tbuckley/cabot-search huggingface dataset:
Randomized controlled trial comparing docetaxel (D)-cisplatin (P) combination with D alone in elderly patients (pts) with advanced non-small cell lung cancer (NSCLC): JCOG0207
Authors: H. Tsukada, A. Yokoyama, Y. Nishiwaki, T. Shinkai, M. Harada, M. Ando, T. Shibata, Y. Ohe, T. Tamura, N. Saijo
Journal: Journal of Clinical Oncology (2007)

7629 Background: Platinum-based chemotherapy is currently recommended as the standard approach for pts with advanced NSCLC. However prospective clinical trials specifically designed for elderly pts demonstrating the P benefit are still lacking. Therefore, we conducted a phase III trial to determine whether the addition of P to single agent-chemotherapy for elderly NSCLC pts could improve survival. Methods: Eligibility criteria included; chemotherapy-naive; stage III/IV NSCLC; age=70 and PS 0–1. Pts were randomized to receive either DP or D with minimization method balancing site, age (=74/=75) and stage (III/IV), and both regimens were given every 4 weeks. DP comprised D (20 mg/m 2 ) and P (25 mg/m 2 ) iv on days 1, 8, 15. D comprised D (25 mg/m 2 ) iv on the same schedule. Primary endpoint was overall survival (OS). The planned sample size was 115 pts in each arm to provide 80% power to detect 0.667 hazard ratio for DP to D in OS and 2.5% one-sided alpha. Results: Between Apr 2003 and Apr 2006, 126 pts were randomized (D/DP: 63/63). The second planned interim analysis was performed on 112 assessable pts (D/DP:56/56, median age 76, =74/=75: 39/61%, male/female: 77/23%, PS 0/1: 39/61%, III/IV: 30/70%). Maturity of information, defined proportion of interim events to the planned events, was 26% (=49/191). As the one-sided p-value(p=0.00515) of the stratified log-rank test by age and stage was not lower than the critical value for the interim analysis, the formal criterion for stopping the trial failed to meet. However the Data and Safety Monitoring Board recommended study termination and disclosure of the results based on the strong interaction (two-sided p=0.077, hazard ratios [95% C.I.] for =74/=75: 0.23 [0.09–0.62]/0.72 [0.35- 1.49]) that DP may be beneficial for subgroup of age between 70- 74. Major Grade 3–4 toxicities were (%D/DP): neutropenia 4.9/13.1, anemia 1.6/16.4, anorexia 8.3/24.2, infection 11.7/8.1, pneumonitis 1.7/1.6. TRD occurred in 1 pt in DP arm. Conclusions: The interpretation of study results is limited due to early stopping and resultant loss of statistical power. But these data indicated that =74 young elderly have no more need to evaluate tolerability and efficacy of P. No significant financial relationships to disclose.
Reduced-intensity versus reduced-toxicity myeloablative fludarabine/busulfan-based conditioning regimens for allografted non-Hodgkin lymphoma adult patients: a retrospective study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire
Authors: A. Le Bourgeois, M. Labopin, D. Blaise, P. Ceballos, S. Vigouroux, R. Peffault de Latour, A. Marçais, C.E. Bulabois, J.O. Bay, S. Chantepie, E. Deconinck, E. Daguindau, N. Contentin, I. Yakoub-Agha, J. Cornillon, M. Mercier, P. Turlure, A. Charbonnier, P.S. Rorhlich, S. N’Guyen, N. Maillard, T. Marchand, M. Mohty, P. Chevallier
Journal: Annals of Oncology (2017)
Impact of killer-immunoglobulin-like receptor and human leukocyte antigen genotypes on the efficacy of immunotherapy in acute myeloid leukemia
Authors: E Bernson, A Hallner, F E Sander, O Wilsson, O Werlenius, A Rydström, R Kiffin, M Brune, R Foà, J Aurelius, A Martner, K Hellstrand, F B Thorén
Journal: Leukemia (2017)

