tbuckley/cabot-search huggingface dataset:
Personalized biomarker-based treatment strategy for patients with squamous cell carcinoma of the head and neck: EORTC position and approach
Authors: R. Galot, C. Le Tourneau, J. Guigay, L. Licitra, I. Tinhofer, A. Kong, C. Caballero, C. Fortpied, J. Bogaerts, A.-S. Govaerts, D. Staelens, T. Raveloarivahy, L. Rodegher, J.-F. Laes, E. Saada-Bouzid, J.-P. Machiels
Journal: Annals of Oncology (2018)

The molecular landscape of squamous cell carcinoma of the head and the neck (SCCHN) has been characterized and actionable or targetable genomic alterations have been identified. However, targeted therapies have very limited activity in unselected SCCHN, and the current treatment strategy is still based on tumor location and disease stage and not on tumor biology. Trying to select upfront the patients who will benefit from a specific treatment might be a way to improve patients' outcome. With the objective of optimizing the activity of targeted therapies and immunotherapy, we have designed an umbrella biomarker-driven study dedicated to recurrent and/or metastatic SCCHN patients (EORTC-1559-HNCG, NCT03088059). In this article, we review not only the different trial designs for biomarker-driven studies with their respective advantages and opportunities but also the potential pitfalls that led to the design of the EORTC-1559-HNCG protocol. We also discuss the scientific and logistic challenges of biomarker-driven trials.
Abstract 17733: Association of Left Ventricular Longitudinal Strain With Cardiac Events in Dilated Cardiomyopathy Patients With Myocardial Fibrosis
Authors: Misato Chimura, Tetuari Onishi, Yasue Tukishiro, Hiroya Kawai
Journal: Circulation (2013)

INTRODUCTION: Myocardial fibrosis is associated with worse outcome in dilated cardiomyopathy (DCM) patients. Global strain in left ventricle (LV) is a sensitive measure of LV mechanics. However, it...
Refining criteria of hyperprogression (HPD) with immune checkpoint inhibitors (ICIs) to improve clinical applicability
Authors: I. Matos Garcia, A. García Ruiz, J. Martin-Liberal, C. Hierro, M. Ochoa De Olza Amat, C. Viaplana, G. Mur, M. Vieito Villar, I. Brana, A. Azaro, C. Perez, V. Rodriguez Freixinos, G. Argiles, M. Oliveira, E. Felip Font, E. Muñoz-Couselo, J. Tabernero, R. Dienstmann, E. Garralda
Journal: Annals of Oncology (2018)
A case of incontinentia pigmenti associated with congenital absence of portal vein system and nodular regenerative hyperplasia
Authors: R. Romano, F. Grasso, V. Gallo, E. Cirillo, R. Prencipe, G. Mamone, C. Mollica, V.M. Ursini, J. De Ville De Goyet, C. Pignata, G. Giardino
Journal: British Journal of Dermatology (2018)
OP0122 Validation of remission and lupus low disease activity state as predictors of organ damage in sle
Authors: M. Petri, D.W. Goldman, L.S. Magder
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Outcome measures that combine control of SLE activity and prednisone reduction are clinically relevant. A clinical goal in SLE is to reduce risk of long-term organ damage. <h3>Objectives</h3> We assessed whether two recently proposed disease activity outcomes were predictive of future damage. <h3>Methods</h3> For each month of follow-up in a large SLE cohort, we determined whether the patient was in Clinical Remission (as defined by the DORIS working group) or lupus low disease activity state (LLDAS) (as defined by Franklyn et al). Clinical Remission was defined as a PGA&lt;0.5, clinical SLEDAI=0 and no prednisone or immunosuppressants. Clinical Remission on Treatment allowed for prednisone ≤5 mg/day and immunosuppressant use. LLDAS was defined as a SLEDAI ≤4, PGA≤1.0, no major organ activity, and no new activity. LLDAS on treatment allowed for prednisone use ≤7.5 mg/d and immunosuppressants. Damage was defined using the SLICC/ACR Damage index. <h3>Results</h3> There were 81 118 person-months observed among 2026 patients (92% female, 53% Caucasian, 39% African-American). table 1 shows the rates of damage, per person month, in subgroups defined by Remission or LLDAS. Damage rates were relatively low when LLDAS was achieved at least 50% of the time. These rates were similar to those experienced by patients who met a more stringent treatment restriction with Remission on Treatment at least 50% of the time. <h3>Conclusions</h3> Percent time in LLDAS had a clear dose response for rate ratios of organ damage. The equivalence of LLDAS and DORIS remission on treatment is welcome news, as LLDAS on treatment &gt;50% of the time is an easier goal to achieve (3 times more person-months observed in our cohort) and more realistic as a clinical trial outcome. <h3>Disclosure of Interest</h3> None declared
Hyperchloremia is associated with acute kidney injury in pediatric patients with septic shock
Authors: Erin K. Stenson, Natalie Z. Cvijanovich, Geoffrey L. Allen, Neal J. Thomas, Michael T. Bigham, Scott L. Weiss, Julie C. Fitzgerald, Parag N. Jain, Keith Meyer, Michael Quasney, Mark Hall, Rainer Gedeit, Robert J. Freishtat, Jeffrey Nowak, Riad Lutfi, Shira Gertz, Jocelyn R. Grunwell, Hector R. Wong, Nick Anas
Journal: Intensive Care Medicine (2018)
The optimal treatment strategy in primary central nervous system lymphoma, 32 cases in our hospital
Authors: Yuki Takeuchi, Yuichiro Inagaki, Hirofumi Yokota, Hitomi Sawa, Shihomi Taniyama, Kanae Imai, Tomonori Kato, Junko Arima, Eiji Yoneyama, Masashi Sawa
Journal: Annals of Oncology (2018)
Association of Blood Concentrations of Complement Split Product <scp>iC</scp>3b and Serum C3 With Systemic Lupus Erythematosus Disease Activity
Authors: Alfred H. J. Kim, Vibeke Strand, Deepali P. Sen, Qiang Fu, Nancy L. Mathis, Martin J. Schmidt, Robin R. Bruchas, Nick R. Staten, Paul K. Olson, Chad M. Stiening, John P. Atkinson
Journal: Arthritis & Rheumatology (2018)

