bluuebunny/crossref_metadata_2025 huggingface dataset:
Training Pharmacy Technicians in Support of Rural Health Initiatives: A South Carolina Experience
Authors: Ballington Don A , Hammett Sharon D
Published: July 2017

Objective:

To provide an overview of pharmacy technician distance learning based on an established program.

Setting:

Technical college pharmacy technician training program cooperating with similar institutions located in remote areas of South Carolina.

Discussion:

Midlands Technical College, Columbia, SC, developed a project to provide pharmacy technician training in underserved rural South Carolina. Didactic instruction is by live television broadcast that is received in the students' local technical college. Laboratory instruction is conducted in two auxiliary laboratories geographically located within reasonable driving distances of the students' local college; instruction is scheduled to require a minimum number of trips. Experiential training is received in the students' home community. Midlands faculty make monthly visits into distance communities to review student progress.

Conclusions:

The performance of distance-learning students has thus far matched the performance of Columbia-based students. Student performance, both Columbia and distance-learning, was compared using earned grade points. A statistical analysis was not applied to this comparison. Results from the first two years of this project demonstrated a slightly higher grade-point performance for distance-learning students. Success of distance-learning students has shown that pharmacy technician instruction can be delivered successfully into remote sites in South Carolina.
Somnambulism Precipitated by Selective Serotonin-Reuptake Inhibitors
Authors: Alao Adekola O , Yolles Jennifer C , Aumenta Wendy C , Dewan Mantosh J
Published: July 2017

Objective:

To report a case of somnambulism (sleepwalking) potentially precipitated by selective serotonin-reuptake inhibitors (SSRIs) in an HIV-positive woman.

Case Summary:

A 34-year-old HIV-positive white woman without a prior history of somnambulism began sleepwalking following treatment for depression with two different SSRIs. The sleepwalking episodes disappeared completely with a reduction of the dosages of the SSRIs and began again when the dosages were increased.

Discussion:

Somnambulism has been associated with psychoactive drugs that affect the physiology of sleep, awareness, arousal, and memory. A biologic plausibility is supported by the fact that SSRIs alter electroencephalogram and sleep patterns and may be prone to precipitating somnambulism in susceptible individuals. Because people who sleepwalk may not be aware of their actions during such episodes, there is a potential for injury if this adverse effect were to occur.

Conclusions:

Given the widespread use of SSRIs, clinicians should be aware of the possibility that somnambulism may occur with this class of drugs.
Acute Angioedema Associated with Long-Term Benazepril Therapy
Authors: Maliekal James , Rio Gerald Del
Published: July 2017

Objective:

To report a case of acute angioedema associated with long-term use of benazepril in an elderly patient.

Case Summary:

A 78-year-old white woman with no past history of angioedema presented to the emergency department in respiratory distress. The patient failed to improve after receiving intravenous methylprednisolone, diphenhydramine, and famotidine. Due to pending airway compromise, the patient required emergency tracheostomy. Based on her presentation and medical history, we attributed the angioedema to long-term benazepril use.

Discussion:

Angiotensin-Converting enzyme (ACE) inhibitors are known to be associated with angioedema. Most cases of angioedema occur within the first week of therapy. The association of acute onset of angioedema early in the course of ACE inhibitor therapy is well described in published reports. However, angioedema associated with long-term ACE inhibitor therapy has rarely been reported.

Conclusions:

ACE inhibitor-induced angioedema occurring late in therapy is not well understood and has been infrequently reported in published articles. Aggressive intervention is often needed in severe cases of angioedema, which may compromise airway integrity.
Impact of Protease Inhibitors on Drug Use and Cost for Hospital Patients with HIV
Authors: Peyron Florence , Rahmouni Saïd , Flori Angelise , Moreau Jacques , Charbit Jean-Jacques , Buès-Charbit Martine , Balansard Guy
Published: July 2017

Objective:

To evaluate the impact of protease inhibitors on drug cost and frequency of admission-defining events for HIV-infected patients in the infectious diseases unit of F Houphouët Boigny Hospital in Marseilles, France, which provides conventional hospitalization and outpatient care.

Methods:

Data from a prospective eight-year study conducted from January 1, 1990, to December 31, 1997, were used. Data from nurse records were collected daily by a pharmacy resident. Statistical analyses were performed to compare 1997 data with previous years, since protease inhibitors were not available in France until March 1996.

