tbuckley/cabot-search huggingface dataset:
Abstract 13221: Efficacy and Safety of Therapeutic Angiogenesis by Basic Fibroblast Growth Factor With Atelocollagen Solution in Patients With Critical Limb Ischemia
Authors: Kazunori Ohno, Shinsuke Kojima, Makoto Ariyoshi, Satoshi Kaimoto, Motoki Uchihashi, Hideaki Kaneda, Tatsuo Kagimura, Masanori Fukushima, Satoaki Matoba
Journal: Circulation (2016)

Objectives: To evaluate efficacy and safety of a treatment comprising basic fibroblast growth factor (bFGF) with atelocollagen solution in patients with critical limb ischemia (CLI) due to peripheral artery disease (PAD) or Burger’s disease (TAO). Methods: Human recombinant bFGF (200μg) with 4.8 mL of 3% atelocollagen solution was prepared and injected into forty administration sites in the gastrocnemius muscle of the ischemic leg. The primary endpoint was the safety of the treatment, as evaluated by adverse events. The secondary endpoint was the efficacy of the treatment, as defined by improvements in Fontaine stage, the Rutherford category, rest pain, 6-minute walking distance, ankle brachial pressure index (ABPI), ulcerous/necrotic lesions, and cyanosis 2, 4, 8, 12, 24, and 48 weeks after the treatment from baseline values. Results: 10 CLI subjects received the treatment between November 2009 and November 2011. No serious procedure-related adverse events were observed during the follow-up. Within 48 weeks, the Fontaine stage improved in 4 subjects and was stable in 6 other subjects. The rest pain scale improved in 9 subjects while pain disappeared in 7 subjects. The maximum 6-minute walking distance increased in 7 subjects while 2 regained the ability to walk. Conclusions: The results of the present study demonstrated that angiogenic therapy using bFGF with atelocollagen solution was safe and feasible in patients with CLI.
Abstract 13982: Derivation of Functional Smooth Muscle Cells From Integration-free Induced Pluripotent Stem Cells Through Cardiovascular Progenitor Cell Intermediates for Vascular Regeneration
Authors: Yongyu Wang, Jiang Hu, Jiao jiao, Zhou Zhou, Eugene Y Chen, Peter Ma, Bo Yang
Journal: Circulation (2014)

Tissue-engineered blood vessels (TEBVs) hold great promise for replacement of damaged or defective vascular tissues in vascular disease therapies, such as coronary and peripheral bypass graft surgeries. However, it remains a great challenge to obtain sufficient numbers of functional smooth muscle cells (SMCs) in the practice of constructing patient-specific TEBVs. This study aimed to develop an efficient method to generate a large number of functional SMCs in a short term for constructing tissue-engineered vascular tissues. Human induced pluripotent stem cells (iPSCs) were established by integration-free episomal vector-based reprogramming of donor peripheral blood mononuclear cells (PBMCs). These established iPSCs expressed pluripotency markers and were demonstrated to be able to differentiate into all three germ layer cells. Cardiovascular progenitor cell (CVPC) intermediates were then promptly and efficiently induced and expanded in chemically defined medium. Vascular smooth muscle cells (SMCs) were further induced under differentiation condition, which expressed typical SMCs markers including smooth muscle α-actin (α-SMA), calponin and SM22α validated by quantitative real-time PCR and immunocytochemistry stain. Importantly, the derived SMCs showed functional properties, validated by contraction responsiveness to carbachol treatment, up-regulation of specific collagens gene expression under transforming growth factor β1 treatment and up-regulation of specific matrix metalloproteinases gene expression under cytokine stimuli. Future studies will be focused on using these functional SMCs to construct functional TEBVs on biomimetic scaffolds. Taken together, our study established a facile procedure to generate large amount of functional and safe SMCs for vascular regeneration, via establishment of donor-specific integration-free human iPSCs and directed differentiation through CVPC intermediates.
Evaluation of dosimetric variance in whole breast forward intensity modulated radiotherapy based on 4D CT and 3D CT.
Authors: Wei Wang, Jianbin Li
Journal: Journal of Clinical Oncology (2012)

