tbuckley/cabot-search huggingface dataset:
Impact of neuropathic cancer pain on quality of life in Korean patients with cancer: Findings from the Korean Cancer Study Group Neuropathic Cancer Pain Survey.
Authors: So Yeon Oh, Sang Won Shin, Sun Jin Sym, Sang Young Roh, Seung-Sei Lee, So Young Yoon, Sun Kyung Baek, Keon Uk Park, Sang Cheul Oh, Jung Lim Lee, Jeanno PARK, Jooseop Chung, In Sil Choi, Dae-Sik Hong, Hyun Chang, Yeul Hong Kim, Hyo-Jin Kim, Ju Ho Sim
Journal: Journal of Clinical Oncology (2014)

e20660 Background: Identifying and adequate management of neuropathic cancer pain (NCP) in patients with cancer is complicated and challenging task. Korean Cancer Study Group Neuropathic Cancer Pain Survey (KCSG-NCPS) assessed the prevalence, characteristics and impact of NCP on quality of life (QOL). Methods: In this cross-sectional non-interventional study, patients presenting pain higher than visual analogue scales (VAS) score 1 were enrolled from 28 hospitals in Korea. NCP was diagnosed via neuropathic pain diagnostic questionnaire (DN4) if the patient scored above 4. The characteristics, history, treatment of pain, and pain severity were assessed via patient case report forms (CRFs), the Brief Pain Inventory-Short Form (BPI-SF). The QOL were assessed via EuroQOL visual analogue scale (EQ-VAS) and EQ-5D Health Questionnaire. Results: The survey recruited 1,505 Korea patients with cancer with median age 60 years and 54% of male. The prevalence of NCP in cancer patients was estimated at 36.9% (95% CI 34.5-39.3). Anticonvulsant and antidepressants were prescribed to 38.8% (95% CI 36.3-41.3) and 10.4% (95% CI 8.9-11.9) of the patients with NCP. Approximately 55% of the NCP patients with having VAS≥4 did not have NCP specific therapy. Comparison of symptom and QOL score according to presence of NCP and NCP specific treatment is presented in the Table. Conclusions: Nationwide NCP survey in Korea showed that significant portion of patients with NCP are not adequately managed and related to poor quality of life. Better strategy to detect and management of NCP is urgently needed. Clinical trial information: KCSG PC13-02. With NCP; DN4≥ 4 (N=556) Without NCP; DN4< 4 (N=949) P* With NCP specific treatment Without NCP specific treatment Pain VAS 4.91±2.23 4.05±2.17 <0.001 4.78±2.17 5.02±2.28 0.206 EQ-5D 0.51±0.22 0.48±0.23 0.007 0.53±0.20 0.50±0.22 0.035 Pain severity from BPI-SF 4.45±1.79 3.64±1.82 <0.001 4.37±1.72 4.50±1.84 0.407 Pain interference score from BPI-SF 4.95±2.75 4.33±2.90 <0.001 4.63±2.65 5.22±2.81 0.014 * Student’s t-test.
Symptomatic Congenital Hemangioma and Congenital Hemangiomatosis Associated With a Somatic Activating Mutation in <i>GNA11</i>
Authors: Tracy Funk, Young Lim, Ann M. Kulungowski, Lori Prok, Timothy M. Crombleholme, Keith Choate, Anna L. Bruckner
Journal: JAMA Dermatology (2016)

