bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neoadjuvant atezolizumab in resectable NSCLC patients: Updated clinical and immunophenotyping results from a multicenter trial.
Authors: Oezkan Filiz , He Kai , Owen Dwight Hall , Pietrzak Maciej , Rusch Valerie W. , Chaft Jamie E. , Kitzler Rhonda , Nicholas Alan , Schulze Katja , Johnson Ann , Phan See , Bunn Paul A. , Kris Mark G. , Kwiatkowski David J. , Johnson Bruce E. , Wistuba Ignacio Ivan , Lee Jay M. , Hirsch Fred R. , Lozanski Gerard , Carbone David Paul 
Published: July 2019

99 Background: Targeting PD-L1/PD-1 to activate anti-tumor immunity is associated with improved response and survival compared to chemo in NSCLC pts. We present a preliminary analysis of the clinical efficacy, safety and peripheral blood (PB) immunophenotyping from an ongoing multicenter atezolizumab (atezo) neoadjuvant immunotherapy study in resectable NSCLC. Methods: Pts received 2 cycles of atezo, 1200mg, days 1, 22 before resection. Tumor biopsies and PB were obtained pre-atezo & pre-surgery. The biomarker evaluable population (BEP) included pts with paired PB analyzed within 72 hrs by 10-color flow cytometry (IMMUNOME) and major pathological response (MPR) assessment (defined as ≤ 10% residual tumor). The primary endpoint was MPR. Secondary endpoints included safety, MPR by PD-L1, OS, and DFS. Immunophenotypic analyses were correlated with treatment, MPR and PD-L1 expression. Results: 116 patients have been enrolled as of October 31, 2018 and here we report on 54 of 180 planned pts with follow-up through surgery. 15 pts had Gr 3-4 AEs (3 treatment related), one Gr 5 AE (sudden death) was unrelated. By RECIST there were 3 PR, 49 SD, and 2 PD. 50/54 pts underwent the planned surgery, 47 pts had MPR assessment: 4 pts discontinued study preop (2 radiographic PD, 2 other reasons); 3 were unresectable. Excluding 5 pts with EGFR or ALK mutations, MPR rate was 10/45 (22%, 95% CI 11-37%). Baseline PD-L1 status was evaluable in 44/54 pts; BEP included 31 pts, 23 had tissue PD-L1 status: 16 PD-L1+. We observed significant increases in natural killer (NK) cells, CD8+ T-cells, Th1-response related dendritic cells (DC), and decreases in B-cells after atezo. Non-MPR pts showed significant increases in late activated NK cells, monocytic myeloid cells and Th2 and Th17-response–related DCs. PD-L1+ pts showed significant decreases of senescent T cells, monocytic myeloid cells, and increases of Th1-response–related DCs. We analyzed 22/54 tumor pairs, PD-L1+ cells increased in most pts after atezo treatment. Conclusions: Neoadjuvant atezo was well tolerated and the MPR rate is encouraging. Preliminary immunophenotyping data showed significant changes in PB with immunotherapy. Clinical trial information: NCT02927301.
A study of REGN3767, an anti-LAG-3 antibody, alone and in combination with cemiplimab (REGN2810), an anti-PD1 antibody in advanced cancers.
Authors: Papadopoulos Kyriakos P. , Lakhani Nehal , Johnson Melissa Lynne , Park Haeseong , Wang Ding , Yap Timothy A. , Moore Kathleen N. , Sims Tasha Nicholle , Emeremni Chetachi A. , Karasarides Maria , Kroog Glenn S. 
Published: July 2019

