tbuckley/cabot-search huggingface dataset:
Receptor Tyrosine Kinase Fusions and BRAF Kinase Fusions are Rare but Actionable Resistance Mechanisms to EGFR Tyrosine Kinase Inhibitors
Authors: Alexa B. Schrock, Viola W. Zhu, Wen-Son Hsieh, Russell Madison, Benjamin Creelan, Jeffrey Silberberg, Dan Costin, Anjali Bharne, Ioana Bonta, Thangavijayan Bosemani, Petros Nikolinakos, Jeffrey S. Ross, Vincent A. Miller, Siraj M. Ali, Samuel J. Klempner, Sai-Hong Ignatius Ou
Journal: Journal of Thoracic Oncology (2018)

We analyzed a large set of EGFR-mutated (EGFR+) NSCLC to identify and characterize cases with co-occurring kinase fusions as potential resistance mechanisms to EGFR tyrosine kinase inhibitors (TKIs).EGFR+ (del 19, L858R, G719X, S768I, L851Q) NSCLC clinical samples (formalin-fixed paraffin-embedded tumor and blood) were analyzed for the presence of receptor tyrosine kinase (RTK) and BRAF fusions. Treatment history and response were obtained from provided pathology reports and treating clinicians.Clinical samples from 3505 unique EGFR+ NSCLCs were identified from June 2012 to October 2017. A total of 31 EGFR+ cases had concurrent kinase fusions detected: 10 (32%) BRAF, 7 (23%) ALK receptor tyrosine kinase (ALK), 6 (19%) ret proto-oncogene (RET), 6 (19%) fibroblast growth factor receptor 3 (FGFR3), 1 (3.2%) EGFR, and 1 (3.2%) neurotrophic receptor tyrosine kinase 1 (NTRK1), including two novel fusions (SALL2-BRAF and PLEKHA7-ALK). Twenty-seven of 31 patients had either a known history of EGFR+ NSCLC diagnosis or prior treatment with an EGFR TKI before the fusion+ sample was collected. Twelve of the 27 patients had paired pre-treatment samples where the fusion was not present before treatment with an EGFR TKI. Multiple patients treated with combination therapy targeting EGFR and the acquired fusion had clinical benefit, including one patient with osimertinib resistance due to an acquired PLEKHA7-ALK fusion achieving a durable partial response with combination of full-dose osimertinib and alectinib.RTK and BRAF fusions are rare but potentially druggable resistance mechanisms to EGFR TKIs. Detection of RTK and BRAF fusions should be part of comprehensive profiling panels to determine resistance to EGFR TKIs and direct appropriate combination therapeutic strategies.
Remote control of movement disorders using a photoactive adenosine A2A receptor antagonist
Authors: Jaume Taura, Ernest G. Nolen, Gisela Cabré, Jordi Hernando, Lucia Squarcialupi, Marc López-Cano, Kenneth A. Jacobson, Víctor Fernández-Dueñas, Francisco Ciruela
Journal: Journal of Controlled Release (2018)
Factors associated with lymphedema in patients/women with node positive breast cancer treated with neoadjuvant chemotherapy and axillary dissection on a prospective clinical trial.
Authors: Judy Caroline Boughey, Karla V. Ballman, Linda Mackie McCall, Henry Mark Kuerer, Kelly Hunt, Jane M. Armer
Journal: Journal of Clinical Oncology (2018)