Congenital hemangiomas are uncommon benign vascular tumors that present fully formed at birth. They are rarely associated with transient hematologic abnormalities, which are typically less severe than the Kasabach-Merritt phenomenon associated with kaposiform hemangioendotheliomas. Congenital hemangiomas are typically solitary and have not been reported to occur in a multifocal, generalized pattern.To describe a male infant born with an unusual, large vascular mass complicated by anemia, thrombocytopenia, and disseminated intravascular coagulopathy, as well as innumerable small vascular papules in a generalized cutaneous distribution.This case report is a descriptive observation of the results of clinical, pathologic, and genetic studies performed in a single male infant observed for 2 years (May 2013 to June 2015) for vascular anomalies at a tertiary care referral center.Histopathologic, immunohistochemical, and genetic study results of tumor specimens and saliva.Careful pathologic study of 3 tumor specimens revealed similar lobular proliferations of bland endothelial cells. Lesional vessels did not express GLUT1 or the lymphatic marker D2-40, whereas WT1 was expressed. A somatic c.A626C, p.Q209P mutation in the GNA11 gene was identified in tumoral tissue.These findings support a unifying diagnosis of congenital hemangioma for these vascular tumors. To date, this is the first-reported case of a hemangiomatosis presentation of congenital hemangioma. In addition to highlighting this novel phenotype, this case indicates the rare association of congenital hemangioma with hematologic abnormalities and verifies somatic activating mutations as the underlying cause of congenital hemangioma.
Abstract 2473: Combined BET-bromodomain and CDK2 inhibition in MYC-driven medulloblastoma
Authors: Sara Bolin, Anna Borgenvik, Camilla Persson, Gabriela Rosén, Anders Sundström, Jun Qi, James E. Bradner, William A. Weiss, Yoon-Jae Cho, Holger Weishaupt, Fredrik J. Swartling
Journal: Cancer Research (2016)

Abstract Misexpression of MYC genes (MYC and MYCN) occurs commonly in medulloblastoma (MB), the most frequent malignant childhood brain tumor. We previously showed that tumors are addicted to MYCN and that MYCN stabilization is required for MB development in mice (Swartling et al, Genes &amp; Dev, 2010; Cancer Cell, 2012). Targeted MYCN suppression completely depleted MYCN-driven MB cells in vivo. Immediate transcriptional changes from such MYCN blockade were found by RNA-Seq and showed similarities to changes that occurred after CDK2 suppression or when inhibiting BET bromodomains. CDK2 and BET inhibitors both inhibited MYC protein expression and effectively induced cell cycle arrest or apoptosis. Compared with either agent alone a sustained combination treatment over 7-10 days displayed synergy and effectively abolished tumor cell proliferation in vitro. The combined treatment further reduced tumor growth in orthotopical MB transplants and significantly prolonged survival as compared to single agent therapy. Our data suggest that dual inhibition of CDK2 and BET Bromodomains could be a novel treatment approach in suppressing medulloblastoma by targeting MYC proteins. Citation Format: Sara Bolin, Anna Borgenvik, Camilla Persson, Gabriela Rosén, Anders Sundström, Jun Qi, James E. Bradner, William A. Weiss, Yoon-Jae Cho, Holger Weishaupt, Fredrik J. Swartling. Combined BET-bromodomain and CDK2 inhibition in MYC-driven medulloblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2473.
Prognostic factors in stage 4 neuroblastoma treated with busulphan-melphalan: Report from the European HR-NBL1/Siopen trial.
Authors: Ruth Ladenstein, Ulrike Poetschger, Martin Elliott, Roberto Luksch, Victoria Castel, Isaac Yaniv, Vassilios Papadakis, Genevieve Laureys, Josef Malis, Walentyna Balwierz, Ellen Ruud, Per Kogner, Henrik Schroeder, Ana Forjaz De Lacerda, Maja Beck Popovic, Pavel Bician, Miklos Garami, Toby Trahair, Andrew DJ Pearson, Dominique Valteau Couanet
Journal: Journal of Clinical Oncology (2016)