TPS41 Background: Lymphocyte activation gene 3 (LAG-3) is an immune checkpoint receptor with a biological role in T-cell regulation. Analysis of immune-cell infiltrates from human tumors show that a subset of CD4+ and/or CD8+ cells co-express LAG-3 and PD-1 and may be associated with decreased T-cell effector function and tumor escape (Baitsch, 2011; Jie, 2013). Preclinical models provide evidence that dual inhibition of LAG-3 and PD-1 blockade offer synergistic anti-tumor effects and suggest a promising immunotherapy combination that warrants clinical investigation (Woo, 2012). This first in human study will evaluate the safety and efficacy of REGN3767 alone and in combination with cemiplimab in advanced malignancies. Methods: Phase 1 study enrolling patients with advanced malignancies. Dose escalation phase employs a modified 3+3 (4+3) design to assess the tolerability and pharmacokinetics (PK) of REGN3767 monotherapy and in combination with cemiplimab. Monotherapy and combination therapy are exploring multiple escalating REGN3767 dose levels. After tolerability and PK evaluation, doses of REGN3767 will be selected for monotherapy and combination therapy tumor-specific expansion cohorts. Solid tumor expansion cohorts will enroll per Simon’s two-stage design to evaluate safety and preliminary efficacy. Lymphoma expansion cohorts will enroll 15 patients. Patients who are anti-PD-1/PD-L1 therapy naïve and experienced are eligible for separate cohorts. Patients previously exposed to anti-LAG-3 therapy are not eligible. The primary objectives are the determination of the recommended dose for expansion (dose escalation) and ORR (dose expansion). Secondary objectives include characterization of PK and immunogenicity in all patients, as well as anti-tumor efficacy in dose escalation, and safety in dose expansion. This trial is actively enrolling eligible patients in the US, UK, Ireland, and South Korea. 1. Baitsch L et al. J Clin Investig. 2011;121:2350–2360. 2. Jie HB et al. Br J Cancer. 2013;109:2629–2635. 3. Woo SR et al. Cancer Res. 2012;72(4): 917–927. Clinical trial information: NCT03005782.
Phase I study of durvalumab and tremelimumab together with radiotherapy for the adjuvant treatment of intermediate-risk head and neck squamous cell carcinoma.
Authors: Sheth Siddharth , Chera Bhishamjit S. , Vincent Benjamin Garrett , Shen Colette J. , Weissler Mark Christian , Blumberg Jeffrey , Patel Samip , Zanation Adam M. , Yarbrough Wendell Gray , Patel Shetal Arvind , Grilley-Olson Juneko E. , Hackman Trevor , Weiss Jared 
Published: July 2019

TPS73 Background: When surgery is used as the primary therapeutic modality for locally-advanced HNSCC, radiation therapy (XRT) is frequently recommended post-operatively due to high rates of recurrence. In high-risk patients; i.e., those with positive surgical margins or extra-nodal extension (ENE) on surgical pathology, the addition of chemotherapy to post-operative XRT (cCRT) provides a survival benefit. In contrast, there is no standard indication for adjuvant systemic therapy in intermediate risk HNSCC—defined in this study as having a T3/T4 primary tumor, perineural or lymphovascular space invasion, and/or lymph node metastasis without ENE. The anti-programmed cell death-ligand 1 (PD-L1) antibody durvalumab (D) has a manageable safety profile and encouraging clinical activity studies across multiple tumor types. Combining D with the anti-cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody tremelimumab (T) may amplify antitumor T-cell responses and provide synergistic activity. D+T showed antitumor activity and manageable tolerability in advanced NSCLC. Furthermore in preclinical studies, D+T combined with XRT decreased regulatory T-cells and myeloid derived suppressor cells and increased CD8 T-cell recruitment to the tumor microenvironment. Methods: This two-part phase I study will include a safety run-in period using a 3+3 dose de-escalation design based on dose limiting toxicities (DLT). In Cohort 1, D (q3 weeks) +T (q3 weeks) will be given on cycle 1 followed by concurrent XRT for Cycles 2-4. Cycle 5 and 6 will include D only. If DLT’s are met, Cohort -1 will include D (q3 weeks) and T (q6 weeks). If DLT's are found in Cohort -1, Cohort -2 would include only D. A dose expansion cohort (N=24) will follow based on the safest combination in the safety run-in. Translational studies include correlation of pre-treatment immune characteristics including PD-L1 score, TMB, and IFN-gamma signature with disease free survival. DNA and RNA sequencing of pre-treatment tissue and at treatment failure/recurrence will attempt to identify genetic and molecular determinants of IO treatment resistance. (NCT02000947). Clinical trial information: NCT03529422.
Adultification of Black Children in Pediatric Anesthesia
Authors: Baetzel Anne , Brown David J. , Koppera Prabhat , Rentz Andrea , Thompson Aleda , Christensen Robert 
Published: July 2019

