bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular signatures and responses to targeted therapies in over 300 relapsed and therapy-refractory young adult (AYA) and childhood cancers.
Authors: Breese Erin Haag , Turpin Brian , Dexheimer Phillip , Mizukawa Benjamin , Agresta Laura , Gurunathan Arun , Pfeiffer Thomas , Rubinstein Jeremy , Smart Luke , Frampton Garrett Michael , Sarangdhar Mayur , Weiss Brian D. , Pressey Joseph Gerald , Geller James I. , O'Brien Maureen Megan , Fouladi Maryam , Perentesis John Peter ,   CCHMC Leukemia/Lymphoma, Solid, and Brain Tumor Teams
Published: July 2017

11514 Background: Contemporary chemotherapy-based regimens provide cures for most pediatric & AYA cancers. However, for patients with relapsed/refractory malignancies, outcomes are poor & imply a distinct and aggressive biology. Identifying common themes in the molecular architecture & oncogenic mechanisms in these patients is a critical priority for drug development. We hypothesized that the molecular signature of cancers in these patients would be independent of histology. We also assessed the response to molecular alteration (MA)-targeted therapies. Methods: IRB-approved analysis of MAs in 306 relapsed/refractory pediatric & AYA malignancies (116 hematologic malignancies, 68 sarcomas, 46 neuroblastomas, 36 CNS, 14 liver, 9 renal, 17 other) was performed. DNA was analyzed for MAs (Foundation Medicine, Cambridge, MA; Univ of Washington, Seattle, WA); additional MAs were identified by cytogenetic & fluorescent in situ hybridization analyses. Results: Median age was 8 years (range birth - 44 yrs). MAs were identified in 90.1% of patients & included a median of 2 mutations (range 0-18) in 133 cancer-related genes. In contrast to genomic analyses of de novo malignancies in children, a high frequency of TP53 MAs was identified (20.4% of patients) and was associated with inferior survival. MAs were identified in targetable pathways including cell cycle regulation (32.6%), DNA repair (7.2%), epigenetic (28.6%), RAS/RAF/MEK (24%), tyrosine kinase (TK; 18.4%), PI3K/AKT/mTOR (11.8%), and NOTCH/WNT (8.9%). A higher number of MAs was associated with inferior survival. Patients with alterations in epigenetic & TK pathways also had inferior outcomes. MAs were frequently independent of histology & the spectrum of mutations was similar to adult cancers. Exceptional responses were observed with MA-based assignment of therapies (epigenetic, NTRK, RAS/RAF/MEK & ALK). Conclusions: Relapsed/refractory pediatric & AYA cancers have frequent MAs independent of histology. The spectrum of MAs is distinct from de novo disease & potentially reflects tumor evolution & resistance mechanisms. These findings support MA-guided approaches to new drug development paired with adult trials.
Comprehensive genomic profiling (CGP) with loss of heterozygosity (LOH) to identify therapeutically relevant subsets of ovarian cancer (OC).
Authors: Elvin Julia Andrea , He Yuting , Sun James , Odunsi Kunle , Szender James Brian , Moore Kathleen N. , Gay Laurie M. , Frampton Garrett Michael , Vergilio Jo-Anne , Suh James , Ramkissoon Shakti , Severson Eric Allan , Daniel Sugganth , Lin Kevin K. , Hou June YiJuan , Gunderson Camille Catherine , Holman Laura L. , Stephens Phil , Raponi Mitch , Ross Jeffrey S. 
Published: July 2017

