bluuebunny/crossref_metadata_2025_split huggingface dataset:
Factors and Predictors of Response with Epoetin Alfa for Chemotherapy-Related Anemia
Authors: Goram Adrian L 
Published: July 2017

Objective: To describe the value of specific factors and predictors that influence the use of epoetin alfa for anemia in adults with cancer receiving chemotherapy with or without radiation therapy. Data Sources: Data search restricted to English-language literature on epoetin alfa identified by MEDLINE searches (1990-July 2000) and other pertinent literature was conducted. Data Synthesis: Anemia of chronic disease (ACD) is a common finding among cancer patients. Patients receiving repeated or multiple chemotherapy regimens alone or with radiation therapy may worsen ACD. Blood transfusion is the cornerstone of treatment. Risks associated with allogeneic blood transfusion are clearly established. This includes alteration of the immune system, acute allergic reactions, viral and bacterial infections, tumor reappearance, and reduced quality of life (QOL). As the demand for blood increased and periodic supply shortages occurred, healthcare centers began seeking alternatives to blood transfusion. Recombinant human erythropoietin (epoetin alfa) is a prophylactic or treatment option that can reduce the need for blood transfusion with an improved QOL. Albeit clinically beneficial, epoetin alfa is expensive. Using predictors during early use with epoetin alfa, clinicians can identify patients most likely and least likely to benefit from further therapy, thus preventing costly outcomes. The change in hemoglobin (>0.5–1.0 g/dL) combined with either endogenous erythropoietin concentration (<100 mU/mL) or absolute reticulocyte count increase (>40,000 cells/uL) two to four weeks after starting therapy provided the most powerful prediction of response to epoetin alfa. Conclusions: Key factors and predictors with epoetin alfa can optimize therapy outcomes in cancer patients receiving chemotherapy.
Compliance Issues and Extemporaneous Preparation of Medications for Pediatric Patients
Authors: Schell Kenneth H. 
Published: July 2017

Objective: Medications often are produced in a form that makes administration to pediatric patients difficult. Even when available in liquid forms, some medications can pose compliance problems in children. Various strategies and techniques are discussed which provide information on how to increase compliance in this special group of patients by providing preparations that can be rapidly formulated and easily administered. Conclusions: The pharmacist and pharmacy technician can benefit from an increased awareness of the special needs of the pediatric patient regarding drug therapy. With the increasing probability of an expanded scope of practice for technicians, this information can be of interest to both pharmacists and technicians.
Effect of Low Temperatures on Drug-Delivery Efficacy of Aerosols
Authors: Martí-Bonmatí Ezequiel , Juan Gustavo , Martí-Bonmatí Luis , Ramon Mercedes 
Published: July 2017

Objective: To determine how low temperatures affect the pharmaceutical properties of oral inhalation aerosols pressurized with chlorofluorocarbons (CFCs). Design: Inhalation aerosols of the beta-adrenergic receptor agonist terbutaline sulfate were exposed at three different environmental temperatures [22, 0, and −10 °C; (±2)]. Three groups of 10 canisters each, at different drug loads (100%, 50%, and 20%), were studied at these temperatures. Canisters with mouthpieces were weighed before and after 40 actuations in order to study the mass propelled in each experimental condition. Photographs were also taken of the aerosol mist at each temperature. Results: A statistically significant decrease in the average mass of the aerosol discharged was evidenced at low temperatures. The temperature and aerosol output were linearly correlated. The weight loss at–10 °C was 35.4%. At this temperature the emitted doses were discharged as liquefied droplets. This effect was quickly manifested and proved reversible. Conclusions: Low temperatures modify the pharmaceutical properties of oral inhalation aerosols pressurized with CFCs. This technical information should be included as a note of caution in the prescribing information.
Optimisation of rocker sole footwear for prevention of first plantar ulcer: comparison of group‐optimised and individually‐selected footwear designs
Authors: Preece Stephen J. , Chapman Jonathan D. , Braunstein Bjoern , Brüggemann Gert‐Peter , Nester Christopher J. 
Published: July 2017