BACKGROUND:
Unconscious racial bias in anesthesia care has been shown to exist. We hypothesized that black children may undergo inhalation induction less often, receive less support from child life, have fewer opportunities to have a family member present for induction, and receive premedication with oral midazolam less often.

METHODS:
We retrospectively collected data on those <18 years of age from January 1, 2012 to January 1, 2018 including age, sex, race, height, weight, American Society of Anesthesiologists (ASA) physical status, surgical service, and deidentified anesthesiology attending physician. Outcome data included mask versus intravenous induction, midazolam premedication, child life consultation, and family member presence. Racial differences between all outcomes were assessed in the cohort using a multivariable logistic regression model.

RESULTS:
A total of 33,717 Caucasian and 3901 black children were eligible for the study. For the primary outcome, black children 10–14 years were 1.3 times more likely than Caucasian children to receive mask induction (adjusted odds ratio [AOR], 1.3; 95% confidence interval [CI], 1.1–1.6; P = .001). Child life consultation was poorly documented (<0.5%) and not analyzed. Black children <15 years of age were at least 31% less likely than Caucasians to have a family member present for induction (AOR range, 0.4–0.6; 95% CI range, 0.31–0.84; P < .010). Black children <5 years of age were 13% less likely than Caucasians to have midazolam given preoperatively (AOR, 0.9; 95% CI, 0.8–0.9; P = .012).

CONCLUSIONS:
This study suggests that disparities in strategies for mitigating anxiety in the peri-induction period exist and adultification may be 1 cause for this bias. Black children 10 to 14 years of age are 1.3 times as likely as their Caucasian peers to be offered inhalation induction to reduce anxiety. However, black children are less likely to receive premedication with midazolam in the perioperative period or to have family members present at induction. The cause of this difference is unclear, and further prospective studies are needed to fully understand this difference.
Continuous Noninvasive Hemoglobin Monitoring Reflects the Development of Acute Hemodilution After Consecutive Fluid Challenges
Authors: Bubenek-Turconi Şerban Ion , Văleanu Liana , Popescu Mihai , Panaitescu Eugenia , Tomescu Dana , Cacoveanu Mihai Cătălin , Perel Azriel 
Published: July 2019

BACKGROUND:
Consecutive fluid challenges (FCs) are frequently administered to maximize the stroke volume (SV) as part of a goal-directed therapy (GDT) strategy. However, fluid administration may also cause acute hemodilution that might lead to an actual paradoxical decrease in oxygen delivery (DO2). The aim of this study was to examine whether continuous noninvasive hemoglobin (SpHb) monitoring can be used to detect the development of acute hemodilution after graded fluid administration.

METHODS:
In 40 patients who underwent major vascular or gastrointestinal surgery, an FC, consisting of 250 mL colloid solution, was administered. When the SV increased by ≥10%, the FC was repeated up to a maximum of 3 times. Laboratory-measured hemoglobin concentrations (BHb), SpHb, SV, cardiac output (CO), and DO2 values were recorded after each FC.

