tbuckley/cabot-search huggingface dataset:
A phase I trial of RAD001 in combination with cetuximab in patients with advanced solid tumors
Authors: A. N. Avadhani, K. Flaherty, M. Rosen, M. L. Veronese, K. Harlacker, S. W. Johnson, E. Sherman, W. Griggs, C. R. Divgi, P. J. O’Dwyer
Journal: Journal of Clinical Oncology (2007)

14075 Background: Cetuximab is a selective epidermal growth factor (EGFR) inhibitor approved for use in EGFR expressing advanced colorectal cancers. RAD001 inhibits mTOR (mammalian target of rapamycin), a downstream effector of the PI3K/AKT pathway. Preclinical studies suggest that RAD001 may restore sensitivity to EGFR inhibitors in resistant cell lines, and that in combination it may augment anti-tumor activity. We assessed safety, pharmacokinetics (PK), and pharmacodynamic (PD) endpoints for mTOR inhibition and tumor vascular permeability in a phase I combination study. Methods: Pts with EGFR-expressing advanced solid tumors were randomized to a 3 week run-in of single agent RAD001 or cetuximab Q wk, followed by RAD001 + cetuximab Qwk. RAD001 was dosed at 30–70 mg PO. Standard dosing of cetuximab was used (400 mg/m 2 IV loading, followed by 250 mg/m 2 IV Qwk). DLT was defined as any grade 4 hematologic or =grade 3 non-hematologic toxicity associated with treatment during cycle 1. In addition to plasma analysis for the PK of RAD001, we performed 18 FDG-PET and dynamic contrast-enhanced (DCE) MRI before and during combination therapy, to assess for early changes in tumor metabolic activity and vascular permeability. Phosphorylation of p70S6K, a biomarker for RAD001 activity, was measured in peripheral blood mononuclear cells. Results: 12 pts (median age 56, 5 M/7F, median PS 0) were treated at dose levels 1–2 (RAD001 30–50mg/cetuximab 250 mg/m 2 ), with 3 per dose order. Observed toxicities were all grade 1–2, and included mucositis (2/12), rash (8/12), fatigue (6/12), anorexia (4/12), nausea (5/12), and vomiting (5/12). 2 pts (parotid and ovarian CA) had SD (4+ mos) as best response, with decreased serum CA-125 in the ovarian CA pt. PET findings in pts with SD confirm decreased tumor metabolic activity. Conclusions: At these doses, neither drug appears to increase the toxicity of the other. Analysis of full dose RAD001 in the combination is nearing completion. Preliminary PET findings suggest biological activity of the combination. No significant financial relationships to disclose.
Abstract 392: Metabolic Signaling Mechanisms Governing Heart Regenerative Capacity
Authors: Song Zhang, Petras Dzeja
Journal: Circulation Research (2015)

