tbuckley/cabot-search huggingface dataset:
Palliative care for people living with heart failure: European Association for Palliative Care Task Force expert position statement
Authors: Piotr Z Sobanski, Bernd Alt-Epping, David C Currow, Sarah J Goodlin, Tomasz Grodzicki, Karen Hogg, Daisy J A Janssen, Miriam J Johnson, Małgorzata Krajnik, Carlo Leget, Manuel Martínez-Sellés, Matteo Moroni, Paul S Mueller, Mary Ryder, Steffen T Simon, Emily Stowe, Philip J Larkin
Journal: Cardiovascular Research (2019)

Abstract Contrary to common perception, modern palliative care (PC) is applicable to all people with an incurable disease, not only cancer. PC is appropriate at every stage of disease progression, when PC needs emerge. These needs can be of physical, emotional, social, or spiritual nature. This document encourages the use of validated assessment tools to recognize such needs and ascertain efficacy of management. PC interventions should be provided alongside cardiologic management. Treating breathlessness is more effective, when cardiologic management is supported by PC interventions. Treating other symptoms like pain or depression requires predominantly PC interventions. Advance Care Planning aims to ensure that the future treatment and care the person receives is concordant with their personal values and goals, even after losing decision-making capacity. It should include also disease specific aspects, such as modification of implantable device activity at the end of life. The Whole Person Care concept describes the inseparability of the physical, emotional, and spiritual dimensions of the human being. Addressing psychological and spiritual needs, together with medical treatment, maintains personal integrity and promotes emotional healing. Most PC concerns can be addressed by the usual care team, supported by a PC specialist if needed. During dying, the persons’ needs may change dynamically and intensive PC is often required. Following the death of a person, bereavement services benefit loved ones. The authors conclude that the inclusion of PC within the regular clinical framework for people with heart failure results in a substantial improvement in quality of life as well as comfort and dignity whilst dying.
Detection of solid tumors by infrared biochemical analysis of peripheral blood mononuclear cells.
Authors: Joseph Kapelushnik, A. Zelig, David Barry Geffen, Irena Gusakova, S. Mordichai
Journal: Journal of Clinical Oncology (2013)

e22069 Background: Detection of malignancies such as breast, colorectal and lung at early stages can improve survival rates from 20% up to 80%. Over the past few years, great efforts have been taken to develop novel, non invasive and effective methods for early diagnosis of cancer; however, a low sensitivity and/or specificity, has prevented their introduction as methods for early detection of cancer in populations at risk Methods: The clinical study was conducted at Todos Medical Ltd., Ben-Gurion University of the Negev and Soroka University Medical Center. 2 ml of peripheral blood was collected from each of 67 cancer patients (breast 26; gastrointestinal 27; lung 13; other 11) and 46 healthy controls. Peripheral blood mononuclear cells (PBMC) were extracted from whole blood and measured under Fourier transformed infrared microscope spectroscopy(FTIR-MSP). The differences between spectra of cancer and controls subjects' PBMCs were analyzed. Results: Significant differences were observed between healthy subjects and cancer patients at multiple bands along the infrared spectra of the PBMCs. Furthermore, we observed a distinct spectral pattern for each type of cancer which may indicate a difference in composition and activity of PBMC population. Several absorption bands may indicate for the stage of the disease.with sensitivity of 84% and specificity 94%. Conclusions: This study suggests the potential of FTIR spectroscopy analysis as a simple, low cost and minimally invasive method for cancer detection. The present research is preliminary and additional clinical trials are required for further validation and verification.
Targeting Mechanoresponsive Proteins in Pancreatic Cancer: 4-Hydroxyacetophenone Blocks Dissemination and Invasion by Activating MYH14
Authors: Alexandra Surcel, Eric S. Schiffhauer, Dustin G. Thomas, Qingfeng Zhu, Kathleen T. DiNapoli, Maik Herbig, Oliver Otto, Hoku West-Foyle, Angela Jacobi, Martin Kräter, Katarzyna Plak, Jochen Guck, Elizabeth M. Jaffee, Pablo A. Iglesias, Robert A. Anders, Douglas N. Robinson
Journal: Cancer Research (2019)

