bluuebunny/crossref_metadata_2025 huggingface dataset:
A comparison of respiratory function in pigs anaesthetised by propofol or alfaxalone in combination with dexmedetomidine and ketamine
Authors: Lervik Andreas , Toverud Simen Forr , Krontveit Randi , Haga Henning Andreas
Published: March 2020

Background

General anaesthesia in pigs maintained with intravenous drugs such as propofol may cause respiratory depression. Alfaxalone gives less respiratory depression than propofol in some species. The aim of the investigation was to compare respiratory effects of propofol–ketamine–dexmedetomidine and alfaxalone–ketamine–dexmedetomidine in pigs. Sixteen pigs premedicated with ketamine 15 mg/kg and midazolam 1 mg/kg intramuscularly were anaesthetised with propofol or alfaxalone to allow endotracheal intubation, followed by propofol 8 mg/kg/h or alfaxalone 5 mg/kg/h in combination with ketamine 5 mg/kg/h and dexmedetomidine 4 µg/kg/h given as a continuous infusion for 60 min. The pigs breathed spontaneously with an FIO2 of 0.21. Oxygen saturation (SpO2), end-tidal CO2 concentration (PE′CO2), respiratory rate (fR) and inspired tidal volume (VT) were measured, and statistically compared between treatments. If the SpO2 dropped below 80% or if PE′CO2 increased above 10.0 kPa, the pigs were recorded as failing to complete the study, and time to failure was statistically compared between treatments.

Results

Alfaxalone treated pigs had significantly higher respiratory rates and lower PE′CO2 than propofol treated pigs, with a fR being 7.3 /min higher (P = 0.01) and PE′CO2 0.8 kPa lower (P = 0.05). SpO2 decreased by 0.6% and fR by 1.0 /min per kg increase in body weight in both treatment groups. Three of eight propofol treated and two of eight alfaxalone treated pigs failed to complete the study, and times to failure were not significantly different between treatments (P = 0.75).

Conclusions

No major differences in respiratory variables were found when comparing treatments. Respiratory supportive measures must be available when using both protocols.
An ethnographic study of the implementation of a transitional discharge model: peer supporters’ perspectives
Authors: Forchuk Cheryl , Martin Mary-Lou , Sherman Deborrah , Corring Deborah , Srivastava Rani , O’Regan Tony , Gyamfi Sebastian , Harerimana Boniface
Published: March 2020

Background

Over the last three decades, there has been worldwide recognition of peer support contributions to improve mental healthcare provision. However, in the current literature, little attention has been paid to exploring perspectives of peer supporters on their involvement in mental health services provision. The purpose of the present study was to examine peer supporters’ perspectives on the implementation of a transitional discharge model (TDM), an intervention for the community integration of people with mental illness.

Methods

This paper represents ethnographic qualitative data collected as part of a study that used mixed methods to evaluate the implementation of TDM across nine hospitals from the Province of Ontario, in Canada. The study involved a sample of 66 peer supporters, who were recruited from participating Consumer/Survivor Initiative Organizations and Peer Support Programs. The study collected data using two sets of focus groups, which were held at 6 months and 1-year post implementation. Data analysis used an ethnography model of qualitative analysis.

Results

Peer supporters expressed that their involvement in mental healthcare enhanced clients’ autonomy and hope about their recovery, as well as established a safety net and reduced hospital readmissions. Peer supporters articulated that they assumed several roles to facilitate clients’ transition from hospital to the community. These roles included: assisting clients in building their capacity and developing healthy routines; attending regular on-ward and community meetings; accompanying clients to their appointments; and working with clients to set goals for their recovery. The study showed hindrances to effective implementation of peer support programs, such as a lack of understanding and appreciation of peer supporter roles, lack of careful allocation of peer supporters to clients, and an absence of appropriate protocols for ensuring the safety and supervision of the peer supporters.

Conclusions

Results of the TDM implementation demonstrated that involving peer supporters in mental healthcare delivery may benefit clients by enhancing autonomy and hope about their recovery, as well as establishing a safety net and reducing hospital readmissions. Results from the study have the potential to inform healthcare professionals and managers of strategies for developing effective peer support programs.
Role of ICU-acquired weakness on extubation outcome among patients at high risk of reintubation
Authors: Thille Arnaud W. , Boissier Florence , Muller Michel , Levrat Albrice , Bourdin Gaël , Rosselli Sylvène , Frat Jean-Pierre , Coudroy Rémi , Vivier Emmanuel
Published: March 2020

Background

Whereas ICU-acquired weakness may delay extubation in mechanically ventilated patients, its influence on extubation failure is poorly known. This study aimed at assessing the role of ICU-acquired weakness on extubation failure and the relation between limb weakness and cough strength.

Methods

A secondary analysis of two previous prospective studies including patients at high risk of reintubation after a planned extubation, i.e., age greater than 65 years, with underlying cardiac or respiratory disease, or intubated for more than 7 days prior to extubation. Patients intubated less than 24 h and those with a do-not-reintubate order were not included. Limb and cough strength were assessed by a physiotherapist just before extubation. ICU-acquired weakness was clinically diagnosed as limb weakness defined as Medical Research Council (MRC) score < 48 points and severe weakness as MRC sum-score < 36. Cough strength was assessed using a semi-quantitative 5-Likert scale. Extubation failure was defined as reintubation or death within the first 7 days following extubation.