Objective To examine correlations between blood levels of complement split product iC 3b and serum component C3 with clinically meaningful changes in disease activity in patients with systemic lupus erythematosus ( SLE ). Methods A total of 159 consecutive patients with SLE , diagnosed according to the American College of Rheumatology or Systemic Lupus International Collaborating Clinics classification criteria, were enrolled in CASTLE (Complement Activation Signatures in Systemic Lupus Erythematosus), a prospective observational study. Patients with 1–7 study visits were included in this longitudinal analysis. In addition, 48 healthy volunteers were enrolled to establish a normal reference value for the ratio of blood iC 3b to serum C3 concentrations. Serum C3 and C4 levels were measured by nephelometry, and blood iC 3b levels were measured by a lateral flow assay. SLE disease activity was monitored with the Responder Index 50 instrument of the SLE Disease Activity Index 2000. Results Relative changes in the iC 3b:C3 ratio, levels of anti–double‐stranded DNA (anti‐ds DNA ) antibodies, and use of a supraphysiologic dose of prednisone (&gt;7.5 mg/day) each independently correlated with SLE disease activity, as determined in multilevel multiple logistic regression analyses. Only the iC 3b:C3 ratio was significantly associated with clinically meaningful improvements in disease activity among patients with SLE who were receiving a supraphysiologic dose of prednisone. The iC 3b:C3 ratio outperformed C3 and C4 levels with regard to discriminating active SLE from inactive SLE , and major flares from no disease activity. The iC 3:C3 ratio, anti‐ds DNA antibody levels, erythrocyte sedimentation rate, and use of a supraphysiologic prednisone dose were each independently associated with the presence of lupus nephritis, whereas none of these measures was associated with SLE rash. The association of the iC 3b:C3 ratio with lupus nephritis was independent of other observed clinical manifestations. Conclusion The ratio of blood iC 3b to serum C3 concentrations correlates with the extent of SLE disease activity and with clinically meaningful changes in disease activity in patients with SLE . Furthermore, the iC 3b:C3 ratio may discriminate between active and inactive SLE , and between major flares and no active disease.
De novo gene mutations in normal human memory B cells
Authors: L. M. Slot, T. A. M. Wormhoudt, M. J. Kwakkenbos, K. Wagner, A. Ballering, A. Jongejan, A. C. M. van Kampen, J. E. J. Guikema, R. J. Bende, C. J. M. van Noesel
Journal: Leukemia (2018)
Molecular Pharmacology and Neurobiology of Rapid-Acting Antidepressants
Authors: Todd D. Gould, Carlos A. Zarate, Scott M. Thompson
Journal: The Annual Review of Pharmacology and Toxicology (2018)