Results:

A total of 1,558 inpatients, accounting for 2,717 admissions, participated in the study. From 1995 to 1997, we observed a decrease in the percentage of hospitalized patients compared with the total number of patients (48.8%). We also noticed a reduction in number of stays (52%) and mean duration of stays (from 16.06 ± 1.81 to 11.08 ± 1.80 d). Total drug cost in the inpatient care unit dropped by one-half (based on 100 patients/y). The number of hospital admissions and mean drug cost per stay also decreased for some opportunistic infections described as late complications of AIDS; at the same time, drug costs in the outpatient unit rose sharply.

Conclusions:

This study confirms recent advances in HIV management. Use of protease inhibitors has reduced the relative risk of opportunistic infections and cost of inpatient treatment. This reduction has been associated with a sharp cost increase for outpatient therapy, resulting from widespread use of protease inhibitors.
Fosinopril Overdose in an Infant
Authors: Stokes Kimberly A , Lanski Steven L , Leikin Jerrold B
Published: July 2017

Objective:

To report an accidental fosinopril overdose in an infant.

Case Summary:

A 20-month-old African-American girl ingested approximately 16 mg/kg of fosinopril. Following aggressive gastric decontamination, the patient experienced an uneventful hospital course.

Discussion:

This appears to be the first report of accidental fosinopril ingestion in an infant. Virtually no adverse effects were noted after an ingestion that was approximately 10 times a therapeutic adult dose. It seems that fosinopril toxicity was minimal in the accidental overdose following early gastric decontamination (within 1 h of ingestion).

Conclusions:

Observation of vital signs with no invasive procedures appears to be the primary treatment method following early gastric decontamination for an accidental fosinopril overdose in an infant.
Stress Relaxation in Semi-Crystalline PEN Films: Physical Aging Effects
Authors: Gillmor J. R. , Greenert J.
Published: July 2017

The effect of physical aging on the stress relaxation response of a semicrystalline PEN film was studied at temperatures ranging from the secondaryB* transition (-70'C) up to its "amorphous" glass transition temperature (-120'C). Within this temperature range, the response is thermorheologically simple, i.e., the effect of physical aging is to shift the stress relaxation function along the log timescale to longer times following a simple powerlaw superposition rule with a characteristic temperaturedependent exponents (= aging rate parameter). They (T) function peaks at -80'C, and it follows a general pattern commonly observed in other polymer systems. Within the temperature range studied, the relaxation function also obeys timetemperature superposition and the corresponding shift factor appears to follow Arrhenius activation. The apparent activation energy is, however, strongly dependent on aging timeit increases nearly threefold over the range of aging times coveredwhich can be rationalized on the basis of the effective time theory.
Chemical Compatibility of Geomembranes-Sorption, Diffusion and Swelling Phenomena
Authors: Aminabhavi T. M. , Naik H. G.
Published: July 2017

The chemical compatibility results studied by measurement of sorption, diffusion and swelling of seven aromatic liquids into four geomembranes viz. high density polyethylene (HDPE), linear low density polyethylene (LLDPE), very low density polyethylene (VLDPE) and polypropylene (PP) are presented at 25, 50 and 70'C. Diffusion coefficients have been calculated using Fick's equation. The swelling of geomembranes was measured by monitoring the dimensional response of the membranes and thereby calculating the increase in volume. Results of this research would be useful in the proper selection of a suitable geomembrane for a specific application involving exposure to organic liquids.
Effect of Ethylene-Propylene Rubber Concentration and Composition on the Properties of Unipol Polypropylene Impact Copolymer Cast Film
Authors: Chatterjee Ananda M.
Published: July 2017

The effects of ethylenepropylene rubber content (Fc) and ethylene content of rubber (Ec) on the mechanical properties of UNIPOL® polypropylene (PP) impact copolymer cast film have been studied. Thermal analysis has been found to be useful in explaining the structureproperty relationship of the film. In general, with increasing Fc: (a) tensile modulus and stress at break decreased and (b) tear and impact strengths increased. At higher Ec: (a) modulus, break tensile strength and puncture resistance increased and (b) tear and impact strengths decreased. With increasing Ec the polyethylenelike crystalline phase became more prominent in the rubber phase, and melting and crystallization temperatures and crystallinity of this phase increased. There was comparatively less effect on these thermal properties when Fc was increased at constant Ec.
Functional and prognostic effects when emphysema complicates idiopathic pulmonary fibrosis
Authors: Jacob Joseph , Bartholmai Brian J. , Rajagopalan Srinivasan , Kokosi Maria , Maher Toby M. , Nair Arjun , Karwoski Ronald , Renzoni Elisabetta , Walsh Simon L.F. , Hansell David M. , Wells Athol U.
Published: July 2017

