bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of a Multidisciplinary, Collaborative Approach to Implement and Enforce an Automatic Stop Order Policy
Authors: Pena Veronica , Guharoy Sudip Roy
Published: July 2017

Although an automatic stop order (ASO) policy is mandated by the Joint Commission on Accreditation of Healthcare Organizations, the policy remains unenforced or exists only “on paper” in some hospitals. Strict enforcement of an ASO can lead to improvement of patient care by requiring physicians and other healthcare professionals to periodically review a patient's drug regimen. Following the approval of an ASO policy by our facility's pharmacy and therapeutics (P&T) committee, an audit of 160 orders of controlled substances revealed that 75 orders (47 percent) were continued for more than one dose without a physician's renewal order. This problem was then brought to the attention of the P&T committee where a decision was made to resolve the situation using a multidisciplinary, collaborative approach. With the help of all of the healthcare professionals involved in this issue, as well as our computer network, a system for strict enforcement of the ASO policy was subsequently implemented and has proven to be successful.
The Phenomenon of Substance Abuse among the Elderly: Part I
Authors: Pagliaro Louis A. , Pagliaro Ann M.
Published: July 2017

Because substance abuse, already a major problem among elderly people, is expected to worsen significantly during the 1990s, healthcare providers must be better prepared to identify and deal effectively with this important area of geriatric care. We present an overview of the phenomenon of substance abuse among the elderly with particular attention to the abuse of alcohol and benzodiazepines, the two substances most commonly abused by elderly people. Traditionally, substance abuse among the elderly has gone largely unrecognized because of a low level of suspicion, misdiagnosis, and concealment. It is axiomatic that problems cannot be solved unless they are first identified and appropriately characterized. To respond to the increasing problem of substance abuse among the elderly, healthcare providers must recognize that elderly people are at particular risk for substance abuse, and because of their heterogeneity, they require individualized and diverse prevention and treatment approaches. Once the abuse is identified and properly characterized, specific prevention and treatment strategies can be developed and implemented.
Potential for Microbial Contamination of ADD-Vantage Admixtures
Authors: Hudson Teresa J. , Ambroziak Ellen M. , Coley Rebecca M.R.
Published: July 2017

Objective:

To test for potential bacterial contamination of the ADD-Vantage system when the components are assembled in various hospital environments.

Study Design:

One hundred fifty ADD-Vantage units were assembled by three different people in three separate locations within a hospital. Each person assembled ten units per day; the study spanned five days. After 72 hours of incubation, units were inspected for evidence of contamination.

Setting:

ADD-Vantage units were assembled by a pharmacist in a laminar-flow hood, a pharmacy student using the pharmacy counter, and a nurse at a patient's bedside table. Personnel at each site wore their regular work attire. Each person observed handwashing techniques normally used during routine working hours.

Data Extraction:

Positive results were sent to the hospital microbiology laboratory for determination of growth type.

Results:

After 72 hours, none of the systems exhibited microbial growth on visual inspection. No differences in microbial contamination of the ADD-Vantage systems relative to assembly site, day of assembly, or person performing the assembly were observed. The incidence of contamination was calculated at less than seven percent.

Conclusions:

There is minimal risk of bacterial contamination when ADD-Vantage systems are compounded either on a pharmacy counter or at a patient's bedside. Larger samples must be studied in order to detect differences in the incidence of contamination among assembly sites.
Buspirone and Sertraline in the Treatment of a Patient with Refractory Obsessive-Compulsive Disorder
Authors: Veivia Amy J. , Levin Gary M. , Powell Hannah S.
Published: July 2017

Objective:

To describe a hospitalized patient with refractory obsessive-compulsive disorder (OCD) and to briefly review the supporting literature.

Case Summary:

A 33-year-old man was admitted with a diagnosis of depression and OCD. Prior drug therapy included numerous medications, but none improved the OCD. Clonazepam therapy was initiated for treatment of anxiety and propranolol was begun to treat his headaches. Sertraline and buspirone were added sequentially to control the symptoms of depression and OCD. Subjective improvement was noted within a few weeks after the combination therapy was begun. Six and four weeks after starting sertraline and buspirone, respectively, the patient's symptoms remain improved.

Discussion:

Fluoxetine has been shown to be effective in the management of OCD. Sertraline, another selective serotonin-reuptake inhibitor, also looks promising for OCD therapy. Buspirone is a serotonin1A-receptor agonist, and theoretically could augment the effect of selective serotonin-reuptake inhibitors in the treatment of OCD.

Conclusions:

This patient's OCD symptoms responded to a combination of sertraline and buspirone therapy. It is difficult to confirm whether buspirone augmented the effects of sertraline in this patient. Clinical trials should be developed to determine whether these regimens are, in fact, beneficial in patients with refractory OCD.
Interactions of Acetaminophen, Opiates, and Their Combinations with Warfarin and other Oral Anticoagulants
Authors: Chan Thomas YK
Published: July 2017

Objective:

To determine whether acetaminophen, opiates, or acetaminophen–opiate combinations potentiate the effect of warfarin.

Data Sources:

Previous studies or reports of interactions between warfarin and acetaminophen, opiates, or acetaminophen–opiate combinations (MEDLINE search, January 1976 to January 1996).

Study Selection:

All articles were included in the review. Pertinent information was selected for discussion.