Results

Among 344 patients at high risk of reintubation, 16% experienced extubation failure (56/344). They had greater severity and lower MRC sum-score (41 ± 16 vs. 49 ± 13, p < 0.001) and were more likely to have ineffective cough than the others. The prevalence of ICU-acquired weakness at the time of extubation was 38% (130/244). The extubation failure rate was 12% (25/214) in patients with no limb weakness vs. 18% (12/65) and 29% (19/65) in those with moderate and severe limb weakness, respectively (p < 0.01). MRC sum-score and cough strength were weakly but significantly correlated (rho = 0.28, p < .001). After multivariate logistic regression analyses, the lower the MRC sum-score the greater the risk of reintubation; severe limb weakness was independently associated with extubation failure, even after adjustment on cough strength and severity at admission.

Conclusion

ICU-acquired weakness was diagnosed in 38% in this population of patients at high risk at the time of extubation and was independently associated with extubation failure in the ICU.
Effectiveness of LiuZiJue Qigong versus traditional core stability training for poststroke patients complicated with abnormal trunk postural control: study protocol for a single-center randomized controlled trial
Authors: Wang Chen , Yu Long , Yang Jian , Wang Ren Wei , Zheng Ya Nan , Zhang Ying
Published: March 2020

Background

Trunk function in stroke patients with hemiplegia is associated with respiration and core stability and is also found to be associated with balance and postural control and activities of daily living. LiuZiJue Qigong (LQG) is a traditional Chinese method of fitness based on breath pronunciation. The purpose of this study is to compare the clinical efficacy of LQG and traditional core stability training in the treatment of stroke patients with abnormal trunk posture. This protocol is written according to the SPIRIT 2013 statement.

Methods/design

This study is a single-center randomized controlled trial in which 160 stroke patients are randomly divided into a study group and a control group. Patients in the study group will receive LQG combined with conventional rehabilitation therapy, and patients in the control group will receive traditional core stability training combined with conventional rehabilitation therapy. All treatments will be done for 45 min/day, five times per week, for 2 weeks. The primary outcome (Trunk Impairment Scale) and secondary outcomes (Berg Balance Scale, Fugl-Meyer Assessment, Modified Barthel Index, Maximum Phonation Time, Dynamic and Static balance testing, and thickness and the mobile degrees of diaphragm) will be measured at baseline, 2 weeks, and the end of the rehabilitation course.

Discussion

The aim purpose of this research study is to compare the clinical efficacy of LQG and traditional core stability exercise in the treatment of stroke patients with abnormal trunk posture.

Trial registration

Chinese Clinical Trial Register, ChiCTR1800014864. Registered on 24 November 2018.
Outcome reporting in neonates experiencing withdrawal following opioid exposure in pregnancy: a systematic review
Authors: Shan Flora , MacVicar Sonya , Allegaert Karel , Offringa Martin , Jansson Lauren M. , Simpson Sarah , Moulsdale Wendy , Kelly Lauren E.
Published: March 2020

Background

Neonatal withdrawal secondary to in utero opioid exposure is a growing global concern stressing the psychosocial well-being of affected families and scarce hospital resources. In the ongoing search for the most effective treatment, randomized controlled trials are indispensable. Consistent outcome selection and measurement across randomized controlled trials enables synthesis of results, fostering the translation of research into practice. Currently, there is no core outcome set to standardize outcome selection, definition and reporting. This study identifies the outcomes currently reported in the literature for neonates experiencing withdrawal following opioid exposure during pregnancy.

Methods

A comprehensive literature search of MEDLINE, EMBASE and Cochrane Central was conducted to identify all primary research studies (randomized controlled trials, clinical trials, case-controlled studies, uncontrolled trials, observational cohort studies, clinical practice guidelines and case reports) reporting outcomes for interventions used to manage neonatal abstinence syndrome between July 2007 and July 2017. All “primary” and “secondary” neonatal outcomes were extracted by two independent reviewers and were assigned to one of OMERACT’s core areas of “pathophysiological manifestation”, “life impact”, “resource use”, “adverse events”, or “death”.

Results

Forty-seven primary research articles reporting 107 “primary” and 127 “secondary” outcomes were included. The most frequently reported outcomes were “duration of pharmacotherapy” (68% of studies,N = 32), “duration of hospital stay” (66% of studies,N = 31) and “withdrawal symptoms” (51% of studies,N = 24). The discrepancy between the number of times an outcome was reported and the number of articles was secondary to the use of composite outcomes. Frequently reported outcomes had heterogeneous definitions or were not defined by the study and were measured at different times. Outcomes reported in the literature to date were mainly assigned to the core areas “pathophysiologic manifestations” or “resource use”. No articles reported included parent or former patient involvement in outcome selections.

Conclusions

Inconsistent selection and definition of primary and secondary outcomes exists in the present literature of pharmacologic and nonpharmacologic interventions for managing opioid withdrawal in neonates. No studies involved parents in the process of outcome selection. These findings hinder evidence synthesis to generate clinically meaningful practice guidelines. The development of a specific core outcome set is imperative.
A phase 2 randomised controlled trial of serelaxin to lower portal pressure in cirrhosis (STOPP)
Authors: Gifford Fiona J. , Dunne Philip D. J. , Weir Graeme , Ireland Hamish , Graham Catriona , Tuck Sharon , Hayes Peter C. , Fallowfield Jonathan A.
Published: March 2020

Background

In preclinical models, recombinant human relaxin-2 (serelaxin) had anti-fibrotic effects and ameliorated portal hypertension (PH). A small exploratory study in patients with cirrhosis also suggested that serelaxin could reduce portal pressure.

