD) trial of NGR-hTNF given at high doses in patients with refractory solid tumors.
Authors: Paolo Andrea Zucali, Matteo Simonelli, Fabio De Vincenzo, Elena Lorenzi, Matteo Perrino, Monica Bertossi, Luca Balzarini, Cristina Bonifacio, Antonio Lambiase, Claudio Bordignon, Armando Santoro
Journal: Journal of Clinical Oncology (2012)

2580 Background: NGR-hTNF exploits the asparagine-glycine-arginine (NGR) peptide for selectively targeting tumor necrosis factor (TNF) to a CD13 overexpressed by tumor vasculature. Maximum tolerated dose (MTD) of NGR-hTNF was previously established at 45 µg/m 2 , when given as 1-h infusion every 3 weeks (q3w), with dose limiting toxicities (DLT) being grade 3 infusion-related reactions (IRRs). We explored further dose escalation by prolonging infusion time (2-h) and using premedication (paracetamol). Methods: DLTs were defined as drug-related grade 3/4 adverse events (AEs). PK and soluble TNF receptors (sR1-sR2) were tested in 46 pts. The volume transfer coefficient (K trans ) and initial area under gadolinium concentration (IAUGC) were assessed before and 2 hours after dosing by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in 37 pts. Results: 12 dose levels (DLs) from 60 to 325 μg/m² q3w were evaluated. 48 pts (PS 0/1: 21/27; M/F: 37/11; median age: 61 years) received a total of 117 cycles (range 1-6). Prior regimens ranged from 1 to 7 (median 3). No DLT occurred and MTD was not reached. Study-emergent grade 3 and 4 AEs were reported in 12 (25%) and 5 (10%) pts, respectively. Grade 1/2 IRRs included chills (58%) and pyrexia (56%). Both C max (p&lt;.0001) and AUC (p=.0001) increased with dose. Post-treatment peaks of sR2 were higher than sR1 (9.6 v 4.9 ng/mL; p&lt;.0001). However, changes in sRs did not differ across DLs, with a plateau in shedding kinetics. By DCE-MRI assessment, median pre- and post-first cycle values declined from 0.15 to 0.09 min -1 for K trans (p=.02) and from 10.2 to 7.2 mM/L/sec for IAUGC (p =.0005). Over treatment, 28 pts (76%) showed decreases in IAUGC (-47%, p&lt;.0001) and K trans (-59%; p&lt;.0001) that were inversely correlated with baseline K trans values (p&lt;.0001) and NGR-hTNF C max (p=.03). Of 41 evaluable pts, 12 (29%) had stable disease for a median time of 2.9 months. Survival at 1 year was 34%, with improved survival observed in pts with lower sTNF-R2 levels (p=.01) and greater K trans reductions (p=.05) after 1st cycle. Conclusions: NGR-hTNF can be safely escalated at doses higher than MTD and induces low shedding of receptors and early antivascular effects.
Using social network knowledge to enhance customer churn prediction
Authors: Wai Tsang, Dries Benoit
Journal: Eurosurveillance (2016)

Customer churn prediction plays a crucial role in Customer Relationship
Management (CRM). Early detection whether a customer will
leave the company or not, can prevent potential damage to the customer
base. Basic churn models do not fully take advantage of the
connectivity between customers and mostly consider a limited form of
network information. A suitable approach to fully exploit the interrelatedness
between customers is provided by probabilistic graphical
models that can model the probability to churn by making use of graph
structures and probability theory. By analyzing network information
in a framework of probabilistic graphical models, knowledge about the
connectivity among customers can be exploited to enhance churn prediction.
Listeria monocytogenes-associated endovascular infections: A study of 71 consecutive cases
Authors: Michka Shoai-Tehrani, Benoit Pilmis, Mylène M. Maury, Olivier Robineau, Olivier Disson, Gregory Jouvion, Gabrielle Coulpier, Pierre Thouvenot, Hélène Bracq-Dieye, Guillaume Valès, Alexandre Leclercq, Marc Lecuit, Caroline Charlier
Journal: Journal of Infection (2019)
The influence of radiotherapy and chemotherapy on survival and quality of life of patients with cerebral metastases
Authors: L. Markulin-Grgi, F. Santek
Journal: Journal of Clinical Oncology (2007)