10527 Background: Evaluation of prognostic factors in high risk stage 4 neuroblastoma (HRNBL) patients (pts) treated with busulfan-melphalan (BUMEL) within HR-NBL1/SIOPEN. Methods: Between 2002-2009 (prior antiGD2 immunotherapy) BUMEL was given to 475 pts (275 males) in 149 centres / 20 countries. Pts < 1year (yr) had MYCN amplification (MNA). After induction (COJEC ± 2-4 TVD) BUMEL/SCR (stem cell reinfusion) was given once pts achieved at least PR. Local control aimed at gross surgical resection (achieved in 76%) and for radiotherapy (21Gy) to the primary tumour site. Maintenance was 13-cis retinoid acid only. The median age at diagnosis was 3 yrs (1 month-19 yrs). The median observation time is 7.4 yrs. Outcomes are reported as 5-yr EFS rates. Results: EFS was 0.64±0.12 for age < 1yr (17 pts), 0.62±0.08 for 1-1.5 yrs (42 pts), 0.40±0.03 for 1.5-5 yrs (317 pts) and 0.20±0.04 for pts > 5yrs (99 pts)(p = 0.0001). EFS was better with BUMEL/SCR given ≤ 240days (421pts) after diagnosis (0.41±0.02) than for 54 pts taking longer (0.16±0.05; p < 0.0001). Outcome was not different in 221 pts randomised for BUMEL (221/475). Pts with TVD have a significantly different EFS (0.41±0.03 (214pts) vs.106 pts +TVD: 0.30±0.05) (p = 0.026). CR pts prior to BUMEL (172 pts; 36 pts +TVD) had an EFS of 0.45±0.04, whilst EFS was 0.38±0.04 for VGPR pts (165 pts; 36pts +TVD) and 0.31 ±0.04 for PR pts (138 pts; 34pts+TVD) (p = 0.004). Earlier CR of pts without TVD appears superior (0.48±0.04 vs. 0.33±0.08 for CR after TVD: NS). EFS in PR pts prior BUMEL with ≤ 3 mIBG avid skeletal spots was better (0.38±0.05) than with more spots (0.13±0.06; p = 0.014). Also involvement of only one metastatic compartment results in significantly better EFS (0.50±0.07 vs. 0.37±0.02 for multiple compartments, p = 0.037). Severe toxicity rate was 7% (ICU, toxic deaths), the VOD rate 24% (grade 3:4%). Conclusions: Multivariable analysis (stage 4 patients > 1 yr and BUMEL ≤ 240days) reveals as independent unfavourable prognostic factors: age group 5-10yrs (Hazard-Ratio 2.77, p < 0.0001), age group 1.5-5yrs (Hazard-Ratio 1.73; p = 0.043) and PR prior BUMEL (HR = 1.46; p = 0.008). These findings enable guidance to future altered treatment approaches. Clinical trial information: NCT01704716.
Abstract 350: Visualizing alectinib distribution in mice brain by using MALDI mass spectrometry imaging technique
Authors: Hiroaki Aikawa, Mitsuhiro Hayashi, Shoraku Ryu, Makiko Yamashita, Naoto Ohtsuka, Masanobu Nishidate, Akinobu Hamada
Journal: Cancer Research (2016)