RESULTS:
All 40 patients received the first FC, 32 patients received the second FC, and 20 patients received the third FC (total of 750 mL). Out of the 92 administered FCs, only 55 (60%) caused an increase in SV ≥10% (“responders”). The first and the second FCs were associated with a significant increase in the mean CO and DO2, while the mean SpHb and BHb decreased significantly. However, the third and last FC was associated with no statistical difference in CO and SV, a further significant decrease in mean SpHb and BHb, and a significant decrease in DO2 in these patients. Compared to their baseline values (T0), BHb and SpHb decreased by a mean of 5.3% ± 4.9% and 4.4% ± 5.2%, respectively, after the first FC (T1; n = 40), by 9.7% ± 8.4% and 7.9% ± 6.9% after the second FC (T2; n = 32), and by 14.5% ± 6.2% and 14.6% ± 5.7% after the third FC (T3; n = 20). Concordance rates between the changes in SpHb and in BHb after the administration of 250, 500, and 750 mL colloids were 83%, 90%, and 100%, respectively.

CONCLUSIONS:
Fluid loading aimed at increasing the SV and the DO2 as part of GDT strategy is associated with acute significant decreases in both BHb and SpHb concentrations. When the administration of an FC is not followed by a significant increase (≥10%) in the SV, the DO2 decreases significantly due to the development of acute hemodilution. Continuous noninvasive monitoring of SpHb does not reflect accurately absolute BHb values, but may be reliably used to detect the development of acute hemodilution especially after the administration of at least 500 mL of colloids.
Bone and lymph node metastases from occult mammary carcinoma: a case report of carcinoma of unknown primary (CUP) Syndrome
Authors: Cattafi Antonino , Santarpia Mariacarmela , Micalizzi Martina Francesca , Sofia Carmelo , Condorelli Elvira , Dottore Alessia , Altavilla Giuseppe , Blandino Alfredo , Ascenti Giorgio , Marino Maria Adele 
Published: July 2019

Cancer of unknown provenance is a rare disease, accounting approximately for up to 1% of all breast cancers. A 68-year-old female was admitted to the Medical Oncology Unit of Policlinico Universitario G.Martino because of diffused bone-involvement, with mixed (osteolytic/osteoblastic) features, which interested almost every skeletal structure of the body (vertebral bodies of the entire column, costal skeleton, sternum, proximal third of both humeri, scapulae, clavicles, pelvis and femurs), suspicious for metastatic disease.
Pipeline analysis of a vaccine candidate portfolio for diseases of poverty using the Portfolio-To-Impact modelling tool
Authors: Gunn Alexander , Bandara Shashika , Yamey Gavin , D´Alessio Flavia , Depraetere Hilde , Houard Sophie , Viebig Nicola K , Jungbluth Stefan 
Published: July 2019

Background: The Portfolio-To-Impact (P2I) P2I model is a recently developed product portfolio tool that enables users to estimate the funding needs to move a portfolio of candidate health products, such as vaccines and drugs, along the product development path from late stage preclinical to phase III clinical trials, as well as potential product launches over time. In this study we describe the use of this tool for analysing the vaccine portfolio of the European Vaccine Initiative (EVI). This portfolio includes vaccine candidates for various diseases of poverty and emerging infectious diseases at different stages of development. Methods: Portfolio analyses were conducted using the existing assumptions integrated in the P2I tool, as well as modified assumptions for costs, cycle times, and probabilities of success based on EVI’s own internal data related to vaccine development. Results: According to the P2I tool, the total estimated cost to move the 18 candidates currently in the EVI portfolio along the pipeline to launch would be about US $470 million, and there would be 0.69 cumulative expected launches during the period 2019-2031. Running of the model using EVI-internal parameters resulted in a significant increase in the expected product launches. Conclusions: The P2I tool's underlying assumptions could not be tested in our study due to lack of data available. Nevertheless, we expect that the accelerated clinical testing of vaccines (and drugs) based on the use of controlled human infection models that are increasingly available, as well as the accelerated approval by regulatory authorities that exists for example for serious conditions, will speed up product development and result in significant cost reduction. Project findings as well as potential future modifications of the P2I tool are discussed with the aim to improve the underlying methodology of the P2I model.
Efficacy of a bacterial fluorescence imaging device in an outpatient wound care clinic: a pilot study
Authors: Hurley Ciaran M. , McClusky Pat , Sugrue Ryan M. , Clover James A. , Kelly Jason E. 
Published: July 2019

