tbuckley/cabot-search huggingface dataset:
Natural selection and metaphors of “selection”
Authors: Adolf Heschl
Journal: Behavioral and Brain Sciences (2001)

Natural selection in the sense of Darwin always means physical propagation (positive case) or disappearance (negative case) of living organisms due to differential reproduction. If one concentrates on this simple materialist principle, one arrives at a much better method of discerning true selection processes from largely nonrandom processes of internal rearrangement (somatic mutations) and reorganisation (operant learning).
Retroperitoneal soft tissue sarcoma (RPS): Recent outcome improvement and refinement of treatment strategies at a single institution.
Authors: Marco Fiore, Max Almond, Francesco Barretta, Dario Callegaro, Chiara Colombo, Stefano Radaelli, Sandro Pasquali, Marta Barisella, Carlo Morosi, Roberta Sanfilippo, Claudia Sangalli, Silvia Stacchiotti, Rosalba Miceli, Paolo Giovanni Casali, Alessandro Gronchi
Journal: Journal of Clinical Oncology (2019)

11041 Background: Extended surgery in retroperitoneal sarcoma (RPS) has resulted in less recurrences and better survival. We investigated whether outcome further improved, after the recent understanding of behavior of different RPS subtypes and introduction of multimodal therapies. Methods: Consecutive primary RPS operated at a single center were analyzed comparing 3 periods (2002-2006; 2007-2011; 2012-2016). Primary endpoints were overall survival (OS), crude cumulative incidence (CCI) of local recurrence and distant metastasis (LR, DM) for each subgroup: well differentiated (WDLPS), dedifferentiated G2 (G2DDLPS), G3 (G3DDLPS) liposarcoma, and leiomyosarcoma (LMS). Secondary endpoints: morbidity and post-relapse OS. Fisher/Chi-squared and Cochran–Armitage trends test were used. Survival was analysed by Kaplan-Meier/Cox PH or CCI/Fine Gray models in the competitive risk framework and compared with log-rank/Wald Gray tests. Multivariable analyses were performed. Results: Overall 437 RPS were operated: 82, 128 and 227 in the 1st, 2nd and 3rd period. Median follow-up was 125, 86 and 39 months. Complete resection (R0/R1) improved from 93.9% to 98.2% (p=0.059), median number of resected organs increased from 2 to 4 (p&lt;.0001). Postoperative morbidity did not change (18.3%, 16.4%, 22.5%; p=0.269). Administration of radiotherapy and chemotherapy (CT) differed over time according to different subtypes. 5-yr OS improved (63.2% to 74.7%, p=0.005), along with a non-significant reduction in LR CCI (18.2% to 16.4%, p=0.379) and no change in DM CCI. At multivariable analysis, study period remained an independent prognostic factor for OS among the other known risk factors (3rd vs 1st period HR: 0.33, p&lt;0.001). Subgroup analysis showed the following associations with better prognosis: 1. Improvement in 5-yr OS (from 55.0% to 70.7%, p=0.024) and LR (from 45.0% to 19.8%, p=0.060) in G2DDLPS, associated with more organs resected 2. Improvement in 5-yr OS (from 18.2% to 49.7%, p=0.035) and DM (from 70.0% to 19.8%; p=0.015) in G3DDLPS, associated with more anthracycline-based CT 3. A better 2-yr post-relapse OS (from 46.3% to 65.2%, p=0.122). Conclusions: OS of patients with DDLPS improved over time: in G2 this was associated with a refinement in the surgical approach, while in G3 with a more liberal use of anthracycline-based CT. New available therapies for recurring RPS may also have extended post-relapse OS. Prospective studies on perioperative CT for high risk RPS subtypes are eagerly awaited.
A single-center experience with CELLSEARCH system circulating tumor cell test on patients with metastatic breast cancer.
Authors: Alberto J. Montero, Sara Eapen, Ryan M. Andrews, Brian Gorin
Journal: Journal of Clinical Oncology (2013)