For decades, symptoms of depression have been treated primarily with medications that directly target the monoaminergic brain systems, which typically take weeks to exert measurable effects and months to exert remission of symptoms. Low, subanesthetic doses of ( R,S)-ketamine (ketamine) result in the rapid improvement of core depressive symptoms, including mood, anhedonia, and suicidal ideation, occurring within hours following a single administration, with relief from symptoms typically lasting up to a week. The discovery of these actions of ketamine has resulted in a reconceptualization of how depression could be more effectively treated in the future. In this review, we discuss clinical data pertaining to ketamine and other rapid-acting antidepressant drugs, as well as the current state of pharmacological knowledge regarding their mechanism of action. Additionally, we discuss the neurobiological circuits that are engaged by this drug class and that may be targeted by a future generation of medications, for example, hydroxynorketamine; metabotropic glutamate receptor 2/3 antagonists; and N-methyl-d-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, and γ-aminobutyric acid receptor modulators.
Maria Bitner-Glindzicz: clinical and molecular geneticist
Authors: Adrian O’Dowd
Journal: BMJ (2018)

Maria Bitner-Glindzicz was born in 1963 in Fleetwood, Lancashire, to a Polish father and Irish mother, who had both come to live in the UK. A renowned clinician and research scientist who made her mark in the specialism of deafness, Bitner-Glindzicz finished her training with first class honours at University College London (UCL) in 1987, having undertaken an intercalated BSc in genetics.

After gaining her PhD in genetics at UCL’s Institute of Child Health in 1996, she went on to become one of the world’s leading specialist academic consultants in clinical genetics with a key focus on deafness and blindness. She was promoted to professor of clinical and molecular genetics at UCL in 2012.

Appointed in 2000 as a consultant clinical geneticist at Great Ormond Street Children’s Hospital (GOSH), Maria established the UK’s first and only clinical service to provide comprehensive diagnostics and follow-up care for children with genetic forms of deafness.

Subsequently, she went on to …
P3.17-01 PD-L1 Expression, EGFR Mutations and ALK Expression in Non-Small Cell Lung Cancer (NSCLC) Patients from Brazil
Authors: A.V. Alves Da Silva, F. Tavora, F. Martins Neto, A.C.D.S. Oliveira, M. Alves, B. Carneiro, A.M. Lima
Journal: Journal of Thoracic Oncology (2018)
Establishing the need for immuno-oncology (IO) therapy (tx) in second-line (2L) small cell lung cancer (SCLC)
Authors: L. Schwartzberg, J.R. Penrod, Y. Yuan, T. Gu, T.K. Le, P. Abraham, B. Korytowsky, G. Selvaggi
Journal: Annals of Oncology (2018)
DREADD technology reveals major impact of Gq signalling on cardiac electrophysiology
Authors: Elisabeth Kaiser, Qinghai Tian, Michael Wagner, Monika Barth, Wenying Xian, Laura Schröder, Sandra Ruppenthal, Lars Kaestner, Ulrich Boehm, Philipp Wartenberg, Huiyan Lu, Sara M McMillin, Derek B J Bone, Jürgen Wess, Peter Lipp
Journal: Cardiovascular Research (2018)