AbstractBackgroundAppropriate footwear for individuals with diabetes but no ulceration history could reduce the risk of first ulceration. However, individuals who deem themselves at low risk are unlikely to seek out bespoke footwear which is personalised. Therefore, our primary aim was to investigate whether group‐optimised footwear designs, which could be prefabricated and delivered in a retail setting, could achieve appropriate pressure reduction, or whether footwear selection must be on a patient‐by‐patient basis. A second aim was to compare responses to footwear design between healthy participants and people with diabetes in order to understand the transferability of previous footwear research, performed in healthy populations.MethodsPlantar pressures were recorded from 102 individuals with diabetes, considered at low risk of ulceration. This cohort included 17 individuals with peripheral neuropathy. We also collected data from 66 healthy controls. Each participant walked in 8 rocker shoe designs (4 apex positions × 2 rocker angles). ANOVA analysis was then used to understand the effect of two design features and descriptive statistics used to identify the group‐optimised design. Using 200 kPa as a target, this group‐optimised design was then compared to the design identified as the best for each participant (using plantar pressure data).ResultsPeak plantar pressure increased significantly as apex position was moved distally and rocker angle reduced (p < 0.001). The group‐optimised design incorporated an apex at 52% of shoe length, a 20° rocker angle and an apex angle of 95°. With this design 71–81% of peak pressures were below the 200 kPa threshold, both in the full cohort of individuals with diabetes and also in the neuropathic subgroup. Importantly, only small increases (<5%) in this proportion were observed when participants wore footwear which was individually selected. In terms of optimised footwear designs, healthy participants demonstrated the same response as participants with diabetes, despite having lower plantar pressures.ConclusionsThis is the first study demonstrating that a group‐optimised, generic rocker shoe might perform almost as well as footwear selected on a patient by patient basis in a low risk patient group. This work provides a starting point for clinical evaluation of generic versus personalised pressure reducing footwear.
Frontline Science: Corticotropin-releasing factor receptor subtype 1 is a critical modulator of mast cell degranulation and stress-induced pathophysiology
Authors: Ayyadurai Saravanan , Gibson Amelia J , D'Costa Susan , Overman Elizabeth L , Sommerville Laura J , Poopal Ashwini C , Mackey Emily , Li Yihang , Moeser Adam J 
Published: July 2017

AbstractLife stress is a major risk factor in the onset and exacerbation of mast cell–associated diseases, including allergy/anaphylaxis, asthma, and irritable bowel syndrome. Although it is known that mast cells are highly activated upon stressful events, the mechanisms by which stress modulates mast cell function and disease pathophysiology remains poorly understood. Here, we investigated the role of corticotropin-releasing factor receptor subtype 1 (CRF1) in mast cell degranulation and associated disease pathophysiology. In a mast cell–dependent model of IgE-mediated passive systemic anaphylaxis (PSA), prophylactic administration of the CRF1-antagonist antalarmin attenuated mast cell degranulation and hypothermia. Mast cell–deficient KitW-sh/W-sh mice engrafted with CRF1−/− bone marrow–derived mast cells (BMMCs) exhibited attenuated PSA-induced serum histamine, hypothermia, and clinical scores compared with wild-type BMMC-engrafted KitW-sh/W-sh mice. KitW-sh/W-sh mice engrafted with CRF1−/− BMMCs also exhibited suppressed in vivo mast cell degranulation and intestinal permeability in response to acute restraint stress. Genetic and pharmacologic experiments with murine BMMCs, rat RBL-2H3, and human LAD2 mast cells demonstrated that although CRF1 activation did not directly induce MC degranulation, CRF1 signaling potentiated the degranulation responses triggered by diverse mast cell stimuli and was associated with enhanced release of Ca2+ from intracellular stores. Taken together, our results revealed a prominent role for CRF1 signaling in mast cells as a positive modulator of stimuli-induced degranulation and in vivo pathophysiologic responses to immunologic and psychologic stress.
IL-23 restoration of Th17 effector function is independent of IL-6 and TGF-β in a mouse model of alcohol and burn injury
Authors: Li Xiaoling , Cannon Abigail R , Hammer Adam M , Morris Niya L , Choudhry Mashkoor A 
Published: July 2017

