tbuckley/cabot-search huggingface dataset:
A phase I study of PF-06647263, a novel EFNA4-ADC, in patients with metastatic triple negative breast cancer.
Authors: Ignacio Garrido-Laguna, Ian E Krop, Howard Burris, Erika Paige Hamilton, Fadi S. Braiteh, Amy Weise, Maysa M. Abu-Khalaf, Christopher Zopf, Mani Lakshminarayanan, Jaymes S. Holland, Raffaele Baffa, David S. Hong, Raffit Hassan
Journal: Journal of Clinical Oncology (2017)

2511 Background: PF-06647263 is an anti-Ephrin-A4 (EFNA4) antibody drug conjugate (ADC) composed of a humanized mAb, a hydrazone cleavable linker, and calicheamicin, a potent DNA damaging agent. Higher levels of EFNA4 expression have been shown in tumor versus normal tissue, including in two thirds of triple negative breast cancers (TNBC). In vivo preclinical studies demonstrate PF-06647263 induced tumor regression in TNBC models. Methods: In Part 1 of a dose escalation, cohorts of 2-12 patient (pts) with solid tumors that were unselected for EFNA4 expression received escalating doses of PF-06647263 once every 3 weeks (Q3W, Cohort A) or weekly (QW, Cohort B). Escalations were based on mTPI design. An expansion cohort enrolled TNBC patients (n=12) unselected for EFNA4 expression. Efficacy, safety, EFNA4 RNA expression, pharmacokinetic (PK) and anti-drug antibody development were assessed. Results: Part 1 (dose escalation):A total of 48 pts (25 in A and 23 in B) wereenrolled. The most common treatment related adverse events (AE) were fatigue (65%), and nausea (60%), thrombocytopenia (40%), and decreased appetite (38%). DLTs were observed in 6 and 2 pts in the Q3W and QW regimens, respectively. One confirmed VOD and one suspected VOD were observed in two patients in the Q3W schedule. The maximum tolerated dose (and RP2D) was determined to be 0.015 mg/kg QW. Confirmed partial responses (PR) were observed in 5 pts (3 Ovarian Ca and 2 TNBC). Part 2 (TNBC dose expansion at RP2D)data are available on 10 of 12 pts treated (2 ongoing). The most common adverse events (AE) were nausea (40%), asthenia (30%), vomiting (30%) and mucosal inflammation (30%). No objective RECIST response was observed; there was no dependency with duration of treatment relative to EFNA4 expression. Conclusions: In Part 1 of this study, PF-06647263 was generally well-tolerated in the QW schedule and some anti-tumor activity was observed in heavily pretreated pts with EFNA4 unselected advanced malignancies. However, in the expansion cohort (Part 2) at RP2D in TNBC no objective responses were observed regardless of EFNA4 expression. Final safety, efficacy, expression and PK data will be reported at the meeting. Clinical trial information: NCT02078752.
Long-term responders to first-line bevacizumab-based therapy in metastatic breast cancer (MBC) patients: Results of the observational study LORENA.
Authors: Manuel Ramos Vazquez, Andres Redondo, Luis Manso, Miquel Gil, Isabel Garau, Ramon Perez-Carrion, Elisa Garcia-Garre, Cesar Augusto Rodriguez, Jose Ignacio Chacon, Guillermo Lopez-Vivanco
Journal: Journal of Clinical Oncology (2017)

e12563 Background: Randomized controlled trials in MBC patients evaluating bevacizumab as first-line treatment showed improvements in tumor response and progression-free survival (PFS) when added to chemotherapy. The aim of the LORENA study was to describe the clinical features, prognosis factors and safety of bevacizumab and chemotherapy treatment for MBC in routine practice. Methods: Observational, multicentre, ambispective study conducted in Spain. The study had a retrospective and a prospective phase. Data were obtained from March 2012 to October 2013. In the retrospective phase, eligible patients were women with metastatic or locally-advanced breast cancer, treated with bevacizumab as a first-line therapy, and progression-free survival for ≥ 12 months. In the prospective phase, patients were followed-up and assessed as per routine clinical practice. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Univariate and multivariate analyses of prognostic factors were performed. Results: 148 women from 38 centers were included. The mean age was 52 (±11) years. Bone, lung and liver were the most frequent metastasis sites. 138 patients were HER2-neg. on diagnosis (data unknown in 10 patients). The mean exposure to bevacizumab was 18 (±11) months. Most patients had objective response, 23% complete response, and 57% partial response. Median OS was 58.2 months and median PFS was 22.7 months. In multivariate analyses, OS was higher in patients with hormonal maintenance therapy (HMT) (p = 0.009; HR = 2.0) and in patients not treated with taxanes before the metastatic diagnosis (p &lt; 0.0001; HR = 3.3); also, PFS was higher in patients with HMT (p = 0.002; HR = 1.8). No adverse events were observed other than those reported previously. Conclusions: Outcomes of OS and PFS suggest a benefit from bevacizumab maintained therapy. HMT was a PFS prognosis factor. HMT and not having been treated with taxanes before the metastatic diagnosis were two independent OS prognosis factors. Our results could provide further evidence supporting the use of bevacizumab as maintenance therapy for MBC patients.
ISOWN: accurate somatic mutation identification in the absence of normal tissue controls
Authors: Irina Kalatskaya, Quang M. Trinh, Melanie Spears, John D. McPherson, John M. S. Bartlett, Lincoln Stein
Journal: Genome Medicine (2017)

