tbuckley/cabot-search huggingface dataset:
Neoadjuvant chemotherapy followed by chemoradiation in selected locally advanced squamous cervical cancer.
Authors: Juan Fernando Cueva, Nieves Martinez Lago, Maria Vieito, Ezequiel Gonzalez Patino, Maria Teresa Curiel Garcia, Nuria salvador Garrido, Patricia Palacios Ozores, Sonia Candamio, Rafael López López
Journal: Journal of Clinical Oncology (2013)

5603 Background: Although there has not been a direct comparison between neoadjuvant chemotherapy followed by chemoradiation with chemoradiation alone, neoadjuvant chemotherapy is active in squamous cervical cancer. Methods: In this one arm phase II trial we accrued 25 patients from 2007 to 2012 diagnosed with squamous cervical cancer deemed poor candidates to initial chemoradiation (decided by a multidisciplinary committee). Patients had &gt; 18 years of age, PS 0-1, adequate organ function an gave informed consent. They received neoadjuvant paclitaxel and cisplatin (80 and 33 mg/m 2 respectively) on days 1,7, 15 of every 28 for two cycles and then external radiation in 1.8 Gy/ fraction with concurrent weekly cisplatin 40 mg/m 2 followed by brachytherapy in 5-6 applications. Dose intensity and toxicity was accrued, and both after neoadjuvant and chemoradiation patients were evaluated by RECIST 1.1 criteria for response with CT scan and pelvic MNR. Results: Baseline characteristics of the patients are listed in Table. 24 patients were evaluable for efficacy and safety. Response rate after neoadjuvant chemotherapy was 84 % (complete and partial responses in 24 and 60% of patients, respectively), without progression disease. Response rate after radiochemotherapy was 93 % (complete and partial responses in 52 and 41% of patients, respectively). After a mean of 29 months of follow up, 11 patients (45%) thus far have developed recurrent disease. Median progression-free survival and overall survival were 33 (23- 42) and 34+ m (29 – not reached). Treatment was well tolerated, without toxicities grade 3-4. Conclusions: Our weekly cisplatin-paclitaxel neoadjuvant regimen has been feasible and very effective in terms of dose delivery, tolerance and radiological responses without compromising definitive treatment with chemoradiation. If this approach is superior than the standard chemoradiation alone in this population should be explored in a randomized trial. [Table: see text]
Faltering growth in children: summary of NICE guidance
Authors: Eva Gonzalez-Viana, Katharina Dworzynski, M Stephen Murphy, Russell Peek
Journal: BMJ (2017)

#### What you need to know

Growth in infants and preschool children is a common cause for parental and professional concern. Some weight loss is common in the early days of life, while establishing feeding, and is usually a physiological phenomenon associated with fluid shifts.1 The term “faltering growth” is used to describe a pattern of slower weight gain than expected for age and sex in infants and preschool children after these early days and is most often due to inadequate nutritional intake. 

Concerns about faltering growth arise in up to 5% of infants and preschool children, depending on the definition used.23 Concerns are usually raised in primary care, by parents, health visitors, or general practitioners (GPs). Current practice in assessment and management varies across the UK.4 This article summarises the recent National Institute for Health and Care Excellence (NICE) guidance on the recognition and management of infants and preschool children with faltering growth,5 focusing …
Labour calls for £500m winter bailout fund to ease NHS pressure
Authors: Gareth Iacobucci
Journal: BMJ (2017)

The Labour party has called on the government to commit to a £500m (€565m; $675m) bailout fund for the NHS this winter to reduce waiting lists for treatment.

In a keynote speech to the Labour Party’s annual conference in Brighton on Tuesday 26 September, the shadow health secretary, Jonathan Ashworth, emphasised that ministers must not repeat the mistakes of last year that led to lengthening waiting lists during Theresa May’s first winter as prime minister.

A Labour analysis of official NHS figures1 shows that if the NHS suffered a similar collapse in performance this winter an additional 10 000 people would be waiting more than four hours for emergency treatment each day, with hundreds of operations cancelled and waiting lists growing.