5512 Background: Defective homologous recombination DNA repair (HRD) is associated with high grade serous (OC-S) histology, longer survival, and platinum (Pt) or PARP inhibitor (PARPi) sensitivity. HRD causes LOH, a pattern of allelic imbalance detectable by CGP. BRCAwt OC-S can have LOH and respond to PARPi, while non-serous (OC-NS) or difficult to classify (OC-NOS) OC are often less responsive to Pt-based therapy. Integrating multiple genomic features derived from CGP may define other therapeutically relevant subsets. Methods: DNA from FFPE tumor tissue obtained during clinical care for 4114 advanced OC was analyzed for all classes of genomic alterations (GA) by hybrid-capture, next-generation sequencing of up to 315 genes. Tumor subtype counts were OC-S, n = 2770; OC-NOS, n = 807; OC-NS, n = 537 (mucinous, clear cell, endometrioid, neuroendocrine, carcinosarcomas, and low grade serous). Algorithms evaluated microsatellite instability (MSI), tumor mutation burden (TMB; TMB-H ≥ 10 muts/Mb), and LOH (LOH-H ≥ 14, LOH-L < 14). Results: 706/4114 (17.2%) OC had ≥1 deleterious BRCA GA, OC-S (18.7%) more so than OC-NS (4.4%). Median LOH score for OC-S was significantly higher than OC-NS (12.8 vs. 5.8, p < 0.05). BRCAmut OC-S and OC-NS were similarly LOH-H (86% and 75%), unlike BRCAwt OC-S (38.4%) or OC-NS (18%). Regardless of LOH, similar co-occurrence of MYC (26.9%) and/or NF1 (19%) GA was seen in BRCAmut OC. BRCAwt LOH-L OC commonly had CCNE1 (19.7%), KRAS (19%), PIK3CA (16.2%), AKT2 (7.4%), ERBB2 (4.7%), or BRAF(3.3%) GA. Frequency of TMB-H was 2.5% and MSI-H 1%. Correlation of GA with treatment, clinical histories and outcomes for some patients will be presented. Conclusions: BRCAmut or OC-S are commonly LOH-H; ~1 in 5 BRCAwt OC-NS, including carcinosarcomas and mucinous, are also LOH-H. Genes co-mutated in late stage LOH-H OC may be linked to treatment resistance. CGP of this large OC cohort reveals molecular, rather than histologic, patient subsets that may benefit from PARPi (46.2% BRCAmut or LOH-H), targeted therapy ( > 50% BRCAwt LOH-L, excluding TP53) or immunotherapy (3.5% TMB-H or MSI-H), providing more support for insurance coverage and integration into OC clinical trials.
BRCA1/2 reversion mutations revealed in breast and gynecologic cancers sequenced during routine clinical care using tissue or liquid biopsy.
Authors: Mayor Paul , Gay Laurie M. , Gornstein Erica , Morley Samantha , Frampton Garrett Michael , Heilmann Andreas , Sun James , Chung Jon , Daniel Sugganth , Ramkissoon Shakti , Severson Eric Allan , Suh James , Vergilio Jo-Anne , Stephens Philip J. , Lele Shashikant B. , Ross Jeffrey S. , Elvin Julia Andrea 
Published: July 2017

5551 Background: Tumors with genomic alteration (GA) of BRCA1 or BRCA2 ( BRCA) may be more sensitive to platinum (Pt) therapies and PARP inhibitors (PARPi). However, secondary reversion mutations (revGA) can arise that may restore BRCA function and underlie reduced sensitivity to Pt compounds or PARPi. Methods: DNA extracted from FFPE tumor tissue or blood samples obtained during routine clinical care for patients with predominantly relapsed, refractory or metastatic breast cancer (10967) or ovarian/peritoneal cancer (8352) was analyzed by hybrid-capture, next-generation sequencing for all classes of GA: base substitutions, indels, rearrangements, and copy number changes. RevGA were any GA that could restore the reading frame if in cis with a nonsense or frameshift (fs) GA. Results: 1900/19329 (9.8% ± 0.4%) tumors had ≥1 deleterious BRCA GA. 38 samples harbored potential revGA in BRCA1 (16) or BRCA2 (22): breast carcinoma (Ca) (21), ovarian or peritoneal serous Ca (10), ovarian or peritoneal adenocarcinoma (3), and ovarian epithelial Ca NOS (4). 35/38 sequenced samples were metastases. All potential revGA were somatic and fell into 3 classes: overlapping indel (21), compensatory fs (6), and missense mutation (11). One case harbored both an overlapping indel and a missense mutation with potential to revert a nonsense alteration. For 6 patients, testing of multiple tissue samples reveals the acquisition of revGA over time. RevGA are generally observed at allele frequencies lower than the deleterious GA they may revert. Clinical histories for patients with reversion mutations will be presented. Conclusions: Genomic profiling of breast and gynecological carcinomas, using either tissue or liquid biopsies, reveals potential revGA that may restore some level of BRCA function. RevGA, although rare, can be acquired during the course of treatment. We identified potentially compensatory missense, fs and indel mutations with CGP. Comparison of allele frequencies suggests that revGA often arise as subclones. The acquisition of a revGA over time can be observed through testing of multiple samples, either tissue or liquid biopsy.
BRAF fusions in clinically advanced non-small cell lung cancer: An emerging target for anti-BRAF therapies.
Authors: Reddy Venkataprasanth P. , Gay Laurie M. , Elvin Julia Andrea , Vergilio Jo-Anne , Suh James , Ramkissoon Shakti , Daniel Sugganth , Severson Eric Allan , Ali Siraj Mahamed , Schrock Alexa Betzig , Chung Jon , Frampton Garrett Michael , Fabrizio David , Stephens Phil , Miller Vincent A. , Ross Jeffrey S. 
Published: July 2017

