tbuckley/cabot-search huggingface dataset:
Identification of pharmacogenetic markers in cancer supportive care.
Authors: Min Wei
Journal: Journal of Clinical Oncology (2018)

109 Background: Precision medicine has become increasingly critical in cancer supportive care, with implications for treatment selection, medication dosing, and side effect prediction. The presence of clinically actionable germline variants brought the hope that accurate prediction of drug efficacy and toxicity would be in the future. This will greatly improve the comprehensive oncology care, where supportive care treatment options can be subjective and personalized. Methods: The changes in drug effect and toxicity caused by genetic variations were characterized in 4,287 patients submitted for clinical pharmacogenetics testing using a gene panel including key pharmacokinetic and pharmacodynamic genes. For each patient, the need to select an alternate medication and adjust medication dose was determined for the treatment of pain (CYP2D6, CYP1A2, OPRM1), nausea/vomiting (CYP2D6), antifungal prophylaxis (CYP2C19), and depression (CYP2D6, CYP2C19). It is recognized that there are many other factors playing in the variations of the response and toxicity to these classes of medications. Results: Of the 4,287 patients, 964 (22%) would have a recommendation to choose alternatives of oxycodone, codeine, or tramadol therapy and 3,394 patients (79%) for a non-standard dosage. A change in certain antiemetics such as ondansetron would be suggested for 171 patients (4%). If voriconazole antifungal prophylaxis was clinical required, 1,228 (29%) would need a dose increase, while 133 (3%) should be switched to a different regimen. 2,727 patients (64%) should avoid or adjust dosage on some of the commonly used agents for depression due to reduced efficacy or heightened risk of toxicity. Conclusions: Pharmacogenetics markers associated with reduced drug efficacy and higher rate of ADRs were commonly observed for medications used in cancer supportive care. Identification of these markers would help clinicians achieve optimal treatment outcome with manageable time and cost. This provides great opportunities to apply precision medicine principles to patient management.
Re: Tuan Zea Tan, Mathieu Rouanne, Kien Thiam Tan, Ruby Yun-Ju Huang, Jean-Paul Thiery. Molecular Subtypes of Urothelial Bladder Cancer: Results from a Meta-cohort Analysis of 2411 Tumors. Eur Urol 2019;75:423–32
Authors: Pontus Eriksson, Gottfrid Sjödahl
Journal: European Urology (2018)
Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial
Authors: Carol Moreno, Richard Greil, Fatih Demirkan, Alessandra Tedeschi, Bertrand Anz, Loree Larratt, Martin Simkovic, Olga Samoilova, Jan Novak, Dina Ben-Yehuda, Vladimir Strugov, Devinder Gill, John G Gribben, Emily Hsu, Chih-Jian Lih, Cathy Zhou, Fong Clow, Danelle F James, Lori Styles, Ian W Flinn
Journal: The Lancet Oncology (2018)
Association of Pallidal Neurostimulation and Outcome Predictors With X-linked Dystonia Parkinsonism
Authors: Norbert Brüggemann, Aloysius Domingo, Dirk Rasche, Christian K. E. Moll, Raymond L. Rosales, Roland Dominic G. Jamora, Henrike Hanssen, Alexander Münchau, Julia Graf, Anne Weissbach, Vera Tadic, Cid C. Diesta, Jens Volkmann, Andrea Kühn, Thomas F. Münte, Volker Tronnier, Christine Klein
Journal: JAMA Neurology (2018)