513 Background: Lymphedema (LE) is a known complication of breast cancer treatment. Herein we report the factors associated with LE after neoadjuvant chemotherapy (NAC) and axillary dissection (ALND) in the ACOSOG Z1071 (Alliance for Clinical Trials in Oncology) trial of patients with node-positive breast cancer. Methods: Patients who consented to the LE substudy underwent prospective arm measurements and symptom assessment after completion of NAC and at 6, 12, 18, 24, and 36 months after surgery. All patients had node-positive disease and underwent ALND after NAC. LE was defined based on symptoms of arm heaviness or swelling (LE-symptoms) or by arm volume increase of > 10% (LE-V10); severe LE was defined as volume increase > 20%. Kaplan-Meier methods were used to determine cumulative incidence. Results: 488 of 701 eligible patients consented to the LE substudy. Cumulative incidence of LE at 3 years was 37.8% (33.0-43.1%) by LE-symptoms; 58.6% (53.4-64.4%) by LE-V10; 37.2% (32.2-42.9%) for severe LE. In a univariable analysis, patient age, type of chemotherapy regimen used, breast surgical procedure, number of positive lymph nodes, and use of adjuvant radiation were not associated with risk of LE. Incidence of LE-symptoms was higher in obese patients (BMI > 30, p = 0.02) and in patients with NAC duration > 144 days (p = 0.029). Severe LE incidence was also higher with longer duration of NAC (p = 0.01). LE-V10 incidence was highest in patients with 30+ lymph nodes removed and lower when fewer lymph nodes were removed (p = 0.009). On multivariable analysis, obesity and length of NAC remained significant for LE-symptoms. Conclusions: In patients treated with NAC and ALND for node-positive breast cancer, risk of LE-symptoms increases with longer duration of neoadjuvant chemotherapy and obesity. Patients in these groups may benefit from closer surveillance for LE to allow early intervention. Support: U10CA180821, U10CA180882, UG1CA189823; Clinical trial information: NCT00881361.
Abstract 15530: Omega-3 Fatty acids Supplementation Attenuates the Progression of Microalbuminuria in Diabetics With Coronary Artery Disease
Authors: Dharshan K Lakshminarayan, Tarec K Elajami, Michael Soliman, Abdulhamied Alfaddagh, Francine K Welty
Journal: Circulation (2015)

Introduction: Microalbuminuria is a marker of generalized endothelial dysfunction, a key step in the pathogenesis of coronary artery disease (CAD). It is also an independent predictor of cardiovascular morbidity and mortality. Angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) therapy is considered a standard of care to attenuate progression of albuminuria in diabetic patients. Hypothesis: Omega-3 fatty acids (FAs) supplementation will attenuate progression of microalbuminuria in diabetic subjects with stable CAD. Method: In our study, 262 subjects with stable CAD were randomized to 3.6 g of omega-3 FAs (1.86 g of eicosapentaenoic acid + 1.5 g of docosahexaenoic acid) per day or no omega-3 FA (control) for one year. Urine microalbumin to creatinine ratio (urine MCR mg/g) was calculated as a measure of microalbuminuria at baseline and one year follow-up. Results: Mean age was 63.3 ± 7.6 yrs, 17% were women, 30% had diabetes, and 74% were on ACEI or ARB therapy. At one year follow-up in non-diabetics, there was no significant difference in the % change in urine MCR between the omega-3 FAs and control groups (see table). In contrast in diabetics, those not receiving omega-3 FAs had a significant 72.3% increase in urine MCR whereas those receiving omega-3 FAs had no change (table). In subgroup analysis, diabetics on an ACEI or ARB receiving omega-3 FAs had no change in urine MCR whereas those not receiving omega-3 FAs had a 64.2% increase at one year follow-up. Conclusions: Omega-3 FAs attenuated worsening of urine MCR in diabetics with CAD compared to diabetics not receiving omega-3 FAs over a one year period. Our results suggest that a combination of omega-3 FAs and ACEI or ARB is better in attenuating the progression of microalbuminuria than ACEI or ARB alone in diabetics with CAD. This suggests that omega-3 FAs may provide additional benefit when added to ACEI/ARB in diabetics with CAD.
Abstract 15353: JNK2 RNA Silencing Promotes Plaque Healing and Reduces Thrombotic Risk in Atherosclerotic Mice
Authors: John Bacon, Rohun Palekar, Kirk Hou, John S Allen, Paul Schlesinger, Hua Pan, Sam Wickline
Journal: Circulation (2016)

