tbuckley/cabot-search huggingface dataset:
Cambridge Brain Mets Trial 1 (CamBMT1): A proof of principle study of afatinib penetration into cerebral metastases (mets) for patients (pts) undergoing neurosurgical resection, combined with low-dose, targeted radiotherapy (RT)—Phase 1b results.
Authors: Richard D. Baird, Javier Garcia-Corbacho, Constanza Linossi, Sanjeev Srinivas Kumar, Donna Smith, Michael Williams, Wendi Qian, Andrea Machin, Saif Ahmad, Tomasz Matys, Raj Jena, Simon Pacey, Carlos Caldas, Duncan Ian Jodrell, Sarah Jefferies, Stephen Price, Colin Watts, Nicola Ramenatte
Journal: Journal of Clinical Oncology (2017)

2008 Background: Failure of drugs to cross the blood brain barrier (BBB) can be a major reason for treatment failure in pts with brain tumours. Preliminary data suggest that low-dose RT may disrupt the BBB, and could facilitate increased drug delivery into brain tumours. CamBMT1 is a phase 1b/2 pre-operative window-of-opportunity trial designed to test if the delivery of afatinib into brain mets might be enhanced by targeted, low dose-RT. Methods: Pts with operable brain mets from breast or lung origin were treated with afatinib for 11 days prior to surgery on day 12. Pts also received a single fraction of targeted RT on day 10 (pts in either 2Gy or 4Gy arm). In phase 1b, afatinib dose (20, 30, or 40mg QD) was escalated in each arm using an accelerated titration design. Primary endpoint: steady-state afatinib concentration in resected brain mets, compared with plasma. Secondary endpoints: safety and tolerability. Results: 10 pts were treated (4 breast, 6 lung), with no dose-limiting toxicities seen, thus completing recruitment to phase 1b. Treatment was generally well tolerated. Median afatinib concentrations on day 12 were: plasma 22.7ng/mL (range 9.94-179); and tumour 405ng/g (range 120-1129). Conclusions: It was feasible to conduct a window-of-opportunity study of afatinib plus RT in pts with operable brain mets. The recommended phase 2 dose of afatinib was 40mg QD for both 2Gy and 4Gy arms. Afatinib concentrations in resected tumour were on average &gt;15-fold higher than those in plasma. Phase 2 of CamBMT1 is now underway in multiple UK sites, and randomises patients into 3 treatment arms (n=20 per arm): 1. afatinib 40mg QD; 2. afatinib 40mg QD + 2Gy# RT; 3. afatinib 40mg QD + 4Gy# RT. Clinical trial information: NCT02768337. [Table: see text]
Clinical implementation of whole genome multi-omics analyses for patients with refractory cancers.
Authors: Milan Radovich, Patrick Kiel, Katie Ratcliff, Andrew Geiser, Shannon Jones, Cynthia Hunter, Rebecca Finder, Teresa Moller, Allison Spradlin, Elizabeth Koselke, Thomas Jones, Sulfikar Ibrahim, Bryan Paul Schneider
Journal: Journal of Clinical Oncology (2017)

1531 Background: Relative lack of prior success of genomic technology has been a function of suboptimal target detection and poor timely implementation. We set out to improve patient access to targeted therapy through use of whole genome sequencing (WGS) to optimize targets and operational implementation to identify clinical trials and secure off-label drugs. Methods: We performed a retrospective analysis of our first 100 patients (Feb-Nov 2016) with metastatic disease whose tumors and matched blood were analyzed using whole genome (WGS) and transcriptome sequencing, as well as targeted proteomic analysis in a CLIA setting (NantOmics). Most common tumor types were Colorectal (20%), Breast (15%), and Ovarian (10%). Patients were seen in dedicated precision genomics clinics with results reviewed by a multi-disciplinary molecular tumor board. A dedicated service line with staff to match patients to clinical trials, medication acquisition, and genetic counseling for germline findings was provided. Results: 85% of patients had a finding either on WGS or proteomic analysis that pointed to an FDA approved drug or clinical trial. Common findings included: mutations in the PI3K pathway (15%), BRCA1&amp;2/ATM (15%), and cell cycle genes (11%). Other markers of note include: HER2, TMB/MSI for immune checkpoint therapy, IDH1/2, and MET. WGS also enabled identification of rare actionable findings, particularly translocations, and viral integration for trials requiring HPV-positivity. Cancer predisposition germline findings were observed in 3 patients. Of the 85 patients with actionable findings, 22 went on to be treated with a genomically-directed agent, 13 did not follow recommendations or were sent to hospice, 4 were lost to follow-up, and 46 still remain on their therapy prescribed prior to sequencing. Conclusions: A higher proportion of patients in our program went on to be treated with a genomically-directed agent than previously reported in the literature secondary to comprehensive whole genome multi-omics profiling and a clinical service line dedicated to medication acquisition and matching to clinical trials.
Personal knowledge
Authors: Kieran Sweeney
Journal: BMJ (2006)