Methods

In a phase 2, double-blind, randomised controlled study conducted in a single centre (Royal Infirmary of Edinburgh, UK), male and female adult participants with cirrhosis and clinically significant PH (CSPH; hepatic venous pressure gradient (HVPG) > 10 mmHg) were enrolled. Participants were allocated to serelaxin or placebo in a 3:1 ratio. The placebo was matched to serelaxin on appearance and administration protocol to create and maintain blinding. The primary endpoint was the change from baseline in fasting HVPG after 2 h of peripheral i.v. serelaxin infusion (80 μg/kg/day for 60 min followed by 30 μg/kg/day for at least 60 min). Secondary endpoints included the change from baseline in hepatic blood flow and systemic haemodynamics (cardiac index, systemic vascular resistance index and aortic pulse wave velocity). Short-term safety and tolerability of serelaxin were assessed.

Results

A total of 17 participants were screened, 15 were randomised and 11 completed the study (n = 9 serelaxin, n = 2 placebo). Reasons for withdrawal were baseline HVPG < 10 mmHg (n = 2) and technical failure (n = 2). The trial ended early due to manufacturer discontinuation of the study drug. The median age was 56 (range 43–69) years and 73% of participants were male. Alcohol was the commonest cirrhosis aetiology (n = 10). Participants had a median Model for End-Stage Liver Disease score of 10 (range 6–14). The mean baseline HVPG was 16.3 (range 10.3–21.7) mmHg. Individual responses were variable, but overall there was no statistically significant change in HVPG after 2 h of i.v. serelaxin (arithmetic mean of difference ± SD was 0.4 ± 3.5 mmHg (95% CI –2.3, 3.1; p = 0.76)). There were also no substantial changes from baseline in hepatic or systemic haemodynamics. We recorded 12 adverse events in 7 participants treated with serelaxin; none were significant, and most were unrelated to the investigational medicinal product. There were no serious adverse events.

Conclusion

In a small randomised, phase 2, proof-of-concept study in patients with cirrhosis and CSPH, serelaxin infusion was safe and well-tolerated but had a neutral effect on HVPG.

Trial registration

ClinicalTrials.gov, NCT02669875. Registered on 1 February 2016.
On the coexistence of broadcast and unicast in hybrid networks for the transmission of video services using stochastic geometry
Authors: Shokair Ahmad , Nasser Youssef , Bazzi Oussama , Hélard Jean-François , Crussière Matthieu
Published: March 2020

Following the increasing growth in the demand on mobile TV, hybrid broadcast/broadband networks emerged as a suitable approach to overtake the challenges introduced by each network separately in order to enhance users’ experience. This paper presents two possible scenarios for a hybrid, spatially separated, broadcast/broadband network to offer mobile TV linear services for the end users. Namely, the first scenario is based on shared spectrum access for both networks while the second one proposes a dedicated spectrum. Using a stochastic geometry approach, the paper derives analytical formulations for both the probability of coverage and ergodic capacity. These formulations are then used to optimize the hybrid network in terms of its key design parameters including the broadcast (BC) coverage radii, the broadband (BB) base stations’ (BS) density, and spectral capacity. The results have shown that an optimal BC radius maximizing the probability of coverage and capacity exists and it depends on the BS density of the BB network. Other design parameters have been provided and analyzed leading to an optimal network deployment. To the best of the author’s knowledge, this paper presents a first reference work dealing with the optimization of the hybrid network with the coexistence of broadband and broadcast networks, from stochastic geometry perspective, taking into account the inter-cell interference.
Effectiveness of pharmacological agents for the treatment of non-infectious scleritis: a systematic review protocol
Authors: Ingaralingam Sathana , Rauz Saaeha , Murray Philip I. , Barry Robert J.
Published: March 2020

Background

Non-infectious scleritis is a potentially sight-threatening condition in which the sclera, the white outer layer of the eye, becomes inflamed. Whilst scleritis can be infective, the majority of cases are due to non-infectious causes, often occurring in association with an underlying systemic autoimmune or auto-inflammatory condition. Thorough systemic work-up is crucial to identify disease aetiology and exclude infection; however, a significant proportion of disease remains idiopathic with the underlying cause unknown. Non-infectious scleritis is normally managed with systemic corticosteroid and immunosuppression, yet there is no widely agreed consensus on the most appropriate therapy, and no national or international guidelines exist for treatment of non-infectious scleritis.

Methods

Standard systematic review methodology will be used to identify, select and extract data from comparative studies of pharmacological interventions used to treat patients with non-infectious scleritis. Searches of bibliographic databases (Cochrane Library, MEDLINE, CINAHL and EMBASE) and clinical trial registers will be employed. No restrictions will be placed on language or date of publication. Non-English articles will be translated where necessary. The primary outcome of interest will be disease activity measured by reduction in scleritis grading according to standardised grading systems. Secondary outcomes will include change in best corrected visual acuity, reduction in concurrent dose of systemic corticosteroid, time to treatment failure, adverse events and health-related quality of life. Risk of bias assessment will be conducted appropriate to each study design. Study selection, data extraction and risk of bias assessment will be completed by two reviewers independently. Data will be presented in a table and a narrative synthesis will be undertaken. Meta-analysis will be performed where methodological and clinical homogeneity exists. Subgroup and sensitivity analysis will be undertaken if appropriate.