12535 Background: The problem of cerebral metastases is a great one and seams to become more and more important thanks to the earlier diagnosis of malignant tumors and to the possibility of effective treatment of carcinomas which leads to prolongation of life of patients with malignant disease. Although many patients with malignant tumors develop symptoms of cerebral metastases in course of their disease, even more cerebral metastatses are found at the post mortem. Because autopsies are undertaken very rarely, the true incidence of cerebral metstases can only be estimated. Surgery is indicated in patients with solitary or 2 adjacent metastases. Radiotherapy is the most common method of treatment, sometimes after surgery, but mostly as the only method and in combination with chemotherapy. Methods: 165 patients with cerebral metastases treated at the Clinic of Radiotherapy and Oncology, School of Medicine, University Hospital Center Zagreb from 1995 to 2000 are discussed. The commonest primary tumor was bronchial carcinoma in 87/165 of patients (52,8%) followed by breast carcinoma in 36/165 (21,8%). In 10/165 (6,1%) of the patients the primary tumor was unknown. The patient were treated by radiotherapy, chemotherapy and surgery in various combinations. Results: The survival was significantly better in younger patients taking into account the median of age as 56 years (p&lt;0,05). In the group of 78/165 patients who were treated only by radiotherapy (47,2%) the median survival was 6 months (1–38 months). In the group of 87/165 (52,8%) treated by radiotherapy and chemotherapy the median survival was 8 months (1–48 months) (p&lt;0,001) There was no influence of duration of the symptoms on survival of our patients (p&gt;0,05) Conclusions: According to treatment modalities, the best survival results were observed in patients treated by a combination of surgery, radiotherapy and chemotherapy (p&lt;0,001). No significant financial relationships to disclose.
Unbounded—Parent-Physician Communication in the Era of Portal Messaging
Authors: Tracy A. Lieu, Gary L. Freed
Journal: JAMA Pediatrics (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Efficacy and safety of ingenol mebutate gel in field treatment of actinic keratosis on full face, balding scalp, or approximately 250 cm2 on the chest: A phase 3 randomized controlled trial
Authors: C. William Hanke, Lorne Albrecht, Torsten Skov, Thomas Larsson, Marie Louise Østerdal, Lynda Spelman
Journal: Journal of the American Academy of Dermatology (2019)
Blood Pressure Variability and Arterial Stiffness—Chicken or Egg?—Reply
Authors: Donald Clark, Rishi Puri
Journal: JAMA Cardiology (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal
A PHD in immunosuppression: oxygen-sensing pathways regulate immunosuppressive Tregs
Authors: Weiping Zou, Yatrik M. Shah
Journal: Journal of Clinical Investigation (2019)

The oxygen-sensing prolyl hydroxylase domain (PHD) enzymes are key to maintaining tissue homeostasis during hypoxia via their regulation of the expression and activity of HIF, the master transcription factor for the hypoxic response. In this issue of the JCI, Yamamoto, Hester, and colleagues show that temporal and reversible inhibition of PHD2 in vivo leads to systemic autoimmune disorder. The work demonstrates that a reduction of PHD2 leads to impairment of immunosuppressive Treg cell function via a HIF2α-dependent mechanism, without altering Foxp3 expression. This study indicates that a PHD2/HIF2α axis is critical for maintaining proper Treg function.
Should patients with peritoneal carcinomatosis of colorectal origin with synchronous liver metastases be treated with curative intent? A case-control study.
Authors: Goere Diane, Leon Maggiori, Benjamin Viana, Frédéric Dumont, Charles Honoré, David Malka, Dominique Elias
Journal: Journal of Clinical Oncology (2012)

e14158 Background: This aim of this case-control study was to assess the prognostic impact of the presence of liver metastases (LM) in patients operated on colorectal peritoneal carcinomatosis (PC) who underwent complete cytoreductive surgery (CRS) and LM resection followed by intraperitoneal chemotherapy. Methods: From a prospectively maintained database, all patients with colorectal PC and synchronous LM who underwent CRS followed by intraperitoneal chemotherapy, were manually matched to all identical patients with isolated PC, operated on over the same period, on the following matching criteria: age, peritoneal cancer index (PCI), site of the primary colorectal cancer (colon or rectum), lymph node involvement on the primary colorectal cancer specimen (pN), and postoperative chemotherapy. Results: From 1993 to 2009, 37 patients with PC and LM were matched to 61 patients with isolated PC. After a mean follow-up of 36 months, 3-year overall (OS) and disease free survival rates were significantly lower in patients with PC and LM, respectively 40% and 66% (p=0.04) and 6% and 27% (p=0.001). In Cox regression analysis, a PCI ≥ 12 (Odds-ratio (OR): 4.6), a pN+ status (OR: 3.3), no adjuvant chemotherapy (OR: 3.0) and presence of LM (OR: 2.0) were identified as independent factors of poor OS. Thus, 3 groups could be identified: 1) patients with a low PCI (&lt;12) and no LM, with an associated a median OS of 76 months; 2) patients with a low PCI (&lt;12) and 1 or 2 LM, with an associated OS of 40 months; and 3) patients with a high PCI (≥12) or patients with ≥ 3 LM, with an associated OS of 27 months. Conclusions: This first case-control study confirms that prolonged survival can be achieved in highly selected patients operated on limited carcinomatosis and liver metastases less than 3. When the peritoneal and the liver involvement are greater, the complete surgical treatment followed by intraperitoneal chemotherapy should be discussed according to criteria of aggressiveness of the tumor disease.
Prescribing plans (PP) of American Oncologists for first-line therapy (Rx) for patients with stage III (wet)/IV non-small cell lung cancer (NSCLC) and PS 2: Overall selection and impact of gender and smoking status
Authors: M. Shabbir, L. Daniels, K. Shirai, S. Cole, J. Willey, L. Iovino, K. Labarre, M. R. Green
Journal: Journal of Clinical Oncology (2009)