A key step in cancer genome analysis is the identification of somatic mutations in the tumor. This is typically done by comparing the genome of the tumor to the reference genome sequence derived from a normal tissue taken from the same donor. However, there are a variety of common scenarios in which matched normal tissue is not available for comparison. In this work, we describe an algorithm to distinguish somatic single nucleotide variants (SNVs) in next-generation sequencing data from germline polymorphisms in the absence of normal samples using a machine learning approach. Our algorithm was evaluated using a family of supervised learning classifications across six different cancer types and ~1600 samples, including cell lines, fresh frozen tissues, and formalin-fixed paraffin-embedded tissues; we tested our algorithm with both deep targeted and whole-exome sequencing data. Our algorithm correctly classified between 95 and 98% of somatic mutations with F1-measure ranges from 75.9 to 98.6% depending on the tumor type. We have released the algorithm as a software package called ISOWN (Identification of SOmatic mutations Without matching Normal tissues). In this work, we describe the development, implementation, and validation of ISOWN, an accurate algorithm for predicting somatic mutations in cancer tissues in the absence of matching normal tissues. ISOWN is available as Open Source under Apache License 2.0 from https://github.com/ikalatskaya/ISOWN .
Warnings for Anesthetic Drugs
Authors: Rebecca Voelker
Journal: JAMA (2017)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
Phase I/II study of an implantable device delivering low intensity pulsed ultrasound (LIPU) to disrupt the blood-brain barrier (BBB) followed by intravenous carboplatin chemotherapy in patients with recurrent glioblastoma (GBM).
Authors: Ahmed Idbaih, Michael Canney, Alexandre Vignot, Bruno Law-Ye, Caroline Dehais, Caroline Houillier, Florence Laigle-Donadey, Jean-Yves Delattre, Alexandre Carpentier
Journal: Journal of Clinical Oncology (2017)

2034 Background: The BBB prevents the passage of most drugs from the blood to the brain and may be responsible for the limited efficacy of current chemotherapies in GBM patients. Two to four minutes of LIPU in combination with injection of micron-sized microbubbles has been shown to be a safe method for disrupting the BBB for a duration of 6 hours to increase the passage of drugs such as carboplatin by 5 to 7 fold in normal brain. Methods: Patients with recurrent GBM were implanted with a 1 MHz, 10-mm diameter pulsed ultrasound device in a burr hole during additional debulking surgery or during a dedicated procedure under local anesthesia. Ultrasound dose was escalated using a 3+3 Simon design. The device was activated monthly in combination with injection of a sulfur hexafluoride microbubble to transiently disrupt the BBB in 5 cm 3 of the tumor field before IV administration of carboplatin chemotherapy (AUC4-6). Patients received 150-270 seconds of pulsed ultrasound &lt; 1 hour prior to chemotherapy. BBB disruption was visualized using contrast-enhanced T1w MRI, and patients were monitored clinically and with T2, FLAIR, DWI and SWI sequences. Tumor progression was evaluated using the RANO criteria. Results: Nineteen patients were treated by LIPU until tumor progression. In 65 ultrasound sessions, 52 showed BBB disruption. The median number of monthly sonications per patient was 3 and ranged from 1-10. No significant adverse events related to ultrasound sonications were observed. Six patients (31%) had long PFS (19, 20, 35, 38, 40, 52 weeks). When tumor recurrence occurred, it was predominantly outside of the ultrasound sonication field. Conclusions: This trial has demonstrated that LIPU is a safe modality for disrupting the BBB in GBM patients and may increase the effectiveness of drug therapies in the brain. The sonication of larger volumes of brain may further increase the effectiveness of this therapy in patients with GBM. Clinical trial information: NCT02253212.
A phase 3 randomized placebo-controlled trial of darbepoetin alfa in patients with anemia and lower-risk myelodysplastic syndromes
Authors: U Platzbecker, A Symeonidis, E N Oliva, J S Goede, M Delforge, J Mayer, B Slama, S Badre, E Gasal, B Mehta, J Franklin
Journal: Leukemia (2017)