Data Synthesis:

Studies of the effects of acetaminophen on anticoagulation with warfarin and other oral anticoagulants have yielded conflicting results. In three placebo-controlled studies of patients or healthy men, acetaminophen 2–4 g/d for 2–3 weeks potentiated the anticoagulant effect of warfarin and other related drugs compared with placebo. Similar findings were seen in one uncontrolled study of patients taking acetaminophen 2.6 g/d for 4 weeks, but not in another in which patients took acetaminophen 3.25 g/d for 14 days. Other studies showed that two doses of acetaminophen 650 mg for 1 day did not influence the prothrombin time. There were six reports of adverse interactions between warfarin and acetaminophen–opiate combinations. Of five patients who were given an acetaminophen–propoxyphene combination, the equivalent daily doses of acetaminophen and propoxyphene were specified for four and ranged from 1.95 to 6.5 g and from 195 to 1,000 mg, respectively. The duration of therapy in the five patients ranged from less than 1 day to 10 days. One of these patients also received ibuprofen. Another patient took an unspecified acetaminophen–codeine product equivalent to acetaminophen 1.56 g/d. The exact mechanism underlying such interactions is not clear.

Conclusions:

During the combined use of warfarin and acetaminophen (in high daily doses for 2–3 wk) or acetaminophen–propoxyphene combinations, patients should be closely monitored for anticoagulant control and bleeding complications.
Vocal Cord Dysfunction Presenting as “Steroid-Dependent” Asthma
Authors: Knoell Daren L , Marsh Clay B
Published: July 2017

Objective:

To describe a case of paroxysmal vocal cord dysfunction (PVCD) in a patient presenting with an initial diagnosis of severe asthma.

Case Summary:

A 42-year-old obese white woman with a 5-year history of severe asthma symptoms was referred to The Ohio State University Comprehensive Asthma Outpatient Clinic. The patient said she had experienced frequent “asthma attacks” despite increased use of multiple asthma medications. Additionally, she often required nebulization therapy with bronchodilators and supplemental oxygen, and had a variable response. During the clinic visit, the patient presented with clear airways uncharacteristic of a person with severe asthma. A diagnosis of PVCD was made on the basis of results of videolaryngostroboscopy, and asthma medications were gradually discontinued.

Setting:

The Ohio State University Comprehensive Asthma Outpatient Clinic.

Discussion:

Patients with PVCD often present with symptoms characteristic of asthma. As a result, misdiagnosis of severe asthma often occurs, and the patient undergoes unnecessary treatment. The cornerstone for diagnosis of PVCD is laryngoscopic viewing of the adducted vocal cord during an acute attack. Following diagnosis, treatment for PVCD includes a multidisciplinary approach that includes speech therapy and psychiatric counseling. Pharmacologic therapy in patients with pure PVCD is not required, thus preventing medication-related morbidity and associated costs.

Conclusions:

PVCD must be considered in patients who are refractory to asthma therapy and have dyspneic symptoms out of proportion to observed clinical findings. We suggest that all patients with episodes of acute asthma undergo objective testing to document acute airway obstruction. Oral corticosteroid therapy and treatment-associated morbidity can be avoided in patients with PVCD if the appropriate diagnosis is made early.
Multiple Episodes of Phenytoin Toxicity in an Elderly Patient
Authors: Namjoshi Anjali A , Aruna Augustine S
Published: July 2017

Objective:

To describe a case involving multiple episodes of phenytoin toxicity leading to hospitalization over a period of 13 months in an elderly man and to review the risk factors contributing to drug toxicity in this individual.

Case Summary:

A 70-year-old African-American man presented four times with phenytoin toxicity manifested as ataxia and bilateral nystagmus, leading to multiple hospitalizations over 13 months. Each time the phenytoin concentration was dangerously high, and each time the symptoms of toxicity resolved without serious consequences when phenytoin therapy was temporarily stopped. Each toxicity episode was characterized by a variety of risk factors.

Discussion:

The risk factors contributing to the drug toxicity in this elderly individual are discussed.

Conclusions:

This case illustrates that age is not an independent risk factor for adverse drug reactions and that appropriate and comprehensive geriatric pharmaceutical care approaches are necessary to prevent and/or reduce the incidence of these reactions.
Emesis after Intravenous Meperidine Administration to Emergency Department Patients
Authors: Watson William A , Pauls Scott W , Schwab Robert A
Published: July 2017

Objective:

To determine the frequency of emesis after intravenous administration of meperidine, with and without concurrent intravenous antiemetics, in emergency department (ED) patients.

Design:

Record review of consecutive patients who received intravenous meperidine in the ED.

Setting:

The ED of an urban teaching hospital.

Patients:

All patients who received intravenous meperidine during a 5-month period.

Main Outcome Measures:

Documentation of emesis and therapeutic measures commonly used to treat emesis.

Results:

Meperidine was administered intravenously at 173 patient visits; at 81 visits, meperidine was administered alone, and at 92 visits, concurrent antiemetics were administered. The prevalence of emesis was similar in both treatment groups (8.6%; p = 0.79).

Conclusions:

The prevalence of emesis associated with intravenous administration of meperidine is relatively infrequent in ED patients and generally associated with abdominal signs and symptoms at presentation. The concurrent administration of an intravenous antiemetic did not decrease the frequency of meperidine-associated emesis.
The ExACT CM Microprocessor-Based Compliance Recording Device: Product Description and Field Testing Results
Authors: Bealmear Brackett K , Draugalis JoLaine R , Coons Stephen Joel , Jones William N , Barreuther Christine
Published: July 2017

Objective:

To conduct field testing of the ExACT CM compliance monitoring device and provide results to the manufacturer.