Discussion

Many studies have investigated the effectiveness of pharmacological agents used in the management of non-infectious scleritis. A systematic review is needed to collate and analyse this evidence. Findings of this systematic review will help guide ophthalmologists managing patients with non-infectious scleritis and may form the basis for evidence-based recommendations for future clinical practice and encourage standardisation of treatment protocols.

Systematic review registration

PROSPERO CRD42019125198
New shrinking iterative methods for infinite families of monotone operators in a Banach space, computational experiments and applications
Authors: Wei Li , Chen Rui , Zhang Yanan , Agarwal Ravi P.
Published: March 2020

New shrinking iterative algorithms for approximating common zeros of two infinite families of maximal monotone operators in a real uniformly convex and uniformly smooth Banach space are designed. Two steps of multiple choices can be made in the new iterative algorithms, two groups of interactive containment sets $C_{n}$Cn and $Q_{n}$Qn are constructed and computational errors are considered, which are different from the previous ones. Strong convergence theorems are proved under mild assumptions and some new proof techniques can be found. Computational experiments for some special cases are conducted to show the effectiveness of the iterative algorithms and meanwhile some inequalities are proved to guarantee the strong convergence. Moreover, the applications of the abstract results on convex minimization problems and variational inequalities are exemplified.
A framework for assessing 16S rRNA marker-gene survey data analysis methods using mixtures.
Authors: Olson Nathan D. , Kumar M. Senthil , Li Shan , Braccia Domenick J. , Hao Stephanie , Timp Winston , Salit Marc L. , Stine O. Colin , Bravo Hector Corrada
Published: March 2020

Background

There are a variety of bioinformatic pipelines and downstream analysis methods for analyzing 16S rRNA marker-gene surveys. However, appropriate assessment datasets and metrics are needed as there is limited guidance to decide between available analysis methods. Mixtures of environmental samples are useful for assessing analysis methods as one can evaluate methods based on calculated expected values using unmixed sample measurements and the mixture design. Previous studies have used mixtures of environmental samples to assess other sequencing methods such as RNAseq. But no studies have used mixtures of environmental to assess 16S rRNA sequencing.

Results

We developed a framework for assessing 16S rRNA sequencing analysis methods which utilizes a novel two-sample titration mixture dataset and metrics to evaluate qualitative and quantitative characteristics of count tables. Our qualitative assessment evaluates feature presence/absence exploiting features only present in unmixed samples or titrations by testing if random sampling can account for their observed relative abundance. Our quantitative assessment evaluates feature relative and differential abundance by comparing observed and expected values. We demonstrated the framework by evaluating count tables generated with three commonly used bioinformatic pipelines: (i) DADA2 a sequence inference method, (ii) Mothur a de novo clustering method, and (iii) QIIME an open-reference clustering method. The qualitative assessment results indicated that the majority of Mothur and QIIME features only present in unmixed samples or titrations were accounted for by random sampling alone, but this was not the case for DADA2 features. Combined with count table sparsity (proportion of zero-valued cells in a count table), these results indicate DADA2 has a higher false-negative rate whereas Mothur and QIIME have higher false-positive rates. The quantitative assessment results indicated the observed relative abundance and differential abundance values were consistent with expected values for all three pipelines.

Conclusions

We developed a novel framework for assessing 16S rRNA marker-gene survey methods and demonstrated the framework by evaluating count tables generated with three bioinformatic pipelines. This framework is a valuable community resource for assessing 16S rRNA marker-gene survey bioinformatic methods and will help scientists identify appropriate analysis methods for their marker-gene surveys.
Image quality analysis of 44Sc on two preclinical PET scanners: a comparison to 68Ga
Authors: Rosar Florian , Buchholz Hans-Georg , Michels Sebastian , Hoffmann Manuela A. , Piel Markus , Waldmann Christopher M. , Rösch Frank , Reuss Stefan , Schreckenberger Mathias
Published: March 2020

Background

44Sc has been increasingly investigated as a potential alternative to 68Ga in the development of tracers for positron emission tomography (PET). The lower mean positron energy of 44Sc (0.63 MeV) compared to 68Ga (0.83 MeV) can result in better spatial image resolutions. However, high-energy γ-rays (1157 keV) are emitted at high rates (99.9%) during 44Sc decay, which can reduce image quality. Therefore, we investigated the impact of these physical properties and performed an unbiased performance evaluation of 44Sc and 68Ga with different imaging phantoms (image quality phantom, Derenzo phantom, and three-rod phantom) on two preclinical PET scanners (Mediso nanoScan PET/MRI, Siemens microPET Focus 120).

Results

Despite the presence of high-energy γ-rays in 44Sc decay, a higher image resolution of small structures was observed with 44Sc when compared to 68Ga. Structures as small as 1.3 mm using the Mediso system, and as small as 1.0 mm using the Siemens system, could be visualized and analyzed by calculating full width at half maximum. Full widths at half maxima were similar for both isotopes. For image quality comparison, we calculated recovery coefficients in 1–5 mm rods and spillover ratios in either air, water, or bone-equivalent material (Teflon). Recovery coefficients for 44Sc were significantly higher than those for 68Ga. Despite the lower positron energy, 44Sc-derived spillover ratio (SOR) values were similar or slightly higher to 68Ga-derived SOR values. This may be attributed to the higher background caused by the additional γ-rays. On the Siemens system, an overestimation of scatter correction in the central part of the phantom was observed causing a virtual disappearance of spillover inside the three-rod phantom.

