tbuckley/cabot-search huggingface dataset:
Nivolumab (nivo) vs docetaxel (doc) in patients (pts) with advanced NSCLC: CheckMate 017/057 2-y update and exploratory cytokine profile analyses.
Authors: Hossein Borghaei, Julie R. Brahmer, Leora Horn, Neal Ready, Martin Steins, Enriqueta Felip, Luis G. Paz-Ares, Oscar Arrieta, Fabrice Barlesi, Scott Joseph Antonia, Jerome Fayette, Naiyer A. Rizvi, Lucio Crino, Martin Reck, Wilfried Ernst Erich Eberhardt, Matthew David Hellmann, Kaushal Desai, Ang Li, Diane I. Healey, David R. Spigel
Journal: Journal of Clinical Oncology (2016)

9025 Background: Nivo, afully human IgG4 programmed death-1 immune checkpoint inhibitor, is approved in the US for pts with previously treated metastatic NSCLC and in the EU for pretreated locally advanced or metastatic squamous (SQ) NSCLC, based on results of 2 ph III trials. Methods: Pts with SQ (CheckMate 017) or non-squamous (NSQ; CheckMate 057) NSCLC received nivo 3 mg/kg Q2W or doc 75 mg/m2 Q3W (1:1 randomization) until progression or discontinuation due to toxicity/other reasons. The primary objective in each study was OS. Multivariate exploratory analyses of baseline serum cytokines were performed separately in pts with SQ and NSQ NSCLC. A 6:4 training:test validation was used. A SQ-cytoscore derived from evaluable pts in CheckMate 017 and CheckMate 063 (single-arm phase II study of nivo in SQ NSCLC) and a NSQ-cytoscore derived from evaluable pts in CheckMate 057 were generated to quantify the effect of each identified cytokine set on OS (using 18-mo data cutoffs). Cytoscores were defined as high or low based on the median cutoffs. Results: In CheckMate 017, median OS (mOS) was 9.2 vs 6.0 mo with nivo vs doc (18-mo OS: 28% vs 13%; HR: 0.62 [0.48, 0.81]; P= 0.0004). In CheckMate 057, mOS was 12.2 vs 9.4 mo with nivo vs doc (18-mo OS: 39% vs 23%; HR: 0.72 [0.60, 0.88]; P= 0.0009). A greater magnitude of benefit was noted for pts with PD-L1–expressing NSQ NSCLC; PD-L1 expression was neither prognostic nor predictive of benefit in pts with SQ NSCLC. Treatment-related AEs were less frequent with nivo vs doc in both trials. Preliminary results show an association of SQ- and NSQ-cytoscores with OS (Table). Conclusions: Nivo resulted in improved OS and a favorable safety profile vs doc across NSCLC histologies; updated 2-y OS and safety will be presented. Select sets of baseline serum cytokines (details to be presented) were found to be associated with OS benefit in pts with adv SQ and NSQ NSCLC; prospective validation of these results is needed. Clinical trial information: NCT01642004, NCT01673867.mOS, mo SQ-cytoscore High Low Nivo (n = 222) 15.6 5.3 HR 0.48 (0.36, 0.64) P< 0.0001 Doc (n = 118) 9.1 4.9 HR 0.39 (0.27, 0.56) P< 0.0001 mOS, mo NSQ-cytoscore High Low Nivo (n = 240) 17.9 5.9 HR 0.52 (0.39, 0.71) P< 0.0001 Doc (n = 240) 11.5 8.5 HR 0.60 (0.45, 0.79) P= 0.0001
Rituximab plus CVP chemotherapy vs. CVP alone as first-line treatment for follicular lymphoma: Treatment effect according to baseline prognostic factors
Authors: K. Imrie, A. Belch, R. Pettengell, A. Rueda, J. McKendrick, P. Solal-Céligny, F. Offner, I. Bence-Buckler, J. Walewski, J. Raposo, R. Marcus
Journal: Journal of Clinical Oncology (2005)