9072 Background: Although far less common than BRAF V600E base substitutions (subs) classically associated with melanomas and colorectal carcinomas, BRAF subs occur in 1-2% of non-small cell lung cancer (NSCLC). BRAF fusions are emerging treatment targets for Spitzoid melanomas and other solid tumors. The frequency of BRAF fusions and targeting potential in NSCLC has not been widely described. Methods: Hybridization capture-based comprehensive genomic profiling (CGP) was performed on 17,128 NSCLC FFPE samples sequenced to a mean coverage depth of > 550X for up to 315 cancer-related genes plus 37 introns from 19 genes frequently rearranged in cancer. Genomic alterations (GA) included short variant (SV) base subs and insertions/deletions, copy number alterations, and rearrangements/fusions. Tumor mutational burden (TMB; mut/Mb) was calculated on up to 1.1 Mb of sequenced DNA. Results: BRAF fusions were identified in 42/17,128 (0.2%) NSCLC profiled. Median patient age was 67 (range 44-93 yrs). Of the BRAF fusion positive NSCLC, 55% were female. Biopsies were obtained from primary lung tumor (48%) and metastatic sites (52%). The most frequent 5’ partners were AGK, DOCK4, and TRIM24. Multiple novel BRAF fusions were identified. The genes most frequently co-altered with BRAF fusions were TP53(67%), CDKN2A(31%), EGFR (29%) and CDKN2B (26%). Overall TMB in the BRAFfusion positive cohort was low (median 3.8 mut/Mb), although 3/42 cases (7%) had > 20 mut/Mb. Of the BRAF fusion driven NSCLC, 10 cases (24%) featured EGFR SV alterations. Two BRAF fusion/ EGFR SV cases featured primary exon 19 deletion and T790M mutation. Examples of BRAF fusion driven NSCLC responding to a combination of BRAFand MEK inhibitors (MEKi) will be presented. Conclusions: NSCLC BRAF fusions are a rare GA that may be associated with acquired resistance in a subset of EGFR-mutated NSCLC progressing on anti- EGFR TKI therapies. Given clinical evidence for the activity of targeted therapy approaches, molecular eligibility for clinical trials of MEKi should include these variants. The clinical evidence for responsiveness of BRAF fusion driven NSCLC provides an opportunity to personalize treatments and improve clinical outcomes for patients.
Interfraction Variation and Dosimetric Changes in Patients With Cervical Cancer Treated With Intracavitary Brachytherapy
Authors: Co Jayson L. , Bojador Maureen R. , Mejia Michael Benedict A. , Ortin Teresa T. Sy , Ganzon Domingo E. 
Published: July 2017

Purpose Intracavitary brachytherapy is integral in the treatment of cervical cancer. Because of interfraction variation, the current standard is replanning with every fraction. This study aimed to determine whether there was a difference in relative dosimetry if the source position and dwell time of the first fraction were applied to subsequent fractions. Materials and Methods The authors performed a retrospective review of charts and films from 2007 to 2012. Eligible cases were patients with cervical cancer treated with brachytherapy with the same dose prescription to point A. Replanning was done on the first set of orthogonal plates. Source position and dwell time were subsequently applied to the remaining fractions using actual films. Results Twenty-nine patients were included in this study. The results showed that cervical, rectal, and bladder dose between the actual plan and the hypothetical plan were not statistically different. In the hypothetical plan, the source activity and dwell time of the first plan were applied to the orthogonal films of the subsequent fractions and showed no significant difference in all dose points. Conclusion The results of this study showed proof of concept of the safety of using the source position and dwell time of the first plan for subsequent fractions. Until further studies are performed (also using three-dimensional planning software), the concept should be considered investigational because of the small sample size of the study. Until such research is performed, it is still strongly recommended that replanning be performed with every fraction whenever it is feasible.
The New World Health Organization Recommendations on Perioperative Administration of Oxygen to Prevent Surgical Site Infections: A Dangerous Reductionist Approach?
Authors: Wenk Manuel , Van Aken Hugo , Zarbock Alexander 
Published: July 2017