e13530 Background: To explore and compare the dosimetric variance in forward intensity modulated radiotherapy (IMRT) based on 4D CT and 3D CT after breast conserving surgery. Methods: Seventeen patients after breast conserving surgery underwent the 3D CT simulation scans followed by respiration-synchronized 4D CT simulation scans on the state of free breathing. The treatment plan constructed using the end inspiration (EI) scan was then copied and applied to the end expiration (EE) and 3D scans and the dose distribution was calculated separately. Dose–volume histograms (DVHs) parameters for the CTV, PTV, ipsilateral lung (IPSL) and heart were evaluated and compared. Results: The CTV volume amplitude was 11.93 ± 28.64 cm 3 , and volume of the CTV receiving 95%, 100%, and 103% prescription dose among different scans were all differed by &lt; 0.4%. Mean PTV dose at EE was lower than EI (t = 2.87, p = 0.011), but there were no statistice significance between 3D CT scan and EI, EE scans (t = 1.06, -1.59; p = 0.304, 0.132). The homogeneity index (HI) at EI, EE, 3D plans were 0.156 ± 0.02, 0.162 ± 0.02, 0.161 ± 0.02, respectively, and difference only between EI and EE (t = -2.56, p = 0.021). The highest conformal index (CI) was at EI phase (t = 4.55, 2.70; p = 0.000, 0.016), and there was no significant difference between EE and 3D (t = 0.04, p = 0.967). The V 20 , V 30 , V 40 , V 50 and D mean of IPSL at EE phase were lower than EI (t = 2.39~5.54, p = 0.000~0.030). There were no significant differences in all the indexes for heart (t = -1.77~1.40, p = 0.128~0.693). Conclusions: The breast deformation during respiration may be disregarded in whole breast IMRT; PTV dose distribution was changed significantly between EI and EE phase, and the differentiation of the lung high dose area between EI and EE phase may induced by thorax expansion. 3D treatment planning is sufficient for whole breast forward IMRT, but 4D CT scans assist with respiratory gating ensure precise delivery of radiation dose.
Treatment of Bladder Stones in Adults and Children: A Systematic Review and Meta-analysis on Behalf of the European Association of Urology Urolithiasis Guideline Panel
Authors: James F. Donaldson, Yasir Ruhayel, Andreas Skolarikos, Steven MacLennan, Yuhong Yuan, Robert Shepherd, Kay Thomas, Christian Seitz, Aleš Petrik, Christian Türk, Andreas Neisius
Journal: European Urology (2019)
Trainees are unsure of where to get help with everyday work problems, survey finds
Authors: Abi Rimmer
Journal: BMJ (2019)

A national survey of doctors in training has found that many are unsure of where to go for wellbeing and occupational health support.

Just under 95% of all UK doctors in training (53 477) responded to the GMC’s 2019 national training survey, as did 45% of trainers (21 812).1

In a report on its initial findings, the GMC said that a third of trainees (33%) were unsure of who to contact in their trust or board to discuss matters relating to occupational health and wellbeing.

For the first time, the GMC survey also asked trainees about the facilities available to them at work, including wifi, common rooms, and hot food at night.

Just over one in eight trainees (13%) said that no common room or mess was available to them, while a fifth (19%) said the space they had was poor or very poor. A third (33%) rated their …
Predictive factors of no response during neoadjuvant chemotherapy in breast cancer.
Authors: Jungmin Jo, Changhoon Yoo, Jeong-Eun Kim, Jin-Hee Ahn, Sung-Bae Kim, Hak-Hee Kim, Joo Hee Cha, Hee Jung Shin, Sei-Hyun Ahn, Byung Ho Son, Jong Won Lee, Hee Jeong Kim, Gyungyub Gong, Kyung Hae Jung
Journal: Journal of Clinical Oncology (2012)