Abstract [Introduction] In the development of anticancer drug, measurement of drug concentration in target tissue has been thought to be crucial for predicting its efficacy and safety. However, measuring homogenized tissue by using quantitative liquid chromatography tandem mass spectrometry (LC-MS/MS) completely loss the spatial information of the compound in a target tissue. Mass spectrometry imaging (MSI) has been recently applied as innovative tools to detect pharmaceutical distributions in heterogeneous targets; however, it still needs to be improved in quantitative capability or reproducibility. [Purpose] We propose quantitative approach for MSI (qMSI) that administere matrix-assisted laser desorption ionization (MALDI)-MSI, concurrently with LC-MS/MS by using serial sections. We applied qMSI for visualizing spatial distribution of alectinib, novel ALK inhibitor, in mouse brain and examined the effect of MDR1 (p-glycoprotein) on the pharmacokinetic profiles in FVB and Mdr1a/b knockout mice. [Method] Pharmacokinetic study of alectinib was conducted in FVB and Mdr1a/b KO mice. Plasma, cerebrospinal fluid (CSF) and brain tissue were collected at 1, 1.5, 2, and 4 hours after a single oral administration dose of 4 and 20 mg/kg. The concentration of alectinib in plasma, CSF and brain tissue sections was measured by LC-MS/MS. The distribution of alectinib in mice brain tissue section was visualized by qMSI that we established. [Results] Developing qMSI showed the brain distribution of alectinib in the range from 1.2 to 952.6 pg/mm2 per each section, and the results made with qMSI were in excellent agreement with the complementary measurements by using laser-micro dissection to verify the exposure level. While plasma alectinib concentrations had no difference between both mice, the diffuse alectinib distributions in brain were observed in Mdr1a/b knockout compared with that in FVB mice. The dominant localization of alectinib in choroid plexus and brain blood vessels of FVB mice was observed by 20 μm resolution MSI analysis. [Conclusion] Our qMSI technique is expected to contribute to the development of anticancer drugs and translational research by visualizing drug distribution in target organs and tumors. Citation Format: Hiroaki Aikawa, Mitsuhiro Hayashi, Shoraku Ryu, Makiko Yamashita, Naoto Ohtsuka, Masanobu Nishidate, Akinobu Hamada. Visualizing alectinib distribution in mice brain by using MALDI mass spectrometry imaging technique. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 350.
Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition
Authors: Leonid Cherkassky, Aurore Morello, Jonathan Villena-Vargas, Yang Feng, Dimiter S. Dimitrov, David R. Jones, Michel Sadelain, Prasad S. Adusumilli
Journal: Journal of Clinical Investigation (2016)

Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1-mediated (PD-1-mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB-based second-generation CAR T cells achieved tumor eradication. CAR-mediated CD28 and 4-1BB costimulation resulted in similar levels of T cell persistence in animals treated with low T cell doses; however, PD-1 upregulation within the tumor microenvironment inhibited T cell function. At lower doses, 4-1BB CAR T cells retained their cytotoxic and cytokine secretion functions longer than CD28 CAR T cells. The prolonged function of 4-1BB CAR T cells correlated with improved survival. PD-1/PD-1 ligand [PD-L1] pathway interference, through PD-1 antibody checkpoint blockade, cell-intrinsic PD-1 shRNA blockade, or a PD-1 dominant negative receptor, restored the effector function of CD28 CAR T cells. These findings provide mechanistic insights into human CAR T cell exhaustion in solid tumors and suggest that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies.
Abstract 832: Preventing the progression of estrogen receptor-negative/HER2-overexpressing early stage breast disease by lapatinib
Authors: Sunil Acharya, Jia Xu, Xiao Wang, Shalini Jain, Hai Wang, Qingling Zhang, Joseph Bower, Rebecca Richards-Kortum, Dihua Yu
Journal: Cancer Research (2016)

Abstract Tamoxifen and aromatase inhibitors (AIs) have shown efficacy to prevent estrogen receptor positive (ER+) breast cancer; however, there is no effective prevention strategy for ER- breast cancer. HER2 overexpression (HER2+) can be detected in up to 40% of ER- breast cancers and it has been reported to promote the progression of early stage breast cancer. Here, we tested the feasibility of lapatinib to prevent ER-/HER2+ early stage breast disease. Our data showed that lapatinib reduced the proliferation and increased the apoptosis in an in vitro ER-/HER2+ early breast disease model. Furthermore, lapatinib treatment in the HER2-driven MMTV-neu mouse model from early stage of disease development (atypia, at 10 weeks of age) significantly delayed tumor initiation and progression as detected by mammary gland biopsy and fiber optic micro-endoscope (FOME) imaging. Mechanistically, we found that lapatinib inhibited GLUT4 upregulation and increased glucose up-taking in HER2-overexpressing cells. These results suggested that lapatinib is a promising agent for the prevention/intervention of ER- and HER2+ breast cancers. Our study brings better understanding of the mechanism underlying ER-/HER2+ early stage breast disease progression to cancer and our strategy of cancer prevention with low-dose kinase inhibitor could be rapidly translated into the clinic for other cancer types in the near future. Citation Format: Sunil Acharya, Jia Xu, Xiao Wang, Shalini Jain, Hai Wang, Qingling Zhang, Joseph Bower, Rebecca Richards-Kortum, Dihua Yu. Preventing the progression of estrogen receptor-negative/HER2-overexpressing early stage breast disease by lapatinib. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 832.
Is Advanced Imaging in Early-Stage Breast Cancer Ever Warranted? Reconciling Clinical Judgment With Common Quality Measures
Authors: Arif Kamal, Tian Zhang, Steve Power, P Kelly Marcom
Journal: Journal of the National Comprehensive Cancer Network (2016)