Conclusion

Based on these findings, 44Sc appears to be a suitable alternative to 68Ga. The superior image resolution makes it an especially strong competitor in preclinical settings. The additional γ-emissions have a small impact on the imaging resolution but cause higher background noises and can effect an overestimation of scatter correction, depending on the PET system and phantom.
Single-site 123I-FP-CIT reference values from individuals with non-degenerative parkinsonism—comparison with values from healthy volunteers
Authors: Fahmi Rachid , Platsch Günther , Sadr Alexandre Bani , Gouttard Sylvain , Thobois Stephane , Zuehlsdorff Sven , Scheiber Christian
Published: March 2020

Purpose

Iodine 123-radiolabeled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) SPECT can be performed to distinguish degenerative forms of movement disorders/parkinsonism/tremor from other entities such as idiopathic tremor or drug-induced parkinsonism. For equivocal cases, semi-quantification and comparison to reference values are a necessary addition to visual interpretation of 123I-FP-CIT scans. To overcome the challenges of multi-center recruitment and scanning of healthy volunteers, we generated 123I-FP-CIT reference values from individuals with various neurological conditions but without dopaminergic degeneration, scanned at a single center on the same SPECT-CT system following the same protocol, and compared them to references from a multi-center database built using healthy volunteers’ data.

Methods

From a cohort of 1884 patients, we identified 237 subjects (120 men, 117 women, age range 16–88 years) through a two-stage selection process. Every patient had a final clinical diagnosis after a mean follow-up of 4.8 ± 1.3 years. Images were reconstructed using (1) Flash3D with scatter and CT-based attenuation corrections (AC) and (2) filtered back projection with Chang AC. Volume-of-interest analysis was performed using a commercial software to calculate specific binding ratios (SBRs), caudate-to-putamen ratios, and asymmetry values on different striatal regions. Generated reference values were assessed according to age and gender and compared with those from the ENC-DAT study, and their robustness was tested against a cohort of patients with different diagnoses.

Results

Age had a significant negative linear effect on all SBRs. Overall, the reduction rate per decade in SBR was between 3.80 and 5.70%. Women had greater SBRs than men, but this gender difference was only statistically significant for the Flash3D database. Linear regression was used to correct for age-dependency of SBRs and to allow comparisons to age-matched reference values and “normality” limits. Generated regression parameters and their 95% confidence intervals (CIs) were comparable to corresponding European Normal Control Database of DaTscan (ENC-DAT) results. For example, 95% CI mean slope for the striatum in women is − 0.015 ([− 0.019, − 0.011]) for the Flash3D database versus − 0.015 ([− 0.021, − 0.009]) for ENC-DAT. Caudate-to-putamen ratios and asymmetries were not influenced by age or gender.

Conclusion

The generated 123I-FP-CIT references values have similar age-related distribution, with no increase in variance due to comorbidities when compared to values from a multi-center study with healthy volunteers. This makes it possible for sites to build their 123I-FP-CIT references from scans acquired during routine clinical practice.
Integrated reservoir characterization of a Utica Shale with focus on sweet spot discrimination
Authors: Zhu Jinming
Published: March 2020

Multiclient 3D seismic data were acquired in 2015 in eastern Ohio for reservoir characterization of the Utica Shale consisting of the Utica and Point Pleasant Formations. I attained accurate, high-fidelity acoustic impedance, shear impedance, density, and [Formula: see text], from elastic inversion. These accurate inversion results allow consistent calculation of reservoir and geomechanical properties of the Utica Shale. I found density critically important affecting the accuracy of other reservoir and geomechanical properties. More than a dozen properties in geologic, geomechanical, and reservoir categories were acquired from logs, cores, and seismic inversion, for this integrated reservoir characterization study. These properties include buried depth, formation thickness, mineralogy, density, Young’s modulus, Poisson’s ratio (PR), brittleness, total organic carbon (TOC), porosity, water saturation, permeability, clay content, and natural fractures. A ternary diagram of core samples from 18 wells demonstrates that the Point Pleasant is dominant with calcite, whereas the Utica mainly contains clay. Inverted density clearly divides Point Pleasant as low density from the overlying Utica. Calculated reservoir properties undoubtedly delineate the traditional Utica Shale as two distinctive formations. I calculated that the Utica Formation contains 1%–2% TOC, 3.5%–4.8% porosity, 10%–24% water saturation, and 40%–58% clay content, whereas Point Pleasant contains 3%–4.5% TOC, 5%–9% porosity, 2%–10% water saturation, and 15%–35% clay content. The PR and brittleness clearly separate Point Pleasant from the overlying Utica, with a lower PR and a higher brittleness index in Point Pleasant than in Utica. The higher brittleness in Point Pleasant makes it easier to frac, leading to enhanced permeability. Both formations exhibit spatial variations of reservoir and geomechanical properties. Nevertheless, the underlying Point Pleasant is obviously better than the Utica Shale with favorable reservoir and geomechanical properties for optimal development and production, although Utica is thicker and shallower. The central and southeastern portions of Point Pleasant have the sweetest reservoirs.
Phase Ib study combining ibrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with CD20-positive B-cell non-Hodgkin lymphoma (NHL).
Authors: Younes Anas , Flinn Ian , Berdeja Jesus G. , Friedberg Jonathan W. , Alberti Sara , Thieblemont Catherine , Morschhauser Franck , Hellemans Peter , Hall Brett , Smit Johan , Skee Donna , de Vries Ronald , Todorovic Marija , Khan Imran , Fourneau Nele , Oki Yasuhiro
Published: March 2020