6525 Background: In patients with advanced previously untreated follicular lymphoma (FL), the addition of 8 cycles of rituximab to standard CVP (cyclophosphamide, vincristine, prednisone) chemotherapy (R-CVP) resulted in highly clinically and statistically significant improvements in major clinical endpoints compared with CVP alone, without increased toxicity (Marcus R et al. Blood 2004; Epub ahead of print). Median time to progression (TTP) was 32 vs 15 months for R-CVP and CVP, respectively (p< 0.0001). Treatment efficacy according to baseline risk factors had to be analyzed. Methods: A multivariate Cox regression analysis of TTP following the intention-to-treat principle was performed to assess the benefit of R-CVP on patient subgroups according to baseline prognostic factors. Results: 321 patients were randomized; the majority had intermediate or high risk disease according to the Follicular Lymphoma International Prognostic Index (FLIPI) (126 patients with FLIPI 2; 146 patients with FLIPI > 3). Patients in both prognostic groups who received R-CVP achieved significantly longer TTP (Table 1) than those who received CVP chemotherapy alone (p< 0.0001). The same observation was made if patients were scored according to the IPI. R-CVP significantly prolonged TTP compared to CVP regardless of histologic subtype of FL (IWF classes B, C, D), presence of B symptoms or bulky disease (p< 0.05 for all). The impact of Hemoglobin levels was also analyzed. The only subgroup where the difference between R-CVP and CVP was not significant is the group of patients with Hb < 12 g/dl. Conclusions: The addition of 8 cycles of rituximab to CVP chemotherapy as first-line treatment in FL significantly improves clinical outcomes, irrespective of baseline patient or disease characteristics, without adding toxicity. The R-CVP regimen may overcome adverse prognostic factors in previously untreated patients with FL. Table 1.Median TTP according to baseline prognostic factors Prognostic factor CVP n CVP median(months) R-CVP n R-CVP median (months) p value FLIPI score 2 65 17 61 39 <0.0001 3–5 75 12 71 26 <0.0001 B 46 17 38 32 0.0021 IWF class C 69 15 82 36 <0.0001 D 19 14 19 38 0.0023 B-Symptoms Yes 51 16 65 39 0.01 No 108 14 97 32 <0.0001 Bulky disease Yes 73 12 63 36 <0.0001 No 86 16 99 32 <0.0001 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Roche
Pearson Marrow Pancreas Syndrome In a Cohort Of Diamond Blackfan Anemia Patients
Authors: Katelyn E Gagne, Roxanne Ghazvinian, Daniel Yuan, Rebecca L. Zon, Kelsie Storm, Magdalena Mazur-Popinska, Laura Andolina, Halina Bubala, Sydonia Golebiowska, Meghan A. Higman, Krzysztof Kalwak, Peter Kurre, Michal Matysiak, Edyta Niewiadomska, Salley Pels, Mary Jane Petruzzi, Aneta Pobudejska-Pieniazek, Tomasz Szczepanski, Mark D Fleming, Hanna T. Gazda, Suneet Agarwal
Journal: Blood (2013)
Capitalizing on Advances in Science to Reduce the Health Consequences of Early Childhood Adversity
Authors: Jack P. Shonkoff
Journal: JAMA Pediatrics (2016)

Advances in biology are providing deeper insights into how early experiences are built into the body with lasting effects on learning, behavior, and health. Numerous evaluations of interventions for young children facing adversity have demonstrated multiple, positive effects but they have been highly variable and difficult to sustain or scale. New research on plasticity and critical periods in development, increasing understanding of how gene-environment interaction affects variation in stress susceptibility and resilience, and the emerging availability of measures of toxic stress effects that are sensitive to intervention provide much-needed fuel for science-informed innovation in the early childhood arena. This growing knowledge base suggests 4 shifts in thinking about policy and practice: (1) early experiences affect lifelong health, not just learning; (2) healthy brain development requires protection from toxic stress, not just enrichment; (3) achieving breakthrough outcomes for young children facing adversity requires supporting the adults who care for them to transform their own lives; and (4) more effective interventions are needed in the prenatal period and first 3 years after birth for the most disadvantaged children and families. The time has come to leverage 21<sup>st</sup>-century science to catalyze the design, testing, and scaling of more powerful approaches for reducing lifelong disease by mitigating the effects of early adversity.
Dual‐Stage Crosslinking of a Gel‐Phase Bioink Improves Cell Viability and Homogeneity for 3D Bioprinting
Authors: Karen Dubbin, Yuki Hori, Kazuomori K. Lewis, Sarah C. Heilshorn
Journal: Advanced Healthcare Materials (2016)