Design:

Questionnaires, interviews, and patient diaries were used to collect data on targeted product attributes of interest.

Setting:

The Veterans Affairs Medical Center outpatient anticoagulation clinic in Tucson, AZ.

Subjects:

A convenience sample of 31 ambulatory male patients (average 68 ± 0.5 y) who had been stabilized on warfarin therapy for at least one month.

Main Outcome Measures:

Scaled attitudinal scores and open-ended comments on device attributes.

Results:

Data were collected for 28 days per patient. The device was determined to be both functional and acceptable to patients.

Conclusions:

Results suggest that it is feasible to market ExACT CM for use by the pharmaceutical industry in clinical research.
Ohio Institutional Pharmacy Technicians' Demographics and Attitudes toward National Voluntary Pharmacy Technician Certification: An Exploratory Analysis
Authors: Mott David A , Vanderpool William H , Smeenk David A
Published: July 2017

Objective:

To collect demographic information from pharmacy technicians working in Ohio hospitals and to determine their attitudes toward national voluntary pharmacy technician certification.

Methods:

A survey was developed and sent to directors at 58 hospitals in Ohio for distribution to an exploratory sample of 735 technicians.

Results:

The response rate was 19.9%. Men comprised the majority of certified technicians and had been in their current job fewer years than the women surveyed. Technicians' attitudes toward certification differed depending on certification status. More certified technicians than uncertified technicians agreed with the beneficial aspects of certification. All technicians agreed that certification is not a substitute for on-the-job training and that certified technicians will not replace pharmacists. Technicians unsure of certification questioned its impact on improving qualifications, skills, likelihood of being hired, and opportunities for promotion.

Conclusions:

The use of technical personnel in pharmacies likely will increase because of pressures from the healthcare system to control costs. Future research should continue to document the characteristics of technicians and the benefits and costs of certification to technicians, employers, and pharmacists.
The Role of Chlamydia Pneumoniae in the Pathogenesis of Coronary Heart Disease
Authors: Olson Kari , Marra Fawziah , Sunderji Rubina
Published: July 2017

Objective:

To review the role of Chlamydia pneumoniae in the pathogenesis of coronary heart disease (CHD).

Data Sources:

Articles indexed in MEDLINE from 1966 to April 1998 as well as references identified in these articles were searched.

Data Extraction:

Studies investigating seroepidemiologic and pathologic evidence for an association of C. pneumoniae with CHD and randomized clinical trials evaluating the effectiveness of antibiotic therapy on cardiovascular outcomes are presented.

Data Synthesis:

Seroepidemiologic and pathologic studies provide circumstantial evidence of an association between C. pneumoniae and CHD. Results of initial small trials suggest a reduction in CHD events in patients treated with macrolide antibiotics.

Conclusions:

Direct evidence implicating chlamydial infection in CHD is lacking. Formal recommendations for antimicrobial therapy should not be made until results of additional clinical trials are available.
Influence of Packaging Material/Sealing on the Quality of Biscuits
Authors: Alves Rosa M. Vercelino , Garcia Eloisa E. C. , Bordin Mauricio R.
Published: July 2017

This investigation concentrated on determining the water vapor transmission rates (WVTR) of some of the packaging materials most commonly used to wrap biscuits (BOPP/pearlized BOPP, BOPP/BOPP, BOPP/ LDPE/ BOPP, BOPP/met-BOPP, BOPP/LDPE/met-BOPP, PET/met-BOPP)** and theoretical WVT-values were then calculated for the different types of package, based on the WVTR of the material and the total surface area of the packages exposed to ambient. The next phase of the project aimed at verifying whether or not the type of seal brings about an increase of the permeability to water vapor of the biscuit packages by comparing the theoretical value (WVTt) of the biscuit packages with the experimental (WVTp). Packages of biscuits were purchased from regular retail outlets in Brazil (9 different types of biscuit/6 manufacturers). The packages had been produced with three types of form-fill-seal machines. Among the packaging materials tested, those that contained a metallized BOPP-layer in their structure provided the best barrier against moisture (0.5 to 1.0 g water/m2/day) whereas the WVTR of all the other materials varied from 2.3 to 4.0 g water/m2/day at 380C/90% RH. The packages sealed with rollpack and horizontal flowpack machines presented impaired seal integrity, particularly at the transversal seal, which caused the WVTp of the packages to be 1.1 to 3.0 times (depending on the material/manufacturer) higher than the corresponding theoretical WVTt values previously calculated. Vertical flowpack machines produced packages with seals of good integrity so the permeability of these packages depends directly on the type of packaging material used.
Defining asthma and assessing asthma outcomes using electronic health record data: a systematic scoping review
Authors: Al Sallakh Mohammad A. , Vasileiou Eleftheria , Rodgers Sarah E. , Lyons Ronan A. , Sheikh Aziz , Davies Gwyneth A.
Published: July 2017

There is currently no consensus on approaches to defining asthma or assessing asthma outcomes using electronic health record-derived data. We explored these approaches in the recent literature and examined the clarity of reporting.

We systematically searched for asthma-related articles published between January 1, 2014 and December 31, 2015, extracted the algorithms used to identify asthma patients and assess severity, control and exacerbations, and examined how the validity of these outcomes was justified.