In October 2016, the World Health Organization (WHO) published recommendations for preventing surgical site infections (SSIs). Among those measures is a recommendation to administer oxygen at an inspired fraction of 80% intra- and postoperatively for up to 6 hours. SSIs have been identified as a global health problem, and the WHO should be commended for their efforts. However, this recommendation focuses only on the patient’s “wound,” ignores other organ systems potentially affected by hyperoxia, and may ultimately worsen patient outcomes.
The WHO advances a “strong recommendation” for the use of a high inspired oxygen fraction even though the quality of evidence is only moderate. However, achieving this goal by disregarding other potentially lethal complications seems inappropriate, particularly in light of the weak evidence underpinning the use of high fractions of oxygen to prevent SSI. Use of such a strategy thus should be intensely discussed by anesthesiologists and perioperative physicians.
Normovolemia, normotension, normoglycemia, normothermia, and normoventilation can clearly be safely applied to most patients in most clinical scenarios. But the liberal application of hyperoxemia intraoperatively and up to 6 hours postoperatively, as suggested by the WHO, is questionable from the viewpoint of anesthesia and perioperative medicine, and its effects will be discussed in this article.
Copolymers Composed of Perfluoroalkyl and Ammonium-Functionalized Fluorenyl Groups as Chemically Stable Anion Exchange Membranes
Authors: Ozawa Mizuki , Kimura Taro , Akiyama Ryo , Miyake Junpei , Inukai Junji , Miyatake Kenji 
Published: July 2017

Abstract
We report synthesis and properties of a novel series of ammonium-functionalized perfluoroalkylene/aromatic copolymers. In particular, the effect of number and position of ammonium groups on the properties of the copolymer thin membranes was investigated. Fluorenylidene biphenylene groups were used as a scaffold for the ammonium groups. By controlling the chloromethylation reaction conditions, the ammonium groups could be introduced up to 4.0 per fluorenylidene biphenylene unit, resulting in the ion exchange capacity (IEC) of the resulting copolymers ranging from 1.0 to 1.8 meq g−1. The copolymers provided bendable and transparent membranes by solution casting. The membranes exhibited phase-separated morphology based on the hydrophilic/hydrophobic differences in the copolymer components. A copolymer membrane with IEC = 1.0 meq g−1 showed high hydroxide ion conductivity (ca. 70 mS cm−1) at 80 °C in water and good alkaline stability in 1 M KOH aq. over 1000 h at 60 °C. The membrane showed only minor degradation after the long-term alkaline stability test.
Review of Nikolaos Papadogiannis', Militant around the Clock? Left-Wing Youth Politics, Leisure, and Sexuality in Post-Dictatorship Greece, 1974–1981
Authors: Kornetis Kostis 
Published: July 2017

Nikolaos Papadogiannis. Militant around the Clock? Left-Wing Youth Politics, Leisure, and Sexuality in Post-Dictatorship Greece, 1974–1981. New York: Berghahn, 2015. x + 329 pp.
An Exact Algorithm for the Green Vehicle Routing Problem
Authors: Andelmin Juho , Bartolini Enrico 
Published: July 2017

We propose an exact algorithm for solving the green vehicle routing problem (G-VRP). The G-VRP models the optimal routing of an alternative fuel vehicle fleet to serve a set of geographically scattered customers. Vehicles’ fuel autonomy and possible refueling stops en route are explicitly modeled and maximum duration constraints are imposed on each vehicle route. We model the G-VRP as a set partitioning problem in which columns represent feasible routes corresponding to simple circuits in a multigraph. Each node in the multigraph represents one customer and each arc between two customers represents a nondominated path through a set of refueling stations visited by a vehicle when traveling directly between the two customers. We strengthen the set partitioning formulation by adding valid inequalities including k-path cuts and describe a method for separating them. We provide computational results on benchmark instances showing that the algorithm can optimally solve instances with up to ∼110 customers. The online appendix is available at https://doi.org/10.1287/trsc.2016.0734 .
Outcomes of an innovative training course in laparoscopic hernia repair
Authors: Light D , Bawa S , Gallagher P , Horgan L 
Published: July 2017