The use of darbepoetin alfa to treat anemia in patients with lower-risk myelodysplastic syndromes (MDS) was evaluated in a phase 3 trial. Eligible patients had low/intermediate-1 risk MDS, hemoglobin ⩽10 g/dl, low transfusion burden and serum erythropoietin (EPO) ⩽500 mU/ml. Patients were randomized 2:1 to receive 24 weeks of subcutaneous darbepoetin alfa 500 μg or placebo every 3 weeks (Q3W), followed by 48 weeks of open-label darbepoetin alfa. A total of 147 patients were randomized, with median hemoglobin of 9.3 (Q1:8.8, Q3:9.7) g/dl and median baseline serum EPO of 69 (Q1:36, Q3:158) mU/ml. Transfusion incidence from weeks 5–24 was significantly lower with darbepoetin alfa versus placebo (36.1% (35/97) versus 59.2% (29/49), P=0.008) and erythroid response rates increased significantly with darbepoetin alfa (14.7% (11/75 evaluable) versus 0% (0/35 evaluable), P=0.016). In the 48-week open-label period, dose frequency increased from Q3W to Q2W in 81% (102/126) of patients; this was associated with a higher hematologic improvement–erythroid response rate (34.7% (34/98)). Safety results were consistent with a previous darbepoetin alfa phase 2 MDS trial. In conclusion, 24 weeks of darbepoetin alfa Q3W significantly reduced transfusions and increased rates of erythroid response with no new safety signals in lower-risk MDS (registered as EudraCT#2009-016522-14 and NCT#01362140).
BISPHOSPHONATES DECREASE HTERT IN PC3 AND DU-145 PROSTATE CANCER CELLS
Authors: Bertoldo Francesco, Valenti Maria Teresa, Carbonare Luca Dalle, Azzarello Giuseppe, Balducci Elena, Zanatta Mirko, Zenari Sonia, Cascio Vincenzo Lo, Vinante Orazio
Journal: Annals of Oncology (2005)
Give patients direct access to physiotherapy. They want it, and it would benefit GPs too
Authors: Middleton Karen
Journal: British Journal of Sports Medicine (2017)

You could say that parliament first approved the idea of direct access to physiotherapy in 1977, when it granted clinical autonomy to physiotherapists in the United Kingdom. Since the following year any patients seeking private treatment have been able to refer themselves directly to a physiotherapist.

It's a global concept, too: a 2012 survey found that direct referral for physiotherapy was available in 40 countries, including Australia, Brazil, South Africa, Sweden, and parts of the United States.1 

Yet a freedom of information audit conducted by the Chartered Society of Physiotherapy in 2014 showed a strangely inconsistent approach in the NHS.2 In Scotland, 12 of the 14 health boards confirmed that they have full self referral, and the remainder offer it partially, either in selected areas or only for specific conditions. Patients in Wales can access physiotherapy directly in five of seven health board areas. But …
Association of discovered novel SNPs of FGFR2 and MAP3K1 genes from next-generation sequencing with the prognosis of hormone receptor-positive early breast cancer patients.
Authors: Sung Hsin Kuo, Po-Han Lin, Shi-Yi Yang, Chiun-Sheng Huang
Journal: Journal of Clinical Oncology (2016)