Abstract
T cells play a critical role in host defense against intestinal bacteria. We have shown that ethanol combined with burn injury suppresses Peyer's patch (PP) Th17 cytokines 1 d after injury. We assessed the mechanism of suppressed Th17 effector functions. Mice were gavaged with ethanol 4 h before burn injury and euthanized 1, 3, and 7 d after injury. Mesenteric lymph nodes (MLNs), PPs, and spleen Th1 and Th17 cytokines were assessed. A significant decrease in IL-17, IL-22, IL-2, and IFN-γ were observed in all 3 lymphoid organs 1 and 3 d after injury. We used splenic cells to study the role of IL-6, IL-23, TGF-β, and aryl hydrocarbon receptor (AHR) in suppressing Th17 cytokines. We also assessed whether the AHR agonist 6-formylindolo (3, 2-b) carbazole (FICZ) modulates Th17 cytokines. We found a significant decrease in IL-6 and TGF-β after ethanol and burn; IL-23 was undetectable. The reconstitution of IL-23 in culture medium increased IL-17 by 2-fold and IL-22 by 20-fold in cells from burn ethanol mice. The restoration of IL-6 and TGF-β combined did not influence the release of Th17 cytokines. We observed that AHR was necessary for IL-23 restoration of IL-22 after ethanol and burn injury. The AHR agonist FICZ enhanced IL-22, but not IL-17. None of these treatments influenced the release of Th1 cytokines. Together, these results suggest that IL-23 plays a critical role in regulation of Th17 cytokines. Furthermore, IL-6 and TGF-β do not appear to influence IL-23-mediated restoration of Th17 cytokines after ethanol and burn injury.
Genomic profiling of circulating tumor DNA (ctDNA) from patients (pts) with metastatic breast cancer (mBC).
Authors: Pusztai Lajos , Chung Jon , Young Lauren , Schrock Alexa Betzig , Hartmaier Ryan , Frampton Garrett Michael , Gay Laurie M. , Stephens Phil , Miller Vincent A. , Ali Siraj Mahamed , Ross Jeffrey S. , Vahdat Linda T. , O'Shaughnessy Joyce 
Published: July 2017