Interactions between killer-immunoglobulin-like receptors (KIRs) and their HLA class I ligands are instrumental in natural killer (NK) cell regulation and protect normal tissue from NK cell attack. Human KIR haplotypes comprise genes encoding mainly inhibitory receptors (KIR A) or activating and inhibitory receptors (KIR B). A substantial fraction of humans lack ligands for inhibitory KIRs (iKIRs), that is, a 'missing ligand' genotype. KIR B/x and missing ligand genotypes may thus give rise to potentially autoreactive, unlicensed NK cells. Little is known regarding the impact of such genotypes in untransplanted acute myeloid leukemia (AML). For this study, NK cell phenotypes and KIR/HLA genotypes were determined in 81 AML patients who received immunotherapy with histamine dihydrochloride and low-dose IL-2 for relapse prevention (NCT01347996). We observed that presence of unlicensed NK cells impacted favorably on clinical outcome, in particular among patients harboring functional NK cells reflected by high expression of the natural cytotoxicity receptor (NCR) NKp46. Genotype analyses suggested that the clinical benefit of high NCR expression was restricted to patients with a missing ligand genotype and/or a KIR B/x genotype. These data imply that functional NK cells are significant anti-leukemic effector cells in patients with KIR/HLA genotypes that favor NK cell autoreactivity.
The A946T variant of the RNA sensor IFIH1 mediates an interferon program that limits viral infection but increases the risk for autoimmunity
Authors: Jacquelyn A Gorman, Christian Hundhausen, John S Errett, Amy E Stone, Eric J Allenspach, Yan Ge, Tanvi Arkatkar, Courtnee Clough, Xuezhi Dai, Socheath Khim, Kathleen Pestal, Denny Liggitt, Karen Cerosaletti, Daniel B Stetson, Richard G James, Mohamed Oukka, Patrick Concannon, Michael Gale, Jane H Buckner, David J Rawlings
Journal: Nature Immunology (2017)
24-2 Visual Fields Miss Central Defects Shown on 10-2 Tests in Glaucoma Suspects, Ocular Hypertensives, and Early Glaucoma
Authors: C. Gustavo De Moraes, Donald C. Hood, Abinaya Thenappan, Christopher A. Girkin, Felipe A. Medeiros, Robert N. Weinreb, Linda M. Zangwill, Jeffrey M. Liebmann
Journal: Ophthalmology (2017)
ATRT-11. MARKED RESPONSE TO ATEZOLIZUMAB IN A PATIENT WITH RHABDOID TUMOR: A CASE STUDY FROM THE IMATRIX-ATEZOLIZUMAB TRIAL
Authors: Franck Bourdeaut, Meghna Das Thaku, Guillaume Bergthold, Erin Karski
Journal: Neuro-Oncology (2017)

BACKGROUND: Rhabdoid tumors (RTs) are aggressive, rare tumors usually diagnosed in early childhood. They portend poor prognosis, despite multi-modality treatment. Atezolizumab targets programmed death-ligand 1 (PD-L1), leading to enhanced anti-cancer T-cell activity. The iMATRIX-Atezolizumab study (phase I/II, open-label; NCT02541604) assessed safety, pharmacokinetics, and preliminary activity of atezolizumab in pediatric/young adult patients. METHODS: Patients aged <30 years with relapsed/refractory pediatric solid tumors received atezolizumab every 3 weeks until loss of clinical benefit (<18 years, 15mg/kg [maximum dose, 1200mg]; ≥18 years, 1200mg). RESULTS: In 74 patients for whom data are available (multiple solid tumor types), the pharmacokinetics/safety profile of atezolizumab were consistent with those in adults. One 4-year-old male (palpable malignant RT [left paraspinal soft-parts]) was treated with four doses of atezolizumab over approximately 4 months. The patient experienced one grade 3 treatment-related adverse event (AE; amylase elevation [resolved without treatment or drug interruption]) and one grade 1 AE of special interest (elevated thyroid-stimulating hormone). No other grade 3/4 treatment-related AEs were reported. The patient experienced clinical improvement 3 weeks after first atezolizumab infusion with visible regression of the tumor, decreased use of pain medications, increased Lansky performance score (from 60% to 100%) and a return to school. Imaging revealed a 37% decrease in the target lesion diameter at 6 weeks, and a 32% decrease at 12 weeks. Following the fourth cycle of treatment, the patient stopped atezolizumab treatment to pursue local control therapy. Biomarker analyses of archival tumor tissue revealed strong PD-L1 immunohistochemistry staining (TC3/IC2) and a high percentage of CD8+ cells in the central tumor (3.69%), compared with other enrolled patients (median 0.21%, range 0.0012–10.28%). CONCLUSIONS: Encouraging clinical and biomarker results using atezolizumab were observed. Dedicated cohorts for children with either RTs or atypical teratoid RT types have been opened in the ongoing study to further evaluate this signal.
Mad-Doctors in the Dock: Defending the Diagnosis, 1760–1913by Joel Peter Eigen. Baltimore, Johns Hopkins University Press, 2016, 224 pp., $40.00 (hardcover).
Authors: Rajiv Radhakrishnan
Journal: American Journal of Psychiatry (2017)