Energy metabolism and metabolic signaling circuits orchestrate cell commitment to self-renewal, lineage specification, differentiation and regeneration. When energy resources are plenty, cell can grow, proliferate and regenerate, however when energy is low - augmented adenylate kinase (AK)-mediated AMP signaling turns on AMPK which silences p53/p21/cyclin cell cycle metabolic checkpoint and halts cell division. Using mouse neonatal hearts, with high and low regenerative capacity, we have determined metabolomic profiles and dynamics of phosphotransfer circuits using 18O-phosphoryl labeling mass-spectrometric and 18O-assisted 31P NMR techniques. We demonstrate that loss of heart regenerative capacity after birth is associated with marked changes in heart AK-catalyzed phosphotransfer flux and AMP signaling along with changes in expression levels of p21, cyclin A and E and thymidine kinase. It appears, that in adult heart increased expression of AK isoforms (AK1, AK2 and AK1β) and augmented high energy phosphoryl and AMP signal dynamics is misread by AMPK-sensor as "low energy" state inducing blockade of cell cycle metabolic checkpoint and cardiomyocyte proliferation and renewal. Using AK-GFP constructs and immunocytochemistry we further demonstrate the distribution of AK1, AK1β, AK2 and AMPK between cytosol and nucleus and association with mitotic spindle and cytokinetic apparatus during cell division cycle. AK1 translocation to the nucleus, however, doesn’t occur in adult cardiomyocytes deficient in cytokinesis. Protein knockdown using siRNA indicates that AK2 is critical for cardiomyocyte mitochondrial biogenesis and network formation. Furthermore, we have discovered that deficiency of the AK2 isoform, which is localized in mitochondria intermembrane-intra-cristae space, arrests developmental programming and is embryonically lethal in mice. The uncovered shift in metabolic signaling mechanisms opens new avenues for targeted regulation of heart regenerative potential critical for repair of injured hearts.
Implication of pulmonary hypertension in patients undergoing MitraClip therapy: results from the German transcatheter mitral valve interventions (TRAMI) registry
Authors: Eike Tigges, Stefan Blankenberg, R. Stephan von Bardeleben, Christine Zürn, Raffi Bekeredjian, Taoufik Ouarrak, Horst Sievert, Georg Nickenig, Peter Boekstegers, Jochen Senges, Wolfgang Schillinger, Edith Lubos
Journal: European Journal of Heart Failure (2017)
Noninvasive Ventilation in the Premature Newborn — Is Less Always More?
Authors: Michael D. Schreiber, Jeremy D. Marks
Journal: New England Journal of Medicine (2017)

Endotracheal positive-pressure ventilation with end expiratory pressure has been the cornerstone of the modern approach to care for premature infants with respiratory insufficiency since the publication of a report by Gregory and colleagues in 1971.1 They found that endotracheal continuous positive airway pressure (CPAP) could establish and maintain functional residual capacity in the surfactant-deficient premature lung. However, this invasive, lifesaving approach has long been considered to increase the risk of bronchopulmonary dysplasia,2 the chronic lung disease of survivors of the neonatal intensive care unit. The risk of bronchopulmonary dysplasia increases with the degree of anatomical and biochemical immaturity of the . . .
High sensitivity and specificity NGS analysis of prostate and kidney cancer samples using a novel liquid biopsy workflow.
Authors: Cristian Ionescu-Zanetti, Reynolds Brobey, Hubert Tseng, Kevin P Rosenblatt, Nicholas Kamps-Hughes, Tony Tran, Robert J. Amato
Journal: Journal of Clinical Oncology (2016)

e16607 Background: Next generation sequencing (NGS) of blood-derived nucleic acids is an emerging paradigm for determining the mutational status of cancer patients over time. Circulating tumor cells (CTC) and cell-free circulating DNA have been proposed as possible sample types. Here we present data from a CTC enrichment modality that results in tumor cell purities of > 10% and a high sensitivity NGS data analysis workflow that enables the use of standard amplicon panels typically used for primary tissue. This study was aimed at urological cancers of the kidney and prostate). Methods: Blood samples from prostate and kidney cancer patients were enriched for CTCs using the IsoFlux System, from a starting blood volume of 7.5-14ml. Matched samples were enumerated to determine the CTC load, where CTCs were defined as CK+, CD45- nucleated cells (DAPI+). Cells were lysed and DNA was amplified by whole genome amplification (WGA) using the NGS Kit (Fluxion), and quantified via qPCR. Targeted libraries were sequenced using either the PGM or MiSeq instruments; the analysis used a high sensitivity variant calling pipeline and ERASE algorithm (Elimination of Recurring Artifacts and Stochastic Errors) as well as VarSeq (Golden Helix Inc.) for variant filtering and functional interpretation. Results: Multisite analytical validation data, based on spiking of cells into whole blood, and a matched molecular and bioinformatics approach demonstrates a detection limit down to 10 cells from a blood draw with a false positive rate of below 0.1 calls per sample. DNA spike data shows detection down to 0.4% allele frequency without false positives. Clinical data from two different urological cancer pilot studies demonstrates the detection of somatic variants for a majority of samples, and significant overlap between detected mutations and known somatic mutation sites. We also describe concordance between biological replicates, and a comparison of the liquid biopsy samples to germ line DNA derived from white blood cells. Conclusions: This assay makes possible the detection of somatic variants from urological cancer patients without the need for a tissue biopsy.
Association of MicroRNA‐618 Expression With Altered Frequency and Activation of Plasmacytoid Dendritic Cells in Patients With Systemic Sclerosis
Authors: Marzia Rossato, Alsya J. Affandi, Soley Thordardottir, Catharina G. K. Wichers, Marta Cossu, Jasper C. A. Broen, Frederique M. Moret, Lara Bossini‐Castillo, Eleni Chouri, Lenny van Bon, Femke Wolters, Wioleta Marut, Maarten van der Kroef, Sandra Silva‐Cardoso, Cornelis P. J. Bekker, Harry Dolstra, Jacob M. van Laar, Javier Martin, Joel A. G. van Roon, Kris A. Reedquist, Lorenzo Beretta, Timothy R. D. J. Radstake
Journal: Arthritis & Rheumatology (2017)