e22135 Background: Clinical studies have shown that circulating tumor cell (CTC) detection via the CELLSEARCH assay is a validated prognostic marker that is a predictor of overall survival (OS) in metastatic breast cancer (mBC) patients. By analyzing real-world observational data in one center, we evaluated the impact of CTC testing on predicting OS. Methods: Electronic medical records (EMR) were used to identify patients who were: (i) women &gt; 18 years diagnosed with mBC on or after their date of registration, (ii) registered to the EMR system on or after 4/1/2010, and (iii) followed for at least 2 months from the time of metastases. Patients who had CTC testing were required, on average, to have at least 1 valid CTC test result every 3 months. OS from the date of initial diagnosis of metastases among mBC patients with CTC testing was compared to a cohort of patients without CTC testing (non-CTC) using a Cox model controlling for covariates such as age, race, hormone receptor status, and scanning frequency. Results: Mean (SD) ages of CTC (N=79) and non-CTC (N=1,146) patients were 65 (13) and 64 (14) years, respectively. ER or PR+ patients comprised 67% of the CTC population, and 64% of the non-CTC population. The majority of patients in both cohorts were Caucasian (89% - CTC, 57% - non-CTC). The Cox model showed that the group where CTC testing occurred had a statistically significant 40% reduction in risk of death (HR=0.60, p-value=0.03); this reduction was even greater among ER or PR+ patients who received CTC testing compared to those who did not (51%, HR=0.49, p-value=0.03). Conclusions: This retrospective analysis shows that the CTC population had a better prognosis than the non-CTC population. Thus, the assessment of CTCs could be associated with improved monitoring and prediction of cancer progression, and improved evaluation of response to therapy in mBC patients, possibly guiding more informed care decisions. The reliance on a single center and the relatively small number of CTC patients limits the ability to rule out other potential confounders in the analysis. Further studies using larger CTC samples and data from other centers with CTC testing are needed to verify and better understand this result.
Preclinical testing using novel CT20p petide-nanoparticle combination in breast cancer.
Authors: Priya Vishnubhotla, Rebecca J Boohaker, Michael W Lee, Kathleen N Nemec, Amr Khaled, Santimukul Santra, G.Micheal Perez, J.Manuel Perez, Annette R Khaled
Journal: Journal of Clinical Oncology (2013)