This study aimed to investigate whether the combination of fibrosis and emphysema has a greater effect than the sum of its parts on functional indices and outcome in idiopathic pulmonary fibrosis (IPF), using visual and computer-based (CALIPER) computed tomography (CT) analysis.

Consecutive patients (n=272) with a multidisciplinary IPF diagnosis had the extent of interstitial lung disease (ILD) scored visually and by CALIPER. Visually scored emphysema was subcategorised as isolated or mixed with fibrotic lung. The CT scores were evaluated against functional indices forced vital capacity (FVC), diffusing capacity of the lungs for carbon monoxide (DLCO), transfer coefficient of the lung for carbon monoxide (KCO), composite physiologic index (CPI)) and mortality.

The presence and extent of emphysema had no impact on survival. Results were maintained following correction for age, gender, smoking status and baseline severity usingDLCO, and combined visual emphysema and ILD extent. Visual emphysema quantitation indicated that relative preservation of lung volumes (FVC) resulted from tractionally dilated airways within fibrotic lung, ventilating areas of admixed emphysema (p<0.0001), with no independent effect on FVC from isolated emphysema. Conversely, only isolated emphysema (p<0.0001) reduced gas transfer (DLCO).

There is no prognostic impact of emphysema in IPF, beyond that explained by the additive extents of both fibrosis and emphysema. With respect to the location of pulmonary fibrosis, emphysema distribution determines the functional effects of emphysema.
Discontinuing noninvasive ventilation in severe chronic obstructive pulmonary disease exacerbations: a randomised controlled trial
Authors: Sellares Jacobo , Ferrer Miquel , Anton Antonio , Loureiro Hugo , Bencosme Carolina , Alonso Rodrigo , Martinez-Olondris Pilar , Sayas Javier , Peñacoba Patricia , Torres Antoni
Published: July 2017

We assessed whether prolongation of nocturnal noninvasive ventilation (NIV) after recovery from acute hypercapnic respiratory failure (AHRF) in chronic obstructive pulmonary disease (COPD) patients with NIV could prevent subsequent relapse of AHRF.

A randomised controlled trial was performed in 120 COPD patients without previous domiciliary ventilation, admitted for AHRF and treated with NIV. When the episode was resolved and patients tolerated unassisted breathing for 4 h, they were randomly allocated to receive three additional nights of NIV (n=61) or direct NIV discontinuation (n=59). The primary outcome was relapse of AHRF within 8 days after NIV discontinuation.

Except for a shorter median (interquartile range) intermediate respiratory care unit (IRCU) stay in the direct discontinuation group (4 (2–6)versus5 (4–7) days, p=0.036), no differences were observed in relapse of AHRF after NIV discontinuation (10 (17%)versus8 (13%) for the direct discontinuation and nocturnal NIV groups, respectively, p=0.56), long-term ventilator dependence, hospital stay, and 6-month hospital readmission or survival.

Prolongation of nocturnal NIV after recovery from an AHRF episode does not prevent subsequent relapse of AHRF in COPD patients without previous domiciliary ventilation, and results in longer IRCU stay. Consequently, NIV can be directly discontinued when the episode is resolved and patients tolerate unassisted breathing.
Setting Quality Improvement Priorities for Women Receiving Systemic Therapy for Early-Stage Breast Cancer by Using Population-Level Administrative Data
Authors: Enright Katherine A. , Taback Nathan , Powis Melanie Lynn , Gonzalez Alejandro , Yun Lingsong , Sutradhar Rinku , Trudeau Maureen E. , Booth Christopher M. , Krzyzanowska Monika K.
Published: July 2017

Purpose

Routine evaluation of quality measures (QMs) can drive improvement in cancer systems by highlighting gaps in care. Targeting quality improvement at QMs that demonstrate substantial variation has the potential to make the largest impact at the population level. We developed an approach that uses both variation in performance and number of patients affected by the QM to set priorities for improving the quality of systemic therapy for women with early-stage breast cancer (EBC).