Choudry and colleagues' paper in this issue (p 141) is a brave attempt to quantify the under-recognised notion of personal knowledge in clinical practice.1,2 They carefully analysed the prescribing decisions of hospital doctors caring for patients with atrial fibrillation, before and after their exposure to a patient with an adverse event—either serious haemorrhage when taking warfarin, or a thromboembolic event while not taking warfarin. The researchers wanted to know whether doctors' knowledge of a previous adverse event affected their subsequent prescribing.
Paranoid episodes in manic-depressive psychoses
Authors: W F Fry
Journal: American Journal of Psychiatry (1978)

The author reports on 7 patients with a primary diagnosis of manic-depressive psychosis who had brief but well-defined episodes of paranoid symptomatology. These episodes apparently represent alterations of psychic defense structure during the dynamic flow of the psychosis toward recovery. In manic-depressive psychosis, with its genetic and physiologic components, the paranoid episodes reaffirm the unitary nature of humans, in whom heredity and physical and psychological factors inextricably interact.
Cardiac Sympathetic Denervation for Refractory Ventricular Arrhythmias
Authors: Marmar Vaseghi, Parag Barwad, Federico J. Malavassi Corrales, Harikrishna Tandri, Nilesh Mathuria, Rushil Shah, Julie M. Sorg, Jean Gima, Kaushik Mandal, Luis C. Sàenz Morales, Yash Lokhandwala, Kalyanam Shivkumar
Journal: Journal of the American College of Cardiology (2017)
Borderline ER, PgR expression, and prognostic significance in early breast cancer population.
Authors: Silvia Mihaela Ilie, Oana Gabriela Ion, Inga Botnariuc, Xenia Bacinschi, Anghel Rodica Maricela
Journal: Journal of Clinical Oncology (2016)

e12576 Background: Different cutoffs have been used to define the immunohistochemical positivity of hormone receptors in breast cancer. The guidelines recommend that ER and PgR should be considered positive for at least 1 % of stained cells in the tumor sample. ER, PgR positive 1 to 10 percent are considered borderline. Twenty percent of them have basal-like characteristics and the ER 1-10%, PgR negative has a very poor prognostic. The aim of our study was to explore the clinical significance of borderline entity inside an early breast cancer population. Methods: We retrospectively studied a cohort of 334 stage I-III breast cancer patients, primary treated by surgery and which received adjuvant chemotherapy at Institute of Oncology Prof Dr.Al.Trestioreanu Bucharest between January 2005 and December 2012. Immunohistochemical evaluation was performed on paraffin embedded tissue in an internal laboratory. The comparison between groups was made in term of 3 years event free survival (EFS). Results: According to our classification, we found 45 (13.5%) TNBC patients, 18 (5%) borderline, 23 (6%) HER2 positive and 238 (71.5%) patients with luminal type. Inside borderline population, the mean age was 46 years, 77% (14pts) had 1-10% both ER and PgR expression and all of them have received hormonal treatment. For a median follow up of 59 months, overall relapse rate was 18.2% (59pts) representing 33.3% (35pts) of the borderline category and 22.2 %( 12pts) of the triple negative one. Borderline ER, PgR expression directly correlates to clinical stage (p = 0.0135) and inversely to pT(p = 0,04) and tumor grade (p = 0.04). It represents along with pN a significant prognostic factor regarding 3 years EFS in our breast cancer population (p = 0.049 respectively p = 0.029). For a median follow up of 59 months, overall relapse rate was 18.2% (59pts) representing 33.3 % (35pts) of the borderline category and 22.2% (12pts) from triple negative, HR being 1.5 in TNBC (p = 0.246) respectively 2.4 in borderline(p = 0.046)vs. luminal population. Conclusions: In our small cohort, the ER, PgR borderline expression represents a negative prognostic factor even comparing with triple negative phenotype.
Glucose transporter 1 (GLUT-1) expression and cellular localization in early stage colorectal neoplasia
Authors: S Bakhiet, J Dolan, J O'Sullivan, G Keating, J Gorman, HE Mulcahy, J Hyland, DP O'Donoghue, K Sheahan
Journal: Endoscopy (2005)