1016 Background: Clonal evolution during progression to and treatment of mBC highlights the importance of genomic profiling of recent samples to guide clinical decision making. We undertook this study to characterize genomic alterations (GA) in ctDNA from pts with mBC during the course of clinical care. Methods: Hybrid-capture based genomic profiling of 62 genes (FoundationACT) was performed on ctDNA from 255 BC pts. The fraction of ctDNA in the blood was estimated using the maximum somatic allele frequency (MSAF) for each sample. Results: 168 pts were ER+ [16 HER2+, 134 HER2(-), 18 HER2 unknown (unk)]; 51 were ER(-) [7 HER2+, 38 triple negative (TNBC), 6 HER2 unk]; 36 were ER unk; 95% were stage 4. For pts with treatment information, 90% had prior chemotherapy and 90% ER+ pts had prior aromatase inhibitor therapy (AI). ≥1 GA was reported in 78% of all cases and in 88% of cases with evidence of ctDNA in the blood (MSAF >0). For 226 cases with MSAF >0, an average of 2.7 GA/case were reported. The most common GA for ER+ pts were in TP53 (44%), PIK3CA (39%), ESR1 (36%), CDH1 (11%), KRAS (10%) and ERBB2 ( HER2, 9%). 101 ESR1 GA were identified in 61 pts [54 ER+, 7 ER unk], including 4 HER2+ pts. For ER+ pts with treatment information: 37% (22/60) with prior AI had ESR1 GA; all pts with ESR1 GA had prior AI. 24 pts had >1 ESR1 GA, with instances of GA in cis. Frequent ESR1 GA were Y537S/N (n=47), D538G (n=29) and E380Q (n=7); rearrangement (n=3) and amplification (n=1) were also detected. Concurrent GA with ESR1 were found in PIK3CA (41%), FGFR1 (13%), BRCA1/2 (5%), HER2 (5%) and AKT1 (3%). In ER(-) pts, the most common GA were in TP53 (74%), PIK3CA (17%), NF1 (11%), BRCA1 (9%) and EGFR (9%). HER2 activating mutation occurred in 3% of cases that were HER2(-) by prior testing. Kinase fusions in FGFR2/3 (3 ER+) and EGFR (1 TNBC) were observed. Conclusions: In this study, evidence of ctDNA in the blood was observed in 89% of cases. PIK3CA and ESR1 GA frequencies were similar to those reported in previous studies of ctDNA from ER+ pts after AI. Diverse ESR1 GA and co-occurring GA suggest therapeutic approaches for AI refractory ER+ mBC. Our results demonstrate that genomic profiling of ctDNA may be a complementary approach to tissue-based genomic testing for pts with mBC.
Precision medicine for gallbladder cancer using somatic copy number amplifications (SCNA) and DNA repair pathway gene alterations.
Authors: Javle Milind M. , Catenacci Daniel , Jain Apurva , Young Lauren , Wang Kai , Chung Jon , Hezel Aram F. , Schrock Alexa Betzig , Goyal Lipika , Gay Laurie M. , Ahn Daniel H. , Kelley Robin Kate , Ganesan Shridar , Stephens Phil , Miller Vincent A. , Ali Siraj Mahamed , Bekaii-Saab Tanios S. , Shroff Rachna T. , Ross Jeffrey S. 
Published: July 2017

4076 Background: Gallbladder carcinoma (GBC) is commonly diagnosed at an advanced, unresectable disease stage and has a poor prognosis. Comprehensive genomic profiling (CGP) has a developing role in guiding systemic, precision anti-cancer therapy. Methods: We performed hybrid capture-based CGP on FFPE samples for 491 consecutive advanced GBCs. Mean coverage depth was >550X for up to 315 cancer-related genes plus 37 introns from 28 genes frequently rearranged in cancer. All 4 classes of genomic alterations (GA) were detected. Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA. Results: Median age was 64 (range 25-88) and 69% (337/491) of patients were female. 96% (470), 2.9% (14), and 1.4% (7) of GBC patients had the diagnosis of adenocarcinoma, adenosquamous, or carcinoma not specified (NOS), respectively. Commonly altered genes were TP53 (62%), CDNK2A (31%), ARID1A (18%), and SMAD4 (15%), and most of the genetic aberrations (GA) were short variants. Potentially targetable SCNAs (including ERBB genes, MET, FGFRs, and the CCND1-FGF3/4/19 11q13 amplicon) were identified in 21% of cases (Table). Oncogenic BRAF, ALK, or FGFR2/3 rearrangements were found in 7 cases (1.4%). Moreover, 7.8% of cases had BRCA2 or ATM GA, and 0.8% had INI1loss suggesting benefit from PARP or EZH2 inhibitors, respectively. TMB was low; the 25th, 50th, and 75th percentiles were 2.5, 3.8 and 6.3 mutations/Mb, respectively. Less than 1% of cases had microsatellite instability. Radiological response to TKIs and immunotherapy was noted. Conclusions: In addition to the significant opportunity for anti-HER targeted therapies, other subsets of GBC cases harbored kinase GA (particularly SCNA), the 11q13 amplicon, or BRCA2/ ATM/ INI1mutations that are linked to therapeutic benefit. How the frequency of both driver SCNA and DNA repair alterations in GBC can be linked with inflammation awaits additional investigation. [Table: see text]
BRCA1/2 reversion mutations in pancreatobiliary cancer identified from patient biopsies.
Authors: Gay Laurie M. , Gornstein Erica , Frampton Garrett Michael , Sun James , Morley Samantha , Heilmann Andreas , Chung Jon , Daniel Sugganth , Ramkissoon Shakti , Severson Eric Allan , Suh James , Vergilio Jo-Anne , Stephens Philip J. , Miller Vincent A. , Elvin Julia Andrea , Ross Jeffrey S. 
Published: July 2017