The party wants …
Vascularized Tissue-Engineered Model for Studying Drug Resistance in Neuroblastoma
Authors: A. Villasante, K. Sakaguchi, J. Kim, N.K. Cheung, M. Nakayama, H. Parsa, T. Okano, T. Shimizu, G. Vunjak-Novakovic
Journal: Theranostics (2017)

Neuroblastoma is a vascularized pediatric tumor derived from neural crest stem cells that displays vasculogenic mimicry and can express a number of stemness markers, such as SOX2 and NANOG.Tumor relapse is the major cause of succumbing to this disease, and properties attributed to cancer stem-like cells (CSLC), such as drug-resistance and cell plasticity, seem to be the key mechanisms.However, the lack of controllable models that recapitulate the features of human neuroblastoma limits our understanding of the process and impedes the development of new therapies.In response to these limitations, we engineered a perfusable, vascularized in vitro model of three-dimensional human neuroblastoma to study the effects of retinoid therapy on tumor vasculature and drug-resistance.METHODS: The in vitro model of neuroblastoma was generated using cell-sheet engineering and cultured in a perfusion bioreactor.Firstly, we stacked three cell sheets containing SKNBE(2) neuroblastoma cells and HUVEC.Then, a vascular bed made of fibrin, collagen I and HUVEC cells was placed onto a collagen-gel base with 8 microchannels.After gelling, the stacked cell sheets were placed on the vascular bed and cultured in the perfusion bioreactor (perfusion rate: 0.5 mL/min) for 4 days.Neuroblastoma models were treated with 10μM isotretionin in single daily doses for 5 days.RESULTS: The bioengineered model recapitulated vasculogenic mimicry (vessel-like structure formation and tumor-derived endothelial cells-TECs), and contained CSLC expressing SOX2 and NANOG.Treatment with Isotretinoin destabilized vascular networks but failed to target vasculogenic mimicry and augmented populations of CSLCs expressing high levels of SOX2.Our results suggest that CSLCs can transdifferentiate into drug resistant CD31 + -TECs, and reveal the presence of an intermediate state STEC (stem tumor-derived endothelial cell) expressing both SOX2 and CD31.CONCLUSION: Our results reveal some roles of SOX2 in drug resistance and tumor relapse, and suggest that SOX2 could be a therapeutic target in neuroblastoma.
Continuous intravenous infusion of recombinant human endostatin combined with concurrent etoposide plus cisplatin and radiotherapy for treatment of unresectable stage III non-small-cell lung cancer (HELPER): a phase 2, multicentre study
Authors: Yirui Zhai, Honglian Ma, Zhouguang Hui, Lujun Zhao, Dongming Li, Jun Liang, Xiaozhen Wang, Liming Xu, Bo Chen, Yu Tang, Runye Wu, Yujin Xu, Ming Chen, Luhua Wang
Journal: The Lancet Oncology (2017)
Characterisation of CCS1477: A novel small molecule inhibitor of p300/CBP for the treatment of castration resistant prostate cancer.
Authors: Neil Pegg, Nigel Brooks, Jenny Worthington, Barbara Young, Amy Prosser, Jordan Lane, David Taddei, Richard Brown, Gareth Harbottle, Jonathan Shannon, Silvia Paoletta, Karen E. Knudsen
Journal: Journal of Clinical Oncology (2017)

11590 Background: Targeted degradation of androgen receptor (AR) and AR variants (ARV) remains an attractive therapeutic opportunity for patients with castrate resistant prostate cancer (CRPC). E1A binding protein (p300) and CREB binding protein (CBP) are two closely related transcriptional activators of AR. We have developed CCS1477 which is a potent, selective and orally active small molecule inhibitor of the bromodomain of p300/CBP and investigated its role in regulating androgen receptor expression and function. Methods: Binding of CCS1477 to p300, CBP and BRD4, was measured in a surface plasmon resonance (SPR) assay. Potency and functional activity (proliferation and biomarker knockdown) was demonstrated in prostate cell lines in vitro (22Rv1, VCaP). Cross species in vivo pharmacokinetic (PK) properties were assessed, and in vivo efficacy, linked to inhibition of biomarkers, was determined in 22Rv1 and LNCaP xenograft models. Results: CCS1477 binds to p300 and CBP with high affinity (Kd = 1.3/1.7nM) and selectivity (Kd = 222nM; BRD4). It is a potent inhibitor of cell proliferation in prostate cell lines (IC50 = 96nM,22Rv1; 49nM,VCaP) with minimal effect in AR-ve lines. In 22Rv1 cells, p300/CBP inhibition down-regulates AR-FL, AR-V7 and c-Myc protein by Western, an effect not seen with the BET inhibitor, JQ1 at equivalent proliferation IC50s. Inhibition of p300/CBP also reduces c-Myc, KLK3 and TMPRSS2 gene expression (qPCR) in 22Rv1 cells in vitro. The in vivo PK properties of CCS1477 are consistent with qd or qod oral dosing in mouse. CCS1477 dosed at 10mg, 20mg/kg qd or 30mg/kg qod, caused complete tumour growth inhibition over 28 days in a 22RV1 xenograft model, including extended duration in the absence of the drug for a further 24 days. This was accompanied by complete inhibition of plasma PSA and significant knockdown of tumour AR-FL, AR-V7, and C-Myc protein as well as C-Myc and TMPRSS2 mRNA expression. Conclusions: Taken together these data support the clinical testing of CCS1477 in castrate resistant prostate cancer by down-regulation of AR, AR-SV and c-MYC expression and function.
Relationship between whole-body tumor burden and quality of life in patients with neurofibromatosis.
Authors: Scott Randall Plotkin, Vanessa L. Merker, Miriam A. Bredella, Wenli Cai, Ara Kassarjian, Gordon J Harris, Alona Muzikansky, Manor Askenazi, Rosa Nguyen, Ralph Wenzel, Victor-Felix Mautner
Journal: Journal of Clinical Oncology (2012)