Aim: Glucose Transporter 1(GLUT-1) is a high-affinity glucose transporter. Elevated levels of GLUT-1 have been reported in malignancy, however the significance of GLUT-1 in early colorectal cancer (CRC) has not been elucidated.
Étude prospective sur l'exactitude d'une analyse cytologique immédiate par l'échoendoscopiste de ponctions à l'aiguille fine (PAF)
Authors: B Pujol, G Durivage, M Labadie, B Napoléon
Journal: Endoscopy (2005)

Le rendement de la PAF est accru par la présence du cytopathologiste en salle. Ceci est toutefois impossible dans de nombreux centres où l'échoendoscopiste est alors confronté à 2 choix: augmenter le nombre de passages en majorant les complications ou limiter son nombre au prix de faux négatifs. BUT: A partir d'une étude prospective monocentrique, évaluer l'efficacité de l'échoendoscopiste à déterminer la cellularité d'échantillons immédiatement après la ponction de masses solides ainsi que son impact sur la procédure finale.
Abstract 10970: From Rodents to Man: Confirmation of S1P Signalling as a Central Regulator of Myogenic Responsiveness in Human Resistance Arteries
Authors: Sonya K Hui, Andrew S Levy, Darcy Lidington, Julia Voigtlaender-Bolz, Steffen-Sebastian Bolz
Journal: Circulation (2013)

Pre-capillary resistance arteries are the primary regulators of total peripheral resistance and hence, tissue perfusion and systemic blood pressure. Their tone is determined by their smooth muscle cells’ (i.e. myogenic) ability to adjust their diameter to transmural pressure. In rodents, sphingosine-1-phosphate (S1P) signalling is a key regulator of this response and targeted by several diseases involving microvascular dysfunction (heart failure, diabetes, etc). In these rodent disease models, disruption of S1P signalling normalizes myogenic tone and corrects in vivo microvascular dysfunction. Demonstration of S1P signalling and its role as a regulator of myogenic responsiveness in humans is essential in order to evaluate the therapeutic potential for patients. We aim to establish protocols and infrastructure allowing for routine assessment of human resistance arteries and to confirm S1P-dependent microvascular function. Protocols were optimized for perfusion myography-based functional assessment of human...
Risk factors of colorectal adenoma recurrence among individuals under 50 years of age compared to those 50 years of age or older.
Authors: Christine Louise Sardo Molmenti, Jingyan Yang, Cynthia A Thomson, Elizabeth A Hibler, Gloria Ho, Alfred I. Neugut, M Peter Lance, David S. Alberts, Elizabeth T Jacobs
Journal: Journal of Clinical Oncology (2017)

1554 Background: Colorectal cancer incidence and mortality are increasing among individuals &lt; 50 years of age. Data are limited regarding the epidemiology of colorectal adenomas in this younger age group. This study investigated and compared risk factors associated with recurrence of adenomas in individuals under and over 50 years of age. Methods: Pooled analyses from the Wheat Bran Fiber and Ursodeoxycholic Acid phase III, randomized, controlled clinical trials included 1,623 participants, aged 40-80 years. Each completed baseline questionnaires related to family history and lifestyle habits, had one or more colorectal adenomas removed at baseline, and had a follow-up colonoscopy during the trial (mean follow up 36 months). Univariate and multivariate logistic regression modeling estimated the association between age and colorectal adenoma recurrence, and evaluate multiple risk factors, while controlling for confounding factors. Results: A statistically significant increased trend was found for colorectal adenoma recurrence with increasing age ( P trend = &lt; 0.001). Multivariate logistic regression revealed that risk factors significantly associated with adenoma recurrence in the ≥50 age group (n = 1,523) included history of previous polyps, characteristics of adenomas removed at baseline (multiple adenomas and villous feature), current smoking, and an increased waist circumference. Although risk profile in the &lt; 50 age group (n = 95) shared similarities with that in the ≥50 age group (e.g., current smoking), there were a few notable differences: history of previous polyps was a more prominent predictor for recurrence for the &lt; 50 (OR &lt; 50 = 4.76 and OR ≥50 = 1.33, P interaction = 0.042), whereas baseline characteristics of adenomas were more important for the ≥50 (multiple adenomas: OR &lt; 50 = 0.40 and OR ≥50 = 2.28, P interaction = 0.043). Conclusions: Predisposition to colorectal adenoma is a more important risk factor for recurrence in the &lt; 50 as compared to the ≥50. Future studies need to identify susceptibility factors contributing to the increasing incidence of colorectal cancer in this younger age group.
Derivation and validation of a prediction scale for response to PD-1 monotherapy.
Authors: Adi Nosrati, Simone M. Goldinger, Katy K. Tsai, Kimberly Loo, Paul Tumeh, Omid Hamid, Alain Patrick Algazi, Mitchell P. Levesque, Reinhard Dummer, Adil Daud
Journal: Journal of Clinical Oncology (2016)