4130 Background: Germline genomic alterations (GA) in BRCA1 or BRCA2 ( BRCA) are associated with increased risk of pancreatic cancer. Tumors with BRCA GA may be more sensitive to platinum (Pt) therapies or PARP inhibitors (PARPi). However, secondary reversion mutations (revGA) that may restore BRCA function and underlie reduced sensitivity to Pt compounds or PARPi can arise. Methods: DNA extracted from FFPE tumor tissue obtained during routine clinical care for 7077 patients with predominantly relapsed, refractory or metastatic pancreatobiliary carcinoma was analyzed using comprehensive genomic profiling (CGP) 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. Tumor tissue only was used to predict germline (g BRCA) or somatic status by an algorithm with a call rate of 85% and > 95% accuracy. Results: 417/7077 (5.9% ± 0.5%) tumors had ≥1 deleterious BRCA GA; 205 (2.9% ± 0.4%) had a predicted g BRCA GA. Significantly fewer women had deleterious BRCA GA (182/417; 43.6%)(p = 0.02); g BRCA GA frequency did not differ significantly (96/205; 46.8%)(p = NS). Overall, 49.1% of patients were women. 12 samples harbored potential revGA: pancreatic ductal adenocarcinoma (ACa) (7) or acinar cell carcinoma (Ca) (2), gallbladder ACa (2), and pancreatobiliary Ca NOS (1). 10/12 samples with revGA were metastases. Potential revGA were of 3 types: overlapping indel (7), compensatory fs (4), and missense (2). One case harbored 2 indels, both with potential to excise a fs GA. Apparent g BRCA were present in 7 cases, only somatic BRCA GA in 3 cases, and g BRCA/somatic status was ambiguous in 2 cases. For 2 patients, testing of multiple samples reveals the acquisition of revGA over time. KRAS mutation frequencies were similar for all samples (57.1%), BRCA-mutated samples (58.8%) and revGA-positive samples (58.3%). Clinical histories for patients with revGA will be presented. Conclusions: CGP of 7077 pancreatobiliary carcinomas reveals 5.9% had ≥1 deleterious BRCA GA, nearly 50% of which were g BRCA. Although rare, revGA can be acquired over time and potentially compensatory missense, fs and indel mutations were observed.
ATM/RB1 mutations to predict shorter overall survival (OS) in bladder cancer.
Authors: Joshi Monika , Grivas Petros , Ali Siraj Mahamed , Hsu Joann , Vasekar Monali K. , Emamekhoo Hamid , Pal Sumanta K. , Li Sierra Min , Drabick Joseph J. , Yin Ming 
Published: July 2017