e11508 Background: Neoadjuvant chemotherapy (NACT) has been the standard for patients with inflammatory (IBC) and locally advanced breast cancer (LABC) and increases breast conservation rates in patients with operable tumor. Pathologic complete response (pCR) after NACT has been accepted as a marker for improved long-term outcome and predictors of pCR have been reported in many trials. However, predictors of progression or stable disease have been limitedly reported. We aimed to identify predictors of no response during NACT to identify patients who might benefit from an alternative approach. Methods: The medical records of patients with breast cancer who received NACT were reviewed retrospectively at a single center. Between March 2000 and January 2010, 316 patients were enrolled with stage I to III breast cancer. Statistical analyses were performed to compare patients with any response (RG) with patients with progression or stable disease (NRG). Results: Out of 316 patients, 263 patients (83.2%) had some response, 36 (11.4%) had SD, and 17 (5.4%) had PD during NACT. Factors predictive of NRG included nodal (N) status (p=.007) and clinical stage (p=.004), IBC cancer type (p=.02), negative estrogen receptor (ER) status, and negative HER2 status (p=0.04). Pre-NACT N stage, ER status, cancer type, and treatment with trastuzumab were independent predictors of NRG in multivariate analysis. NRG was a negative predictor of disease-free survival (p=.002) and overall survival (p=.026) in multivariate analysis. Conclusions: Factors predicting NRG include advanced nodal stage, ER negativity, IBC and NACT without trastuzumab in HER2-positve tumors. Because these variables are associated with poor prognosis, novel targeted therapies and molecular predictors are needed to improve outcome
Re: Benoit Peyronnet, Emma Mironska, Christopher Chapple, et al. A Comprehensive Review of Overactive Bladder Pathophysiology: On the Way to Tailored Treatment. Eur Urol 2019;75:988–1000
Authors: Bernhard Liedl, Klaus Goeschen, Florian Wagenlehner
Journal: European Urology (2019)
Response rate and safety of standard-dose nivolumab with reduced-dose ipilimumab in metastatic melanoma.
Authors: Inderjit Mehmi, Jordan Hill
Journal: Journal of Clinical Oncology (2019)

140 Background: Reduced-dose nivolumab in combination with standard-dose ipilimumab was shown to improve overall response rate (58%), progression free survival (11.5 months), and overall survival compared to ipilimumab alone in Checkmate 067. Improved outcomes were accompanied by an increased risk of toxicities with a 59% rate of grade 3-4 toxicities for the combination. Keynote 029 evaluated standard-dose pembrolizumab with reduced-dose ipilimumab with a slightly lower risk of grade 3-4 toxicities at 45%. Here we report outcomes for standard-dose nivolumab combined with reduced-dose ipilimumab in metastatic melanoma. Methods: We conducted a retrospective review of metastatic melanoma patients that received standard-dose nivolumab with reduced-dose ipilimumab at West Virginia University Cancer Institute. Response to therapy and incidence of immune-related adverse events were assessed. Results: From February 2017 to October 2018, 11 patients received the alternative dosing regimen. Only 1 (9%) patient experienced a grade 3-4 toxicity, and 3 (27%) additional patients experienced a grade 1-2 toxicity. The overall response rate was 54%. Conclusions: Standard-dose nivolumab in combination with reduced-dose ipilimumab is better tolerated than reduced-dose nivolumab with standard-dose ipilimumab without a loss in overall response rate.
Застосування сорбційно-трансмембранного діалізу в лікуванні хворих на розповсюджений перитоніт
Authors: V.P. Kryshen, P.V. Lyashchenko, A.L. Aslyaev, R.M. Stepanenko, A.I. Kucheryavenko, A.K. Petrosyan, S.V. Afanasyev
Journal: GASTROENTEROLOGY (2013)