Objective: Subsurface bacterial burden can be missed during standard wound examination protocols. The real-time bacterial fluorescence imaging device, MolecuLight i:X, visualises the presence of potentially harmful levels of bacteria through endogenous autofluorescence, without the need for contrast agents or contact with the patient. The intended use of the imaging device is to assist with the management of patients with wounds by enabling real-time visualisation of potentially harmful bacteria. The aim of this study was to establish the accuracy of the wound imaging device at detecting pathogenic bacteria in wounds. Methods: A single-centre, prospective observational study was conducted in Cork University Hospital in an outpatient plastic surgery wound care clinic. Patients had their wounds photographed under white and autofluorescent light with the imaging device. Auto-fluorescent images were compared with the microbiological swab results. Results: A total of 33 patients and 43 swabs were included, of which 95.3% (n=41) were positive for bacteria growth. Staphylococcus aureus was the most common bacterial species identified. The imaging device had a sensitivity of 100% and specificity of 78% at identifying pathological bacteria presence in wounds on fluorescent light imaging. The positive predictive value (PPV) was 95.4%. The negative predictive value (NPV) was 100%. It demonstrated a sensitivity and specificity of 100% at detecting the presence of Pseudomonas spp. Conclusion: The imaging device used could be a safe, effective, accurate and easy-to-use autofluorescent device to improve the assessment of wounds in the outpatient clinic setting. In conjunction with best clinical practice, the device can be used to guide clinicians use of antibiotics and specialised dressings.
Cost-effectiveness of soluble beta-glucan gel in hard-to-heal wounds: an evaluation
Authors: Elg Fredrik , Posnett John , Hunt Sharon 
Published: July 2019

Objective: To evaluate the cost-effectiveness of a soluble beta-glucan-containing gel as short-term adjunct therapy in the treatment of hard-to-heal wounds in a UK community health-care setting. Methods: A comparative clinical evaluation involving consecutive patients treated for up to eight weeks with a beta-glucan-containing gel as adjunct to standard care. This was compared with consecutive patients as retrospective controls, and using the same standard care protocol from a year previously. The inclusion criteria was wounds that were slow-healing or stalled (<40% healing in four weeks). Results: A total of 300 patients took part. Complete follow-up at 24 weeks was available for 144 patients in the beta-glucan group, and 136 patients in the standard care group. At 24 weeks, the beta-glucan group had a 96% healing rate compared with 75% in the standard care group (p<0.001). The improvement in healing was associated with a reduction in the mean number of weeks of treatment per patient (7.2 and 10.7 for beta-glucan and standard care, respectively), and a reduction in the mean cost of treatment (£576 versus £685 for beta-glucan and standard care, respectively). Treatment costs included nursing time, prescription medications and dressings. In a subset of ulcer wounds (50% of the full sample), at 24 weeks the beta-glucan group had a 92% healing rate compared with 46% in the standard care group (p<0.001). Mean weeks of treatment were 10.4 versus 17.6, leading to a reduction in treatment cost of £388 per patient (£1227 versus £839) over 24 weeks. Conclusion: The results of this evaluation suggest that short-term use of the beta-glucan gel as an adjunct to standard care on slow-healing wounds can shorten healing times and reduce NHS costs.
Cysteine/cystine-rich undenatured whey protein supplement in patients' pressure ulcers outcomes: an open label study
Authors: Gutman Jimmy B.L. , Kongshavn Patricia A.L. 
Published: July 2019