Current bioinks for cell-based 3D bioprinting are not suitable for technology scale-up due to the challenges of cell sedimentation, cell membrane damage, and cell dehydration. A novel bioink hydrogel is presented with dual-stage crosslinking specifically designed to overcome these three major hurdles. This bioink enables the direct patterning of highly viable, multicell type constructs with long-term spatial fidelity.
Association of <i>OCTN1</i> (T1672T) variant with a higher colorectal cancer risk in young individuals and in UC patients.
Authors: M. Martini, A. Ferarra, T. Cenci, L. Larocca, G. Pani
Journal: Journal of Clinical Oncology (2010)

e14059 Background: Ulcerative colitis (UC) is associated to colorectal cancer. Moreover, chronic inflammation may also play a role in the pathogenesis of sporadic colorectal cancer (SCC), particularly in younger patients (< 50 ys). We evaluated whether single nucleotide polymorphisms of OCTN1 and OCTN2, identified as inflammatory response genes, are associated to UC, SCC and to UC cases with cancer progression (high-grade dysplasia or colorectal cancer) (UCCP). We also evaluate if the OCTN polymorphisms are related to higher level of IL-8 in these three groups of patients. Methods: OCTN1 and OCTN2 polymorphisms were evaluated by PCR/RFLP assay or sequencing in 120 patients with UC, 57 patients with UCCP, 200 patients with SCC and 200 clinically healthy controls (HC). IL-8 expression was assessed by real-time PCR. Human colon carcinoma Caco2 cells, homozygous for OCTN1 (T1672T) variant, were transfected with the OCTN1 (C1672T) variant by lipofectamine and Nf-k activity was evaluated by luciferase based reporter assay. Results: Allele frequencies followed the Hardy-Weinberg equilibrium for both single nucleotide variants in patients and HC. OCTN1 and OCTN2 polymorphisms were in strong linkage disequilibrium (D' = 0.8). OCTN2 polymorphisms did not present a significant association with any group of patients and normal control. Conversely, although we did not found a significant distribution of the OCTN1 polymorphisms in UC and SCC versus HC, OCTN1 (T1672T) variant showed a significant association with SCC developing in early age (< 50 ys) (p = 0.012 versus HC) and with malignant progression of UC (UCCP versus UC patients, p = 0.0003). Importantly, IL-8 mRNA expression was higher in UC, SCC (< 50 ys) and UCCP patients carrying the OCTN1 (T1672T) genotype, with respect to the other variants. Moreover, cell lines transfected with OCTN1 (C1672T) variant displayed reduced growth capacity and activity of the proinflammatory factor Nf-kb, in comparison to untransfected control. Conclusions: Our data demonstrate that OCTN1 could have a role in modulating the severity of chronic inflammation associated with SCC in early age and in UC patients, and that its polymorphisms may help to predict malignant progression of IBD. No significant financial relationships to disclose.
Unexpected Detection of Urinary Bladder Cancer on Dual Phase 18F-NaF PET/CT in a Patient With Back Pain
Authors: Fuqiang Shao, Yuting Zou, Liang Cai, Xiaolong Wang, Yue Chen
Journal: Clinical Nuclear Medicine (2016)

A 72-year-old man underwent 18F-NaF PET/CT to evaluate causes of lower back pain. The PET images revealed multiple foci of increased activity in several vertebral bodies, which might account for the patient's symptoms. In addition, the CT image revealed partially calcified soft tissue mass in the posterior wall of the urinary bladder, which was photopenic relative to the radioactive urine on early PET images but became intense on delayed PET images. The diagnosis of transitional cell carcinoma was made pathologically after a transurethral resection of the mass.
Italian surgeon should never have been hired by Karolinska, inquiry concludes
Authors: Nigel Hawkes
Journal: BMJ (2016)

A trail of errors in the recruitment, management, and oversight of the high profile surgeon Paolo Macchiarini has damaged the reputation of clinical research in Sweden, an investigation has concluded.1

Macchiarini carried out three trachea transplants at the Karolinska University Hospital between 2011 and 2013, using artificial tracheas made of polymer and coated with stem cells. All went wrong: two patients died and one has been kept alive only by constant hospital care since her operation.

Macchiarini should never have been hired and the operations should not have been performed, an inquiry led by Kjell Asplund, chairman of the Swedish Council on Medical Ethics, has found.