in the anxiety-generating question of rational suicide in the elderly" (p.217).On the one hand, a book that touches on the existential meaning of life, rational decision making, and the right to selfdetermination should have wide appeal to healers of all disciplines.On the other hand, I believe the book's major appeal will be to clinicians from both the mental and general health arenas who work with older and chronically ill individuals and to teachers interested in educating our trainees to work more collaboratively and empathically with older adults, going above and beyond (or even eschewing) evidencebased practices in favor of listening and learning about the processes of living and dying.
HGG-07. MUTATIONS IN ATRX INCREASE GENETIC INSTABILITY AND SENSITIVITY TO PARP INHIBITORS IN PAEDIATRIC GLIOBLASTOMA CELLS
Authors: Janat Fazal-Salom, Mara Vinci, Diana Carvalho, Helen Pemberton, Steve Pettit, Christopher Lord, Alan Mackay, Lynn Bjerke, Chris Jones
Journal: Neuro-Oncology (2017)

Paediatric high grade glioma (pHGG) and DIPG are defined by recurrent mutations in H3 histones, as well as frequent alterations in the chromatin remodeling protein ATRX. This is strongly associated with the alternative lengthening of telomeres (ALT) phenotype, but their precise interaction with histone mutations and their role in tumorigenesis remain unclear. We collected sequence data from 262 published and 64 unpublished cases of pHGG/DIPG and identified somatic ATRX mutations in 54/326(17%) of cases. The majority of frameshift mutations (37/54,68.5%) were found in the ADD domain, whereas missense mutations (16/54,29.6%) were almost exclusively in the helicase domain (11/54, 20,4%). ATRX mutations commonly co-segregate with H3.3G34 (16/54,29.6%) and TP53 (42/54,77.8%) mutations, and define a subgroup of patients with a longer overall survival (p=0.079), though with a greater number of somatic mutations (p=0.023) and copy number alterations (p=0.0011) than wild-type cases. We subjected a series of fully characterised primary patient-derived pHGG/DIPG cell cultures to high-throughput in vitro cell viability screening of >400 chemotherapeutics and small molecules. We identified a genetic dependency for ATRX mutation and sensitivity to distinct PARP inhibitor chemotypes, including olaparib and rucaparib (catalytic inhibitors), and talazoparib (PARP trapper), validated using CRISPR/Cas9-engineered ATRX knockout targeting either the ADD or helicase domain in pHGG cells. ATRX-deficient cells were also more sensitized to radiation treatment by PARP inhibition compared to wild-type controls. Gene expression analysis of ATRX mutant pHGG/DIPG samples confirmed an intact homologous recombination pathway and overexpression of PARP1, suggesting an underlying mechanism distinct from that observed in BRCA-mutant breast and ovarian cancers. Ongoing work is aimed at unravelling the specific pathways involved, and evaluating the utility of PARP inhibition in orthotopic pGBM xenografts in vivo. These data suggest a synthetic lethality for PARP inhibitors in ATRX-deficient pHGG/DIPG cells, and may represent a novel therapeutic strategy for these highly aggressive tumours.
Стеатоз підшлункової залози в дітей. Частина 1. Етіологія, епідеміологія та патогенез
Authors: Yu.M. Stepanov, N.Yu. Zavgorodnyaya, O.Yu. Lukianenko
Journal: GASTROENTEROLOGY (2017)