Signalling via Gq-coupled receptors is of profound importance in many cardiac diseases such as hypertrophy and arrhythmia. Nevertheless, owing to their widespread expression and the inability to selectively stimulate such receptors in vivo, their relevance for cardiac function is not well understood. We here use DREADD technology to understand the role of Gq-coupled signalling in vivo in cardiac function.We generated a novel transgenic mouse line that expresses a Gq-coupled DREADD (Dq) in striated muscle under the control of the muscle creatine kinase promotor. In vivo injection of the DREADD agonist clozapine-N-oxide (CNO) resulted in a dose-dependent, rapid mortality of the animals. In vivo electrocardiogram data revealed severe cardiac arrhythmias including lack of P waves, atrioventricular block, and ventricular tachycardia. Following Dq activation, electrophysiological malfunction of the heart could be recapitulated in the isolated heart ex vivo. Individual ventricular and atrial myocytes displayed a positive inotropic response and arrhythmogenic events in the absence of altered action potentials. Ventricular tissue sections revealed a strong co-localization of Dq with the principal cardiac connexin CX43. Western blot analysis with phosphor-specific antibodies revealed strong phosphorylation of a PKC-dependent CX43 phosphorylation site following CNO application in vivo.Activation of Gq-coupled signalling has a major impact on impulse generation, impulse propagation, and coordinated impulse delivery in the heart. Thus, Gq-coupled signalling does not only modulate the myocytes' Ca2+ handling but also directly alters the heart's electrophysiological properties such as intercellular communication. This study greatly advances our understanding of the plethora of modulatory influences of Gq signalling on the heart in vivo.
Integrated Analysis of Genetic Ancestry and Genomic Alterations across Cancers
Authors: Jiao Yuan, Zhongyi Hu, Brandon A. Mahal, Sihai D. Zhao, Kevin H. Kensler, Jingjiang Pi, Xiaowen Hu, Youyou Zhang, Yueying Wang, Junjie Jiang, Chunsheng Li, Xiaomin Zhong, Kathleen T. Montone, Guoqiang Guan, Janos L. Tanyi, Yi Fan, Xiaowei Xu, Mark A. Morgan, Meixiao Long, Yuzhen Zhang, Rugang Zhang, Anil K. Sood, Timothy R. Rebbeck, Chi V. Dang, Lin Zhang
Journal: Cancer Cell (2018)
Repeated mutKRAS ctDNA measurements represent a novel and promising tool for early response prediction and therapy monitoring in advanced pancreatic cancer
Authors: S. Kruger, V. Heinemann, C. Ross, F. Diehl, D. Nagel, S. Ormanns, S. Liebmann, I. Prinz-Bravin, C.B. Westphalen, M. Haas, A. Jung, T. Kirchner, M. von Bergwelt-Baildon, S. Boeck, S. Holdenrieder
Journal: Annals of Oncology (2018)

BackgroundThe presence of mutated KRAS (mutKRAS ctDNA) in plasma samples has been consistently shown to be a negative prognostic indicator in pancreatic cancer (PC). Only small pilot studies have evaluated the value of serial mutKRAS ctDNA-measurements in PC.Patients and methodsThe aim of the present study was to explore the potential of repeated mutKRAS ctDNA measurements for response prediction and therapy monitoring in advanced PC patients. We used the BEAMing technology to determine levels of mutKRAS ctDNA, CA 19-9, CEA and CYFRA 21-1 in 284 plasma samples of 54 patients with advanced PC receiving gemcitabine-based chemotherapy. Absolute levels and kinetics of mutKRAS ctDNA, CA 19-9, CEA and CYFRA 21-1 were correlated to radiological response, progression-free and overall survival.ResultsmutKRAS ctDNA was present in a majority of advanced PC patients (n = 36/54, 67%) and indicated tissue KRAS mutation status with a high sensitivity (75%) and specificity (100%). The presence of mutKRAS ctDNA, as well as higher levels of CA 19-9, CEA and CYFRA 21-1 before initiation of the first-line chemotherapy, was significantly correlated to an adverse overall survival. During therapy, changes in mutKRAS ctDNA levels were more rapid and pronounced than changes in protein-based tumor markers. A decrease in mutKRAS ctDNA levels during therapy was an early indicator of response to therapy, while there was no significant correlation between kinetics of CA 19-9, CEA or CYFRA 21-1 and response to chemotherapy during the first four weeks of treatment. Repeated mutKRAS ctDNA measurements during follow-up appeared to be superior to protein-based tumor markers in detecting progressive disease (sensitivity: 83%, specificity: 100%).ConclusionmutKRAS ctDNA kinetics appear to be a powerful and highly specific tool in early response prediction and therapy monitoring of advanced PC patients receiving chemotherapy.
P3.09-05 Significance of the Expression of PD-L1/PD-1 by Tumoral and Immune Cells in Non-Small Cell Lung Cancer.
Authors: C. Ortiz –Villalón, L. De Petris, L. Kis, A. Yoshikawa, H. Ngoc, A. Roden, J. Fukuoka, A. Montero
Journal: Journal of Thoracic Oncology (2018)
Gerald Malcolm Stern: neurologist who championed patients with Parkinson’s disease
Authors: Matt Limb
Journal: BMJ (2018)