Metastasis is complex, involving multiple genetic, epigenetic, biochemical, and physical changes in the cancer cell and its microenvironment. Cells with metastatic potential are often characterized by altered cellular contractility and deformability, lending them the flexibility to disseminate and navigate through different microenvironments. We demonstrate that mechanoresponsiveness is a hallmark of pancreatic cancer cells. Key mechanoresponsive proteins, those that accumulate in response to mechanical stress, specifically nonmuscle myosin IIA (MYH9) and IIC (MYH14), α-actinin 4, and filamin B, were highly expressed in pancreatic cancer as compared with healthy ductal epithelia. Their less responsive sister paralogs-myosin IIB (MYH10), α-actinin 1, and filamin A-had lower expression differential or disappeared with cancer progression. We demonstrate that proteins whose cellular contributions are often overlooked because of their low abundance can have profound impact on cell architecture, behavior, and mechanics. Here, the low abundant protein MYH14 promoted metastatic behavior and could be exploited with 4-hydroxyacetophenone (4-HAP), which increased MYH14 assembly, stiffening cells. As a result, 4-HAP decreased dissemination, induced cortical actin belts in spheroids, and slowed retrograde actin flow. 4-HAP also reduced liver metastases in human pancreatic cancer-bearing nude mice. Thus, increasing MYH14 assembly overwhelms the ability of cells to polarize and invade, suggesting targeting the mechanoresponsive proteins of the actin cytoskeleton as a new strategy to improve the survival of patients with pancreatic cancer. SIGNIFICANCE: This study demonstrates that mechanoresponsive proteins become upregulated with pancreatic cancer progression and that this system of proteins can be pharmacologically targeted to inhibit the metastatic potential of pancreatic cancer cells.
A risk-based individualized follow-up after complete surgery as an effective procedure to reduce the relapse (R) impact in GIST patients (pts).
Authors: Erica Palesandro, Danilo Galizia, Lorenzo D'Ambrosio, Paola Boccone, Sandra Aliberti, Tiziana Venesio, Antonio Manca, Ilaria Bertotto, Gabriele Chiara, Filippo Russo, Delia Campanella, Ymera Pignochino, Massimo Aglietta, Giovanni Grignani
Journal: Journal of Clinical Oncology (2013)

10552 Background: FU care poses a burden on both pts and health system. FU aims to precociously identify recurrences, metastases or treatment-related adverse events so to undertake the appropriate therapy as soon as possible. Guidelines (NCCN, ESMO) admit lack of knowledge on optimal surveillance, but suggest FU based on experts’ opinion and risk stratification. Moreover, tumor burden (TB) is a well known negative prognostic factor (Van Glabbeke 2005). Therefore, low-TB at R might affect final outcome. To identify the impact, if any, of regular FU, we examined our prospectively collected database looking for Rs in which the early detection affected both clinical management and, likely, the outcome. Methods: 140 pts were stratified (AFIP classification). High risk (HR) pts had complete history + physical examination (H&amp;P) and CT every 3 mos for 2 years, 4 mos in 3 rd year, 6 mos in the 4 th and 5 th yrs, yearly thereafter; intermediate (IR), low (LR) and very low risk (VLR) pts had H&amp;P + CT every 4 mos for 2 years, every 6 mos up to the 5 th year, then yearly. Rs were divided in: low-TB + completely resectable R (Group 1) and high-TB + disseminated R (Group 2). The number of CT needed to detect (NND) one R and the incidence of early (&lt;6 mos) R was calculated. Overall survival (OS) was estimated by Kaplan-Meier method. Results: In 73 male and 67 female, median age 63 (23-82), risk stratification was: HR 73, IR 31, LR 28, VLR 8. After a median FU of 63 mos we observed 58 Rs: 25 (43%) and 33 (57%) in group 2 and 1, respectively. Relapsed pts genotype was KIT Ex11 72%; Ex9 10%; Ex13 3%; wild-type 15%. Median time to R was 16 mos (1-120). 21 pts underwent surgical resection of their R. 16 pts remained free from progression for a median of 90 mos. We detected 15 (26%) early Rs. NND was 17 and 32 CT for HR and non-HR pts, respectively. Group 1 and 2 median estimated OS was 112 and 87 mos (p=.05), respectively. Conclusions: Though retrospective, this series shows that FU may detect low-TB Rs. In principle, this might affect pts final outcome and, therefore, justify this costly effort. Since it is difficult to foresee a prospective randomized trial, a confirmation of these data in a different series might increase their reliability.
Valproic acid enhances etoposide induced cytotoxicity in neuroblastoma cells
Authors: D. G. Aguilera, C. Das, J. Wolff, P. Zage, V. Gopalakrishnan
Journal: Journal of Clinical Oncology (2007)