Patients and Methods

Patients with EBC diagnosed from 2006 to 2010 in Ontario, Canada, were identified in the Ontario Cancer Registry and linked deterministically to multiple health care databases. Individual QMs within a panel of 15 QMs previously developed to assess the quality of systemic therapy across four domains (access, treatment delivery, toxicity, and safety) were ranked on interinstitutional variation in performance (using interquartile range) and the number of patients who were affected; then the two rankings were averaged for a summative priority ranking.

Results

We identified 28,427 patients with EBC who were treated at 84 institutions. The use of computerized physician electronic order entry for chemotherapy, emergency room visits or hospitalizations during chemotherapy, and timely receipt of chemotherapy were identified as the QMs that had the largest potential to improve quality of care at a system level within this cohort.

Conclusion

A simple ranking system based on interinstitutional variation in performance and patient volume can be used to identify high-priority areas for quality improvement from a population perspective. This approach is generalizable to other health care systems that use QMs to drive improvement.
BRAF: An emerging target for triple-negative breast cancer.
Authors: Albanell Joan , Elvin Julia Andrea , Ali Siraj Mahamed , Schrock Alexa Betzig , Chung Jon , Vergilio Jo-Anne , Suh James , Ramkissoon Shakti , Severson Eric Allan , Daniel Sugganth , Miller Vincent A. , Stephens Philip J. , Gay Laurie M. , Ross Jeffrey S.
Published: July 2017

1099

Background: A series of reports demonstrating the successful use of BRAF and MEK inhibitors in clinically advanced non-melanoma cancers has recently emerged. BRAF alterations in metastatic breast cancer (mBC) are rare and BRAF is not currently considered a target for the disease. Methods: DNA was extracted from 40 microns of FFPE sections from a series of 10,428 cases of metastatic breast cancer (mBC). Comprehensive genomic profiling (CGP) was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of > 550X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Results: 135 (1.2%) of the mBC featured alterations in BRAF. The median age of the 135 female patients was 66 years (range 27 to 83 years). The primary tumor was used for CGP in 50 (37%) and from metastatic sites including lymph nodes, liver, bone, lung, brain, adrenal and soft tissue in 85 (67%). Using CDH1 mutation as the definition of lobular mBC, 126 (93%) were ductal and 9 (7%) were lobular histology. Activating BRAF alterations included amplifications (48%), SV mutations (39%) and rearrangements (13%). No (0%) mBC had multiple BRAF GA in the same case. 34% of BRAF SV were V600E and 66% were a wide variety of non-V600E GA. 10 (7.4%) of 135 BRAF mutated mBC featured ERBB2 amplification with 1 (1%) having an ERBB2 SV mutation and 1 (1%) having both ERBB2 amplification and SV GA. Of the 115 BRAF GA cases with known hormone receptor status 71 (62%) were ER negative, 44 (38%) were ER positive and 63 (55%) were triple negative (TNBC). Other targetable genes enriched in mBC with BRAF GA included CDK6 (p = 0.001), HGF (p < 0.001) and MET(p < 0.001). The median TMB was 4.5 with 17 (13%) of cases with TMB > 10 mut/Mb and 7 (5%) of cases with > 20 mut/Mb. Conclusions: BRAF alterations, although uncommon in mBC representing only 1.2% of cases, are enriched in TNBC and feature both targetable base substitutions and rare fusions. BRAF GA may be a rare cause of anti-HER2 therapy resistance in a subset of ERBB2 driven mBC. Targetable genes co-altered with BRAF in mBC include CDK6, HGF and MET. The TMB in BRAF altered mBC is significantly higher than that for mBC in general and indicates potential role for immunotherapy for these patients.
Genomic profiling of squamous malignancies across anatomic sites.
Authors: Chung Christine H. , Frampton Garrett Michael , Chalmers Zachary Rockow , Chung Jon , Khan Saad A. , Schrock Alexa Betzig , Gay Laurie M. , Sharma Neelesh , Elvin Julia Andrea , Fabrizio David , Connelly Caitlin F. , Kang Hyunseok , Stephens Philip J. , Miller Vincent A. , Johnson Jennifer Maria , Ross Jeffrey S. , Ali Siraj Mahamed , Ganesan Shridar
Published: July 2017