Anecdotal evidence suggests that deep brain stimulation (DBS) of the internal globus pallidus (GPi) is effective in ameliorating dystonia in X-linked dystonia parkinsonism (XDP), a disease that is usually refractive to medical therapy.To determine the efficacy of GPi-DBS in a cohort of patients with XDP in a prospective study and identify predictors of postoperative outcomes.This observational prospective cohort study enrolled patients in February 2013 and was completed in December 2014. The patients were followed up for up to 46 months. Patients from the Philippines were treated in a single center in Lübeck, Germany and followed up in the Philippines. Sixteen men with XDP (mean [SD] age, 40.9 [7.3] years; disease duration, 1-6 years) from the Philippines with predominant dystonia were selected.All patients underwent bilateral GPi-DBS in Lübeck, Germany.Clinical assessment included the motor parts of the Burke-Fahn-Marsden scale (BFMDRS-M) and the Unified Parkinson's Disease Rating Scale (UPDRS-III). T1-based basal ganglia volumetry was performed and correlated with postoperative outcomes.The study participants included 16 Filipino men (mean age, 40.9 years). Masked video ratings revealed significant improvements of dystonia severity 1 week (-55%; range, -94% to 59%; P < .01) and 6 months (-59%; range, -100% to 22%; P < .001) after surgery. The UDPRS-III score also improved, albeit to a lesser extent (-19%; range, -54% to 95%; and -27%; range, -70% to 124%; respectively). Unmasked long-term follow-up confirmed the continued efficacy of GPi-DBS up to 46 months after surgery. Important secondary end points improved, including activities of daily living, pain severity, weight, and quality of life. Caudate atrophy was a predictor of a less beneficial outcome (r = 0.817, P = .004).Internal globus pallidus DBS had a positive association in XDP with predominant dystonia (the primary end point) and contributed to an improved quality of life (the secondary end point). The response to DBS occurred within 1 week. Given the inverse correlation of postoperative benefit and caudate atrophy, GPi-DBS should be considered early during the disease course. Close international collaboration, training, and funding from multiple sources enabled the sustainable follow-up of patients with XDP in the Philippines.
Disentangled: A single institutional analysis comparing differences in end-of-life patterns and resource utilization in acute leukemia and bone marrow transplant units.
Authors: Gene Decastro, Samuel Anandan, Adam Ginsberg, Santiago Lopez
Journal: Journal of Clinical Oncology (2018)

90 Background: The impact of palliative medicine in patients with hematologic malignancies is a growing area of investigation. Over the last year, the Palliative Medicine service at North Shore University Hospital (NSUH) has developed and sustained a co-management model for patients admitted to the acute leukemia (ALU) or bone marrow transplant (BMTU) units. Methods: The primary outcome measure was the time from admission to initial consult. The secondary outcome measure was length of stay in a goal concordant setting to receive end of life (EOL) care, namely our inpatient palliative care unit (PCU). Results: There were 106 new consults in twelve months (45 acute leukemia/lymphoma consults and 61 bone marrow transplant consults). The principal diagnosis seen on the ALU was acute myeloid leukemia (56%), whereas on the BMTU it was multiple myeloma (28%). The average time to consult for the ALU decreased from 18.8 days at 6 months to 8.8 days at 12 months. For the BMTU, time to consult decreased from 10.2 days at 6 months to 4.6 days at 12 months. The mortality rate of patients seen from the ALU and BMTU was 40% and 12%, respectively. Of the ALU population deaths, 83% were 65 or older, compared to 29% of the BMTU deaths. Mortality events in the ICU were greater for BMTU patients (43%) relative to ALU patients (11%). Fifty percent of the ALU inpatient expirations were able to receive EOL care in our PCU. The remaining deaths were in the ALU (39%) or ICU (11%). For BMT patients, 57% died on the BMTU, and 43% in the MICU. Despite comparable numbers of PCU transfers during the pre- and post-intervention period, our initiative increased the average LOS in the PCU from 1.1 to 5.7 days. Of the ALU patients electing DNR prior to death (83%), the average DNR-to-death days was 10.6 days, whereas BMTU patients who elected DNR prior to death (50%) had an average of 6.5 DNR-to-death days. Conclusions: This partnership allowed for recognition of differences in EOL care patterns across these populations. It has demonstrated a benefit by accelerating time to consult and enhancing transitions to goal concordant settings for patients with hematologic malignancies at the end of their lives.
Baseline Genotype Testing to Assess Drug Resistance Before Beginning HIV Treatment—Reply
Authors: Michael S. Saag, Huldrych F. Günthard, Davey M. Smith
Journal: JAMA (2018)

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Financially effective test algorithm to identify an aggressive, EGFR-amplified variant of IDH-wildtype, lower-grade diffuse glioma
Authors: Tejus A Bale, Justin T Jordan, Otto Rapalino, Nisha Ramamurthy, Nicholas Jessop, John C DeWitt, Valentina Nardi, Maria Martinez-Lage Alvarez, Matthew Frosch, Tracy T Batchelor, David N Louis, A John Iafrate, Daniel P Cahill, Jochen K Lennerz
Journal: Neuro-Oncology (2018)