6136 Background: NF1, NF2, and schwannomatosis are a group of related genetic disorders in which affected individuals share the predisposition to develop multiple nerve sheath tumors. While previous studies have investigated the relationship between cutaneous tumor burden and quality of life, the relation between internal tumors and quality of life is unknown. Methods: As part of an IRB-approved research study, we performed whole-body MRI and administered the short form (SF)-36 to 245 adult subjects with NF. The number and location of internal nerve sheath tumors in each patient was identified by a board-certified radiologist and tumor volume was calculated using semi-automated volumetric analysis. One sample t-tests were used to compare subjects’ SF-36 scores to general population means. Independent linear regression analyses controlling for age and gender effects were used to relate whole-body tumor count, volume, and distribution (via Gini coefficient) to each domain of the SF-36. Results: 245 patients (142 with NF1, 53 with NF2, 50 with schwannomatosis) completed the study. On the SF-36, subjects with NF1 showed reduced quality of life in the physical role, emotional role, and mental health domains compared to the normal population (p&lt;0.05). Subjects with NF2 showed reductions in the physical functioning, physical role, general health, and social functioning domains while subjects with schwannomatosis showed reductions in the physical role and bodily pain domains (p&lt;0.05). In linear regression analysis, increased tumor number, increased tumor volume, and decreased Gini coefficient were correlated with decreased physical functioning in patients with NF2 (p&lt;0.01). There was also a trend for increasing tumor volume to be correlated with decreased physical role and increased bodily pain in patients with NF1 and with increased bodily pain in patients with schwannomatosis (p&lt;0.10). Conclusions: In our multi-institutional cohort, patients with all forms of neurofibromatosis show selected deficits in quality of life. Internal tumor burden does not correlate with these deficits, with the exception of physical function in NF2 patients.
Abstract 14313: Simulation Training Enables Emergency Medicine Providers to Rapidly and Safely Initiate Extracorporeal Cardiopulmonary Resuscitation During Simulated Cardiac Arrest
Authors: Sage P Whitmore, Kyle J Gunnerson, Jonathan W Haft, William R Lynch, Deborah M Rooney, John A Waldvogel, Paula Baldridge, Robert W Neumar
Journal: Circulation (2016)