Plasmacytoid dendritic cells (PDCs) are a critical source of type I interferons (IFNs) that can contribute to the onset and maintenance of autoimmunity. Molecular mechanisms leading to PDC dysregulation and a persistent type I IFN signature are largely unexplored, especially in patients with systemic sclerosis (SSc), a disease in which PDCs infiltrate fibrotic skin lesions and produce higher levels of IFNα than those in healthy controls. This study was undertaken to investigate potential microRNA (miRNA)-mediated epigenetic mechanisms underlying PDC dysregulation and type I IFN production in SSc.We performed miRNA expression profiling and validation in highly purified PDCs obtained from the peripheral blood of 3 independent cohorts of healthy controls and SSc patients. Possible functions of miRNA-618 (miR-618) on PDC biology were identified by overexpression in healthy PDCs.Expression of miR-618 was up-regulated in PDCs from SSc patients, including those with early disease who did not present with skin fibrosis. IFN regulatory factor 8, a crucial transcription factor for PDC development and activation, was identified as a target of miR-618. Overexpression of miR-618 reduced the development of PDCs from CD34+ cells in vitro and enhanced their ability to secrete IFNα, mimicking the PDC phenotype observed in SSc patients.Up-regulation of miR-618 suppresses the development of PDCs and increases their ability to secrete IFNα, potentially contributing to the type I IFN signature observed in SSc patients. Considering the importance of PDCs in the pathogenesis of SSc and other diseases characterized by a type I IFN signature, miR-618 potentially represents an important epigenetic target to regulate immune system homeostasis in these conditions.
Association of Cost Sharing With Mental Health Care Use, Involuntary Commitment, and Acute Care
Authors: Bastian Ravesteijn, Eli B. Schachar, Aartjan T. F. Beekman, Richard T. J. M. Janssen, Patrick P. T. Jeurissen
Journal: JAMA Psychiatry (2017)