From 113 eligible articles, we found significant heterogeneity in the algorithms used to define asthma (n=66 different algorithms), severity (n=18), control (n=9) and exacerbations (n=24). For the majority of algorithms (n=106), validity was not justified. In the remaining cases, approaches ranged from using algorithms validated in the same databases to using nonvalidated algorithms that were based on clinical judgement or clinical guidelines. The implementation of these algorithms was suboptimally described overall.

Although electronic health record-derived data are now widely used to study asthma, the approaches being used are significantly varied and are often underdescribed, rendering it difficult to assess the validity of studies and compare their findings. Given the substantial growth in this body of literature, it is crucial that scientific consensus is reached on the underlying definitions and algorithms.
Solar ultraviolet B exposure and global variation in tuberculosis incidence: an ecological analysis
Authors: Boere Tjarda M. , Visser Douwe H. , van Furth A. Marceline , Lips Paul , Cobelens Frank G.J.
Published: July 2017

Epidemiological evidence supports vitamin D deficiency as a risk factor for tuberculosis. Differences in solar ultraviolet B (UV-B) exposure, the major source of vitamin D, might therefore partially explain global variation in tuberculosis incidence.

In a global country-based ecological study, we explored the correlation between vitamin D-proxies, such as solar UV-B exposure, and other relevant variables with tuberculosis incidence, averaged over the period 2004–2013.

Across 154 countries, annual solar UV-B exposure was associated with tuberculosis incidence. Tuberculosis incidence in countries in the highest quartile of UV-B exposure was 78% (95% CI 57–88%, p<0.001) lower than that in countries in the lowest quartile, taking into account other vitamin D-proxies and covariates. Of the explained global variation in tuberculosis incidence, 6.3% could be attributed to variations in annual UV-B exposure. Exposure to UV-B had a similar, but weaker association with tuberculosis notification rates in the multilevel analysis with sub-national level data for large countries (highestversuslowest quartile 29% lower incidence; p=0.057).

The potential preventive applications of vitamin D supplementation in high-risk groups for tuberculosis merits further investigation.
Home monitoring improves endpoint efficiency in idiopathic pulmonary fibrosis
Authors: Johannson Kerri A. , Vittinghoff Eric , Morisset Julie , Lee Joyce S. , Balmes John R. , Collard Harold R.
Published: July 2017

The objective of this study was to investigate the reliability, feasibility and analytical impact of home-based measurement of forced vital capacity (FVC) and dyspnoea as clinical endpoints in idiopathic pulmonary fibrosis (IPF).

Patients with IPF performed weekly home-based assessment of FVC and dyspnoea using a mobile hand-held spirometer and self-administered dyspnoea questionnaires. Weekly variability in FVC and dyspnoea was estimated, and sample sizes were simulated for a hypothetical 24-week clinical trial using either traditional office-based interval measurement or mobile weekly assessment.

In total, 25 patients were enrolled. Mean adherence to weekly assessments over 24 weeks was greater than 90%. Compared with change assessment using baseline and 24-week measurements only, weekly assessment of FVC resulted in enhanced precision and power. For example, a hypothetical 24-week clinical trial with FVC as the primary endpoint would require 951 patients using weekly home spirometry compared with 3840 patients using office spirometry measures at weeks 1 and 24 only. The ability of repeated measures to reduce clinical trial sample size was influenced by the correlation structure of the data.

Home monitoring can improve the precision of endpoint assessments, allowing for greater efficiency in clinical trials of therapeutics for IPF.
Monocytes inhibit NK activityviaTGF-β in patients with obstructive sleep apnoea
Authors: Hernández-Jiménez Enrique , Cubillos-Zapata Carolina , Toledano Victor , Pérez de Diego Rebeca , Fernández-Navarro Isabel , Casitas Raquel , Carpio Carlos , Casas-Martín Jose , Valentín Jaime , Varela-Serrano Anibal , Avendaño-Ortiz Jose , Alvarez Enrique , Aguirre Luis A. , Pérez-Martínez Antonio , De Miguel Maria P. , Belda-Iniesta Cristobal , García-Río Francisco , López-Collazo Eduardo
Published: July 2017

Obstructive sleep apnoea (OSA) is associated with cancer incidence and mortality. The contribution of the immune system appears to be crucial; however, the potential role of monocytes and natural killer (NK) cells remains unclear.

Quantitative reverse transcriptase PCR, flow cytometry andin vitroassays were used to analyse the phenotype and immune response activity in 92 patients with OSA (60 recently diagnosed untreated patients and 32 patients after 6 months of treatment with continuous positive airway pressure (CPAP)) and 29 healthy volunteers (HV).

We determined that monocytes in patients with OSA exhibit an immunosuppressive phenotype, including surface expression of glycoprotein-A repetitions predominant protein (GARP) and transforming growth factor-β (TGF-β), in contrast to those from the HV and CPAP groups. High levels of TGF-β were detected in OSA sera. TGF-β release by GARP+monocytes impaired NK cytotoxicity and maturation. This altered phenotype correlated with the hypoxic severity clinical score (CT90). Reoxygenation eventually restored the altered phenotypes and cytotoxicity.