Стаття присвячена стеатозу підшлункової залози в дітей — патологічному стану, що характеризується акумуляцією жиру в підшлунковій залозі. Стеатоз підшлункової залози в пацієнтів з ожирінням і надлишковою вагою при виключенні вторинних причин розвитку стеатозу визначається терміном «неалкогольна жирова хвороба підшлункової залози». В огляді подано дані, що стосуються історії вивчення, етіології, епідеміології та патогенезу даної патології. Показано, що важливим компонентом патогенезу захворювання є надлишок вільних жирних кислот, що призводить до акумуляції жиру в паренхіматозних органах, у тому числі в підшлунковій залозі, порушення функції острівцевих і ацинарних клітин і, як наслідок, до розвитку панкреатичної екзо- та ендокринної недостатності. Для написання огляду здійснювався пошук даних із використанням баз даних Scopus, Web of Science, MedLine, PubMed, Google Scholar, CyberLeninka, РІНЦ за такими ключовими словами: «стеатоз підшлункової залози», «неалкогольна жирова хвороба підшлункової залози», «діти».
Non-invasive postmortems using CT scans are feasible, study finds
Authors: Zosia Kmietowicz
Journal: BMJ (2017)

Postmortems using a minimally invasive computed tomography (CT) technique with targeted coronary angiography was successful in identifying the cause of death in 92% of cases, a study has found.1

Researchers from the University of Leicester argue that, in most sudden natural deaths investigated by coroners, this technique can be used instead of invasive autopsy.

A previous study of postmortem CT in 2012 showed promise for using medical imaging to investigate the cause of natural death, but it was not able to diagnose coronary artery disease, the most common cause of natural death, because cadavers …
The association between previous history of concussion and sport-specific skills in youth ice hockey players
Authors: Paul H Eliason, Carly D McKay, Willem H Meeuwisse, Brent E Hagel, Luc Nadeau, Carolyn A Emery
Journal: British Journal of Sports Medicine (2017)

Objective To determine the association between previous history of concussion and sport-specific skill performance in youth ice hockey players. Design Cross-sectional. Setting Arenas in Calgary, Alberta, Canada over three seasons of play (2012–2015). Participants Five hundred and ninety-six players were recruited from youth hockey teams [525 males and 71 females, aged 11-17, representing elite (upper 30% by division of play) and non-elite (lower 70%)]. Assessment of risk factors Players completed a baseline questionnaire including the number, date of occurrence, and length of recovery following any previous concussions. Outcome measures On-ice skills performance was measured using the Hockey Canada Skills Test (HCST) battery including forward agility weave, forward to backward transition agility, forward/backward speed skate, and a 6-repeat endurance skate Results Previous history of concussion and time since most recent concussion were not associated with any HCST component. Players reporting two or more concussions were faster than those with no history of concussion on forward agility weave with the puck [−7.32 (95% CI: −11.05, −3.59)]. For every additional day of recovery post-concussion, a player’s time was significantly faster on forward agility weave with [−0.11 (95% CI: −0.16, −0.05] and without the puck [−0.08 (95% CI: −0.13, −0.04], transition agility without the puck [−0.01 (95% CI: −0.02, −0.01], and backward speed with [−0.06 (95% CI: −0.1, −0.03)] and without the puck[−0.05 (95% CI: −0.07, −0.03)]. Conclusions Players with a concussion history had similar HCST performance scores to those without. A longer post-concussion recovery was associated with better performance. These results provide reference values which will inform risk assessment and future injury prevention studies. Competing interests None.
Participant-Reported Symptoms and Their Effect on Long-Term Adherence in the International Breast Cancer Intervention Study I (IBIS I)
Authors: Samuel George Smith, Ivana Sestak, Anthony Howell, John Forbes, Jack Cuzick
Journal: Journal of Clinical Oncology (2017)