A higher out-of-pocket price for mental health care may lead not only to cost savings but also to negative downstream consequences.To examine the association of higher patient cost sharing with mental health care use and downstream effects, such as involuntary commitment and acute mental health care use.This difference-in-differences study compared changes in mental health care use by adults, who experienced an increase in cost sharing, with changes in youths, who did not experience the increase and thus formed a control group. The study examined all 2 780 558 treatment records opened from January 1, 2010, through December 31, 2012, by 110 organizations that provide specialist mental health care in the Netherlands. Data analysis was performed from January 18, 2016, to May 9, 2017.On January 1, 2012, the Dutch national government increased the out-of-pocket price of mental health services for adults by up to €200 (US$226) per year for outpatient treatment and €150 (US$169) per month for inpatient treatment.The number of treatment records opened each day in regular specialist mental health care, involuntary commitment, and acute mental health care, and annual specialist mental health care spending.This study included 1 448 541 treatment records opened from 2010 to 2012 (mean [SD] age, 41.4 [16.7] years; 712 999 men and 735 542 women). The number of regular mental health care records opened for adults decreased abruptly and persistently by 13.4% (95% CI, -16.0% to -10.8%; P < .001) per day when cost sharing was increased in 2012. The decrease was substantial and significant for severe and mild disorders and larger in low-income than in high-income neighborhoods. Simultaneously, in 2012, daily record openings increased for involuntary commitment by 96.8% (95% CI, 87.7%-105.9%; P < .001) and for acute mental health care by 25.1% (95% CI, 20.8%-29.4%; P < .001). In contrast to our findings for adults, the use of regular care among youths increased slightly and the use of involuntary commitment and acute care decreased slightly after the reform. Overall, the cost-sharing reform was associated with estimated savings of €13.4 million (US$15.1 million). However, for adults with psychotic disorder or bipolar disorder, the additional costs of involuntary commitment and acute mental health care exceeded savings by €25.5 million (US$28.8 million).Higher cost sharing for seriously ill and low-income patients could discourage treatment of vulnerable populations and create substantial downstream costs.
Response to Comment on Nachum et al. Glyburide Versus Metformin and Their Combination for the Treatment of Gestational Diabetes Mellitus: A Randomized Controlled Study. Diabetes Care 2017;40:332–337
Authors: Zohar Nachum, Enav Yefet
Journal: Diabetes Care (2017)

The comment by Barbour and Davies (1) acknowledges that our study (2) is important given the increasing popularity of oral agents to treat gestational diabetes mellitus (GDM) but raises concerns whether the study design and conclusions can be generalized to other GDM populations.

With regard to treatment efficacy before 24 weeks, in our study the success rate of oral treatments before and after 24 weeks was similar: 67% vs. 69% after first-line therapy and 89% vs. 90% for second-line therapy, …
Modern Systemic Therapy for Metastatic Renal Cell Carcinoma of the Clear Cell Type
Authors: Mamta Parikh, Primo N. Lara
Journal: Annual Review of Medicine (2017)

In the last 30 years, there have been many advances in the treatment of metastatic renal cell carcinoma of the clear cell type. Renal cell carcinoma has long been understood to have a component of immune mediation and has been responsive to immune-based therapies; in addition to early cytokine therapy, newer checkpoint inhibition therapies have also demonstrated activity. Molecular characterization of the genome of clear cell renal cell carcinoma enabled identification of the roles of angiogenesis and hypoxic stress. This led to development of small-molecule tyrosine kinase inhibitors and inhibitors of mammalian target of rapamycin that have provided additional benefit to patients. Ongoing strategies of combinations of immune and antiangiogenic therapies may lead to further advancements.
Thiotepa‐based conditioning versus total body irradiation as myeloablative conditioning prior to allogeneic stem cell transplantation for acute lymphoblastic leukemia: A matched‐pair analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Authors: Sandra Eder, Jonathan Canaani, Eric Beohou, Myriam Labopin, Jaime Sanz, William Arcese, Reuven Or, Juergen Finke, Agostino Cortelezzi, Dietrich Beelen, Jakob Passweg, Gerard Socié, Gunhan Gurman, Mahmoud Aljurf, Matthias Stelljes, Sebastian Giebel, Mohamad Mohty, Arnon Nagler
Journal: American Journal of Hematology (2017)