This study demonstrates that GARP+monocytes from untreated patients with OSA have an NK-suppressing role through their release of TGF-β. Our findings show that monocyte plasticity immunomodulates NK activity in this pathology, suggesting a potential role in cancer incidence.
Effectiveness of dapagliflozin on vascular endothelial function and glycemic control in patients with early-stage type 2 diabetes mellitus: DEFENCE study
Authors: Shigiyama Fumika , Kumashiro Naoki , Miyagi Masahiko , Ikehara Kayoko , Kanda Eiichiro , Uchino Hiroshi , Hirose Takahisa
Published: July 2017

Background

Recent studies reported that sodium glucose cotransporter 2 (SGLT2) inhibitors can potentially reduce the risk of cardiovascular mortality in patients with type 2 diabetes mellitus (T2DM). However, there is little or no information on the therapeutic effects of SGLT2 inhibitors on the progression of atherosclerosis. This dapagliflozin effectiveness on vascular endothelial function and glycemic control (DEFENCE) study was designed to determine the effects of dapagliflozin, a SGLT2 inhibitor, on endothelial function in patients with early-stage T2DM.

Methods

DEFENCE is a prospective, randomized, open-label, blinded-endpoint, parallel-group, comparative clinical trial. Between October 2015 and August 2016, 80 T2DM patients treated with 750 mg of metformin (hemoglobin A1c ≥6.0 and <8.0%, n = 80) were enrolled and randomized to receive either 1500 mg/day metformin (the metformin group, n = 40), or 750 mg/day metformin supplemented with 5 mg/day dapagliflozin (the dapagliflozin group, n = 40), for 16 weeks. The primary endpoint was a change in flow-mediated dilation (FMD) from baseline to the end of the 16-week treatment period. The secondary outcomes include changes in indexes of glycemic control, lipid metabolism, and oxidative stress, body composition, and safety evaluation.

Results

Although FMD tended to improve only in the dapagliflozin group, ΔFMD was comparable between the two groups. Analysis of patients with HbA1c >7.0% showed significant improvement of FMD in the dapagliflozin group than metformin group (P < 0.05). HbA1c, fasting plasma glucose, plasma glucagon, and body weight significantly decreased in both groups. Interestingly, urine 8-hydroxy-2′-deoxyguanosin, a biomarker of oxidative stress, was significantly lower in the dapagliflozin group than metformin group at 16 weeks (P < 0.001).

Conclusions

Dapagliflozin add-on therapy to metformin for 16 weeks improved endothelial function, as assessed by FMD, in patients with inadequately controlled early-stage T2DM. Improvement in oxidative stress may contribute to the improvement in FMD.

Trial registration University Hospital Medical Information Network Clinical Trial Registry (UMIN000018754)
α-Glucosidase inhibitor miglitol attenuates glucose fluctuation, heart rate variability and sympathetic activity in patients with type 2 diabetes and acute coronary syndrome: a multicenter randomized controlled (MACS) study
Authors: Shimabukuro Michio , Tanaka Atsushi , Sata Masataka , Dai Kazuoki , Shibata Yoshisato , Inoue Yohei , Ikenaga Hiroki , Kishimoto Shinji , Ogasawara Kozue , Takashima Akira , Niki Toshiyuki , Arasaki Osamu , Oshiro Koichi , Mori Yutaka , Ishihara Masaharu , Node Koichi ,   on behalf of the Collaborators on the Effect of Miglitol on Glucose Metabolism in Acute Coronary Syndrome (MACS) Study
Published: July 2017

Background

Little is known about clinical associations between glucose fluctuations including hypoglycemia, heart rate variability (HRV), and the activity of the sympathetic nervous system (SNS) in patients with acute phase of acute coronary syndrome (ACS). This pilot study aimed to evaluate the short-term effects of glucose fluctuations on HRV and SNS activity in type 2 diabetes mellitus (T2DM) patients with recent ACS. We also examined the effect of suppressing glucose fluctuations with miglitol on these variables.

Methods

This prospective, randomized, open-label, blinded-endpoint, multicenter, parallel-group comparative study included 39 T2DM patients with recent ACS, who were randomly assigned to either a miglitol group (n = 19) or a control group (n = 20). After initial 24-h Holter electrocardiogram (ECG) (Day 1), miglitol was commenced and another 24-h Holter ECG (Day 2) was recorded. In addition, continuous glucose monitoring (CGM) was performed throughout the Holter ECG.

Results

Although frequent episodes of subclinical hypoglycemia (≤4.44 mmo/L) during CGM were observed on Day 1 in the both groups (35% of patients in the control group and 31% in the miglitol group), glucose fluctuations were decreased and the minimum glucose level was increased with substantial reduction in the episodes of subclinical hypoglycemia to 7.7% in the miglitol group on Day 2. Holter ECG showed that the mean and maximum heart rate and mean LF/HF were increased on Day 2 in the control group, and these increases were attenuated by miglitol. When divided 24-h time periods into day-time (0700–1800 h), night-time (1800–0000 h), and bed-time (0000–0700 h), we found increased SNS activity during day-time, increased maximum heart rate during night-time, and glucose fluctuations during bed-time, which were attenuated by miglitol treatment.

Conclusions

In T2DM patients with recent ACS, glucose fluctuations with subclinical hypoglycemia were associated with alterations of HRV and SNS activity, which were mitigated by miglitol, suggesting that these pathological relationships may be a residual therapeutic target in such patients.