Purpose To assess the role of participant-reported symptoms on long-term adherence to preventive therapy in the United Kingdom sample of the International Breast Cancer Intervention Study (IBIS-I). IBIS-I was a randomized controlled trial that investigated the effectiveness of tamoxifen in reducing the risk of breast cancer among women at increased risk of the disease. Participants and Methods Women were randomly assigned to tamoxifen versus placebo (20 mg/day; n = 4,279). After 456 exclusions, 3,823 women were included in this analysis. Adherence (&lt; 4.5 years or ≥ 4.5 years) was calculated using data from six monthly clinical visits. Analyses were adjusted for age, Tyrer-Cuzick risk, smoking, use of hormone replacement therapy, menopausal status, baseline menopausal symptoms, and treatment. Results Overall, 69.7% of women were adherent for at least 4.5 years (tamoxifen: 65.2% v placebo: 74.0%; P &lt; .001). Differences in adherence between treatment arms were observed from 12 months onward (all P &lt; .01) and were largest at 54 months. Dropout rates were highest in the first 12 to 18 months and decreased thereafter. Women reporting nausea/vomiting were less likely to be adherent in both the tamoxifen (odds ratio [OR], 0.57; 95% CI, 0.37 to 0.86; P = .007) and placebo (OR, 0.58; 95% CI, 0.37 to 0.93; P = .023) arms. Headaches were associated with adherence only in the placebo arm (OR, 0.62; 95% CI, 0.42 to 0.91; P = .016), whereas gynecologic symptoms were significant only in the tamoxifen arm (OR, 0.77; 95% CI, 0.62 to 0.97; P = .024). Effect sizes for each symptom on adherence were not significantly different between the treatment groups ( P &gt; .05). In both treatment arms, we observed significant trends for lower adherence with increasing severity for all symptoms ( P &lt; .01) except headaches ( P = .054). Conclusion In the IBIS-I trial, experiencing predefined symptoms in the first 6 months reduced long-term adherence. Effects were similar between treatment arms, suggesting that women were attributing age-related symptoms to preventive therapy. Interventions were required to support symptom management.
Response to: ‘Is optimizing gout treatment the key to closing the mortality gap in gout patients?’ by Brinck <i>et al</i>
Authors: Mark C Fisher, Sharan K Rai, Na Lu, Yuqing Zhang, Hyon K Choi
Journal: Annals of the Rheumatic Diseases (2017)

We thank Dr Ten Brinck and colleagues for their comments.1 Regarding the first comment, we have stated in our manuscript discussion that we did not have sufficient detail on the cause of death in our data set, precluding investigations …
Real-time quantitative PCR for rapid detection of translocations, amplifications, polymorphisms, and viral/bacterial load in blood or formalin-fixed paraffin embedded tissues
Authors: Chantal Courtemanche, Marie-Guylaine Gagnon, Lise Gosselin, Luc Belanger
Journal: Clinical Cancer Research (2007)