20010 Background: Metastastic neuroblastoma is resistant to treatment and prolonged response is difficult to achieve therefore new therapies are necessary. Etoposide, a topoisomerase II inhibitor is often used for its treatment. Valproic acid (VPA) has histone deacetylase inhibitor (HDI) activity. Epigenetic alterations described in neuroblastoma tumors make VPA a good candidate to evaluate for potentiation of etoposide-mediated cytotoxicity. We evaluate the effects of VPA in combination with etoposide in neuroblastoma cells. Methods: Human neuroblastoma cell lines SKNAS and SKNSH were incubated with 1.5 mM VPA and increasing concentrations of etoposide from 1x10 -6 to 1 mM. Cell viability assay were measured with MTT assays. Results: We observed that VPA and etoposide independently decreased cell viability in a time and concentration dependent manner. The co-incubation with both drugs greatly enhanced the cytotoxicity of etoposide. IC50 for SKNSH cells treated with etoposide were approximately 1x10–3, 1.8x10–4, and 3x10- 5mM at 24, 72 and 96 hours, respectively. With the addition of VPA we found that cell viability was reduced approximately by 10 fold at each time point. At 72 and 96 hours 100 percent cell death was achieved at 0.1 mM of etoposide. IC50 for SKNAS cells treated with etoposide were approximately 1.8x10–3 mM and 6x10–4 mM at 72 and 96 hours, respectively. With the addition of VPA, IC50s were reduced by approximately 5 fold at the same exposure times. Further confirmation of synergistic activity was demonstrated with the use of the fraction product method of Webb formula. Conclusions: Our results demonstrate that VPA potentiates the cytotoxic effects of etoposide on neuroblastoma cells. by altering gene expression and rendering the cells more sensitive to etoposide induced cell death. Finally, since these agents have a proven track record of safety and efficacy in patients with neuroblastoma, this data supports the use of this combination in a phase I trial in patients with neuroblastoma. No significant financial relationships to disclose.
Refining the Definition of US Safety-Net Hospitals to Improve Population Health
Authors: Tyler N. A. Winkelman, Katherine Diaz Vickery
Journal: JAMA Network Open (2019)

Ioana Popescu, MD, MPH; Kathryn R. Fingar, PhD, MPH; Eli Cutler, PhD; Jing Guo, PhD; H. Joanna Jiang, PhD
Dovitinib (TKI258): Exploration of pharmacokinetics and pharmacodynamics (PK/PD) for dose and regimen consideration.
Authors: Samira Merali Garonzik, Jerry Nedelman, Eugene Tan, Ovidiu Chiparus, Margaret Han Dugan
Journal: Journal of Clinical Oncology (2012)

2603 Background: Dovitinib is a potent oral inhibitor of Receptor Tyrosine Kinases with activity against FGFR, VEGFR and PDGFR. The objectives of this analysis are to describe the PK/PD of dovitinib to characterize the differences between two different dosing regimens, 400 mg once daily (qd) or 500 mg 5 days on, 2 days off (int) in terms of exposure and biomarker response. Methods: PK/PD data from 127 patients receiving dovitinib, 100-600 mg int and 50 – 600 mg qd were available. Duration of therapy was 15 to 859 days. Plasma concentration-time data + sparse biomarker (BM) data were available after the first dose and at steady state (SS). Data was analyzed using non-linear mixed effects modeling to characterize nonlinearities in PK as well as BM response. VEGF, sVEGFR2 and PDGF were described by indirect response models and FGF23 was described using a mechanism based model to characterize acute drop, rebound, tolerance and increase to a new SS over time. Results: Raw data revealed prolonged absorption, linear clearance after the first dose, but dose dependent ↓ in clearance at SS (leading to over-proportional accumulation), and apparent linear clearance at doses below 400 mg qd. ↓ exposure for doses up to 400 mg at SS compared to 1st dose implied auto-induction. The PK was well described by a 1-compartment (CMT) model with 3 transit CMTs to characterize absorption lag. Auto-induction and over-proportional accumulation at SS were modeled as depending on cumulative exposure through a time-dependent process with half-life of 18 h. In our study, median (10 th – 90 th percentile) Clearance was 30 (17 – 80) L/h on Day 1, and 96 (51 – 185) L/h at SS. The model predicted 36%↑in VEGF, 18% ↓ in sVEGFR2, 82% and 57% ↑in PDGF and FGF23 respectively at SS, for median exposure at a dose of 400 mg qd. Simulations of PK and biomarker responses were performed for different dosing regiments to assess relative safety and target effects. Conclusions: The PK/PD model suggests 400 mg qd may lead to over-proportional accumulation of dovitinib in &lt;5% of subjects while int dosing minimizes this. 500 mg int may be a more tolerable regimen while maintaining adequate PD response, and is being used in the pivotal phase III study for dovitinib in patients with mRCC.
Serial pro-gastrin-releasing peptide and neuron specific enolase in predicting radiological response and overall survival of patients with small-cell lung cancer
Authors: A. Ono, T. Naito, A. Tsuya, Y. Nakamura, H. Murakami, K. Kaira, T. Takahashi, M. Endo, N. Yamamoto
Journal: Journal of Clinical Oncology (2009)