“Much went wrong,” said Asplund when he presented the results of the inquiry in Stockholm on 31 August. “Macchiarini should not even have been employed at the hospital. There was never a job interview. Hospitals where …
Epinephrine: the drug of choice for anaphylaxis. A statement of the World Allergy Organization
Authors: S. F. Kemp, R. F. Lockey, F. E. R. Simons
Journal: Allergy (2008)

Anaphylaxis is an acute and potentially lethal multi‐system allergic reaction. Most consensus guidelines for the past 30 years have held that epinephrine is the drug of choice and the first drug that should be administered in acute anaphylaxis. Some state that properly administered epinephrine has no absolute contraindication in this clinical setting. A committee of anaphylaxis experts assembled by the World Allergy Organization has examined the evidence from the medical literature concerning the appropriate use of epinephrine for anaphylaxis. The Committee strongly believes that epinephrine is currently underutilized and often dosed suboptimally to treat anaphylaxis, is under‐prescribed for potential future self‐administration, that most of the reasons proposed to withhold its clinical use are flawed, and that the therapeutic benefits of epinephrine exceed the risk when given in appropriate i.m. doses.
Transgenic GATA1ie3.9int - DAPK2 Mice Exhibit Low-Grade Anemia, Deficient Stress Erythropoiesis, and Compromised Erythroblast Survival.
Authors: Jing Fang, Madhu P. Menon, Diya Zhang, Mario Tschan, Bruce Torbett, Nayani Pramanik, Estelle Houde, Don M. Wojchowski
Journal: Blood (2006)
68Ga-NODAGA-RGDyK PET/CT Imaging in Esophageal Cancer
Authors: Axel Van Der Gucht, Anastasia Pomoni, Mario Jreige, Pierre Allemann, John O. Prior
Journal: Clinical Nuclear Medicine (2016)

Ga-NODAGA-RGDyK(cyclic) and FDG PET/CT were performed in a 39-year-old man for the work-up of a moderately differentiated carcinoma of the gastro-esophageal junction within a clinical study protocol. Although FDG PET images showed intense, diffuse hypermetabolic lesion activity, NODAGA-RGDyK illustrated the neo-angiogenesis process with tracer uptake clearly localized in non-FDG-avid perilesional structures. Neo-angiogenesis is characterized by ανβ3 integrin expression at the lesion surface of newly formed vessels. This case supports evidence that angiogenesis imaging might therefore be a crucial step in early disease identification and localization, metastatization potential, and in monitoring the efficacy of antiangiogenic therapies.
Endobronchial Valve Therapy in Patients with Homogeneous Emphysema. Results from the IMPACT Study
Authors: Arschang Valipour, Dirk-Jan Slebos, Felix Herth, Kaid Darwiche, Manfred Wagner, Joachim H. Ficker, Christoph Petermann, Ralf-Harto Hubner, Franz Stanzel, Ralf Eberhardt
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Rationale: Endobronchial valves (EBVs) have been successfully used in patients with severe heterogeneous emphysema to improve lung physiology. Limited available data suggest that EBVs are also effective in homogeneous emphysema.Objectives: To evaluate the efficacy and safety of EBVs in patients with homogeneous emphysema with absence of collateral ventilation assessed with the Chartis system.Methods: Prospective, multicenter, 1:1 randomized controlled trial of EBV plus standard of care (SoC) or SoC alone. Primary outcome was the percentage change in FEV1 (liters) at 3 months relative to baseline in the EBV group versus the SoC group. Secondary outcomes included changes in FEV1, St. George's Respiratory Questionnaire (SGRQ), 6-minute-walk distance (6MWD), and target lobe volume reduction.Measurements and Main Results: Ninety-three subjects (age, 63.7 ± 6.1 yr [mean ± SD]; FEV1, % predicted, 29.3 ± 6.5; residual volume, % predicted, 275.4 ± 59.4) were allocated to either the EBV group (n = 43) or the SoC group (n = 50). In the intention-to-treat population, at 3 months postprocedure, improvement in FEV1 from baseline was 13.7 ± 28.2% in the EBV group and −3.2 ± 13.0% in the SoC group (mean between-group difference, 17.0%; P = 0.0002). Other variables demonstrated statistically and clinically significant changes from baseline to 3 months (EBV vs. SoC, respectively: SGRQ, −8.63 ± 11.25 vs. 1.01 ± 9.36; and 6MWD, 22.63 ± 66.63 m vs. −17.34 ± 52.8 m). Target lobe volume reduction at 3 months was −1,195 ± 683 ml (P < 0.0001). Of the EBV subjects, 97.2% achieved volume reduction in the target lobe (P < 0.0001). Procedure-related pneumothoraces occurred in 11 subjects (25.6%). Five subjects required removal/replacement of one or more valves. One subject experienced two valve migration events requiring removal/replacement of valves.Conclusions: EBV in patients with homogeneous emphysema without collateral ventilation results in clinically meaningful benefits of improved lung function, exercise tolerance, and quality of life.
Association of Infection in Early Life and Risk of Developing Type 1 Diabetes—Reply
Authors: Andreas Beyerlein, Ewan Donnachie, Anette-Gabriele Ziegler
Journal: JAMA (2016)