8502

Background: Ibrutinib, a first-in-class oral Bruton’s tyrosine kinase inhibitor, has demonstrated single-agent activity in a variety of relapsed or refractory B-cell malignancies with limited toxicity, making it an appropriate drug to combine with standard R-CHOP chemotherapy in patients with previously untreated NHL. Methods: Patients received oral daily dose of ibrutinib (280, 420, or 560 mg) in combination with standard doses of R-CHOP (rituximab, cyclophosphamide, doxorubicin, and vincristine on day 1, and prednisone on days 1 through 5 of each 21-day cycle for up to 6 cycles). The primary objective was to determine the recommended phase 2 dose (RP2D) of ibrutinib in combination with standard R-CHOP (IR-CHOP). The secondary objectives were to assess safety, overall response rate, pharmacokinetics, and pharmacodynamic biomarkers. Results: Seventeen patients (7, 4, and 6 in increasing ibrutinib doses) were enrolled: 59% male, median age 65 (range 46-81) years, diffuse large B-cell lymphoma 47%, mantle cell lymphoma 29% and follicular lymphoma 24%. In the 280 mg cohort, 2 patients had dose-limiting toxicity (DLT): 1 with transient syncope and 1 with periorbital cellulitis; at 560 mg, 1 patient had gastritis (grade 2). The RP2D was established at 560 mg ibrutinib. The most common (≥ 20% of patients) adverse events (AEs) were neutropenia (77%), thrombocytopenia (65%), vomiting (59%), anemia (53%), nausea (47%), fatigue (35%), headache (29%), constipation (24%), diarrhea (24%), and dizziness (24%). To date, 6 patients completed 6 cycles of treatment, and 2 patients discontinued treatment (1 due to noncompliance with the study drug and 1 due to non-DLT AE). At the time of this analysis, of the 10 patients had at least one post baseline tumor, the overall response rate was 100% (7 complete and 3 partial responses). Conclusions: The combination of IR-CHOP has an acceptable safety profile. No new toxicities were noted with adding ibrutinib to R-CHOP. An expansion cohort 560 mg ibrutinib (RP2D) is being opened to further explore the safety and efficacy of IR-CHOP in patients with newly diagnosed diffuse large B-cell lymphomas. Clinical trial information: NCT01569750.
Utility of post-therapy surveillance scans in DLBCL.
Authors: Thompson Carrie A. , Maurer Matthew J. , Ghesquieres Herve , Macon William R , Habermann Thomas Matthew , Witzig Thomas E. , Cerhan James Robert , Link Brian K.
Published: March 2020

8504

Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma. The optimal follow-up strategy for patients (pts) in remission is not clear. The goal of this study is to determine the utility of surveillance scans in a large, prospective, multi-institutional cohort of DLBCL pts. Methods: Patients were enrolled in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER), a prospective cohort of newly diagnosed lymphoma pts. All pts were followed for events including relapse, re-treatment, and death with events verified by medical records. Patients eligible for this study had biopsy proven DLBCL and were treated with anthracycline based immunochemotherapy (IC). Initial and post-treatment management was per treating physician. Medical records were re-reviewed in pts with events for clinical details at relapse and relationship to planned follow-up visits and surveillance scans. Results: 644 pts with DLBCL treated with IC were enrolled in MER from 2002-2009. Median age was 63 years (range 18-92), 54% were men, and median f/u was 59 months (range 8-116). 537 pts entered post-treatment observation; 109 (20%) of the 537 pts relapsed and 41 died from other causes. 42% of relapses were in the first 12 months following diagnosis, 27% between 12-24 months, and 31% >24 months. In the 109 who relapsed, 62% of pts (62/100, 9 unknown) presented to their physician earlier than a planned follow-up visit due to symptoms. At the time of relapse, 68% were symptomatic, 42% of pts had abnormal physical exam, and 55% had elevated LDH; 87% of pts had ≥1 of these features. Of the 38 pts with relapse detected at a planned visit, 26 had clinical features of relapse and 12 pts had relapse detected solely by planned surveillance scan; 4 pts had relapse of low-grade or other subtype and 8 had DLBCL relapse (4 of whom had equivocal/positive PET at the end of IC). Thus, surveillance scanning detected DLBCL relapse prior to clinical manifestations in only 8/537 pts (1.5%) observed post DLBCL therapy. Conclusions: The vast majority of DLBCL relapses occur outside of planned follow-up visits and are accompanied by symptoms, physical exam, or laboratory abnormalities. Routine surveillance scans post-therapy add little to detection of DLBCL relapse.
Definition of a high-risk population among patients with AL amyloidosis not undergoing autologous stem cell transplantation using bone marrow plasmacytosis and the presence of CRAB.
Authors: Kourelis Taxiarchis , Gertz Morie , Lacy Martha , Buadi Francis , Hayman Suzanne R. , Kumar Shaji , Zeldenrust Steven R. , Leung Nelson , Kyle Robert A. , Russell Stephen , Dingli David , Lust John Anthony , Lin Yi , Kapoor Prashant , Rajkumar Vincent , Dispenzieri Angela
Published: March 2020