Update 3 of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) recognizes amplification of epidermal growth factor receptor (EGFR) as one important aberration in diffuse gliomas (World Health Organization [WHO] grade II/III). While these recommendations endorse testing, a cost-effective, clinically relevant testing paradigm is currently lacking. Here, we use real-world clinical data to propose a financially effective diagnostic test algorithm in the context of new guidelines. To determine the prevalence, distribution, neuroradiographic features (Visually Accessible REMBRANDT Images [VASARI]), and prognostic relevance of EGFR amplification in lower-grade gliomas, we assembled a consecutive series of diffuse gliomas. For validation we included publicly available data from The Cancer Genome Atlas. For a cost-utility analysis we compared combined EGFR and isocitrate dehydrogenase (IDH) testing, EGFR testing based on IDH results, and no EGFR testing. In n = 71 WHO grade II/III gliomas, we identified EGFR amplification in 28.2%. With one exception, all EGFR amplifications occurred in IDH-wildtype gliomas. Comparison of overall survival showed that EGFR amplification denotes a significantly more aggressive subset of tumors (P < 0.0001, log-rank). The radiologic phenotype in the EGFR-amplified tumors includes diffusion restriction (15%, P = 0.02), >5% tumor contrast enhancement (75%, P = 0.016), and mild (not avid) enhancement (P = 0.016). The proposed testing algorithm reserves EGFR fluorescence in situ hybridization (FISH) testing for IDH-wildtype cases. Implementation would result in ~37.9% cost reduction at our institution, or about $1.3–4 million nationally. EGFR-amplified diffuse gliomas are "glioblastoma-like" in their behavior and may represent undersampled glioblastomas, or subsets of IDH-wildtype diffuse gliomas with inherently aggressive biology. EGFR FISH after IDH testing is a financially effective and clinically relevant test algorithm for routine clinical practice.
An Aptamer-Based Probe for Molecular Subtyping of Breast Cancer
Authors: Mei Liu, Zhifei Wang, Ting Tan, Zhongsi Chen, Xianbo Mou, Xiaocheng Yu, Yan Deng, Guangming Lu, Nongyue He
Journal: Theranostics (2018)

Molecular subtyping of breast cancer is of considerable interest owing to its potential for personalized therapy and prognosis.However, current methodologies cannot be used for precise subtyping, thereby posing a challenge in clinical practice.The aim of the present study is to develop a cell-specific single-stranded DNA (ssDNA) aptamer-based fluorescence probe for molecular subtyping of breast cancer.Methods: Cell-SELEX method was utilized to select DNA aptamers.Flow cytometry and confocal microscopy were used to study the specificity, binding affinity, temperature effect on the binding ability and target type analysis of the aptamers.In vitro and in vivo fluorescence imaging were used to distinguish the molecular subtypes of breast cancer cells, tissue sections and tumor-bearing mice.Results: Six SK-BR-3 breast cancer cell-specific ssDNA aptamers were evolved after successive in vitro selection over 21 rounds by Cell-SELEX.The Kd values of the selected aptamers were all in the low-nanomolar range, among which aptamer sk6 showed the lowest Kd of 0.61 ± 0.14 nM.Then, a truncated aptamer-based probe, sk6Ea, with only 53 nt and high specificity and binding affinity to the target cells was obtained.This aptamer-based probe was able to 1) differentiate SK-BR-3, MDA-MB-231, and MCF-7 breast cancer cells, as well as distinguish breast cancer cells from MCF-10A normal human mammary epithelial cells; 2) distinguish HER2-enriched breast cancer tissues from Luminal A, Luminal B, triple-negative breast cancer tissues, and adjacent normal breast tissues (ANBTs) in vitro; and 3) distinguish xenografts of SK-BR-3 tumor-bearing mice from those of MDA-MB-231 and MCF-7 tumor-bearing mice within 30 min in vivo. Conclusion:The results suggest that the aptamer-based probe is a powerful tool for fast and highly sensitive subtyping of breast cancer both in vitro and in vivo and is also very promising for the identification, diagnosis, and targeted therapy of breast cancer molecular subtypes.
Perceiving hope from oncologists and prognostic understanding and treatment planning.
Authors: Login George, Heather M Derry, Keiko Kurita, Paul K Maciejewski, William Breitbart, Holly Gwen Prigerson
Journal: Journal of Clinical Oncology (2018)