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Ronald David Gregg Tunbridge
Authors: Dian Donnai
Journal: BMJ (2016)

Ronald David Gregg Tunbridge (known as David) was a hypertension specialist who contributed to medical education; he had a passion for canals, photography, and croquet. He was the second son of Dorothy (Gregg) and Sir Ronald Tunbridge, professor of medicine in Leeds and president of the BMA. His brother, Michael, qualified as a doctor, but David at first started a geology degree at Durham University. However, he soon enrolled on the 1st MB course at St Mary’s Hospital Medical School in London. He spent his elective period in Ethiopia, where he analysed the educational needs for an effective healthcare system, given the social and political context. Even as a …
Phase 1/2 trial of bevacizumab plus TPI 287, a brain penetrable anti-microtubule agent, in patients with recurrent glioblastoma.
Authors: Samuel Aaron Goldlust, Louis B. Nabors, Nimish Mohile, Tara L. Benkers, Sigmund H. Hsu, Sandra Silberman, Samuel Singer, George Farmer
Journal: Journal of Clinical Oncology (2016)

2055 Background: Microtubule inhibitors have demonstrated efficacy in preclinical models of glioblastoma (GBM), however, clinical benefit is hampered by subtherapeutic dose delivery. Designed to overcome this limitation, TPI 287 is a third-generation taxane that readily penetrates the blood brain barrier and evades mechanisms of P-glycoprotein mediated efflux. CB-017 is a multi-center phase 1/2 trial designed to determine the maximum tolerated dose and potential efficacy in patients treated with TPI 287 plus bevacizumab (BEV) for treatment of recurrent GBM. Results of the recently completed dose escalation stage of the trial are reported. Methods: GBM patients at first or second relapse after standard therapy and without prior exposure to anti-angiogenic agents were eligible for enrollment. BEV was administered at 10 mg/kg every 2 weeks and TPI 287 every 3 weeks via IV infusion. MRIs were obtained every six weeks with response assessed via RANO. TPI-287 dose escalation was based upon a standard 3+3 design. Results: As of January 2016, 24 patients were enrolled in seven TPI 287 dose-escalation cohorts (140-220 mg/m2). No DLTs were reported and myelosuppression (n = 3) was the only drug-related grade 3/4 adverse event. Increased frequency of myelosuppression and peripheral neuropathy in later cohorts, in conjunction with suggested activity, lead to halting dose escalation at 220 mg/m2. Among 20 patients evaluable for response, ORR was 60% (12/20; 3 complete, 9 partial). The median and 6-month PFS were 5.5 mo. [95% C.I. 4.1-6.9] and 37%, respectively. Median and 1-year OS were 12.9 mo. [95% C.I. 10.9-17.9] and 63%, respectively, after 20.1 mo. median follow-up. Conclusions: TPI 287 in combination with BEV is safe and well tolerated at doses up to 220 mg/m2, and survival compares favorably with historical controls. Advancement to the phase 2 stage of the trial is underway. Updated safety and efficacy results will be presented. Clinical trial information: NCT01933815.
Outer membrane vesicles in service as protein shuttles, biotic defenders, and immunological doppelgängers
Authors: Richard C. Laughlin, Robert C. Alaniz
Journal: Gut Microbes (2016)

Characterization of host microbial interactions typically occurs on the cellular or protein level. Recently, a more thorough and accurate appreciation of cellular interactions has come into better focus with improved understanding of membrane vesicles (OMV). While OMVs are documented primarily in Gram-negative bacteria, certain Gram-positive species generate these structures, despite the obvious physical limitations of the cell envelope. Here, we briefly review the current understanding of OMVs in content and function, their role in pathogenesis, and the consequences of somatic cell gene expression on these events.