B9  The Unite d9Interface clinique of the Hotel-Dieu de Quebec Research Center is a laboratory specialized in cellular and molecular diagnostic. We offer an array of in-house diagnostic assays to the scientific and medical communities for the detection of translocations involved in leukemia, lymphoma and sarcoma, detection of monoclonality in T cell and B cell malignancies, detection of oncogene amplification, genotyping of polymorphisms, and quantification of virus and bacteria. In order to offer faster and more precise molecular diagnostic results, we have developed many qPCR assays and have evaluated their accuracy and sensitivity as compared to the method previously used. We have compared Her2/neu gene amplification detection using qPCR, FISH and IHC in formalin-fixed paraffin embedded tissues (FFPE) tissues, and have found an excellent concordance (96%) between qPCR and FISH results, while it was only 83% between FISH and IHC, and 90% for FISH performed in two different laboratories. The sensitivity of BCR-ABL translocation detection has been measured for RT-qPCR, RT-PCR and nested RT-PCR in chronic myelogenous leukemia patients. RT-qPCR could detect ratio of BCR-ABL/G6PDH as low as 0.003%, which was more sensitive than RT-PCR and slightly less than nested RT-PCR, although only RT-qPCR allows ratio quantification to monitor disease progression. Hybridization probes and qPCR are used to genotype a variety of polymorphisms, including JAK2 V617F mutation involved in myeloproliferative disorders. This genotyping method is safe and simple and does not require any subsequent step such as RFLP or sequencing. Synovial sarcoma is characterized by the translocation t(x;18) which involves the SYT gene with the SSX1 or the SSX2 gene; both rearrangement can be detected and distinguished in the same RT-qPCR reaction without electrophoresis of PCR products. Using hybridization probes and qPCR, we have developed a sensitive method to detect Mycobacterium tuberculosis in FFPE tissues and to simultaneously distinguish tuberculosis from other mycobacterium strains. A similar method was used to quantify polyomavirus (BK and JC) in the blood or urine of renal transplant recipients, allowing to monitor nephropathy risks without biopsies. Our tests have shown that qPCR is equally or more sensitive than other methods to detect translocations, amplifications, polymorphisms, and viral/bacterial load. In addition, the use of hybridization probes can allow simultaneous identification or genotyping without the need to perform another step, such as culture, electrophoresis or sequencing. qPCR can be a good choice to develop rapid, efficient and precise assays for molecular diagnostic and personalized therapy.
IMMU-05. MOLECULAR ANALYSES DEMONSTRATE AN IMMUNOSUPPRESSIVE PHENOTYPE IN THE CYST AND SOLID TUMOR COMPARTMENTS OF ADAMANTINOMATOUS CRANIOPHARYNGIOMA
Authors: Andrew Donson, Andrea Griesinger, Vladimir Amani, Davis Witt, John Apps, Gerald Grant, Roy Dudley, Eric Jackson, James Johnston, Jeffrey Greenfield, Robert Naftel, David Limbrick, Richard C.E. Anderson, Toba Niazi, Michael Handler, Jean Mulcahy-Levy, Juan Pedro Martinez-Barbera, Nicholas Foreman, Todd C. Hankinson
Journal: Neuro-Oncology (2017)

BACKGROUND: Adamantinomatous Craniopharyngioma (ACP) is associated with considerable short and long-term morbidity. There are currently no well-established directed therapies. Recent studies demonstrated pro-inflammatory characteristics in both the solid and cyst compartments, but no data have examined whether immunosuppressive mechanisms are active in these tumors. METHODS: This study utilized a variety of platforms to examine immunosuppressive markers in cyst fluid and associated solid tumor components of ACP. Analyte levels in ACP were compared with other common pediatric brain tumors and normal tissue in order to identify immunosuppressive factors that were overexpressed in ACP. Cyst fluid and cells contained therein were analyzed using multiplex cytokine analysis and flow cytometry, respectively. A large transcriptomic database of ACP and other pediatric tumors and normal brain was queried for immunosuppressive gene expression. Immunohistochemistry was used to further validate gene expression data. RESULTS: ACP demonstrated highly elevated levels of IDO-1 (FC 9.43 versus all other tumor/tissue types, p=1.4x10-28), confirmed by IHC staining for IDO-1 in the epithelial tumor compartment. Elevated levels of IL-10 were demonstrated in cyst fluid and solid tumor compartments. Myeloid cells from the ACP cyst compartment demonstrated low levels of CD64 and HLA-DR expression, combined with high levels of CD163 expression. This pattern is most consistent with an immunosuppressive, pro-tumor milieu. Both CD4 and CD8(+) T-cells demonstrated positive staining for PD-1, most consistent with an exhausted phenotype. Consistent with this, PD-L1 mRNA was elevated in ACP tumor samples versus many other tumor types. CONCLUSIONS: Pediatric ACP is characterized by immunosuppressive factors in both the solid and cyst fluid compartments. This finding must be further considered within the context of the pro-inflammatory characteristics that have been previously described. It further raises the prospect of clinical translation through the application of available immune-directed therapies, in particular those that elicit therapeutic benefit through reversal of immunosuppression.