11512

Background: Primary squamous cell carcinomas (SCCs) have diverse etiologies, but can share genomic features. We reviewed the genomic profiles of a series of SCC cases of differing anatomic origin. Methods: Hybrid-capture based genomic profiling of 182 or 236 or 315 genes was performed on 4783 squamous malignancies in the course of clinical care, with baits for HPV6, 11, 16, and 18, and assessment of tumor mutation burden (TMB; mutations/Mb) and microsatellite instability. Results: Sites of origin were head and neck (HNSCC, n = 1300), cervical (cSCC; n = 318), anal (aSCC, n = 248), esophageal (n = 242), lung (lSCC, n = 2386), and cutaneous (sSCC, n = 289) SCC cases. For HNSCC, cSCC, and aSCC (collectively termed HCA SCC), 395 (30%), 215 (68%), and 211 (83%) were HPV positive, respectively. For HCA SCC, the most common GA were in TP53 (45%), CDKN2A (29%), PIK3CA (24%), TERT (21%), and FAT1 (14%). The most frequent GA differentially associated with HPV status were in PIK3CA (34.9% versus 16.0%), CYLD (11.4% versus 1.4%) and PTEN (14.8% versus 6.1%) for HPV+ cases, and TP53 (3.8% versus 76.5%), CDKN2A ()1.4% versus 49.8%), and TERT (4.3% versus 33.0%) for HPV- cases. Mean TMB for HPV+ and HPV- cases were 6.6 (STDEV 7.3) and 13.7 (STDEV 29.7), respectively. TMB of all SCC cases was significantly different (p < 10-12) when stratified by HPV status. For lSCC and eSCC, the most common GA were found in TP53 (86%) CDKN2A (40%), and PIK3CA (26%) and mean TMB was 11.6 with HPV found in 3.1% of cases. In sSCC, the most common GA were in TP53 (85.5%), CDKN2A (54.3%), and TERT(44.0%), and mean TMB was 59.5 with HPV in 3.1% of cases. Subsets of SCC cases had defining and targetable GA including bi-allelic deletion of SMARCB1 ( < 0.3%), amplification of PD-L1 (~2% ), and various kinase fusions. Cases demonstrating radiologic response to immunotherapy and matched targeted therapies, as well as subsequent development of multiple mechanisms of acquired resistance, will be presented. Conclusions: HPV driven SCC have similar genomic profiles regardless of of site origin, and have a significantly lower median TMB than HPV negative SCC. Early consistency of responses of SCC to matched therapies may strengthen the case for site independent genomic predictors of therapy response.
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

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

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 < 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.
AVANÇOS CURRICULARES NA FORMAÇÃO INICIAL DE PROFESSORES
Authors: Keller-Franco Elize , Masetto Marcos Tarciso
Published: July 2017

As questões que se colocam para educação básica brasileira têm direcionado o olhar para os cursos de formação inicial de professores, sugerindo uma ressignificação dos conhecimentos e das práticas vigentes nesses cursos.  Começa a emergir a compreensão de que as intervenções que tornam possível a inovação nos cursos de formação envolve a busca de novas abordagens curriculares que rompam com o paradigma curricular tradicional. O presente estudo traz para reflexão a análise crítica de uma organização curricular alternativa em andamento nas Licenciaturas da Universidade Federal do Paraná-Litoral, tendo como objetivo investigar em que medida a proposta que vem sendo desenvolvida nessa instituição traz elementos com potencial de contribuição para um novo paradigma curricular na formação inicial de professores. Adota-se como caminho metodológico um estudo exploratório de abordagem qualitativa. Para obtenção dos dados, privilegiou-se a análise documental. Os resultados indicam que o currículo em andamento traz novos contornos para o campo da teoria e das práticas curriculares dos programas de formação de professores. Ao colocar em ação os princípios de uma educação emancipatória e de uma proposta pedagógica fundamentada em projetos, o currículo rompe com o paradigma técnico disciplinar e identifica-se com as teorias curriculares críticas e pós-críticas e com a abordagem do currículo integrado. O caráter de construção em movimento do currículo, aberto para que a inteligência coletiva dos educadores em seus contextos institucionais encontre espaço para a diversificação e a inovação, coloca-se diante da possibilidade de um novo paradigma em processo.