Застосування інтраабдомінального сорбційно-трансмембранного діалізу у хворих з розповсюдженим перитонітом у післяопераційному періоді сприяє прискоренню регресу запального процесу в черевній порожнині, а також проявів ендотоксикозу й системного запалення. Крім того, додаткове використання пропонованого способу у хворих з розповсюдженим перитонітом дозволить знизити частоту післяопераційних ускладнень і знизити летальність в 1,7 раза. Зниження абсолютного ризику летальності в групі спостереження становило 5,6 %, відносного ризику — 42,3 %, що пов’язано з темпами зниження інтоксикації, відновленням органних порушень і зменшенням числа післяопераційних ускладнень.
C-met, a new prognostic biomarker in glioblastoma multiforme.
Authors: Rikke Hedegaard Dahlrot, Stine Asferg Petterson, Simon Kjaer Hermansen, Bjarne Winther Kristensen, Steinbjorn Hansen
Journal: Journal of Clinical Oncology (2013)

2088 Background: C-met is a tyrosine kinase receptor involved in growth, invasiveness and malignant progression in glioblastoma multiforme (GBM). Activation of the C-met pathway increases resistance towards DNA damage in glioma cell lines and it has been shown that an orally administrated C-met kinase inhibitor inhibits intracranial glioma growth in immunodeficient mice, suggesting that C-met is a potential target in glioma treatment. The purpose of the present study was to investigate the prognostic value of C-met in GBMs and subsequently correlate the prognostic value to known clinical variables, identified in a population-based cohort. Methods: Tissue samples from 186 GBM patients were analyzed using immunohistochemical staining and advanced quantitative image analysis. This provided continuous measurements based on staining intensity. Results: Median intensity was 70.8 (range 15.5-200.1). When divided at the median C-met was not prognostic. Further exploration showed that dichotomizing at an intensity of 75 (60% vs. 40%), high levels of C-met were associated with poor survival. However; C-met is a time-dependent factor and no prognostic effect was observed within the first 8.5 months after diagnosis (HR 0.97, 95% CI 0.62-1.51, p = 0.892). After 8.5 months, patients with high levels of C-met had a significantly poorer survival as compared to patients with low levels (HR 2.06, 95% CI 1.33-3.18, p = 0.001). This was significant in multivariate analysis adjusted for clinical variables; C-met (HR 1.89, 95% CI 1.22-2.93, p = 0.004), age (HR 1.02, 95% CI 1.00-1.03, p = 0.037), performance status (HR1.55, 95% CI 1.38-1.74, p = 0.004), and tumor crossing midline (HR 1.72, 955 CI 0.75-3.92, p = 0.201). Interestingly; C-met was only prognostic in patients who received post-surgical treatment, whereas no effect was observed in the 31 patients who underwent surgery only (HR 0.54, 95% CI 0.26-1.15, p = 0.113). Conclusions: Using advanced quantitative image analysis, we found that C-met was an independent prognostic factor of poor survival in GBMs. The effect did not appear within the first 8.5 months after the diagnosis and it was only seen in patients who received post-surgical treatment.
Zwitterionic polymer ligands: an ideal surface coating to totally suppress protein-nanoparticle corona formation?
Authors: Manon Debayle, Elie Balloul, Fatimata Dembele, Xiangzhen Xu, Mohamed Hanafi, Francois Ribot, Cornelia Monzel, Mathieu Coppey, Alexandra Fragola, Maxime Dahan, Thomas Pons, Nicolas Lequeux
Journal: Biomaterials (2019)
Circulating VEGF levels as a biomarker to clinical benefit to PTC299, the first inhibitor of VEGF synthesis.
Authors: Claude Paul George, Jason John Luke, J. Winkelman, Yen Thi Kim Hong Cao, LaShaina Shakes, Kerri Donnelly, Charles Harris Darby, Thomas W. Davis, Gary L. Elfring, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2012)