Introduction:  JNK2, one of three isoforms in the c-jun N-terminal kinase family, is a principal mediator of foam cell formation by activating the macrophage scavenger receptor signaling pathway. Although JNK2 is a clear therapeutic target for suppressing atherosclerosis, there are no approved pharmaceutical agents with acceptable isoform specificity and safety profiles. To this end, we report the utility of a new potent peptide-based siRNA delivery nanoplatform that rapidly conveys serum-stable anti-JNK2 oligonucleotides into growing plaques but not to normal vasculature.   Methods and Results:  ApoE null mice were fed a Western diet for 3 months followed by treatment for one month (2x/week i.v.; 7 total doses) with a 55 nm siRNA-p5RHH nanoparticle specific for JNK2. Evaluation of thrombotic risk by conventional dye-laser injury to the carotid artery revealed a 118% increase in clotting times, indicative of attenuated thrombotic risk. Endothelial barrier integrity was restored according to magnetic resonance spectroscopic measurements of ~200 nm semipermeant perfluorocarbon ( 19 F) nanoparticles that penetrated aortic plaques after 2 hours of circulation time, revealing a 60% reduction in plaque permeability in treated mice indicative of endothelial healing. JNK2 knockdown in plaques was confirmed by RT-PCR and Western assays, yielding reduced plaque necrosis and macrophage content. Interestingly, inflammatory signaling through NF-κB was reduced according to confocal images of  nuclear  p65 in plaques where 43% of neointimal cells from the control animals exhibited activated NF-κB signaling, but only 22.48% of cells were positive after JNK2 knockdown, a 47% reduction despite serum cholesterol levels > 1000 mg/dl. Safety was confirmed by normal serum blood test values after multiple doses, and no stimulation of innate or adaptive immunity.   Conclusions:  RNA silencing of c-jun N-terminal kinase 2 (JNK2) in atherosclerotic mice rapidly restores endothelial barrier integrity, reduces thrombotic risk, and decreases plaque inflammation in hypercholesterolemic mice.
Correlation of near-infrared spectral tomography (NIRST) with residual cancer burden (RCB) for prognostic assessment subsequent to neoadjuvant chemotherapy (NAC) in breast cancer.
Authors: Erica Bernhardt, Shudong Jiang, Kristen E. Muller, Bhavina D O Batukbhai, Jiang Gui, Roberta diFlorio-Alexander, Mary D. Chamberlin, Gary N. Schwartz, Keith D. Paulsen, Brian W Pogue, Peter A. Kaufman
Journal: Journal of Clinical Oncology (2018)

e12655 Background: NIRST provides biophysical data including oxy- and deoxy-hemoglobin, water, lipid, and scatter components, useful in distinguishing cancer from normal breast tissue. Unlike anatomic changes characterized by conventional radiographic techniques, these functional changes are uniquely suited to monitor early response to NAC. The Residual Cancer Burden (RCB) is a reproducible pathologic analysis to evaluate residual disease after treatment with NAC and proven useful prognostically. Methods: 19 women with locally advanced breast cancer were enrolled in this NIRST pilot study to evaluate tumor response to NAC. Patients underwent NIRST prior to NAC (HbT-pre), after cycle 1, after cycle 2, at the mid-point of NAC, and at the conclusion of NAC. RCB scores were determined in 16 of the 19 final tissue specimens. RCB scores for two patients were excluded due to positive excisional lymph node biopsy prior to NAC. One patient underwent surgery at an outside hospital and was excluded as pathology slides were unavailable. The RCB class was compared to NIRST biophysical data at time points throughout NAC. Ratios relative to the pretreatment average of the normal contralateral breast were used for statistical analysis to minimize inter-subject variability of breast density and the effect on biophysical data. Results: The best predictor for RCB class was the early change in total hemoglobin (HbT-Δ) (percent change when comparing the first cycle of NAC to HbT-pre), as analyzed by Pearson correlation coefficient of 0.71. The significance of this correlation was evaluated using a two-sided t-test. The resulting P-value of 0.0019 demonstrates a statistically significant correlation. Conclusions: In this pilot study of NIRST, we demonstrate a statistically significant correlation between HbT-Δ change during the first cycle of NAC and the RCB. These findings suggest the potential utility of this approach, and warrant further evaluation in a larger study. The ability to determine response within the first cycle of NAC would be of great clinical utility, and additionally of potential use in clinical trials involving novel neoadjuvant therapies.
Prognostic impact of multifocal and multicentric breast cancer compared with unifocal breast cancer.
Authors: Atsushi Fushimi, Atsushi Yoshida, Hiroshi Yagata, Osamu Takahashi, Naoki Hayashi, Koyu Suzuki, Hiroko Tsunoda, Seigo Nakamura, Hideko Yamauchi
Journal: Journal of Clinical Oncology (2018)