Abstract The optimal conditioning regimen to employ before hematopoietic stem cell transplantation in acute lymphoblastic leukemia (ALL) is still undecided, and while cyclophosphamide/total body irradiation (Cy/TBI) is the most commonly used myeloablative regimen, there are concerns regarding long‐term toxicity for patients conditioned with this regimen. Thiotepa‐based conditioning is an emerging radiation‐free regimen with recent publications indicative of comparable clinical outcomes to TBI‐based conditioning. In this analysis of the acute leukemia working party of the EBMT, we performed a retrospective matched‐pair analysis, evaluating the outcome of adult patients with ALL who received thiotepa‐based conditioning ( n = 180) with those receiving Cy/TBI conditioning ( n = 540). The 2‐year leukemia‐free survival and overall survival (OS) rates of both conditioning regimens were comparable, 33% for thiotepa [95% confidence interval (CI): 26.4‐42.8] versus 39% for Cy/TBI (95% CI: 34.8‐44.5] ( P = .33) and 46.5% [95% CI: 38.6‐56.1] versus 48.8% [95% CI: 44.2‐54] ( P = .9), respectively. There was no significant difference between the two regimens in the incidence of either acute graft versus host disease (GVHD) or chronic GVHD. Multivariate analysis demonstrated increased relapse incidence for thiotepa conditioning compared to Cy/TBI (HR = 1.78, 95% CI, 1.07‐2.95; P = .03) which did not affect OS. Our results indicate that thiotepa‐based conditioning may not be inferior to Cy/TBI for adult patients with ALL.
A randomized, open-label, multicenter trial of the concurrent chemoradiotherapy of capecitabine with or without oxaliplatin versus cisplatin with 5-FU for Chinese squamous esophageal cancer: An interim report from CRTCOESC.
Authors: Ruinuo Jia, Tanyou Shan, Fuyou Zhou, Anping Zheng, Lixin Wan, Zhiqiao Xu, Guobao Zheng, Xiaoyong Luo, Yingjuan Zheng, Yanhui Cui, Guifang Zhang, Dan Zhou, Jiachun Sun, Guoqiang Kong, Xiaozhi Yuan, Ruina Yang, Jing Ren, Wei Wang, Xinshuai Wang, Shegan Gao
Journal: Journal of Clinical Oncology (2017)

4063 Background: CRT with 5- FU and cisplatin (PF) has shown greater clinical efficacy for local advanced esophageal cancer (EC) but with high rate of acute toxicities (ATs). CRTCOESC is a randomized, open-label, multicenter trial designed to evaluate the effect and safety of capecitabine with or without oxaliplatin versus PF with CRT in Chinese EC. Methods: Pts with biopsy-proven squamous EC (T2-4N0-2M0) were randomized to single capecitabine (Arm1), capecitabine plus oxaliplatin (Arm2), or PF (Arm3), while daily radiation 50Gy/2Gy for all. Pts were stratified by different regimens cycles. Both grade3-5 ATs and 2-year OS were the primary endpoint, with a planned accrual of 249 pts to detect a decrease in Grade3-5 ATs from 40% to 20%. The secondary endpoint included objective response rate (ORR) and 2-year progression free survival (PFS). Interim analysis of ATs and ORR was planned for the first 120 pts. Results: The study accrued 128 pts from 2014.10-2016.12, 118 were eligible. 86 patients were finished 16-weeks follow-up at least and analyzed in the interim report (Arm1: Arm2: Arm3 = 24: 37: 25). There was no difference between three arms on pts pretreatment characters (age, gender, weight, performance status, clinical stage, lymphonodus status, and pathology grade). Incidence of grade3-5 ATs in Arm1/2/3 were 25%: 32.4%: 64% ( p = 0.03); it was significantly lower in Arm1/2 than Arm3 (Arm1 vs Arm3, p = 0.041; Arm2 vs Arm3, p = 0.022); and there no meaningful different between Arm1 and Arm2 ( p = 0.738). The pCR rate and ORR were 50%: 48.6%: 48% and 87.5%: 83.8%: 100% in Arm1/2/3 ( p = 0.99; p = 0.133). 56 patients had been finished 1 year follow-up (Arm1: Arm2: Arm3 = 12: 26: 18). The 1-year OS and PFS were 75%: 91.9%: 76% and 66.7%: 62.2%: 60% in Arm1/2/3 ( p = 0.166; p= 0.926). Conclusions: Compared with PF, CRT with single capecitabine with or without oxaliplatin shown lower incidence of ATs and similar ORR and 1-year OS. The single capecitabine seemly carried out a benefit of lower ATs than it plus oxaliplatin; there was no meaningful difference for them on ORR and 1-year OS. Ruinuo Jia and Tanyou Shan did equal work. Clinical trial information: NCT02025036.
Arrhythmia in Bone Marrow Transplant Unit
Authors: Eric E. McClendon, Takeki Suzuki, Tanyanan Tanawuttiwat
Journal: JAMA Cardiology (2017)