e12054 Background: We and other investigators have demonstrated that CYP19TTTA repeat polymorphism, MAP3K1 rs889312, FGFR2 rs2981582, ABCB1 rs2032582, and TOX3 rs3803662 are associated with the prognosis of hormone receptor (HR)-positive early breast cancer patients. In this study, we assessed whether undiscovered single nucleotide polymorphisms (SNPs) of CYP19A1, MAP3K1, FGFR2, ABCB1, and TOX3are associated with clinical outcome of these patients. Methods: Using next-generation sequencing (NGS), we performed target region re-sequencing to analyze unidentified SNPs located in the candidate genes of CYP19A1, MAP3K1, FGFR2, ABCB1, and TOX3 in 84 HR+ early breast cancer patients with negative or 1 to 3 lymph nodal (LN) metastases. Among them, 74 (88.1%) with grade 1-2, 15 (17.9%) with HER2, and 16 (19.0%) with positive LN. The multivariate-adjusted hazard ratio of overall survival (OS) associated with the individual genotypes was assessed after adjusting for age, tumor size, tumor grade, HER2 status, and chemotherapy using Cox regression analyses. Results: Through target region re-sequencing, we identified 69 novel SNPs in 80 patients, whereas another 4 patients had no any genotype data. With the approach of multi-locus association of aforementioned SNPs, 16 MAP3K1 SNPs located in chromosome 5, 18 ABCB1 SNPs located in chromosome 7 (ABCB1), 12 FGFR2 SNPs located in chromosome 10, 18 CYP19A1 SNPs located in chromosome 15, and 5 TOX3 SNPs located in chromosome 16 were found. After multivariate-adjusted analyzing, we discovered that FGFR2 rs2981460 (C/T) (P = 0.0113), and MAP3K1 rs3822625 (A/G) (P = 0.0478), rs702689 (A/G) (P = 0.0279), rs832567 (A/C) (P = 0.0279), and rs9687226 (C/T) (P = 0.0478) were significantly associated with the better OS of these patients. However, SNPs from ABCB1, CYCP19A1, and TOX3 were not associated with the OS of these patients. Conclusions: NGS-discovered novel SNPs (FGFR2 rs2981460, and MAP3K1 rs3822625, rs702689, rs832567, and rs9687226) are closely associated with the prognosis of HR-positive early breast cancer. Further validation of these SNPs in a large series of this group of patients is warranted.
Morphological characteristics and human papillomavirus genotype predict the treatment response in cutaneous warts
Authors: G.K. Hogendoorn, S.C. Bruggink, M.N.C. de Koning, J.A.H. Eekhof, K.E. Hermans, R. Rissmann, J. Burggraaf, R. Wolterbeek, K.D. Quint, S.T.P. Kouwenhoven, J.N. Bouwes Bavinck
Journal: British Journal of Dermatology (2017)

Cutaneous warts have a cure rate after therapy of no more than approximately 50%. Recently, we developed and validated a standard assessment tool for warts (Cutaneous WARTS diagnostic tool, CWARTS) based on phenotypical characteristics.To assess whether patient and morphological wart characteristics predict the human papillomavirus (HPV) type in a specific wart and whether these characteristics as well as the HPV type predict a favourable treatment response.Photographs were used to score nine morphological wart characteristics using the newly developed CWARTS tool. Genotyping of 23 wart-associated HPV types was performed using the hyperkeratotic skin lesion-polymerase chain reaction/multiplex genotyping assay. The results were correlated with a favourable response to treatment with monochloroacetic acid, cryotherapy or a combination of cryotherapy and salicylic acid. Odds ratios were calculated using logistic regression in a generalized estimating equations model.Black dots (capillary thrombosis) strongly predicted the presence of any HPV type in a wart. From all characteristics tested, the HPV type most strongly predicted the treatment response when the warts were treated with monochloroacetic acid or a combination of cryotherapy and salicylic acid with a significantly decreased treatment response if the warts contained HPVs of the alpha genus (HPV2, HPV27 or HPV57). When cryotherapy alone was used for common warts, HPV type did not play a role, but cryotherapy was less effective in the presence of callus and when the wart was located deeper in the skin.Morphological characteristics of the warts and the HPV genotype influence treatment outcome and thus potentially influence future treatment decisions for common and plantar warts.
Abstract 2678: Gender and Age Differences in Idiopathic Ventricular Arrhythmias
Authors: Yasuaki Tanaka, Hiroshi Tada, Shigeto Naito, Koji Kumagai, Shigeru Oshima, Koichi Taniguchi, Sachiko Ito, Kazutaka Aonuma, Hitoshi Hachiya, Kenzo Hirao, Mitsuaki Isobe
Journal: Circulation (2009)
Polymorphisms risk modeling for vascular toxicity in patients with glioblastoma treated on NRG Oncology/RTOG 0825.
Authors: Renke Zhou, Michael E. Scheurer, Mark R. Gilbert, Melissa Bondy, Erik P. Sulman, Ying Yuan, Yanhong Liu, Elizabeth Vera, Merideth M Wendland, David Brachman, James Bearden, Susan Lynne McGovern, Steven S. Wilson, Kevin D. Judy, H. Ian Robins, Grant Kirton Hunter, Stephanie L Pugh, Terri S. Armstrong
Journal: Journal of Clinical Oncology (2016)