Trial registration Unique Trial Number, UMIN000005874 (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000006929)
A homogenization approach for modeling a propagating hydraulic fracture in a layered material
Authors: Dontsov Egor V.
Published: July 2017

Shales are known to have a finely layered structure, which greatly influences the overall material’s response. Incorporating the effect of all these layers explicitly in a hydraulic fracture simulator would require a prohibitively fine mesh. To avoid such a scenario, a suitable homogenization, which would represent the effect of multiple layers in an average sense, should be performed. We consider a sample variation of elastic properties and minimum horizontal stress versus depth that has more than a hundred layers. We evaluate methodologies to homogenize the stress and the elastic properties. The elastic response of a layered material is found to be equivalent to that of a transversely isotropic material, and the explicit relations for the effective parameters are obtained. To illustrate the relevance of the homogenization procedure for hydraulic fracturing, the propagation of a plane strain hydraulic fracture in a finely layered shale is studied. To reduce the complexity of the numerical model, elastic layering is neglected and only the effect of the stress layers is analyzed. The results demonstrate the ability of the homogenized stress model to accurately capture the hydraulic fracture behavior using a relatively coarse mesh. This result is obtained by using a special asymptotic solution at the tip element that accounts for the local stress variation near the tip, which effectively treats the material at the tip element as nonhomogenized.
Impact of next-generation sequencing (NGS) on diagnostic and therapeutic options in soft-tissue and bone sarcoma.
Authors: Gounder Mrinal M. , Ali Siraj Mahamed , Robinson Victoria , Bailey Mark , Ferraro Richard , Patel Nirali M , Krishnan Anita , Millis Sherri Z. , Dickson Mark Andrew , D'Angelo Sandra P. , Keohan Mary Louise , Miller Vincent A. , Schwartz Gary K. , Maki Robert G. , Tap William D.
Published: July 2017

11001

Background: The utility of NGS in management of sarcoma pts remains undefined. Methods: We retrospectively analyzed the NGS profile of patients who were sequenced using a panel of 405 cancer-related genes in DNA and 265 genes rearranged in RNA. Diagnostic and therapeutic implications of mutations (mut) were evaluated through published literature (OncoKb.org, Pubmed). An algorithm was applied to determine germline mut. Following IRB approval, we evaluated the clinical outcomes of pts who underwent NGS at MSKCC. Results: From 2012–2016, 5635 pts worldwide with 56 histologies were tested. Median age of 52 yrs ( < 1-88), 52% females and sarcoma NOS (n = 858) was most frequent. Tumors were sequenced to a mean coverage of 634X; 1165 fusions and > 60,000 mut were found. Mut suspicious for germline defects were seen in 542 pts (9.6%) in known and novel genes ( BRCA, ARID1, FANC). Tumor mutational burden was 2.5/Mb (0–329) and glomus tumors and EHE had the highest and lowest mut, respectively. 16% and 7% of pts had treatment-linked alterations (TLA) known to respond to an FDA approved or study drug, respectively. 42% of pts had TLA eligible for NCI-MATCH, ASCO-TAPUR or other studies. Novel TLA include AKT, ESR1, BRCA, NTRK, PTCH1, SMARCB1 and others. Of the 107 MSKCC pts with clinical data, 60/107 (57%) had at least one TLA, of which 31 (30%) enrolled on a matched trial and 26 pts were ineligible or lacked access to trials. Partial/complete responses were seen with inhibitors to NTRK, IDH1, BRAF, PI3K/mTOR, MDM2, SMARCB1 and others. NGS changed the initial pathology diagnosis and treatments in 5% pts (e.g. LMS to liposarcoma, clear cell to melanoma). Resistance mutations averted futile therapies in 5% pts (e.g. Rb loss and palbociclib in liposarcoma). Conclusions: Our data suggests that NGS has a significant impact in aiding diagnosis and selecting matched therapies in sarcoma. Suspected germline aberrations, while intriguing, needs further validation.
Histopathologic review of suspected disease progression in patients with recurrent glioblastoma (GBM) receiving nivolumab ± ipilimumab: CheckMate 143.
Authors: Sahebjam Solmaz , Ramkissoon Shakti , Baehring Joachim M. , Mulholland Paul James , Grauer Oliver M. , Cloughesy Timothy Francis , Reardon David A. , Lim Michael , Zwirtes Ricardo F. , Latek Robert Raymond , Strauss Lewis C. , Ligon Keith L.
Published: July 2017

2001

Background: Patients treated with immunotherapies can have a transient increase in lesion size due to immune cell infiltration that is suggestive of disease progression, but undergo subsequent regression with continued treatment. For patients with GBM, distinguishing progression from immune-related treatment effects using neuroimaging is challenging. Histopathologic examination of tumors could show the activity of immunotherapies in GBM and potentially minimize premature discontinuation of therapy and increase clinical benefit. Neuropathologic data from patients with recurrent GBM treated in CheckMate 143 who underwent biopsy/resection after suspected progression are presented. Methods: Patients received nivolumab 3 mg/kg (nivo 3) Q2W or nivo 3 + ipilimumab 1 mg/kg (ipi 1) Q3W × 4 doses then nivo 3 Q2W. Tissue collected from patients with suspected radiologic progression was submitted for blinded central review by 2 neuropathologists. Potentially significant treatment effect was defined as ≥30% necrosis/reactive changes and ≤50% viable solid tumor by area in posttreatment samples, or significant morphological changes from a prior biopsy if available. Results were compared with those from automated morphometry, pretreatment biopsy, and control pairs from unrelated patients with GBM treated with standard of care. Results: Of patients treated with nivo 3 (n = 20) or nivo 3 + ipi 1 (n = 1), 13 had potential treatment-related effects and 8 had no evidence of treatment effects (consistent with disease progression). Results were sent in real time to the treating physician to help inform treatment decisions; 4/13 patients with potential treatment effects continued therapy. Treatment effects were unrelated to age, MGMT methylation status, or PD-L1 expression (clone 28-8; archival tissue). Results were similar for automated morphometry analyses and showed differences between patients receiving nivo ± ipi and unrelated controls. Conclusions: These results suggest that histopathologic analyses may help better inform decisions on continuing nivo ± ipi in challenging cases, and show that immunotherapies may have intracerebral biological activity. Clinical trial information: NCT02017717.
Personalized, molecularly matched combination therapies for treatment-na.
Authors: Sicklick Jason K. , Leyland-Jones Brian , Kato Shumei , Hahn Michael , Williams Casey , De Pradip , Miller Vincent A. , Ross Jeffrey S. , Benson Adam , Webster Jennifer , Stephens Phil , Scur Michael , Porter Robert , Tran Lisa , Jepperson Shelby Hintze , Fanta Paul T. , Kurzrock Razelle
Published: July 2017