e13588 Background: Solid tumor growth is dependent on angiogenesis, a process mediated primarily by vascular endothelial growth factor (VEGF). Currently approved anti-angiogenic agents sequester VEGF or block activation of VEGF receptors. Despite extensive investigations, no reliable biomarkers have been identified for these agents. PTC299 is an investigational oral small molecule that differs from existing therapies by inhibiting VEGF synthesis at the translational level while conserving physiologic VEGF expression. Methods: A phase 1b clinical trial is evaluating PTC299 monotherapy (36 pts) or in combination with docetaxel (10 pts) from 0.3 mg/kg to 600 mg bid in patients with advanced incurable cancer. Serum VEGF was assessed at baseline and during therapy. The maximum on‑treatment reduction in VEGF at any post-baseline visit was used for a stratified analysis. Decreases in VEGF, defined as &lt;10% (low) and ≥10% (high), identified the strata. Duration of therapy was used as a surrogate for stable disease in a Kaplan‑Meier analysis. Results: The study enrolled 46 patients (20 males; 26 females; median age: 62 years). Patients with lower VEGF reductions while on therapy (&lt;10%, n=12) had a median duration of stable disease of 5.3 weeks while patients with greater maximal VEGF reductions (≥10%, n=31) had significantly longer stable disease (median 12.0 weeks, log-rank p&lt;0.001). VEGF decreases were greater in patients with higher baseline values. No Grade 3 or 4 hypertension, bleeding, or proteinuria occurred. One patient had an acute liver injury. Conclusions: Reductions in circulating VEGF are associated with prolonged duration of anti-angiogenic therapy and stable disease. Results are consistent with preclinical experiments and support the hypothesis that PTC299 does not affect physiologic VEGF but inhibits pathologic VEGF. In this study, oral administration of PTC299 as monotherapy or in combination with docetaxel therapy has been generally well tolerated at all doses tested.
Activity and safety of cabozantinib in patients with gastrointestinal stromal tumor after failure of imatinib and sunitinib: EORTC phase II trial 1317 CaboGIST.
Authors: Patrick Schoffski, Olivier Mir, Bernd Kasper, Zsuzsanna Papai, Jean-Yves Blay, Antoine Italiano, Charlotte Benson, Katerina Kopeckova, Nasim Ali, Palma Dileo, Axel Le Cesne, Franka Menge, Sophie Cousin, Celine Charon-Barra, Agnieszka Wozniak, Sandrine Marreaud, Saskia Litiere, Axelle Nzokirantevye, Hans Gelderblom
Journal: Journal of Clinical Oncology (2019)

11006 Background: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal malignancy of the gastrointestinal tract. Advanced GIST is treated with tyrosine kinase inhibitors (TKIs). Most patients (pts) develop resistance over time. We reported in 2013 (Van Looy CTOS) that cabozantinib (cabo), a TKI targeting KIT/MET/AXL/VEGFR, showed activity in GIST xenograft models through inhibition of tumor growth, proliferation and angiogenesis, both in imatinib-sensitive and -resistant tumors (Gebreyohannes Mol Cancer Ther 2016;15:2845-28). Cohen (Cancer Res 2015;75:2061-70) found that cabo can overcome compensatory MET signaling in GIST in vitro. EORTC 1317 assessed the safety and activity of cabo in pts who had progressed on imatinib and sunitinib. Methods: In this multi-center, open label, single arm Phase 2 study eligible metastatic GIST pts received 60 mg (freebase weight) cabo p.o./d. Primary endpoint was progression-free survival rate at wk 12, assessed by local investigator per RECIST 1.1. If at least 21 of 41 eligible and evaluable pts were progression-free at wk 12, the activity of cabo was sufficient to warrant further exploration (A’Hern one-stage design). Results: A total of 50 consenting pts were eligible and started treatment between 02/2017 and 08/2018, with 16 (32%) still continuing cabo at the database cut-off in 01/2019. The number of 3 wk treatment cycles ranges from 2-28+. Among the first 41 eligible and evaluable pts, 24 were progression-free at wk 12, satisfying the study decision rule. Among all 50 pts, 30 were progression-free at wk 12 (60%, 95% confidence interval (CI) 45-74%). A total of 7 pts achieved a confirmed partial response (PR) (14%, 95%CI 6-27%) and 33 had stable disease (SD) (66%, 95%CI 51-79%). Progression as best response was seen in 9 pts (18%, 95%CI 9-31%), one was not evaluable. Disease control (PR+SD) was achieved in 40 pts (80%, 95%CI 66-90%). Median progression-free survival was 6.0 mo (95%CI 3.6-7.7). The most common cabo-related grade ≥3 adverse events were diarrhea (74%), hand-foot syndrome (58%), fatigue (46%), hypertension (46%), weight loss (38%) and oral mucositis (28%), with 33 (66%) pts requiring dose reductions, 25 (50%) treatment interruptions and no cabo-related deaths. Conclusions: EORTC 1317 met its primary endpoint, with 24/41 pts (58.5%) being progression-free at wk 12. Results of this trial confirm preclinical data and warrant further exploration of cabo in GIST. Clinical trial information: NCT02216578.
A germline microRNA-based biomarker signature of immune-associated toxicity to anti-PD1/PDL1 therapy.
Authors: Joanne B. Weidhaas, Aaron Wolfe Scheffler, David Salzman, Anusha Kalbasi, Kirk Wilenius, Emily Rietdorf, Mara Heilig, Mattias Pitka, Caroline Desler, Dan Ruan, Antoni Ribas, Alexandra Drakaki, Mark C. Scholz, Donatello Telesca
Journal: Journal of Clinical Oncology (2019)