e22144 Background: Pro-gastrin-releasing peptide (ProGRP: P) and Neuron specific enolase (NSE: N) are specific serological markers in patients (pts) with small-cell lung cancer (SCLC). The aim of this study was to investigate whether decreasing of these tumor markers correlate with radiological response and prognosis in pts with SCLC. Methods: Out of 194 newly diagnosed SCLC pts from September 2002- April 2008 at our institution, we retrospectively reviewed consecutive 118 pts who had measurable lesions and elevated baseline levels of P and N before initial therapy (IT) including chemotherapy or chemoradiotherapy, and survived more than one month. P and N were measured on the first day of the every treatment course and after the final course of IT. Computed tomography (CT) was documented on baseline and every 2 courses of IT. Results: Forty-six (38.9%) pts had limited stage disease (LD) and 72 (61.0%) pts had extensive stage disease (ED). Both P and N levels at baseline were significantly correlated with the sum of longest diameter (SLD) in baseline CT; Spearman's ρ was 0.34 (P=0.001) and 0.44 (p&lt;0.0001), respectively. Also, the decreasing rate of P and N correlated with the decreasing rate of SLD, ρ= 0.45 (p&lt;0.0001) and 0.21 (p=0.03), respectively. Furthermore, the normalization of both P (&lt;46pg/ml) and N (&lt;10ng/ml) levels after 3 courses of IT was significantly associated with radiological response (p=0.015) including partial and complete response assessed by the Response Evaluation Criteria in Solid Tumors. In Cox's multivariate analysis, the normalization of both P and N levels after 3 courses of the IT (p=0.03, hazard ratio: 0.47, 95% CI 0.23–0.93) was significantly associated with prolonged survival, when adjusted by age, PS, and disease extent (LD or ED). Conclusion: Levels of P and N at baseline, and decreasing rate of P and N in IT were both associated with radiological response. In addition, the normalization of both P and N levels might be meaningful in predicting prognosis of SCLC pts. No significant financial relationships to disclose.
Abstract 12311: Impairment of Peripheral Endothelial Function in Patients With Aortic Valve Stenosis in the Aging Population
Authors: Koichiro Fujisue, Seigo Sugiyama, Hisayo Yasuda, Hirofumi Kurokawa, HIrofumi Maeda, Junichi Matsubara, Satomi Iwashita, Eiichiro Yamamoto, Eiichi Akiyama, Yasushi Matsuzawa, Hisao Ogawa
Journal: Circulation (2013)

Background: In the progressive aging society, heart failure (HF) patients with aortic valve stenosis (AS) are increasing. We need to understand the clinical features and pathophysiological conditio...
Reproducible molecular characterization of non-small cell lung cancer from paraffin.
Authors: Matthew Wilkerson, Myla Lai-Goldman, Philip Seth Bernard, Charles M. Perou, David N. Hayes, Juneko E. Grilley-Olson
Journal: Journal of Clinical Oncology (2013)

7576 Background: Recommendations exist to aid the clinically relevant non-small cell lung cancer (NSCLC) classification of squamous (SQ) versus adenocarcinoma (AD), including immunohistochemistry (IHC) for TTF1 and p63. We hypothesize that PCR of RNA gene panels may improve the diagnostic accuracy over IHC. Methods: A multi-institutional cohort of NSCLC patients was abstracted for use of IHC in clinical practice. RNA was isolated from routine paraffin sections and a 54-gene Histology by gene Expression Predictor (HEP) was implemented to distinguish SQ, AD, and other NSCLC variants. IHC for TTF1 and p63 was obtained on a subset of patients in a standardized manner. To compare the reproducibility of PCR diagnostics to morphologic diagnosis, a subset of samples was processed as matched pairs from the same tumor, in blinded manner. Results: 493 clinical samples were analyzed from 419 patients. Pathologists obtained any IHC in 22% of the cases, with TTF1 or p63 in &lt;10% of cases. In the subset of cases where standardized TTF1 and p63 was obtained, the stains were un-evaluable or incompletely obtained in 30% for reasons including technical failure, limited sample, and ambiguous staining (i.e positive for both p63 and TTF1); on this same subset, the HEP technical failure rate was 7%. In cases where staining was successful, both IHC and the HEP agreed with the clinical diagnosis at high rates (93 and 91% respectively). In IHC un-evaluable cases, slides were reviewed by up to 7 additional pathologists. In general such cases failed to produce a consensus diagnosis, suggesting that IHC failure indicates a difficult to diagnose case (kappa statistic &lt;0.5). As another concordance assessment method, we evaluated a second diagnostic property, reproducibility, by taking paired samples from the same case for blinded review. Strikingly, morphologic review in a blinded manner by pathologist generated low agreement with overall agreement of 65% compared to the HEP agreement of 92%. Conclusions: PCR based diagnostics such as the HEP may improve NSCLC diagnostic performance
Do we need to perform pulmonary function tests in non-small cell lung cancer patients never diagnosed as COPD?
Authors: Narongwit Nakwan, Sarayut Lucien Geater
Journal: Journal of Clinical Oncology (2012)