Background: The American Board of Internal Medicine Foundation's Choosing Wisely initiative aims to reduce unnecessary advanced imaging for early-stage breast cancer (ESBC). Additionally, NCCN Clinical Practice Guidelines in Oncology for Breast Cancer permit such images when oncologists perceive clinical clues of advanced disease. The utility of advanced imaging in ESBC is not known. Patients and Methods: We analyzed all patients with ESBC from January 2010 to June 2012 at a large tertiary cancer center. Early-stage was defined as stage IIb or less. We included advanced imaging within 60 days after diagnosis. Three independent reviewers manually abstracted a sample of charts to determine reason for ordering. Results: A total of 1,143 ESBC cases were identified; 21.8% of which had at least one advanced imaging procedure performed. Imaging modalities varied widely (38% CT, 21% PET, 34% bone scans, and 6% MRI). Patients who underwent advanced imaging were more likely to have triple-negative disease, be younger (age <50 years), and have higher stage disease (stage IIb vs ≤ stage IIa; all P<.001). A total of 100 cases (40%) were abstracted; 5 were excluded due to bilateral disease. Of the 95 cases remaining, 62% of the imaging studies were performed for staging, 17% for significant concurrent disease, and 22% for findings atypical of ESBC. Of the studies performed for staging, 15% produced clinically meaningful findings. Overall, 45% of studies were ordered for suspicious findings, complex history, or produced a meaningful result. Conclusions: Of patients with ESBC, 21.8% had at least one advanced imaging procedure within 60 days of diagnosis; almost half were clinically useful. Chart abstraction helped clarify intent. Conversations between clinicians and patients are needed to balance patient preferences and clinician judgment.
Abstract 3759: Inhibition of heat shock protein 27 (Hsp27) expression by apatorsen as a therapeutic strategy in breast cancer
Authors: Emilia Komulainen, Alice Shia, Jasmin Bansal, Francessa Cavicchioli, Karen O’Leary, John Foster, Peter Schmid
Journal: Cancer Research (2016)