9514 Background: Anti-PD-1 therapy has shown significant clinical activity in advanced melanoma. We developed and validated a clinical prediction scale for response to Anti-PD-1 in advanced melanoma patients. Methods: A total of 337 patients with advanced melanoma treated with pembrolizumab (2mg/kg or 10mg/kg Q3W) or nivolumab (3mg/kg Q2W) at 4 cancer centers (UCSF, UCLA, Angeles Clinic and University Hospital of Zürich) between December 2011 to October 2013 served as the setting for the present retrospective cohort study. The patients were divided into derivation (N=223) and validation (N=114) cohorts. The primary outcome measure was tumor response by RECIST v1.1. Pre-treatment demographic and clinical characteristics were analyzed on a univariate analysis. Variables with significant association were entered into a stepwise logistic regression model and were given a score based on ORs to calculate a clinical prediction scale. Results: In the discovery cohort 223 patients were identified. The developed clinical prediction scale included 4 prognostic factors that were significantly correlated with lower response: abnormal LDH (1 point), female sex (1 point), presence of liver metastasis (1 point) and previous ipilimumab treatment (1 point). The scale had an area under the receiver-operating curve (AUC) of 0.718 (95% CI 0.65-0.78) in predicting response to therapy. During the validation phase, 114 patients were identified. The predictive performance of the score was maintained in the validation cohort [AUC of 0.74 (95% CI 0.66-0.83)] and the goodness-to-fit model demonstrated good calibration. A score of 4 on our validation model was associated with 0 response to therapy while a score of 0 was associated with 100% response. Conclusions: Based on a large cohort of patients, we developed a simple 4-factor prediction scale that was validated in a separate cohort of patients. This scale can be used to stratify patients participating in clinical trials. Variable OR 95% CI Score Abnormal LDH* 0.51 0.28-0.92 1 Previous ipilimumab treatment 0.47 0.26-0.84 1 Female 0.36 0.19-0.67 1 Liver metastasis 0.35 0.19-0.67 1 *LDH > 199
GMI-1271, a novel E-selectin antagonist, combined with induction chemotherapy in elderly patients with untreated AML.
Authors: Daniel J. DeAngelo, Brian Andrew Jonas, Pamela S. Becker, Michael O'Dwyer, Anjali S. Advani, Paula Marlton, John Magnani, Helen M. Thackray, Jane Liesveld
Journal: Journal of Clinical Oncology (2017)