TPS9151 Background: Although chronic obstructive pulmonary disease (COPD) and lung cancer share a common risk factor, namely smoking, health care providers usually overlook the symptom of COPD in the management of lung cancer. Should, then, lung cancer patients undergo pulmonary function tests (PFT) to identify the presence of COPD? Our study was performed to describe the results of pulmonary function tests and define risk factors for COPD in non-small cell lung cancer (NSCLC) patients. Methods: A total of 31 eligible patients with NSCLC but no obvious symptoms of COPD participated. We collected baseline characteristics and conducted a detailed assessment of pulmonary function, particularly spirometry, lung volume measurement, and diffusing capacity of carbon monoxide (DLCO). Dyspnea was assessed using modified Borg (mBorg) and modified Medical Research Council (mMRC) scores. Results: Twelve patients had airflow limitation (FEV1/FVC&lt;0.7). These patients had mean percent predicted FEV1, RV and DLCO of 52%, 143% and 66% respectively, and a mean RV/TLC of 0.55. Being male, and having a smoking history, low body mass index and squamous cell carcinoma were significantly associated with obstruction in univariate analysis. However, obstruction was not more common in advanced stage than in locally advanced NSCLC. Neither mBorg nor mMRC differed between obstructive and non-obstructive groups. Discussion: COPD was found in patients with NSCLC who had never been diagnosed as, or showed symptoms of, COPD. Male, smoking history, low BMI and squamous cell carcinoma were significantly associated with obstruction.
Association of Hearing Loss With Dementia
Authors: Chin-Mei Liu, Charles Tzu-Chi Lee
Journal: JAMA Network Open (2019)

Hearing loss (HL) may be a modifiable risk factor for dementia, and longitudinal studies are needed to examine the association of HL and dementia.To investigate the association of HL with incident dementia in Taiwanese adults in the general population.This population-based cohort study collected data from the National Health Insurance Research Database of Taiwan. Patients newly diagnosed with HL from January 1, 2000, through December 31, 2011 (n = 8135), constituted the exposed (HL) group. The HL group patients were matched by sex, age, residence, and insurance premium to individuals without HL (non-HL group) (n = 8135). Data were analyzed from January 1, 2000, to December 31, 2013.Hearing loss defined according to International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes.Dementia classified according to ICD-9-CM codes.Of a total of 16 270 participants (9286 [57.1%] men; mean [SD] age, 65.2 [11.1] years), 1868 developed dementia. The dementia incidence rate in the HL group was higher than that in the non-HL group (19.38 [95% CI, 18.25-20.57] per 1000 person-years vs 13.98 [95% CI, 13.01-15.00] per 1000 person-years) during the follow-up period. In the fully adjusted multivariate Cox proportional hazards regression model applied for risk analysis, patients with HL had a significant risk of dementia (hazard ratio [HR], 1.17; 95% CI, 1.07-1.29; false discovery rate [FDR] P = .003). Subgroup analysis revealed that, among 3 age groups (45-64, 65-74, and ≥75 years), the group aged 45 to 64 years was associated with a risk of dementia (HR, 2.21 [95% CI, 1.57-3.12]; FDR P < .001). In sensitivity analysis, the presence of HL among those aged 45 to 64 years (HR, 1.40; 95% CI, 1.12-1.75; FDR P = .01) was associated with a risk of dementia.In this study, hearing loss was positively associated with a risk of dementia, especially in patients aged 45 to 64 years. Hearing protection, screening, and treatment may be used as strategies for mitigating this potential risk factor.