2512

Background: Precision medicine has been studied in patients (pts) with advanced, heavily-treated cancers by administering molecularly matched monotherapies. With increasing availability of large gene assays and cognate agents, we hypothesized that offering customized combination therapies to treatment-naïve tumors would be feasible and improve response rates. Methods: Investigation of Profile-Related Evidence Determining Individualized Cancer Therapy (I-PREDICT, NCT02534675) targeted metastatic and/or unresectable, untreated lethal cancers ( > 50% 2-yr mortality). Comprehensive genomic profiling (CGP, Foundation Medicine; 315 genes), and, if possible, PD-(L)1 IHC, tumor mutational burden (TMB) and circulating tumor DNA were performed. A molecular tumor board discussed results immediately upon receipt, and emphasized customized combinations. Final decisions were the treating physician’s choice. Results: CGP was evaluable in 40/47 treatment-naïve pts (85.1%); 22 (46.8%) were treated [17 matched (36.2%); 5 unmatched (10.6%); 11 different diagnoses). The other 25 pts (53.2%) are awaiting therapy (8, 17%) or could not be treated (17, 36.2%), mainly due to patient deterioration or payor limitations. Each tumor had a unique genomic portfolio. The median (range) of genomic alterations/patient was 5 (1-12). TMB was available in 17 pts (12 low; 4 intermediate; 1 high). The median (range) Matching Score [(matches (#)/characterized genomic alterations (#)] was 33% (14-100%; 100% designated immunotherapy match or all alterations matched to targeted agents) [Reference PMID 2719717]. Nine/17 matched pts (53%) achieved SD > 6 months (N = 2) or CR (1)/PR (6). The median progression-free survival (PFS) for matched vs. unmatched pts was 4.7 vs. 1.0 months ( P= 0.0019). There were no drug-related deaths. Conclusions: With the use of broad-based DNA sequencing assays, inclusion of pts earlier in their disease course, timely mandated molecular tumor board discussions, and increasing availability of cognate drugs for customized combinations, we report: 1) high molecular matching rates (~36%); 2) high rates of SD > 6 months/CR/PR (~53%); and 3) improved PFS. Study expansion is ongoing. Clinical trial information: NCT0253467.
Mutational burden of tumors with primary site unknown.
Authors: Gay Laurie M. , Fabrizio David , Frampton Garrett Michael , Connelly Caitlin F. , Sun James , Daniel Sugganth , Elvin Julia Andrea , Ramkissoon Shakti , Severson Eric Allan , Suh James , Vergilio Jo-Anne , Stephens Philip J. , Ross Jeffrey S.
Published: July 2017

3039

Background: Higher levels of tumor mutational burden (TMB) can predict sensitivity to immunotherapies (IO), which are FDA approved to treat NSCLC, melanoma, and urothelial carcinoma (Ca). TMB may be a biomarker for sensitivity to IO, irrespective of tumor type. TMB has not been explored widely for tumors of unknown primary site, but may reveal additional treatment options. Methods: Comprehensive genomic profiling of DNA from FFPE tissue samples was performed using hybrid-capture, next-generation sequencing. TMB was calculated by counting all coding short variant alterations (base substitutions and indels), including synonymous alterations, and subtracting from this functionally oncogenic or germline alterations (per ExAC, dbSNPT, or internal algorithmic analysis). To calculate the TMB per Mb, the total number of relevant mutations is divided by the coding region of the bait set (0.8 Mb, 1.1 Mb, or 1.2 Mb). High, intermediate, and low TMB were defined as ≥20 mut/Mb, ≥6 and <20 mut/Mb, or <6 mut/Mb, respectively. Tumor types with >100 samples were analyzed. Results: From a database of 102,878 samples sequenced during routine clinical care, 6116 samples for which the primary tumor site was unclear at sequencing were identified. Table shows TMB metrics (mut/Mb) and median patient age for these cohorts. Conclusions: Significant numbers of patients with each tumor type have high TMB that may indicate benefit from IO, excepting GIST. As expected, urothelial tumors have higher than average TMB and more patients have high TMB. SCC tumors are commonly TMB high (23%), as are tumors difficult to define histologically (15%). For ACUP or CUP, the most common tumors, 8-11% have high TMB. Analysis of responses to treatment with IO are ongoing. [Table: see text]
Tumor mutational burden (TMB) and co-existing actionable mutations in biliary tract cancers (BTC).
Authors: Jain Apurva , Shroff Rachna T. , Zuo Mingxin , Weatherly Jacqueline , Meric-Bernstam Funda , Isaacs Randi , Ali Siraj Mahamed , Bekaii-Saab Tanios S. , Javle Milind M.
Published: July 2017