Neurologist Gerald Stern was a champion for patients with Parkinson’s disease, a widely respected teacher, and an influential researcher whose work advanced clinical treatment. He helped to set up both the Parkinson’s Disease Society (later Parkinson’s UK) in the late 1960s and the influential Parkinson’s Disease Research Group of the UK in the 1980s. Stern was among the first people in the UK to publish a controlled trial of levodopa’s efficacy following its celebrated emergence in the US.1

“He was arguably the best opinion on Parkinson’s disease in the world during his heyday,” says neurology professor Andrew Lees, the Parkinson’s Disease Research Group of the UK’s co-founder and Stern’s “academic son.” Lees says Stern’s bringing together of around 100 neurologists and geriatricians to do clinical trials—unpaid and independent of the pharmaceutical industry—was “quite revolutionary” at the time and led to “some very important findings.”

“He excelled in clinical pharmacology and showed that you could do high quality research outside the straitjacket of the university and also combine it with a busy clinical practice,” says Lees. “I think that’s a good message for young people to learn.”

Levodopa (l-dopa), a chemical building block that the body converts into dopamine, is still one of the main drugs used to reduce the impediment of Parkinson’s disease some 50 years after it was first trialled in the US.

Before then, the disease progressed relentlessly and, apart from stereotactic thalamic surgery and anticholinergic drugs, there was little one could do. Despite these …
Exposure to wild-type AAV drives distinct capsid immunity profiles in humans
Authors: Klaudia Kuranda, Priscilla Jean-Alphonse, Christian Leborgne, Romain Hardet, Fanny Collaud, Solenne Marmier, Helena Costa Verdera, Giuseppe Ronzitti, Philippe Veron, Federico Mingozzi
Journal: Journal of Clinical Investigation (2018)

Recombinant adeno-associated virus (AAV) vectors have been broadly adopted as a gene delivery tool in clinical trials, owing to their high efficiency of transduction of several host tissues and their low immunogenicity. However, a considerable proportion of the population is naturally exposed to the WT virus from which AAV vectors are derived, which leads to the acquisition of immunological memory that can directly determine the outcome of gene transfer. Here, we show that prior exposure to AAV drives distinct capsid immunity profiles in healthy subjects. In peripheral blood mononuclear cells (PBMCs) isolated from AAV-seropositive donors, recombinant AAV triggered TNF-α secretion in memory CD8+ T cells, B cell differentiation into antibody-secreting cells, and anti-capsid antibody production. Conversely, PBMCs isolated from AAV-seronegative individuals appeared to carry a population of NK cells reactive to AAV. Further, we demonstrated that the AAV capsid activates IL-1β and IL-6 cytokine secretion in monocyte-related dendritic cells (moDCs). IL-1β and IL-6 blockade inhibited the anti-capsid humoral response in vitro and in vivo. These results provide insights into immune responses to AAV in humans, define a possible role for moDCs and NK cells in capsid immunity, and open new avenues for the modulation of vector immunogenicity.
One More Reason to Continue Drinking Coffee—It May Be Good for Your Skin
Authors: Mackenzie R. Wehner, Eleni Linos
Journal: JAMA Dermatology (2018)