3085 Background: Patients with metastatic breast cancer may be initially responsive to treatment, but a significant number develop refractory disease. There is a critical unmet need to develop effective therapeutic approaches given the unique metabolism of tumor cells. Methods: We examined the cytotoxic properties of a novel peptide, CT20p, derived from the C-terminus of Bax. For delivery to cells, the amphipathic nature of CT20p allowed it to be encapsulated in polymeric nanoparticles (NPs). NPs were made using aliphatic hyperbranched polyester (HBPE) that incorporated surface carboxylic groups and interior hydrophobic cavities for encapsulation of CT20p. To examine the cytotoxic potential and targeting capacity of CT20p-NP-HBPE, we treated MDA-MB-231 and MCF-10A breast cancer cell lines with the combination and measured changes in mitochondrial function, cell metabolism and induction of cell death. The ability of CT20p-NP-HBPE to cause tumor regression was examined by subcutaneously implanting MDA-MB-231 cells in nude mice. Results: Initial results showed that CT20p caused the release of calcein from mitochondrial-like lipid vesicles, without disrupting vesicle integrity, and, when expressed as a fusion protein in cells, localized to mitochondria. While the peptide alone had little effect upon intact cells, when encapsulated and delivered by nanoparticles, CT20p-HBPE-NPs proved an effective killer of breast cancer cells. CT20p-NP-HBPE initiated non-apoptotic cell death within 3 hours of treatment by targeting mitochondria and deregulating cellular metabolism. Nanoparticles alone or nanoparticles encapsulating a control peptide had minimal effects. The cytotoxicity of CT20p-NP-HPBE was most pronounced in breast cancer cells, sparing normal, epithelial cells. In implanted breast tumors, CT20p-NP-HBPE accumulated in tumors within 24 hours and reduced tumor burden by 50-80%. Conclusions: These results reveal the innovative features of CT20p that allow nanoparticle-mediated delivery to tumors and the potential application in combination therapies that target the unique metabolism of cancer cells.
In Older Men, Higher Plasma Testosterone or Dihydrotestosterone Are Independent Predictors for Reduced Incidence of Stroke but Not Ischaemic Heart Disease Events
Authors: Bu Beng Yeap, Helman Alfonso, Paul Chubb, David J. Handelsman, Graeme J. Hankey, Osvaldo P. Almeida, Jonathan Golledge, Paul E. Norman, Leon Flicker
Journal: Endocrine Reviews (2014)
OS10.1 Survival analysis of IDH wildtype astrocytomas with molecular features of glioblastoma, WHO grade IV
Authors: C M S Tesileanu, J A F Koekkoek, L Dirven, H J Dubbink, J M Kros, S G van Duinen, M Smits, P J French, M J B Taphoorn, M J van den Bent
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Recently, isocitrate dehydrogenase wildtype (IDHwt) lower grade gliomas (LGGs) that have a telomerase reverse transcriptase (TERT) promoter mutation and/or gain of chromosome 7 combined with loss of chromosome 10 and/or epidermal growth factor receptor amplification have been reclassified as IDHwt astrocytomas with molecular features of glioblastoma, WHO grade IV (‘astrocytomas IDHwt, WHO IV’). Survival of these tumors meeting the criteria of these tumors is less well studied. The objective of this study is to compare the overall survival (OS) between the IDHwt astrocytomas, WHO IV and histological glioblastomas (GBMs). MATERIAL AND METHODS In this retrospective multicenter cohort study, all adult patients with a newly diagnosed IDHwt LGG (histologically WHO grade II or III) and with molecular data available were selected from the Erasmus MC and the LUMC from October 2002 to April 2019. LGG patients showing contrast enhancement with necrosis on the MRI at the time of histological diagnosis were excluded. Molecular data were determined using a diagnostic NGS panel. A historical cohort of 195 patients with IDHwt GBMs with molecular data available was used to compare OS. OS was measured from the date of the first diagnostic MR scan. RESULTS 79 IDHwt LGG patients were identified of which 62 patients had molecular features of glioblastoma (‘astrocytomas IDHwt, WHO IV’), 11 patients did not have these molecular features (‘astrocytomas IDHwt, WHO II &amp; III’). In the remaining 6 patients the molecular data were not conclusive (astrocytomas IDHwt, WHO NOS). Patients with astrocytomas IDHwt, WHO IV were slightly older at diagnosis (median age = 57 years) than patients with GBMs IDHwt in the reference cohort or astrocytomas IDHwt, WHO II &amp; III (respectively: median age 55 years, p=0.032 and 47 years, p=0.035). The relatively young age of our GBM IDHwt cohort reflects more extensive molecular testing in younger patients and histologically lower grade tumors. The median OS of astrocytomas IDHwt, WHO IV (23.8 months) was similar to the median OS of GBMs (19.2 months, log-rank test p=0.37). The median OS in 19 patients with only TERT promoter mutations was 16.8 months, similar to GBMs (p=0.94). CONCLUSION There is no statistically significant difference between the OS of IDHwt astrocytomas with molecular features of glioblastoma and the OS of true glioblastomas. Grade II and III IDHwt astrocytoma with molecular features of glioblastoma should be designated WHO grade IV. The presence of TERT promoter mutations alone in this histological context also qualifies for this designation.
P14.111 Successful treatment of extensive metastatic disease with successive use of two different EGF receptor antagonists: case report and review of the literature
Authors: J F Megyesi, D R Macdonald
Journal: Neuro-Oncology (2019)