Introduction The Ethicon™ laparoscopic inguinal groin hernia training (LIGHT) course is an educational course based on three days of teaching on laparoscopic hernia surgery. The first day involves didactic lectures with tutorials. The second day involves practical cadaveric procedures in laparoscopic hernia surgery. The third day involves direct supervision by a consultant surgeon during laparoscopic hernia surgery on a real patient. We reviewed our outcomes for procedures performed on real patients on the final day of the course for early complications and outcomes. Methods A retrospective study was undertaken of patients who had laparoscopic hernia surgery as part of the LIGHT course from 2013 to 2015. A matched control cohort of patients who had elective laparoscopic hernia surgery over the study period was identified. These patients had their surgery performed by the same consultant general surgeons involved in delivering the course. All patients were followed up at 6 weeks postoperatively. Results A total of 60 patients had a laparoscopic inguinal hernia repair and 23 patients had a laparoscopic ventral hernia repair during the course. The mean operative time for laparoscopic inguinal hernia repair was 48 minutes for trainees (range 22–90 minutes) and 35 minutes for consultant surgeons (range 18–80 minutes). There were no intraoperative injuries or returns to theatre in either group. All the patients operated on during the course were successfully performed as daycase procedures. The mean operative time for laparoscopic ventral hernia repair was 64 minutes for trainees (range 40–120 minutes) and 51 minutes for consultant surgeons (range 30–130 minutes). Conclusions The outcomes of patients operated on during the LIGHT course are comparable to procedures performed by a consultant. Supervised operating by trainees is a safe and effective educational model in hernia surgery.
Factors influencing the choice of treatment modality for individual patients with varicose veins
Authors: Campbell B , Chinai N , Hollering P , Wright H , McCarthy R 
Published: July 2017

INTRODUCTION There is evidence of effectiveness for a range of different treatment modalities for varicose veins but limited information about factors that influence treatment choice for individual patients. METHODS A postal survey was sent to 438 UK members of the Vascular Society of Great Britain and Ireland. RESULTS Overall, 251 responses were received (response rate 57%). A total of 222 respondents treated varicose veins using conventional surgery (84%), endothermal ablation (82%) and foam sclerotherapy (68%). The clinical pattern of veins appeared to have the greatest influence on treatment choice. This was followed by guidance from the National Institute for Health and Care Excellence, patient expectations, facilities, cost and whether treatment was carried out in the public or private sector. Respondents were asked to indicate whether each of 13 clinical ‘scenarios’ (eg very extensive varicose veins in both legs) would influence them towards or against using specified treatment modalities. ‘Consensus’ was defined as ≥80% of responses either towards or against any treatment modality; and disagreement as 41–59% both towards and against any modality (i.e. ∼50:50 split). There was consensus towards using endothermal ablation for truncal reflux, towards UGFS for localised varicose veins and towards conventional surgery for large, extensive, bilateral veins. There was consensus against UGFS for large truncal veins, and against surgery for obese patients and those with a history of venous thromboembolism. There were important disagreements about the influence of large or extensive veins, about whether patients were obese or slim and about a prior history of venous thromboembolism. CONCLUSIONS Conventional surgery is still widely available in the UK. Disagreements about treatment choice in different clinical scenarios suggest substantial variation in the treatments patients are offered. Attention to identifying subgroups in trials would help to guide treatment choice for individual patients.
Technical Stability and Biological Variability in MicroRNAs from Dried Blood Spots: A Lung Cancer Therapy-Monitoring Showcase
Authors: Kahraman Mustafa , Laufer Thomas , Backes Christina , Schrörs Hannah , Fehlmann Tobias , Ludwig Nicole , Kohlhaas Jochen , Meese Eckart , Wehler Thomas , Bals Robert , Keller Andreas 
Published: July 2017

Abstract

BACKGROUND
Different work flows have been proposed to use miRNAs as blood-borne biomarkers. In particular, the method used for collecting blood from patients can considerably influence the diagnostic results.

METHODS
We explored whether dried blood spots (DBSs) facilitate stable miRNA measurements and compared its technical stability with biological variability. First, we tested the stability of DBS samples by generating from 1 person 18 whole-genome-wide miRNA profiles of DBS samples that were exposed to different temperature and humidity conditions. Second, we investigated technical reproducibility by performing 7 replicates of DBS again from 1 person. Third, we investigated DBS samples from 53 patients with lung cancer undergoing different therapies. Across these 3 stages, 108 genome-wide miRNA profiles from DBS were generated and evaluated biostatistically.

RESULTS
In the stability analysis, we observed that temperature and humidity had an overall limited influence on the miRNomes (average correlation between the different conditions of 0.993). Usage of a silica gel slightly diminished DBS' technical reproducibility. The 7 technical replicates had an average correlation of 0.996. The correlation with whole-blood PAXGene miRNomes of the same individual was remarkable (correlation of 0.88). Finally, evaluation of the samples from the 53 patients with lung cancer exposed to different therapies showed that the biological variations exceeded the technical variability significantly (P &lt; 0.0001), yielding 51 dysregulated miRNAs.

CONCLUSIONS
We present a stable work flow for profiling of whole miRNomes on the basis of samples collected from DBS. Biological variations exceeded technical variations significantly. DBS-based miRNA profiles will potentially further the translational character of miRNA biomarker studies.