Who does not love a study that validates one of life’s habitual pleasures? Whether it is an iced latte, a double espresso, or simply a hot cup of brown liquid in the hospital cafeteria, many of us in medicine have an emotional attachment as well as a physiologic dependence on coffee.
Germline Mutations in ATM and BRCA1/2 Are Associated with Grade Reclassification in Men on Active Surveillance for Prostate Cancer
Authors: H. Ballentine Carter, Brian Helfand, Mufaddal Mamawala, Yishuo Wu, Patricia Landis, Hongjie Yu, Kathleen Wiley, Rong Na, Zhuqing Shi, Jacqueline Petkewicz, Sameep Shah, Richard J. Fantus, Kristian Novakovic, Charles B. Brendler, S. Lilly Zheng, William B. Isaacs, Jianfeng Xu
Journal: European Urology (2018)
High prevalence of Streptococcus pyogenes Cas9-reactive T cells within the adult human population
Authors: Dimitrios L. Wagner, Leila Amini, Desiree J. Wendering, Lisa-Marie Burkhardt, Levent Akyüz, Petra Reinke, Hans-Dieter Volk, Michael Schmueck-Henneresse
Journal: Nature Medicine (2018)
GW29-e1130 Prevalence Rates of Medical Management of Acute Coronary Syndrome
Authors: Yaling Han, Dajun Chai, Amr Elhadidy, Cetin Erol, Chunjian Li, Alessandro Lupi, Yihong Sun, Shuyang Zhang, Dara Paek, Michael del Aguila, Shalini Girotra
Journal: Journal of the American College of Cardiology (2018)
Telomerase Activation and ATRX Mutations Are Independent Risk Factors for Metastatic Pheochromocytoma and Paraganglioma
Authors: Sylvie Job, Irena Draskovic, Nelly Burnichon, Alexandre Buffet, Jérôme Cros, Charles Lépine, Annabelle Venisse, Estelle Robidel, Virginie Verkarre, Tchao Meatchi, Mathilde Sibony, Laurence Amar, Jérôme Bertherat, Aurélien de Reyniès, Arturo Londoño-Vallejo, Judith Favier, Luis Jaime Castro-Vega, Anne-Paule Gimenez-Roqueplo
Journal: Clinical Cancer Research (2018)

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors. Whereas most PPGLs are benign, up to 20% may become metastatic with SDHB- and FH-mutated tumors showing the higher risk. We aimed at determining the contribution of immortalization mechanisms to metastatic progression.Experimental Design: Immortalization mechanisms were investigated in 200 tumors. To identify telomerase (+) tumors, we analyzed genomic alterations leading to transcriptional activation of TERT comprising promoter mutations, hypermethylation and gain copy number. To identify tumors that activated the alternative lengthening of telomere (ALT) mechanism, we combined analyses of telomere length by slot blot, telomere heterogeneity by telomere FISH, and ATRX mutations by next-generation sequencing. Univariate/multivariate and metastasis-free survival (MFS) and overall survival (OS) analyses were carried out for assessment of risk factors and clinical outcomes.Only 37 of 200 (18.5%) tumors achieved immortalization. Telomerase activation occurred in 12 metastatic tumors and was prevalent in SDHB-mutated paragangliomas (P = 2.42e-09). ALT features were present in 25 tumors, mostly pheochromocytomas, regardless of metastatic status or molecular group (P = 0.169), yet ATRX mutations were found preferentially in SDHB/FH-mutated metastatic tumors (P = 0.0014). Telomerase activation and ATRX mutations were independent factors of poor prognosis: MFS (hazard ratio, 48.2 and 33.1; P = 6.50E-07 and 1.90E-07, respectively); OS (hazard ratio, 97.4 and 44.1; P = 4.30E-03 and 2.00E-03, respectively) and were associated with worse MFS and OS (log-rank tests P < 0.0001).Assessment of telomerase activation and ATRX mutations could be used to identify metastatic PPGLs, particularly in tumors at high risk of progression.