Introduction:  Extracorporeal cardiopulmonary resuscitation (ECPR) is emerging as an effective strategy for managing refractory out-of-hospital cardiac arrest (OHCA). Emergency department (ED) provider training is a barrier to widespread implementation. ECPR simulation training is a potential solution, but published evidence of effectiveness is limited.   Hypothesis:  A 2-day simulation course will enable ED physician-nurse teams to safely and rapidly initiate ECPR in a high-fidelity simulated OHCA scenario.   Methods:  In this single center, IRB-approved study at a U.S. academic medical center, 9 ED physicians and 9 ED nurses were divided into 3 teams and participated in a 2-day simulation course. The course included didactics, hands-on practice with ultrasound-guided percutaneous vascular cannulation, circuit priming, and simulated ECPR resuscitations. Each team was tested in 3 sequential simulations on Day 1 after didactics and a brief practice session, on Day 2 after the simulation course, and at 3 months. Primary outcome was the proportion of simulations in which ECPR was initiated within 30 minutes. Intervals from patient arrival to 1) ECPR cannula placement, 2) primed ECPR circuit, and 3) initiation of ECPR flow were also recorded. Safety data was prospectively collected using a checklist.   Results:  ECPR flow was initiated within 30 minutes in 6/9 simulations (66.7% [95% CI: 36-97]) at baseline; 9/9 (100% [95% CI: 70-100]) on Day 2; and 9/9 (100% [95% CI: 70-100]) at 3 months. Significant improvements between baseline and subsequent simulations were seen (table). No failure to cannulate, failure to heparinize, mismatched connections, or air embolism during connection occurred.   Conclusions:  Our simulation course enabled ED providers to rapidly and safely initiate ECPR in a high-fidelity OHCA simulation and retain these skills at 3 months. These results demonstrate the value of simulation training in the clinical implementation of ED provider ECPR.
Improvement of molecular diagnosis in hymenoptera venom hypersensitivity by the use of the recombinant major allergens Ves v 1 and Ves v 5
Authors: S Blank, H Seismann, I Braren, K Greunke, L Cifuentes, T Grunwald, R Bredehorst, M Ollert, E Spillner
Journal: Allergy (2009)
A single-dose, placebo- and moxifloxacin-controlled 3-period study of the effects of temsirolimus on cardiac repolarization in healthy subjects
Authors: B. Hug, J. Boni, C. Leister, J. Burns, D. Sonnichsen
Journal: Journal of Clinical Oncology (2009)

2551 Background: Temsirolimus (CCI-779) is a novel selective inhibitor of the mammalian target of rapamycin (mTOR) approved by the US FDA for the treatment of patients with advanced renal cell carcinoma. This study was designed to assess the effect of a single dose of 25 mg IV temsirolimus on the corrected QT interval (QTc) in healthy subjects. Methods: Fifty-eight (58) healthy subjects were enrolled in this 3-period crossover study. In periods 1 and 2, subjects were administered IV placebo either alone or with open-label oral moxifloxacin. In period 3, subjects were administered 25 mg IV temsirolimus. Serial ECGs were digitally captured in triplicate and manually over read by a central vendor. The primary statistical objective was to estimate the effect of temsirolimus compared with placebo on change from time-matched baseline QTc at the end of infusion (0.5 hour time point). Secondary endpoints and objectives included estimates of effect at 12 additional time points, population PKPD analyses, and categorical summaries of interval data. Assay sensitivity was evaluated by the effect of moxifloxacin on change from time-matched baseline QTc as compared with placebo. Results: Temsirolimus had no effect on the QTc interval in the primary analysis. At 11 of 12 secondary time points, the upper bound for the temsirolimus QTc 90% CIs for the time-matched change from baseline difference from placebo was less than 10 msec without evidence of QTc trends or relationship to temsirolimus or sirolimus whole blood concentrations. Mean concentrations were comparable to those observed in patients with renal cell carcinoma following administration of 25 mg IV temsirolimus. Moxifloxacin produced a statistically significant increase in the QTc interval as compared with placebo. No relevant PKPD relationship was seen using linear or E max models. No subject in this study had a QTc interval exceeding 450 msec and no subjects had a change from baseline &gt;30 msec. Conclusions: We conclude that therapeutic exposures of temsirolimus are not associated with changes in QTc interval that reach the level of regulatory significance, according to ICH E14 guidance. The findings are consistent with the lack of QTc interval prolongation observed in studies of cancer patients. [Table: see text]
Upregulation of MAPK/MCL-1 Maintaining Mitochondrial Oxidative Phosphorylation Confers Acquired Resistance to BCL-2 Inhibitor Venetoclax in AML
Authors: Qi Zhang, Lina Han, Ce Shi, Rongqing Pan, Man Chun John MA, Jeremy Ryan, Stephen E Kurtz, Hong Mu, Vivian Ruvolo, Helen Ma, Michael Andreeff, Yingchang Mi, Jeffrey W. Tyner, Joel Leverson, Anthony Letai, Richard Eric Davis, Marina Konopleva
Journal: Blood (2016)
The parotid gland connection: ultrasound and biopsies in primary Sjögren’s syndrome
Authors: Esther Mossel, Konstantina Delli, Jolien F van Nimwegen, Alja J Stel, Erlin A Haacke, Frans G M Kroese, Fred K L Spijkervet, Arjan Vissink, Suzanne Arends, Hendrika Bootsma
Journal: Annals of the Rheumatic Diseases (2017)

We would like to thank Alegria et al 1 for their letter to the editor commenting on our recent publication entitled ‘Ultrasonography of major salivary glands compared with parotid and labial gland biopsy and classification criteria in patients with clinically suspected primary Sjogren’s syndrome’.2 Our study was the first that directly compared the validity of ultrasound of major salivary glands (sUS) with parotid gland biopsy outcome. We showed that the agreement between sUS and parotid as well as labial gland biopsies was good but was slightly higher for the former.