4547 Background: DNA repair defect plays an important role in tumorigenesis, progression and treatment outcomes of urothelial cancer. Somatic mutations of ATM/RB1 genes are frequently found in urothelial cancer and have been associated with a better response to cisplatin-based neoadjuvant chemotherapy. However, their prognostic value overall in urothelial cancer have not been determined. Methods: Exome sequencing data of 130 urothelial bladder cancer patients (pts) from The Cancer Genome Atlas (TCGA) dataset were analyzed as a discovery cohort to determine the prognostic value of ATM and RB1 mutations. Results from discovery dataset were further validated by an independent cohort of 79 advanced urothelial cancer pts who received comprehensive genomic sequencing for urothelial cancer with FoundationOne. OS was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI). Results: In the discovery dataset, somatic mutations of ATM/RB1 genes were present in 24% of pts and were associated with significantly shorter OS [all stages: adjusted HR = 2.67, 95% CI, 1.45–4.92, P = 0.002; stage II-III only: adjHR = 2.76, 95% CI, 1.23–6.20, P = 0.014]. There was high mutation load in pts carrying ATM/RB1 mutations (median mutation count: 196 versus 160, P = 0.09). In the validation (stage IV) dataset, ATM/RB1 mutations were present in 31.7% of pts and tended to associate with shorter OS (adjHR = 1.97, 95% CI, 0.89–4.40, P = 0.094) and higher mutation load (median mutation load: 8.1 versus 7.2 per Mb, P = 0.136), although statistical significance was not reached. Conclusions: These results suggest that ATM/RB1 mutations may be considered as a poor prognostic biomarker in unselected urothelial cancer pts and may correlate with higher mutational load. Further studies are required to determine patient characteristics that can further stratify prognosis based on ATM/RB1 mutation status, and evaluate the potential predictive role of ATM/RB1 mutation status in response to immunotherapy.
Association of tumor mutational burden in cutaneous squamous cell carcinoma with genomic alterations in Notch family receptors.
Authors: Severson Eric Allan , Ramkissoon Shakti , Daniel Sugganth , Vergilio Jo-Anne , Gay Laurie M. , Elvin Julia Andrea , Suh James , Frampton Garrett Michael , Ali Siraj Mahamed , Miller Vincent A. , Ross Jeffrey S. 
Published: July 2017

e13031 Background: In Cutaneous Squamous Cell Carcinoma (cSqCC), Notch1, Notch2, and Notch3 have been identified as tumor suppressors with a high rate of inactivating mutations early in cSqCC pathogenesis. Despite the high frequency of alterations, the biologic and therapeutic implications of Notch genomic alterations (GAs) in cSqCC are incompletely understood. Methods: 232 FFPE samples of cSqCC were evaluated by comprehensive genomic profiling (CGP) of 315 genes and analyzed for all classes of GAs, with diagnoses confirmed by central pathology review. Notch GAs with unknown functional impact were excluded. Tumor mutational burden (TMB) was calculated from 1.11 Mb of sequenced DNA and reported as mutations/Mb. Results: The cohort of 232 samples was 78% male and 22% female, aged from 17 to 88, with confirmed metastatic disease in 32% of cases. 115 (50%) samples had a Notch family member GA with a known or predicted functional impact. 96 cases had Notch1 GAs, 43 cases had Notch2 GAs, and 14 cases had Notch3 GAs with 40 cases having GAs in multiple Notch family members. These mutations were 41% missense, 34% nonsense, 15% splice site, 9% frameshift indels, and 1% non-frameshift indels alterations. Patients with Notch GAs were significantly older (median 70 years old vs median 64, p < 0.01). TMB was increased among samples with Notch GAs (median TMB of 63 mutations/mb versus 20 mutations/mb, p < 1x10-6), with similar differences for primary and metastatic samples. Cases with Notch GAs had more total GAs per case (mean 10.4 vs 7.4, p < 1.5x10-10); however, the top co-mutated genes were the same (TP53, CDKN2A, FAT1, MLL2). Both groups had a high proportion of C- > T/G- > A transitions, consistent with UV damage; however, the proportion was higher in cases with Notch GAs (median 83% vs 80%) - a difference seen in primary and metastatic samples. Conclusions: 50% of cSqCC cases had a Notch family member loss of function GA, which was associated with increased TMB in the primary and metastatic setting. With pre-clinical models and case studies showing responses to PD-1 inhibitors in cSqCC, further investigations are warranted into the associations of Notch GAs with mutational burden and response to immunotherapy.