8516

Background: There is consensus that light chain amyloidosis (AL) patients with CRAB criteria (abnormal calcium or renal function, anemia or lytic bone lesions) also have multiple myeloma (MM). These patients are typically excluded from AL trials; however, AL patients with >= 10% bone marrow plasma cells (BMPC) in the absence of CRAB are included in trials along with AL with < 10% BMPC. We postulated that the currently used dichotomy may be incorrect and examined the spectrum of AL with and without MM. Methods: We identified 1,272 patients with AL seen within 90 days of diagnosis, between January 1, 2000, and December 31, 2010. We defined the population of patients with coexisting MM based on the existence of CRAB (AL-CRAB-MM). Patients without CRAB were divided into two groups, AL-only (<10% BMPC) and AL-PC-MM (>=10% BMPC). Results: Among the 1,272 patients, 117 (9%) had AL-CRAB-MM, 476 (37%) had AL-PC-MM, and 679 (53%) had AL only. Their respective median overall survivals (OS) were 16.2, 15.8, and 28.4 months (p<0.0001). Autologous stem cell transplant (ASCT) was performed in 203 (30%), 138 (29%) and 23 (20%) patients respectively. Since the outcomes of AL-CRAB-MM and AL-PC-MM were similar, they were pooled for univariate and multivariate analyses. On multivariate analysis, AL-CRAB-MM and AL-PC-MM retained negative prognostic value independent of age, cardiac stage, prior autologous stem cell transplant (ASCT), beta 2 microglobulin, and dFLC. We next considered whether patients received ASCT as part of their treatment. For those patients who never received ASCT, the 5-year OS were 19%, 14%, and 31%, p<0.001, for AL-CRAB-MM, AL-PC-MM, and AL only respectively. In contrast, for those patients who received ASCT, the respective 5-year OS were 46%, 56%, and 73%, p<0.001. Conclusions: AL patients with >=10% BMPCs have a poor prognosis similar to patients with AL-CRAB-MM and should therefore be considered as AL with MM.
Updated results of a phase I first-in-human study of the BCL-2 inhibitor ABT-199 (GDC-0199) in patients with relapsed/refractory non-Hodgkin lymphoma (NHL).
Authors: Davids Matthew Steven , Seymour John Francis , Gerecitano John F. , Kahl Brad S. , Pagel John M. , Wierda William G. , Anderson Mary Ann , Darden David E. , Nolan Cathy E. , Gressick Lori A. , Yang Jianning , Chyla Brenda J. , Busman Todd A. , Graham Alison M. , Cerri Elisa , Enschede Sari H. , Humerickhouse Rod A. , Roberts Andrew W
Published: March 2020

8520

Background: BCL-2 is highly expressed in NHL, including mantle cell lymphoma (MCL), and is a promising therapeutic target as it is involved in NHL pathogenesis and mediates resistance to many cytotoxics. ABT-199 is a second generation inhibitor with 500-fold higher affinity for BCL-2 (Ki<0.10 nM) than BCL-XL (Ki=48 nM). Methods: Objectives of this Ph 1 dose-escalation study include evaluations of safety, pharmacokinetics and preliminary efficacy in patients (pts) with relapsed or refractory (R/R) NHL. A single oral dose (50-400 mg) was administered followed by 6 days off drug prior to the initiation of continuous once daily dosing. Due to concerns of potential tumor lysis syndrome (TLS), a 2 to 3 wk lead-in period with step-wise escalation to the target cohort dose was implemented. Dose cohorts up to 900 mg have been evaluated to date. Results: As of January 2013, 31 pts have been enrolled (median age 68 y (range 35-85); 20 males; median prior therapies 3 (range 1-7). 13 (42%) and 4 (13%) had bulky adenopathy (>5 and >10 cm, respectively). The most common AEs (≥15% of patients) were nausea (36%), diarrhea (26%), dyspepsia, vomiting, fatigue, pyrexia and cough (16% each). Gr 3/4 AEs occurring in >1 patient were anemia, neutropenia (4 pts each), and febrile neutropenia (2 pts). Two of 14 pts in cohort 5 experienced DLTs at the target dose of 600 mg: Gr 3 febrile neutropenia and Gr 4 neutropenia. Although Gr 3/4 thrombocytopenia was observed in 3 pts, it was not dose dependent. Gr 3 TLS was seen after the initial dose in 1 pt with very bulky MCL (>10 cm). With a median follow-up of 5 months (range 0.5-15), 17 have discontinued: 13 due to PD, 2 due to AEs and 2 who received a BMT. Of the 29 pts evaluable for efficacy, the overall best response rate was 55% with 1 DLBCL pt achieving a CR and 15 (52%) a PR (8/8 MCL, 3/3 Waldenstrom macroglobulinemia, 2/7 follicular lymphoma and 2/7 DLBCL pts). Conclusions: ABT-199 is highly active in R/R NHL, particularly in MCL. Additional dosing and scheduling modifications are currently being explored to optimize the efficacy/safety profile of this active new agent. ABT-199 warrants further single-agent and combination trials in NHL. Clinical trial information: NCT01328626.
A phase II study of single agent mocetinostat, an oral isotype-selective histone deacetylase (HDAC) inhibitor, in patients with diffuse large cell B-cell (DLBCL) and follicular (FL) lymphomas.
Authors: Crump Michael , Andreadis Charalambos , Assouline Sarit E. , Rizzieri David , Copeland Amanda , Van Der Jagt Richard H. C. , Fox Susan , Reid Gregory K. , Besterman Jeffrey M. , Martell Robert E. , Younes Anas
Published: March 2020