e12614 Background: The clinical behavior of multifocal and multicentric breast cancers (MMBCs) is not well characterized. The aim of this study was to assess whether patients with MMBCs have inferior prognosis compared with patients with unifocal breast cancers (UBC). Methods: We retrospectively analyzed 734 consecutive patients with invasive breast carcinoma who underwent definitive surgery at our hospital from January 2004 to December 2006. MMBC was defined as ≥2 separate invasive unilateral breast tumors, regardless of any ductal carcinoma in situ between lesions. We redefined pathological T stage based on the sum of the maximum diameter of each tumor. We evaluated disease-free survival (DFS) using the Kaplan–Meier method and Cox proportional hazards models. Results: Of the 734 patients, 136 (18.5%) had MMBC. The pathological T stage of 36 patients with MMBC was upstaged by adopting the sum of each focus. MMBC did not have any survival impact. MMBC upstaged by the modified pathological T stage affected worse DFS than non-upstaging MMBC (P = 0.004). Upstaging MMBC was an independent poor prognosis factor for DFS in multivariate analysis (HR: 2.757, P = 0.043). Conclusions: Although MMBC did not affect prognosis, upstaging MMBC had a worse predictive factor for DFS. Further studies are needed to confirm the prognosis of MMBC also considering biological characteristics of each invasive focus.
Atezolizumab for First-Line Treatment of Metastatic Nonsquamous NSCLC
Authors: Mark A. Socinski, Robert M. Jotte, Federico Cappuzzo, Francisco Orlandi, Daniil Stroyakovskiy, Naoyuki Nogami, Delvys Rodríguez-Abreu, Denis Moro-Sibilot, Christian A. Thomas, Fabrice Barlesi, Gene Finley, Claudia Kelsch, Anthony Lee, Shelley Coleman, Yu Deng, Yijing Shen, Marcin Kowanetz, Ariel Lopez-Chavez, Alan Sandler, Martin Reck
Journal: New England Journal of Medicine (2018)

The cancer-cell-killing property of atezolizumab may be enhanced by the blockade of vascular endothelial growth factor-mediated immunosuppression with bevacizumab. This open-label, phase 3 study evaluated atezolizumab plus bevacizumab plus chemotherapy in patients with metastatic nonsquamous non-small-cell lung cancer (NSCLC) who had not previously received chemotherapy.We randomly assigned patients to receive atezolizumab plus carboplatin plus paclitaxel (ACP), bevacizumab plus carboplatin plus paclitaxel (BCP), or atezolizumab plus BCP (ABCP) every 3 weeks for four or six cycles, followed by maintenance therapy with atezolizumab, bevacizumab, or both. The two primary end points were investigator-assessed progression-free survival both among patients in the intention-to-treat population who had a wild-type genotype (WT population; patients with EGFR or ALK genetic alterations were excluded) and among patients in the WT population who had high expression of an effector T-cell (Teff) gene signature in the tumor (Teff-high WT population) and overall survival in the WT population. The ABCP group was compared with the BCP group before the ACP group was compared with the BCP group.In the WT population, 356 patients were assigned to the ABCP group, and 336 to the BCP group. The median progression-free survival was longer in the ABCP group than in the BCP group (8.3 months vs. 6.8 months; hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.52 to 0.74; P<0.001); the corresponding values in the Teff-high WT population were 11.3 months and 6.8 months (hazard ratio, 0.51 [95% CI, 0.38 to 0.68]; P<0.001). Progression-free survival was also longer in the ABCP group than in the BCP group in the entire intention-to-treat population (including those with EGFR or ALK genetic alterations) and among patients with low or negative programmed death ligand 1 (PD-L1) expression, those with low Teff gene-signature expression, and those with liver metastases. Median overall survival among the patients in the WT population was longer in the ABCP group than in the BCP group (19.2 months vs. 14.7 months; hazard ratio for death, 0.78; 95% CI, 0.64 to 0.96; P=0.02). The safety profile of ABCP was consistent with previously reported safety risks of the individual medicines.The addition of atezolizumab to bevacizumab plus chemotherapy significantly improved progression-free survival and overall survival among patients with metastatic nonsquamous NSCLC, regardless of PD-L1 expression and EGFR or ALK genetic alteration status. (Funded by F. Hoffmann-La Roche/Genentech; IMpower150 ClinicalTrials.gov number, NCT02366143 .).
Dominant cytotoxic NK cell subset within CLPD-NK patients identifies a more aggressive NK cell proliferation
Authors: Gregorio Barilà, Antonella Teramo, Giulia Calabretto, Chiara Ercolin, Elisa Boscaro, Valentina Trimarco, Samuela Carraro, Matteo Leoncin, Cristina Vicenzetto, Anna Cabrelle, Monica Facco, Francesco Piazza, Gianpietro Semenzato, Renato Zambello
Journal: Blood Cancer Journal (2018)
Surgical procedures: plans to standardise access in London are being rushed through, says BMA
Authors: Jonathan Owen
Journal: BMJ (2018)

Doctors have warned that controversial NHS plans to reform a series of common surgical procedures are being rushed through and will negatively affect patients who need treatment.