2049 Background: Vascular toxicities, including hypertension and thrombosis, are commonly associated with anti-angiogenic agents, such as Bevacizumab. Risk factors for toxicity have yet to be identified. RTOG 0825 evaluated the use of bev in patients with newly diagnosed GBM. This project evaluated the risk of and validated prediction models for vascular toxicity. Methods: Logistic regression with backward selection (p ≤ 0.05) was used to build clinical models for thrombosis (Grade 3-4) and hypertension (Grade 2-4). A genome-wide analysis of genetic variation associated with the vascular toxicities was conducted. The top hits were incorporated into the risk modeling. Tagging variants were selected and examined individually and jointly and a final model developed. Results: Clinical and genotype data from 367 cases were included. The final clinical model for thrombosis included anticonvulsant use, body surface area, and blood urea nitrogen. Bev treatment was not associated with increased risk (12.1% vs 12.6%, bev vs placebo). The genome scan revealed five polymorphisms in protein coding genes of Tetraspanin 33, G protein-coupled receptor, and Cadherin 8 that significantly associated with thrombosis (p < 10-7). Significant genetic variants with adjustment for clinical variables resulted in the best model (AUC = 0.81), yielding a 1.7-fold increase in risk of thrombosis (p < 0.0001, 95% CI: 1.4-2.1). For hypertension only treatment arm (14.8% vs 7.9%, bev vs placebo) remained in the final clinical model. The two most significant variants (p < 10-7) generated the best model (AUC = 0.79), showing a 6.1-fold increase in risk of hypertension per risk allele present (p < 0.0001, 95%CI: 3.3-11.1). Conclusions: Despite the absence of increased thrombosis with bev treatment, potential clinical and polymorphisms that predict increased risk were uncovered. In contrast, hypertension was highly associated with bev and risk assessment was enhanced by polymorphisms. These results support investigation of clinical and genomic factors to help optimize risk–benefit analyses of treatment options. Supported by NCI U10CA21661, U10CA180868, U10CA180822, U10CA37422, U24CA114734, NIH 1R01NR013707 and Genentech.
The vitamin D receptor as a target for the treatment of breast cancer: Studies with the low calcemic vitamin D analog, inecalcitol.
Authors: Alyson M. Murray, Stephen F. Madden, Naoise C Synnott, John Crown, Norma O'Donovan, Michael J. Duffy
Journal: Journal of Clinical Oncology (2016)

e12011 Background: The vitamin D receptor (VDR), like the estrogen receptor (ER) and androgen receptor (AR), belongs to the nuclear family of transcriptional factors. Unlike ER and AR which have been widely exploited as therapeutic targets in cancer (ER in breast cancer and AR in prostate cancer), less work has been carried out on targeting VDR. The aim of this study was therefore to evaluate the anti-cancer activity of targeting VDR with the low calcemic vit D analog, inecalcitol for the treatment of breast cancer (BC). Methods: The effects of inecalcitol (Hybrigenics, Paris) on BC cell growth were investigated in 16 cell lines [triple-negative (TN) = 7, HER2+ = 5, ER+ = 4]. Results: IC50 concentrations for treatment with inecalcitol across the 16 cell lines ranged from 2.5 to 63 nM. Sensitivity to inecalcitol was higher in VDR-positive compared to VDR-negative cell lines (p = 0.031) and in ER-positive vs ER-negative cell lines (p = 0.004). In contrast, sensitivity was independent of HER2 and AR status. Across all of the 16 cell lines, inecalcitol was approximately 1000-fold more potent than calcitriol (active form of vit D). Combined treatment with inecalcitol and tamoxifen yielded additive growth inhibition in the ER-positive cell line, MCF7 (CI = 0.96) but synergistic inhibition in 2 TN cell lines BT20 and Hs578T(i8) (CI = 0.53 and 0.24, respectively). RNAseq analysis showed that 98 genes were differentially regulated by inecalcitol, 79% of which were also modulated by calcitriol. Conclusions: Our preclinical results show that inecalcitol inhibits breast cancer cell growth, especially cells expressing ER and VDR while combined treatment with inecalcitol and tamoxifen syngeristically inhibited growth in TNBC cells. As inecalcitol, is significantly more potent than calcitriol and has low calcemic potential, it should be further investigated for breast cancer treatment.
Résultats d'une étude prospective multicentrique sur la ponction guidée par échoendoscopie de tumeurs pancréatiques de moins de 3cm de diamètre
Authors: M Giovannini, G Monges, P Arcidiacono, C Ardengh, P Deprez, S Guaraldi, R Fogel, J Karamboulis, E Bories, CH Pesenti, V Moutardier, JR Delpero
Journal: Endoscopy (2005)

Le but de cette étude multicentrique a été de savoir quel était le rendement de la ponction guidée par échoendoscopie (PGEE) de petites masses pancréatiques (<3cm). 7 centres (2 au Brésil, 1 en Belgique, 1 au Venezuela, 1 en Italie, 1 en Grèce et 1 en France) ont participé à cette étude.