8535

Background: Mocetinostat (MGCD0103) is an orally available, isotype-selective, non-hydroxamate HDAC inhibitor targeting HDACs 1,2, 3 and 11 with single-agent activity in Hodgkin’s lymphoma and in AML and MDS (in combination with 5-azacitidine). More than 430 patients have been treated to date. Methods: This open-label, phase II trial enrolled patients with DLBCL and FL. Patients received mocetinostat at doses ranging from 70-110 mg 3x/wk every 28 days. Anticancer activity, safety, pharmacokinetics and pharmacodynamics were evaluated. Results: Sixty-nine patients with DLBCL (n=41) and FL (n=28) were enrolled for treatment at starting doses of 85-110 mg. Median age was 62 years (range: 32 to 81). Median duration of treatment was ~3 months (range: <1 to 24). Objective response rate in DLBCL and FL, respectively, was 7/41 (17%; including 2 unconfirmed PRs) and 3/28 (11%; including 1 CR). Median time to response was 2.0 mos (range 1.7-21.0) and 5.3 mos (range 4.3-6.0) respectively. Stable disease was achieved by 13/41 (32%) and 14/28 (50%), respectively, for a disease control rate of 49% and 61%, respectively. Mean duration of SD in patients with DBLCL was ~4.5 mos (range 2-12 mos), with 10 patients remaining stable for ≥3 mos. Among FL patients, mean duration of SD was approximately 4.1 mos (range 1.7-13 mos), with 9 patients remaining stable for ≥3 mos. The FL CR occurred in a 62-year-old female with paratracheal, subcarinal and portal target lesions who achieved a PR after 4 cycles and CR after 12 cycles that persisted through the remaining 4 mos on study. Study drug was discontinued for adverse events in 19/69 (28%). Fatigue, weight loss or anorexia were most common (n=4 each). A total of 26 drug-related SAEs were reported among 12 patients (17%; 1-6 events per pt). There were no drug related deaths. Enrollment is complete and final data will be presented. Conclusions: Single-agent mocetinostat has activity in DLBCL and FL. Fatigue, gastrointestinal, and cardiac symptoms are the most common adverse events resulting in discontinuation of dosing. Based on the acceptable tolerability and clinical activity further development is warranted. Clinical trial information: NCT00359086.
Impact of time from diagnosis to initiation of curative chemotherapy on survival of patients with diffuse large B-cell lymphoma (DLBCL).
Authors: Hay Kevin A. , Lee Benny , Goktepe Ozge , Connors Joseph M. , Sehn Laurie Helen , Savage Kerry J. , Shenkier Tamara Nina , Klasa Richard John , Villa Diego
Published: March 2020

8552

Background: DLBCL is potentially curable with combination chemotherapy such as CHOP-R. Although it is generally regarded appropriate to start chemotherapy promptly after diagnosis, the impact of the time from diagnosis to treatment initiation on treatment outcome is unknown. Methods: Patients diagnosed with DLBCL and treated with at least one cycle of CHOP-R with curative intent during 2003 – 2008 in British Columbia were identified in the Lymphoid Cancer Database. Additional demographic data were obtained from the BC Cancer Registry. The BC Cancer Agency provincial pharmacy database was used to obtain dates of chemotherapy administration. The impact of the time interval from the date of pathologic diagnosis to treatment on overall survival (OS) and progression-free survival (PFS) was evaluated. Results: A total of 793 patients were identified: 199 (25%) received CHOP-R <2 weeks after diagnosis, 244 (31%) at 2-4 weeks, 293 (37%) at 5-8 weeks, and 57 (7%) at >8 weeks. High international prognostic index, primary mediastinal DLBCL, and hospitalization at the time of CHOP-R start were associated with earlier initiation of chemotherapy (p<0.001 for all factors). Distance to chemotherapy from home (p=0.237), rural vs. urban location (p=0.952), geographic region (p=0.458), and median household income (p=0.127) were not associated to treatment start. Five-year PFS and OS respectively were 54% (SD 4%) and 61% (SD 4%) for treatment <2 weeks, 63% (SD 3%) and 66% (SD 3%) for 2-4 weeks, 70% (SD 3%) and 74% (SD 3%) for 5-8 weeks, and 60% (SD 7%) and for 61% (SD 8%) >8 weeks, p=0.006 (PFS) and p=0.024 (OS). A multivariate analysis demonstrated no significant difference between the groups. Conclusions: In a publicly funded healthcare system, earlier initiation of chemotherapy was strongly associated with poor prognostic factors, as well as inferior PFS and OS. The timing of chemotherapy initiation appears to be related to clinical factors instead of system or socioeconomic barriers. Notwithstanding the lack of detrimental outcomes in those commencing CHOP-R after 8 weeks, clinicians should endeavor to initiate curative chemotherapy as soon as possible after a diagnosis of DLBCL is established.