Concerns were raised by the BMA in response to draft policies, being released over the coming weeks, that will restrict when certain treatments are available on the NHS.

NHS England has commissioned a network of clinical commissioning groups (CCGs), health bodies, and councils around London—known as the Healthy London Partnership—to develop a single approach for specific treatments in the capital.

The London Choosing Wisely programme is looking at eight areas of surgery, including removal of benign skin lesions; hip and knee replacements; keyhole knee surgery; procedures for dealing with back pain, shoulder pain, and varicose …
The Efficacy of a Group CBT Relapse Prevention Program for Remitted Anxiety Disorder Patients Who Discontinue Antidepressant Medication: A Randomized Controlled Trial
Authors: Willemijn D. Scholten, Neeltje M. Batelaan, Patricia van Oppen, Johannes H. Smit, Adriaan W. Hoogendoorn, Harold J.G.M. van Megen, Daniëlle C. Cath, Anton J.L.M. van Balkom
Journal: Psychotherapy and Psychosomatics (2018)
Dissecting an adiposity locus with an arsenal of genomics
Authors: Kim Lorenz, Benjamin F. Voight
Journal: Genome biology (2018)

We discuss a recent study that has identified and validated the link between a type-2 diabetes (T2D) association and human adipose biology by means of KLF14 gene expression. In addition to being maternally imprinted, the contributed risk at this locus is greater in female carriers.
Specific Targeting of<i>MTAP</i>-Deleted Tumors with a Combination of 2′-Fluoroadenine and 5′-Methylthioadenosine
Authors: Baiqing Tang, Hyung-Ok Lee, Serim S. An, Kathy Q. Cai, Warren D. Kruger
Journal: Cancer Research (2018)

Abstract Homozygous deletion of the methylthioadenosine phosphorylase (MTAP) gene is a frequent event in a wide variety of human cancers and is a possible molecular target for therapy. One potential therapeutic strategy to target MTAP-deleted tumors involves combining toxic purine analogues such as 6′-thioguanine (6TG) or 2′-fluoroadenine (2FA) with the MTAP substrate 5′-deoxy-5′-methylthioadenosine (MTA). The rationale is that excess MTA will protect normal MTAP+ cells from purine analogue toxicity because MTAP catalyzes the conversion of MTA to adenine, which then inhibits the conversion of purine base analogues into nucleotides. However, in MTAP− tumor cells, no protection takes place because adenine is not formed. Here, we examine the effects of 6TG and 2FA in combination with MTA in vitro and in vivo. In vitro, MTA protected against both 6TG and 2FA toxicity in an MTAP-dependent manner, shifting the IC50 concentration by one to three orders of magnitude. However, in mice, MTA protected against toxicity from 2FA but failed to protect against 6TG. Addition of 100 mg/kg MTA to 20 mg/kg 2FA entirely reversed the toxicity of 2FA in a variety of tissues and the treatment was well tolerated by mice. The 2FA+MTA combination inhibited tumor growth of four different MTAP− human tumor cell lines in mouse xenograft models. Our results suggest that 2FA+MTA may be a promising combination for treating MTAP-deleted tumors. Significance: Loss of MTAP occurs in about 15% of all human cancers; the MTAP protection strategy presented in this study could be very effective in treating these cancers. Cancer Res; 78(15); 4386–95. ©2018 AACR.
Probiotics for the airways: Potential to improve epithelial and immune homeostasis
Authors: K. Martens, B. Pugin, I. De Boeck, I. Spacova, B. Steelant, S. F. Seys, S. Lebeer, P. W. Hellings
Journal: Allergy (2018)

Abstract Probiotics are live microorganisms that, when administered in adequate amounts, confer health benefit on the host. The therapeutic effects of probiotics have been mostly studied in the gastrointestinal tract, but recent evidence points toward the potential of these bacteria to prevent and/or treat chronic airway diseases. In this review, possible mechanisms of action of probiotics in the airways are described, with a particular focus on their capacity to modulate the epithelial barrier function and their mode of interaction with the immune system. Indeed, probiotic bacteria, mostly lactobacilli, can promote the expression and regulation of tight junctions and adherence junctions, resulting in the restoration of a defective epithelial barrier. These bacteria interact with the epithelial barrier and immune cells through pattern recognition receptors, such as Toll‐like receptors, which upon activation can stimulate or suppress various immune responses. Finally, the clinical potential of probiotics to treat inflammatory diseases of the upper and lower respiratory tract, and the difference between their mode of application (eg, oral or nasal) are discussed here.