21 Background: Offering hope during prognostic discussions is widely considered essential to the delivery of humane medical care. However, clinicians always offering hope may undermine realism in patients' prognostic understanding and preparation for what lies ahead. We examine how patients’ perceptions of their oncologists as always offering hope, compared to a more tempered sense of hope, relate to prognostic understanding and treatment planning. Methods: Data came from post-scan baseline assessments of an NCI funded multi-site study on prognostic communication among metastatic cancer patients’ refractory to at least one chemotherapy regimen. The analytic sample consisted of 235 participants, who during structured interviews, rated the question, “how often does your oncologist offer hope,” as “always,” “most of the time” or “sometimes.” A binary variable was created comparing participants endorsing “always” to participants endorsing “most of the time” or “sometimes.” Patients also reported on elements of prognostic understanding, DNR order completion, and preference for either life-extending or comfort care. Results: Patients who rated their oncologists as “always” offering hope (62.1%), compared to those who rated “most of the time” or “sometimes” (37.9%), were more likely to have inaccurate prognostic understanding regarding life-expectancy ( OR = 0.40; 95% CI, 0.16, 0.97), and marginally more likely to have a treatment preference that favored life-extending care over comfort care ( OR = 0.61; 95% CI, 0.35, 1.07). A significant moderation effect was seen ( b = -1.43, p = .04) such that accurate understanding of the incurability of their cancer was associated with DNR completion only among patients who perceived more tempered hope from oncologists ( OR = 5.53; 95% CI, 1.80, 17.02), and not among patients who always perceived hope ( OR = 1.32; 95% CI, 0.63, 2.78). Conclusions: Results suggest that the tempering of hope may have benefits, as perceiving oncologists as always offering hope was associated with worse prognostic understanding and lower advance care planning. Future research examining in a more nuanced way the nature of hope offered (e.g., hope for cure vs. symptom management) in longitudinal designs is needed.
DNA‐Based Biomaterials for Immunoengineering
Authors: Midori Maeda, Taisuke Kojima, Yang Song, Shuichi Takayama
Journal: Advanced Healthcare Materials (2018)

Man-made DNA materials hold the potential to modulate specific immune pathways toward immunoactivating or immunosuppressive cascades. DNA-based biomaterials introduce DNA into the extracellular environment during implantation or delivery, and subsequently intracellularly upon phagocytosis or degradation of the material. Therefore, the immunogenic functionality of biological and synthetic extracellular DNA should be considered to achieve desired immune responses. In vivo, extracellular DNA from both endogenous and exogenous sources holds immunoactivating functions which can be traced back to the molecular features of DNA, such as sequence and length. Extracellular DNA is recognized as damage-associated molecular patterns (DAMPs), or pathogen-associated molecular patterns (PAMPs), by immune cell receptors, activating either proinflammatory signaling pathways or immunosuppressive cell functions. Although extracellular DNA promotes protective immune responses during early inflammation such as bacterial killing, recent advances demonstrate that unresolved and elevated DNA concentrations may contribute to the pathogenesis of autoimmune diseases, cancer, and fibrosis. Therefore, addressing the immunogenicity of DNA enables immune responses to be engineered by optimizing their activating and suppressive performance per application. To this end, emerging biology relevant to the generation of extracellular DNA, DNA sensors, and its role concerning existing and future synthetic DNA biomaterials are reviewed.
A computerized decision support tool to implement asthma guidelines for children and adolescents
Authors: Carolyn M. Kercsmar, Christine A. Sorkness, Agustin Calatroni, Peter J. Gergen, Gordon R. Bloomberg, Rebecca S. Gruchalla, Meyer Kattan, Andrew H. Liu, George T. O'Connor, Jacqueline A. Pongracic, Stanley J. Szefler, Stephen J. Teach, Jeremy J. Wildfire, Robert A. Wood, Edward M. Zoratti, William W. Busse
Journal: Journal of Allergy and Clinical Immunology (2018)
US life expectancy falls for third year in a row
Authors: Owen Dyer
Journal: BMJ (2018)

Life expectancy at birth in the United States fell again in 2017 for the third year running, the longest sustained decline since 1915-18, when the first world war and the 1918 Spanish influenza pandemic were among the causes of death.