e19046 Background: Selection of oral EGFR inhibitors or chemotherapy as 2 nd line in patients with NSCLC may be influenced by patients’ performance status (PS), smoking status, gender; tumor histology; tolerance/response to 1 st -line Rx; and patient expectations/desires. Methods: Between February ’07 and October ’08, we used a core case scenario of stage IV mucin positive adenocarcinoma (Adeno ca) of lung in a 68-year-old former smoker (FS; stopped 6 years ago) with PS 2, to study patient related variations in PP of almost 800 American medical oncologists during 10 live research events [393 MDs/5 events during 2008]. Impact of gender or/and smoking history on 1 st -line Rx selection was assessed. Results: In 2007–08, 97%/97%% MDs planned anti-tumor Rx: 53%/63% combination; 44%/34% single agent. PP for 2008 is shown in the table . [2007 PP data for erlotinb use included]. PP for erlotinib in these 4 scenarios are stable over the 2007 - 08 testing interval. Impact of smoking status dominates over gender. For a female NS with Adeno ca /PS2, ≥2/3 of MDs plan erlotinib 1 st -line. In the absence of testing results for EGFR expression by IHC, EGFR gene copy number by FISH, EGFR gene mutation testing, or kras mutation testing, our data show a direct correlation of patient “phenotype” and PP for erlotinib as 1 st -line Rx, a setting not specifically an approved indications for this agent. The impact of recently reported progression free survival data from an Asian phase III trial (IPASS: gefitinib or chemotherapy or as 1 st -line therapy in non or former light-smoking patients with lung adenoca) on future prescribing plans in this clinical setting will be of great interest. Conclusions: By our observations, smoking status dominates over gender in PP of oncologists when treating wet IIIB/IV Adeno ca of lung. Therefore we plan to continue to assess American oncologists’ PP for this NSCLC setting during 2009. [Table: see text] [Table: see text]
Fractures and health care resource use in cancer patients with chemotherapy-associated peripheral neuropathy (CAPN).
Authors: Arijit Ganguli, Patrick J Reilly, Saurabh Ray
Journal: Journal of Clinical Oncology (2012)

e13038 Background: Chemotherapy has been associated with increased risk of fractures1. This study examines the real-world incidence of fractures and healthcare resource use (HRU) that may be associated with CAPN in cancer patients. Methods: A retrospective analysis utilized a national health insurer claims -database (2001-2009), to identify patients ≥18 yrs with a cancer ICD-9-code (140-239) and a chemotherapy drug code (J9xxx). The 1st chemotherapy date was the "index date." Patients with a record of peripheral neuropathy (PN) in the pre-index date were excluded. Patients with a PN post-index were matched with no-PN post-index (non-PN) based on gender, age and index date. Both groups were compared for number of fractures, HRU (hospital outpatient (OP), office, and emergency-room [ER] visits) and all-cause costs in their 365-days post-index period. Time to 1st fracture post-index was compared using Kaplan Meier time to event analysis. Results: Of 34,625 patient meeting the inclusion criteria, 1675 patients (4.3%) formed the PN group and were matched to non-PN group. At baseline, mean age was 54.9 yrs, 62.5% were females, and no difference in % of bone metastasis (p=0.12) between the groups. In PN group, 5.3% (n=87) had a fracture 365-days post-index compared to 3.5% (n=58) in non-PN group (p&lt;0.05). Mean days to fracture from index date in PN group was shorter than the non-PN group (150.9 vs. 153.4, p&lt;0.05). In PN group, annual mean number of OP visit (14.6 vs. 12.0, p&lt;0.0001), ER visit (0.47 vs. 0.30, p&lt;0.001), and office visits (30.4 vs. 23.3, p&lt;0.0001), were higher compared to non-PN group. Annual healthcare cost of PN patients was 21% higher than non-PN patients ($64,578 vs. $53,221) and CAPN-related cost in PN group was estimated to be $5,580 annually. Conclusions: Patients with CAPN were associated with higher incidence of fractures, HRU and cost.