96 Background: Treatment with anti-PD1/anti-PDL1 agents is associated with toxicity termed immune related adverse events (iRAEs). While the prevalence of Grade 2 and higher iRAEs is approximately 25-30%, biomarkers have not been previously identified. We tested the hypothesis that functional, germ-line mutations would predict iRAEs. Methods: Four classifiers were trained on a set of 61 melanoma patients evaluated for toxicity and response. Subjects were classified as experiencing high toxicity (≥ Grade 2) vs low toxicity (&lt; Grade 2). Performance of the classifiers was tested on a validation set of 89 cancer patients with a variety of cancer types, with the most common being GU and NSCLC. Classifiers were built for each treatment of marker data including classification trees, LASSO-regularized logistic regression, boosted trees (BT), and random forests. The final performance measures, accuracy, specificity, sensitivity, negative predictive value, positive predictive value, area under the curve (AUC), and F1 score, were reported on the categorical treatment of the training data using leave-one-out cross validation on the validation data. We also evaluated the association between our most significant toxicity biomarker and response to anti-PD1/PDL1 therapy. Results: Within the melanoma training sample, we found a biomarker signature where toxicity is predicted with 79.0% accuracy (F1 = .714, AUC = .827) using BT. The same biomarker panel also accurately predicted toxicity in the validation cohort with 85.6% accuracy (F1 = .760, AUC = .883). Of the most predictive biomarkers, three were in microRNA binding sites in RAC1, CD274, and KRAS, two in immune related genes IL2RA and FCGR2A, and one in the DNA repair gene ATM. Our most significant biomarker in RAC1 did not predict response to anti-PD1/PDL1 treatment (p=0.91). Conclusions: We have identified a germ-line biomarker signature which predicts Grade 2 or higher iRAEs for patients treated with anti-PD1/anti-PDL1 therapy, regardless of cancer type, and does not predict an increased likelihood of response to these therapies. These findings are an important step in defining how to better safely personalize immune therapy, whose use is growing rapidly.
Disease Progression on Ibrutinib Therapy Is Associated with a Poor Clinical Outcome in Chronic Lymphocytic Leukemia (CLL) Patients Managed in Standard Clinical Practice
Authors: Othman S. Akhtar, Pallawi Torka, Seema A. Bhat, Ryan Hare, Sheila N. J. Sait, AnneMarie W. Block, Francisco J. Hernandez-Ilizaliturri
Journal: Blood (2017)