A continued increase in deaths by overdose in 2017 was the biggest factor driving rates upward, but seven of the top 10 causes of mortality saw a statistically significant increase while only one, cancer, saw a significant decrease.

Life expectancy at birth for women in 2017 was unchanged at 81.1 years, while for men it fell from 76.2 to 76.1 years, and for both sexes from 78.7 to 78.6 …
Total relaxation: A Buddhist mindfulness-based intervention pilot studies in laypersons and cancer patients.
Authors: Suthida Suwanvecho, Buntharika Suwanvecho, Krit Pongpirul
Journal: Journal of Clinical Oncology (2018)

187 Background: Total relaxation (TR), a mindfulness-based intervention based on the Buddha’s teaching of Sutra on Full Awareness of Breathing (Anapanasati Sutta) and Sutra on the Four Establishments of Mindfulness (Satipatthana Sutta). This study was aimed (1) to explore benefits of TR perceived by laypersons and (2) to share experience in piloting the intervention in cancer patients. Methods: Laypersons who attended the 5 - day retreat program with daily TR sessions at Khao Yai, Nakhon Ratchasima, Thailand during October 22-26, 2014 responded to the Edmonton Symptom Assessment Scale (ESAS) before and after the TR session on the first day (TR1 Before, TR1 After) and after the fourth TR session (TR4 After). ESAS was responded by cancer patients who visited Horizon Cancer Center, Bumrungrad International Hospital before and after their participation in a 45 minute TR group session. Paired t-test was used to evaluate the before-after difference in score of each matched variables. Results: Of 162 laypersons, 90.74% responded. They reported a significant improvement of all ESAS items (p &lt; 0.001). Ten cancer patients (6 breast, 2 colon, and 1 stomach cancers and 1 lymphoma) who participated in the TR group session also saw the improvement of all ESAS items, with the mean differences ranging from 0.36 (feeling depressed) to 3.09 points (fatigue/tiredness). No adverse events were observed. Conclusions: Total relaxation is a Buddhist mindfulness-based technique that can improve undesirable symptoms of layperson and cancer patients.
Abstract 20566: Dissecting How Newly Discovered SERCA2-Regulating Micropeptides Control Heart Function and Disease
Authors: Catherine A Makarewich, Svetlana Bezprozvannaya, Ellen Cho, Seth L Robia, Rhonda Bassel-Duby, Eric N Olson
Journal: Circulation (2017)

Introduction: Our lab has recently identified and characterized a novel transmembrane protein named DWORF (DWarf Open Reading Frame) that binds to SERCA2a and enhances its activity by displacing ph...
Daunorubicin/Cytarabine Liposome: A Review in Acute Myeloid Leukaemia
Authors: Hannah A. Blair
Journal: Drugs (2018)

VYXEOS™ is a liposomal-encapsulated formulation of daunorubicin and cytarabine delivering a fixed, synergistic 1:5 molar ratio (hereafter referred to as daunorubicin/cytarabine liposome). Daunorubicin/cytarabine liposome is approved in several countries worldwide for the treatment of adults with therapy-related acute myeloid leukaemia (tAML) and AML with myelodysplasia-related changes (MRC). Approval was based on its clinical benefit in older patients with newly diagnosed high-risk/secondary AML in a pivotal phase III trial. In this study, daunorubicin/cytarabine liposome significantly prolonged overall survival (OS) and event-free survival (EFS) relative to conventional chemotherapy with cytarabine plus daunorubicin (hereafter referred to as 7 + 3). Daunorubicin/cytarabine liposome was also associated with significantly higher rates of complete remission (CR) and CR with incomplete haematological recovery (CRi) compared with 7 + 3. Daunorubicin/cytarabine liposome had an acceptable tolerability profile in older patients with newly diagnosed high-risk/secondary AML. The safety profile of daunorubicin/cytarabine liposome, including types and severities of adverse events, was generally similar to that of 7 + 3. Therefore, daunorubicin/cytarabine liposome is an important treatment option for adults with newly diagnosed tAML or AML-MRC.