Abstract INTRODUCTION EGFR-targeted agents can be useful in the treatment of systemic metastatic cancer including that which has spread to the brain. We present the case of a patient with two different EGFR mutations that responded to receptor blockade. CASE REPORT A 38 year old right-handed female presented with a one week history of progressive left-sided weakness and focal seizures. Neuroimaging revealed multiple enhancing brain lesions and a lesion in the left maxillary antrum. Body imaging revealed a right lung mass, hilar and mediastinal nodes and multiple bony lesions. Biopsy of the maxillary antrum lesion showed metastatic poorly differentiated adenocarcinoma, TTF-1 positive, suggesting a lung primary. ALK was not mutated but there was an EGFR mutation (exon 19 deletion). The patient underwent treatment with dexamethasone, levetiracetam, whole brain radiation and afatinib, an oral EGFR-targeted agent. Most of the brain lesions responded completely with only two small residual lesions. Seizures were controlled. There was major partial response from the systemic lesions. Two years later the patient was clinically well but the lung lesion, mediastinal nodes and bony lesions were all enlarging. A new pituitary lesion was identified on brain MRI. A liquid biopsy (blood) revealed a T790M mutation and the patient underwent stereotactic body radiation and EGFR-targeted therapy with osimertinib. All lesions responded to treatment and four years after initial diagnosis the patient is clinically well with stable disease. DISCUSSION Successful treatment of widespread metastatic disease is possible with the use of multiple EGFR-targeted agents in certain patients.
P14.58 Extending adjuvant temozolomide longer than six cycles doesn’t add any benefit to glioblastoma patients according to the randomized GEINO-014 TRIAL
Authors: C Balana, J Sepulveda, E Pineda, M Vaz, C Mesia, J Fuster, R Girones, J Muñoz-Langa, M Navarro, M Alonso, M Gil Gil, A Herrero, A Estival, O Gallego, S Peralta, C Olier, P Pérez-Segura, M Covela, M Martinez García, M Domenech, C Carrato, C Sanz, J Velarde, A Berrocal, R Luque, R De las Peñas, S Del Barco
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Standard treatment of glioblastoma (GBM) is focal radiation with concomitant and adjuvant temozolomide (TMZ) for 6 cycles. The GEINO-14-01 trial (NCT02209948) investigated the role of extending adjuvant TMZ to 12 cycles in a randomized multicenter study. MATERIAL AND METHODS Between Aug/2014 and Nov/2018, 166 patients (p) were screened and 159 randomized to extend (80p) or not (79p) TMZ treatment to 12 cycles after proving stable disease in the MRI performed before inclusion. The trial was stratified by MGMT status and presence or absence of residual disease (defined as a residual enhancement larger than 1cm on the MRI). The primary endpoint was differences in 6monthsPFS, secondary endpoints were differences in PFS, OS, toxicity, between arms and per stratification factors. RESULTS Median age was 60.4 (range 29–83), 97p (61%) were methylated and 83 p (52.2%) were reported with residual disease. Median (m) PFS was 7.9 months (95%CI: 6.1–9.8) and mOS: 20.9 (95%CI: 17.6–24.1). A methylated status was a factor of better PFS (HR=0.29, 95% CI 0.46–0.95; p=0.029) and better OS (HR= 0.43: 95% CI 0.28–0.66; p=0.000) as well as the absence of residual disease (PFS: HR = 0.84: 95% CI =0.71–1.01; p=0.068; OS: HR=0.77, 95%CI 0.63–0.96; p=0.019). We didn’t find any difference in PFS (HR=1.02, 95%CI 0.85–1.21; p=0.82), or OS (HR=0.90; 0.73–1.11; p=0.34) on extending treatment with temozolomide longer than 6 cycles. CONCLUSION There is no benefit of continuing TMZ treatment for more than 6 cycles in the adjuvant treatment of glioblastoma. Final data will be presented at the congress. Supported by a Grant of the ISCIII: PI13/01751
Diagnosis and management of hypertension in pregnancy: summary of updated NICE guidance
Authors: Katie Webster, Sarah Fishburn, Mike Maresh, Sarah C Findlay, Lucy C Chappell
Journal: BMJ (2019)

### What you need to know

Hypertension in pregnancy is a common condition, affecting about 10% of pregnant women. This includes women with chronic hypertension—which may be diagnosed before pregnancy or in the early stages of pregnancy (<20 weeks’ gestation)—and women with hypertension related to pregnancy (gestational hypertension and pre-eclampsia) (see box 1). If not identified and treated, hypertension can lead to adverse events for both the woman and her baby, including increased risk of maternal stroke, lower birth weight, and increased risk of the baby requiring neonatal intensive care.