Objective: The prevalence and costs associated with treating pressure ulcers (PU) are at high levels. Frequently, PUs heal slowly or not at all, which may be due to the patient's catabolic state which may include protein energy malnutrition. The objective of this open label clinical trial was to improve healing rates by providing patients with a patented, high-quality protein containing all essential amino acids to ensure positive nitrogen balance. An additional benefit of this protein is the delivery of bioavailable cysteine (cystine) to promote glutathione (GSH) synthesis which supports immune function and heightens antioxidant defences. Methods: Patients with category II, III and IV PUs were fed 20g BID whey protein dietary supplement for 16–120 days, without change in ongoing ‘best practice’ PU management and their progress recorded. Results: A total of 10 patients were recruited, with an average age of 77 years. Most had shown no improvement in healing for ≥2 months before treatment and usually had other complications including chronic obstructive pulmonary disease (COPD), diabetes and various cardiovascular diseases. There were a total of 23 PUs, with some patients having more than one. Of these, 44% (n=10) showed complete resolution 83% (n=19) had better than 75% resolution over the observation period. Healing rates ranged from 16.9–0.2cm2/month (healed PUs) and 60.0–1.6cm2/month for resolving PUs. Conclusion: By providing the necessary amino acids to rebuild tissues and bioactive cysteine (cystine) to promote synthesis of intracellular GSH and positive nitrogen balance, improvement in PUs healing was achieved.
Once-Per-Visit Alerts: A Means to Study Alert Compliance and Reduce Repeat Laboratory Testing
Authors: Szymanski Jeffrey J , Qavi Abraham J , Laux Kari , Jackups Ronald 
Published: July 2019

Abstract

BACKGROUND
Clinical decision support alerts for laboratory testing have poor compliance. Once-per-visit alerts, triggered by reorder of a test within the same admission, are highly specific for unnecessary orders and provide a means to study alert compliance.

METHODS
Once-per-visit alerts for 18 laboratory orderables were analyzed over a 60-month period from September 2012 to October 2016 at a 1200-bed academic medical center. To determine correlates of alert compliance, we compared alerts by test and provider characteristics.

RESULTS
Overall alert compliance was 54.5%. In multivariate regression, compliance correlated with length of stay at time of alert, provider type, previous alerts in a patient visit, test ordered, total alerts experienced by ordering provider, and previous order status.

CONCLUSIONS
A diverse set of provider and test characteristics influences compliance with once-per-visit laboratory alerts. Future alerts should incorporate these characteristics into alert design to minimize alert overrides.
SEMINORM PADA RUANG FUNGSI TERINTEGRAL DUNFORD
Authors: Solikhin Solikhin , Sumanto Y.D. , Aziz Abdul 
Published: July 2019

This article discussed the seminorm on Dunford integrable functional space. We show that the set of all Dunford integrable functions is linear space. The results were shown that $\left( D[a,b],\ \left\| \ \cdot \ \right\| \right)$ is a seminorm space with function defined by $\left\| f \right\|=\underset{\begin{smallmatrix} {{x}^{*}}\in {{X}^{*}} \\ \left\| {{x}^{*}} \right\|\le 1 \end{smallmatrix}}{\mathop{\sup }}\,\ \left\{ \underset{E\subset [a,b]}{\mathop{\sup }}\,\,\left| \left( L \right)\int\limits_{E}{{{x}^{*}}f} \right| \right\}$. Furthermore, $\left( D[a,b],\ d \right)$ is a pseudomatrix space with function defined by $d\left( f,g \right)=\left\| f-g \right\|=\underset{\begin{smallmatrix} {{x}^{*}}\in {{X}^{*}} \\ \left\| {{x}^{*}} \right\|\le 1 \end{smallmatrix}}{\mathop{\sup }}\,\ \left\{ \underset{E\subset [a,b]}{\mathop{\sup }}\,\,\left| \left( L \right)\int\limits_{E}{{{x}^{*}}\left( f-g \right)} \right| \right\}$.