A 35-year-old woman with a history of hypertension and chronic lymphocytic leukemia who underwent allogenic bone marrow transplant presents to an emergency department with shortness of breath and productive cough. What would you do next?
Comparison of Wound Complications After Immediate, Delayed, and Secondary Breast Reconstruction Procedures
Authors: Margaret A. Olsen, Katelin B. Nickel, Ida K. Fox, Julie A. Margenthaler, Anna E. Wallace, Victoria J. Fraser
Journal: JAMA Surgery (2017)

Few data are available concerning surgical site infection (SSI) and noninfectious wound complications (NIWCs) after delayed (DR) and secondary reconstruction (SR) compared with immediate reconstruction (IR) procedures in the breast.To compare the incidence of SSI and NIWCs after implant and autologous IR, DR, and SR breast procedures after mastectomy.This retrospective cohort study included women aged 18 to 64 years undergoing mastectomy from January 1, 2004, through December 31, 2011. Data were abstracted from a commercial insurer claims database in 12 states and analyzed from January 1, 2015, through February 7, 2017.Reconstruction within 7 days of mastectomy was considered immediate. Reconstruction more than 7 days after mastectomy was considered delayed if the mastectomy did not include IR or secondary if the mastectomy included IR.International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes for SSI and NIWCs.Mastectomy was performed in 17 293 women (mean [SD] age, 50.4 [8.5] years); 61.4% of women had IR or DR. Among patients undergoing implant reconstruction, the incidence of SSI was 8.9% (685 of 7655 women) for IR, 5.7% (21 of 369) for DR, and 3.2% (167 of 5150) for SR. Similar results were found for NIWCs. In contrast, the incidence of SSI was similar after autologous IR (9.8% [177 of 1799]), DR (13.9% [19 of 137]), and SR (11.6% [11 of 95]) procedures. Compared with women without an SSI after implant IR, women with an SSI after implant IR were significantly more likely to have another SSI (47 of 412 [11.4%] vs 131 of 4791 [2.7%]) and an NIWC (24 of 412 [5.8%] vs 120 of 4791 [2.5%]) after SR. The incidence of SSI (24 of 379 [6.3%] vs 152 of 5286 [2.9%]) and NIWC (22 of 379 [5.8%] vs 129 of 5286 [2.4%]) after implant SR was higher in women who had received adjuvant radiotherapy. Wound complications after IR were associated with significantly more breast surgical procedures (mean of 1.92 procedures [range, 0-9] after implant IR and 1.11 [range, 0-6] after autologous IR) compared with women who did not have a complication (mean of 1.37 procedures [range, 0-8] after implant IR and 0.87 [range, 0-6] after autologous IR).The incidence of SSI and NIWCs was slightly higher for implant IR compared with delayed or secondary implant reconstruction. Women who had an SSI or NIWC after implant IR had a higher risk for subsequent complications after SR and more breast operations. The risk for complications should be carefully balanced with the psychosocial and technical benefits of IR. Select high-risk patients may benefit from consideration of delayed rather than immediate implant reconstruction to decrease breast complications after mastectomy.