Box 1 
### Definitions for hypertensive disorders of pregnancyRETURN TO TEXT

General practitioners and specialists other than obstetricians play a vital role in the identification of hypertension during pregnancy, first …
Cytosolic PCNA interacts with p47phox and controls NADPH oxidase NOX2 activation in neutrophils
Authors: Delphine Ohayon, Alessia De Chiara, Pham My-Chan Dang, Nathalie Thieblemont, Simon Chatfield, Viviana Marzaioli, Sabrina Sofia Burgener, Julie Mocek, Céline Candalh, Coralie Pintard, Pascale Tacnet-Delorme, Gilles Renault, Isabelle Lagoutte, Maryline Favier, Francine Walker, Margarita Hurtado-Nedelec, Dominique Desplancq, Etienne Weiss, Charaf Benarafa, Dominique Housset, Jean-Claude Marie, Philippe Frachet, Jamel El-Benna, Véronique Witko-Sarsat
Journal: The Journal of Experimental Medicine (2019)

Neutrophils produce high levels of reactive oxygen species (ROS) by NADPH oxidase that are crucial for host defense but can lead to tissue injury when produced in excess. We previously described that proliferating cell nuclear antigen (PCNA), a nuclear scaffolding protein pivotal in DNA synthesis, controls neutrophil survival through its cytosolic association with procaspases. We herein showed that PCNA associated with p47phox, a key subunit of NADPH oxidase, and that this association regulated ROS production. Surface plasmon resonance and crystallography techniques demonstrated that the interdomain-connecting loop of PCNA interacted directly with the phox homology (PX) domain of the p47phox. PCNA inhibition by competing peptides or by T2AA, a small-molecule PCNA inhibitor, decreased NADPH oxidase activation in vitro. Furthermore, T2AA provided a therapeutic benefit in mice during trinitro-benzene-sulfonic acid (TNBS)–induced colitis by decreasing oxidative stress, accelerating mucosal repair, and promoting the resolution of inflammation. Our data suggest that targeting PCNA in inflammatory neutrophils holds promise as a multifaceted antiinflammatory strategy.
β<sub>2</sub>-Adrenergic genotypes and risk of severe exacerbations in COPD: a prospective cohort study
Authors: Truls Sylvan Ingebrigtsen, Jørgen Vestbo, Line Rode, Jacob Louis Marott, Peter Lange, Børge G Nordestgaard
Journal: Thorax (2019)