4086

Background: Mutations in DNA repair pathway were identified in 13% of Biliary Tract Cancers (BTC) [ Cancer2016;122:3838–3847]. High TMB tumors including melanoma, lung cancer and those with microsatellite instability (MSI-H) are associated with susceptibility to immune blockade using checkpoint inhibitors. TMB data in BTC is limited and its association with actionable somatic mutation (mut) profiles in BTC is unknown. Methods: Comprehensive genomic profiling (CGP) of 309 FFPE tissue blocks of BTC pts with a hybrid capture of all coding exons of 236 cancer-related genes and 47 introns of 19 genes rearranged in cancer was done using FoundationOne. Base substitutions, indels, gene fusion/rearrangements, TMB, and MSI status were assessed. TMB was calculated by counting mutations across a 1.25Mb region and classified into high (TMBH; ≥20 mut/Mb), intermediate (TMBI; 6 - 19mut/Mb) and low (TMBL; < 6mut/Mb). MSI high (MSIH) and Stable (MSS) status was assigned by a computational algorithm examining 114 intronic homopolymer loci. Patients with TMB ≥6 mut/Mb (N = 60) were included in the clinical correlative portion of this study. Results: Sixty patients with TMB ≥6 mut were identified out of 309 pts of which 9 (15%) were TMBH and 51 (85%) were TMBI. These included 3 (5%) MSIH and 18 (30 %) MSS. The median age was 59 years (range: 29-86), 35 (58%) were females, majority were intrahepatic cholangiocarcinoma (n = 31; 52%) and 28 (47%) presented with advanced disease at diagnosis. Twenty three (38%) pts had received radiation therapy, 28 (47%) surgery and 3 (5%) received immunotherapy. Most frequent co-existing mut seen was TP53 (N = 35; 58%). APC mut was seen in 7 (12%) pts. DNA repair pathway muts ( MSH6, BRCA1, BRCA2, ATM, MLH1, or MSH2 genes) were identified in 78% of TMBH versus 16% in TMBI cases (p < 0.0001). Frequency of PIK3CA mut differed significantly between TMBH and TMBI (44% vs 10%, p < 0.0001). Pts with TMBI had a significantly better median OS (110 weeks) as compared to TMBH (43 weeks) (p = 0.003). Conclusions: DNA repair pathway and PIK3CA mut maybe associated with TMBH in BTC. A better understanding of TMB and associated actionable mutations in BTC may be of value for the management of BTC patients with targeted agents and immunotherapy.
BRCA1/2 reversion mutations in prostate cancer identified from clinical tissue and liquid biopsy samples.
Authors: Daniel Sugganth , Gornstein Erica , Frampton Garrett Michael , Sun James , Morley Samantha , Heilmann Andreas , Reddy Prasanth , Chung Jon , Suh James , Ramkissoon Shakti , Severson Eric Allan , Vergilio Jo-Anne , Stephens Philip J. , Miller Vincent A. , Elvin Julia Andrea , Ross Jeffrey S. , Gay Laurie M.
Published: July 2017

5024

Background: Prostate tumors with genomic alterations (GA) in BRCA1 or BRCA2 ( BRCA) may be sensitive to treatment with PARP inhibitors (PARPi). However, secondary reversion mutations (revGA) can arise that may restore BRCA function and underlie reduced sensitivity to PARPi or platinum (Pt)-based therapy. Comprehensive genomic profiling (CGP), using either tissue or liquid biopsies, can detect the variety of clinically relevant revGA that can arise. Methods: DNA extracted from FFPE tumor tissue or blood samples obtained during routine clinical care for 1911 patients with predominantly relapsed, refractory or metastatic prostate carcinoma 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: 216/1911 (11.3% ± 1.4%) tumors had ≥1 deleterious BRCA GA. Of these, 7 samples harbored potential revGA in BRCA1 (1) or BRCA2 (6): prostate acinar adenocarcinoma (5), neuroendocrine carcinoma (1), or undifferentiated carcinoma (1). Of these, 2 samples were liquid biopsies (blood), 4 were FFPE tissue samples (liver), and 1 sample was a bone marrow core biopsy. All samples with revGA were metastases. Potential revGA were of 3 types: overlapping indel (4), compensatory fs (2), and missense (1). One case harbored 2 revGA, an overlapping indel and a compensatory fs. Alteration frequencies for TMPRSS2 (fusions), PTEN, and AR were similar with or without BRCA mutations; revGA-positive samples had a modest increase in PTEN alterations (42.9% vs 33.8%, NS). The frequency of CDK12 alterations was significantly reduced in BRCA-mutated tumors (0.9% vs 6.9%, p = 0.00002). Clinical histories for patients with reversion mutations will be presented. Conclusions: CGP of 1911 prostate carcinomas reveals ≥1 deleterious BRCA1/2 in 11.3% of samples. From these, a series of 7 cases, all metastases, with co-occurring potential revGA were identified. Although rare, revGA can be acquired during treatment and may underlie resistance to PARPi or Pt-based therapy. BRCA revGA can be detected from both tissue and liquid biopsies.