Abstract Background: Heat shock protein 27 (Hsp27) is over-expressed in a number of cancers, including breast cancer, and interacts with apoptotic proteins inhibiting the apoptotic process and promoting tumourgenesis. Clinically, Hsp27 expression has been associated with a more aggressive phenotype and resistance to chemotherapy. Apatorsen (OGX-427) is a therapeutic antisense oligonucleotide designed to specifically target Hsp27. Apatorsen has shown single agent clinical activity, and randomised trials in combination with chemotherapy are underway. Here we present pre-clinical validation of inhibition of Hsp27 expression by apatorsen as a novel therapeutic strategy in breast cancer. Results: Basal expression analysis of Hsp27 by qPCR and western blot in a panel of &amp;gt;20 breast cancer cell lines demonstrated a wide variation with up to 3-log difference in expression between cell lines and good correlation of RNA and protein expression levels. Hsp27 expression increased after treatment with chemotherapy agents. Treatment with apatorsen caused rapid reduction of cellular Hsp27 levels within 24-48 hours; effects on Hsp27 levels were sustained for 5 and 7 days. Knockdown of Hsp27 was associated with significant reduction of cell survival with 38-93% loss of cell viability across the cell line panel (compared to mismatched oligonucleotide). There was no association between response to apatorsen and basal Hsp27 expression or molecular breast cancer subtype. Using whole genome mRNA (Illumina Human HT-12 v4 Expression BeadChip Kit) and methylation analysis (Illumina Human 450K Methylation BeadChip), we were unable to define a predictive signature of response to apatorsen. Co-treatment of breast cancer cell lines with apatorsen and Doxorubicin, Paclitaxel and Vinorelbine chemotherapy showed an additive cytotoxic effect. In vivo validation of the effects of apatorsen is ongoing. Conclusions: Therapeutic silencing of Hsp27 expression in breast cancer cell lines with apatorsen presents a novel strategy for the treatment of disease. Here we present data to support the use of apatorsen in combination with conventional chemotherapy for the treatment of breast cancer. Citation Format: Emilia Komulainen, Alice Shia, Jasmin Bansal, Francessa Cavicchioli, Karen O’Leary, John Foster, Peter Schmid. Inhibition of heat shock protein 27 (Hsp27) expression by apatorsen as a therapeutic strategy in breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3759.
Clinical governance: fine words or action?
Authors: N. Black
Journal: BMJ (1998)

The current purchaser efficiency index has resulted in perverse incentives and a distortion of clinical priorities.1 In the name of increased efficiency, cost saving measures have been rewarded while few attempts have been made to assess the quality of care provided. When attempts have been made, variation has often been shown in the quality of care delivered and the outcomes achieved by different providers.

In a significant and welcome change from the previous administration, the new government recognises these problems and proposes several measures to deal with them—at every level of the NHS. At the centre, a National Institute of Clinical Excellence will promote clinical and cost effective care by producing research based guidelines. National service frameworks will also set out the patterns and levels of service which should be provided for major …
Abstract 4219: Surface-displayed RGD enhanced the targeting and therapeutic efficacy of attenuated Salmonella typhimurium
Authors: Seung-Hwan Park, Jin Hai Zheng, Hee-Seung Yun, In-Kyu Park, Yeongjin Hong, Hyun E. Choy, Jung-Joon Min
Journal: Cancer Research (2016)

Abstract Anticancer therapy using engineered bacteria aims to overcome limitations of current cancer therapy by actively targeting and efficiently removing cancer. In order to achieve this goal, new approaches are essential to target therapeutically resistant regions of tumors, to maintain enough number of bacteria in tumor and to deliver drugs at sufficient concentrations during the period of therapeutic process. Therefore, it is necessary to enhance the bacterial targeting efficiency through bacterial surface engineering. Here, we demonstrate that Salmonella tumor tropism can be strengthened significantly via surface displaying of RGD peptide sequence (ACDCRGDCFCG; RGD sequence) in the external loop of outer membrane protein A (OmpA) of attenuated Salmonella typhimurium. RGD-displaying Salmonella strongly bound to αvβ3 over-expressing cancer cells while showed weak binding to non-expressing cancer cells, indicating the feasibility of surface display with preferential homing peptide. In vivo bioluminescence imaging showed strong targeting efficiency of RGD-displayed Salmonella in αvβ3 over-expressing cancer xenografts (MDA-MB-231, MDA-MB-435, M21, and U87MG). The surface engineered bacteria significantly suppressed both human breast tumor (MDA-MB-231) and human melanoma (MDA-MB-435), and prolonged survival in mice. In conclusion, engineered bacteria displaying RGD peptides on the surface could advance both targeting efficiency and therapeutic effects. Citation Format: Seung-Hwan Park, Jin Hai Zheng, Hee-Seung Yun, In-Kyu Park, Yeongjin Hong, Hyun E. Choy, Jung-Joon Min. Surface-displayed RGD enhanced the targeting and therapeutic efficacy of attenuated Salmonella typhimurium. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4219.