2560 Background: The outcomes for elderly patients (pts) with acute myeloid leukemia (AML) remain poor, therefore newer and less toxic therapies are urgently needed. The binding of E-selectin (E-sel), an adhesion molecule expressed in the bone marrow, to the leukemic cell surface activates survival pathways and promotes chemotherapy resistance. GMI-1271, a novel E-sel antagonist, enhances chemotherapy responses and protects from common toxicities in preclinical models (Becker ASH 2013; Winkler ASH 2013 and 2014). We report interim Phase 2 data for GMI-1271 plus chemotherapy in elderly untreated pts with AML. Methods: Pts ≥ 60 yrs with untreated AML, ECOG 0-2, and adequate renal and hepatic function were eligible. Prior treatment of MDS was allowed. GMI-1271 (10 mg/kg) was given 24 hrs prior, during and 48 hrs post induction with infusional cytarabine and idarubicin (7+3). Safety, tolerability, and anti-leukemia activity were assessed. Two cycles of induction were allowed and responders could receive consolidation with GMI-1271 plus intermediate dose cytarabine. Dose-limiting toxicity (DLT), defined as myelosuppression in the absence of disease or related Grade 3 (Gr) non-hematologic toxicity beyond day 42, was assessed in the first 3 pts. Results: 24 pts have been enrolled to date and 17 are evaluable for response. The median age was 68 years (range, 60-79) with 58% male pts, 50% secondary AML (sAML) pts and 25% with high-risk cytogenetics (by SWOG). The first 3 pts had no DLT, allowing enrollment to proceed. Common Gr 3/4 AEs included febrile neutropenia (47%), pneumonia (20%), pulmonary edema (13%) and non-fatal respiratory failure (13%). 2 pts died of sepsis within 60 days. The remission rate (CR/CRi) was 12/17 (71%). CR/CRi rate was 75% for pts with de novodisease and 67% for pts with sAML. E-sel ligand was expressed at high levels on blasts in the majority of pts. Conclusions: The addition of GMI-1271 to anthracycline-based induction chemotherapy in untreated elderly pts with AML demonstrates a high remission rate with acceptable side effect profile and low induction mortality. This study compares favorably to previous studies (Lancet, ASCO 2016). A randomized trial is being planned. Clinical trial information: NCT02306291.
Première Expérience Française de la Capsule Oesophagienne Pill Cam Eso®: A propos de 24 cas
Authors: M Delvaux, G Gay, I Fassler, T Rösch
Journal: Endoscopy (2006)

La capsule oesophagienne (Pill Cam Oeso, Given Imaging, Yoqneam, Israel, basée sur la même technologie que la capsule intestinale, a été récemment proposée pour explorer l'oesophage. Le but de cette étude non contrôlée est de rapporter les résultats de notre expérience initiale avec ce dispositif, afin d'évaluer les possibilités diagnostiques chez des patients nécessitant une endoscopie de l'oesophage.
A genome-wide association study (GWAS) of progression-free survival (PFS) in metastatic breast cancer (MBC) patients treated with letrozole (L) with or without bevacizumab (B) in CALGB 40503.
Authors: Federico Innocenti, Kouros Owzar, Chen Jiang, Alexander Sibley, Flora Mulkey, Lisa A. Carey, Debu Tripathy, Bryan P. Schneider, William Thomas Barry, Eric P. Winer, Clifford A. Hudis, Howard L. McLeod, Maura N. Dickler
Journal: Journal of Clinical Oncology (2016)

538 Background: CALGB 40503 testedwhether therapy with B prolongs PFS when added to first-line L as treatment of hormone receptor-positive (HR+) MBC. We aimed to identify germline variants associated with clinical outcome. Methods: Postmenopausal women with HR+ MBC were randomized 1:1 in a multicenter, open-label, phase III trial of L (2.5 mg orally/day) with or without B (15 mg/kg IV every 3 weeks). 343 patients received treatment. The primary endpoint of the study was PFS. The addition of B resulted in a significant reduction in the hazard of progression (hazard ratio [HR] = 0.75, 95% CI = 0.59-0.96; p = 0.016) and a prolongation in median PFS from 15.6 to 20.2 months with L and L+B, respectively (Dickler MN et al., ASCO 2015). DNA was extracted from peripheral blood and genotyped on the Illumina OmniExpress Exome chip for ~700,000 single-nucleotide polymorphisms (SNPs). The association between SNPs and PFS in 210 patients of estimated European genetic ancestry was tested by a Cox proportional hazards model using B as a stratification factor. Results: Median PFS in genotyped patients was 17.9 months. The top ranked SNP was rs9916211 (HR 2.15, 1.58-2.92, p < 1.04x10-6). rs9916211 (C to T) is a common germline variant (16% frequency) located in close proximity (~4 Kb) of TMEM132E gene. Median PFS for patients with the CC, CT or TT genotypes of rs9916211 was 20.70 (17.7-24.4), 12.71 (10.9-18.2) or 2.33 (2.2-4.6) months, respectively. TMEM132E codes for transmembrane protein 132E. Germline variants in TMEM132E have been reported as genetic modifiers of the risk of breast cancer in menopausal women taking hormone replacement therapy (Rudolph A et al., 2013). Conclusions: To our knowledge, this is the first GWAS ever reported in HR+ MBC patients treated with L. The top hit is a common variant in TMEM132E and confers worse PFS. This study selects TMEM132E as a new putative determinant of MBC progression in HR+ patients treated with endocrine therapy. This result may point towards a role of gene modifiers of breast cancer risk as determinants of clinical outcome. Further replication in additional patients is required.