Background Individual susceptibility to exacerbations in chronic obstructive pulmonary disease (COPD) is likely influenced by genetic factors; however, most such variance is unexplained. We hypothesised that β 2 -adrenergic receptor genotypes, Gly16Arg (rs1042713, c.46G&gt;A) and Gln27Glu (rs1042714, c.79C&gt;G) influence risk of severe exacerbations in COPD. Methods Among 96 762 individuals in the Copenhagen General Population Study, we identified 5262 with COPD (forced expiratory volume in one second divided by forced vital capacity, FEV 1 /FVC, below 0.7, FEV 1 less than 80% of predicted value, age above 40 years and no asthma) who had genotyping performed. Severe exacerbations were defined as acute admissions due to COPD during 5 years of follow-up (mean 3.4 years). 923 individuals with COPD diagnosed similarly in the Copenhagen City Heart Study (CCHS) were used for replication analyses. Results We recorded 461 severe exacerbations in 5262 subjects. The HRs for severe exacerbations were 1.62 (95% CI 1.30 to 2.03, p=0.00002) for 16Gly/Arg heterozygotes and 1.41 (1.04 to 1.91, p=0.03) for 16Arg homozygotes, compared with 16Gly homozygotes. HRs were 1.35 (1.03 to 1.76, p=0.03) for 27Gln/Glu heterozygotes and 1.49 (1.12 to 1.98, p=0.006) for 27Gln homozygotes, compared with 27Glu homozygotes. Similar trends were observed in the CCHS. Among 27Gln homozygotes only, HRs were 5.20 (1.81 to 14.9, p=0.002) for 16Gly/Arg heterozygotes and 4.03 (1.40 to 11.6, p=0.01) for 16Arg homozygotes, compared with 16Gly homozygotes. Conclusion Common β 2 -adrenergic receptor genotypes influence risk of severe exacerbations in COPD, potentially mainly by genetic influence of the 16Arg allele in rs1042713.
Measles-related hospitalizations and associated complications in Jerusalem, 2018–2019
Authors: E. Ben-Chetrit, Y. Oster, A. Jarjou'i, O. Megged, T. Lachish, M.J. Cohen, C. Stein-Zamir, H. Ivgi, M. Rivkin, Y. Milgrom, D. Averbuch, M. Korem, D.G. Wolf, Y. Wiener-Well
Journal: Clinical Microbiology and Infection (2019)
SWOG S0715: Randomized placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy during adjuvant breast cancer therapy.
Authors: Dawn L. Hershman, Joseph M Unger, Katherine D. Crew, Carol Moinpour, Lori M. Minasian, Lisa Hansen, Danika Lew, Patricia OKane, James Lloyd Wade, Siu-Fun Wong, Gabriel N. Hortobagyi, Frank L. Meyskens, Kathy S. Albain
Journal: Journal of Clinical Oncology (2012)

9018 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, disabling side effect of taxanes that leads to suboptimal treatment and diminished quality of life. Acetyl-L-Carnitine (ALC) is a natural compound involved in tubulin acetylation and neuronal protection. Pre-clinical and phase II studies suggest ALC may be effective for the prevention and treatment of CIPN. Methods: A randomized, double-blind, multi-center, phase III trial comparing ALC (1000 mg TID) vs placebo for 24 wks in women with stage I-III breast cancer undergoing adjuvant taxane therapy was conducted. The primary objective was to determine if ALC prevents CIPN as measured by the 11-item neurotoxicity (NTX) component of the FACT-Taxane scale (low score = worse NTX) at 12 wks. Secondary objectives included change at 24 wks, change in the Trial Outcome Index (TOI), fatigue (FACIT Fatigue) and NTX grade. Patients were stratified by planned treatment, and age (&lt;60, ≥60). Results: 409 patients were evaluable (208 ALC, 201 placebo). No imbalances were observed by age, ethnicity, race, planned taxane treatment, performance status, or stage. The mean FACT-NTX score was 5.2 points lower at 12 wks on ALC and 4.5 points lower on placebo. In a linear regression adjusting for baseline score, planned treatment and age, wk 12 scores were 0.9 points lower on ALC than placebo (95% CI: -2.2 to 0.4, p=.17). At 24 wks, the mean observed FACT-NTX score was lower for ALC (5.3 vs. 3.6). In the multivariate model, wk 24 scores were 1.8 points lower on ALC (95% CI: -3.2 to -0.4, p=.01), representing more self-reported NTX. Grade 3/4 NTX was more frequent in the ALC arm (p=.04). Also at 24 wks, 38% on ALC had &gt;5 point decrease score compared to 28% on placebo (OR=1.57, p=.05), and FACT-TOI scores were 3.5 points lower on ALC (95% CI: -6.5 to -0.4, p=.03). No differences between arms were observed for the FACIT-Fatigue scale or for other toxicities. Conclusions: There is no evidence that ALC has a positive impact on CIPN at 12 wks. However, ALC increases CIPN by 24 wks. Correlative studies are ongoing to explain this unexpected finding. Patients should be discouraged from using ALC and other supplements without proven efficacy.