As noted by Alegria et al ,1 we found different results for the positive predictive value (PPV) and negative predictive value (NPV) between sUS versus parotid and sUS versus labial gland biopsies.2 Although these observations may indeed be caused by discordance between the parotid and labial gland biopsy outcome, there are other factors that may equally well contribute to this discrepancy. First, the parotid glands are assessed during the sUS examination and included in the scoring, whereas the labial glands are not.2 Second, in 6%–15% of the general population, the labial gland biopsy is positive, while in only 5% of the general population, the parotid gland biopsy is positive. …
Organ‐on‐a‐Chip Technology for Reproducing Multiorgan Physiology
Authors: Seung Hwan Lee, Jong Hwan Sung
Journal: Advanced Healthcare Materials (2017)

Abstract In the drug development process, the accurate prediction of drug efficacy and toxicity is important in order to reduce the cost, labor, and effort involved. For this purpose, conventional 2D cell culture models are used in the early phase of drug development. However, the differences between the in vitro and the in vivo systems have caused the failure of drugs in the later phase of the drug‐development process. Therefore, there is a need for a novel in vitro model system that can provide accurate information for evaluating the drug efficacy and toxicity through a closer recapitulation of the in vivo system. Recently, the idea of using microtechnology for mimicking the microscale tissue environment has become widespread, leading to the development of “organ‐on‐a‐chip.” Furthermore, the system is further developed for realizing a multiorgan model for mimicking interactions between multiple organs. These advancements are still ongoing and are aimed at ultimately developing “body‐on‐a‐chip” or “human‐on‐a‐chip” devices for predicting the response of the whole body. This review summarizes recently developed organ‐on‐a‐chip technologies, and their applications for reproducing multiorgan functions.
L-carnitine for pegylated-l-asparaginase induced hepatotoxicity.
Authors: Matthew Joseph Wieduwilt, Aaron Goodman, Brian Andrew Jonas, Ryan Daniel Cassaday, Januario E. Castro, Carolyn M. Mulroney, Dimitrios Tzachanis, Edward David Ball
Journal: Journal of Clinical Oncology (2017)

e21626 Background: Pegylated-L-asparaginase (PEG-Asp) treatment causes severe hepatoxicity in about 25% of adults. Two case reports suggest that L-carnitine may rapidly reverse PEG-Asp-induced hepatotoxicity. Methods: We retrospectively analyzed data from 11 consecutive patients from 3 centers receiving L-carnitine for PEG-Asp-related hepatotoxicity from 4/2014 to 4/2016. Eligible adults received L-carnitine for hepatotoxicity probably or definitely related to PEG-Asp. Total bilirubin (Tbili), ALT, or AST stabilization was defined as a variation within 10% from baseline maintained for 3 days. Improvement was defined as a decrease of ≥10% the prior day maintained for 3 days. Liver imaging included CT scans or ultrasounds. Results: The majority of patients were male, 91% (Table 1). Imaging on 7 patients showed hepatic steatosis in 2 (29%) prior to PEG-Asp and 5 (71%) after PEG-Asp. Median peak Tbili, ALT, and AST were 15.4 mg/dL (2.3-27.58), 194 IU/L (120-1491), and 119 IU/L (52-1064), respectively. Median days from hyperbilirubinemia to L-carnitine initiation was 4 (1-13). Median L-carnitine dose was 2,000 mg/day (1,880-4,450). Median days until Tbili, AST, and ALT improvement were 6.5 (4-14), 4 (2-19), and 3.5 (1-8), respectively. Median days until Tbili normalization was 34 (4-52). Improvement in Tbili, ALT, and AST within 8 days of L-carnitine was seen in 5, 19, and 11 patients, respectively. No adverse events were attributable to L-carnitine. Conclusions: L-carnitine for PEG-Asp-induced hepatotoxicity was safe and associated with stabilization and improvement in transaminitis and, to a lesser extent, hyperbilirubinemia. See table. [Table: see text]