bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endoscopic lung volume reduction coil treatment in patients with very low FEV1: an observational study
Authors: Simon Marcel , Harbaum Lars , Oqueka Tim , Kluge Stefan , Klose Hans 
Published: February 2018

Background: Endoscopic lung volume reduction coil (LVRC) treatment is a therapeutic option for selected patients with advanced emphysema. The effects and the safety of endoscopic lung volume reduction in patients with very low forced expired volume in one second (FEV1) remain to be determined. This study was conducted to assess the effects and the safety of LVRC treatment in patients with very low FEV1. Methods: The study was performed as a retrospective observational study in the Department of Respiratory Medicine at the University Medical Center Hamburg-Eppendorf on patients with very low FEV1, defined as an FEV1 ⩽ 20% of predicted at baseline in whom LVRC treatment was performed between 1 April 2012 and 28 February 2017. Results: LVRC treatment was performed in 33 patients with very low FEV1. Of these, 45.5% were female and 54.5% were male. At baseline, mean FEV1 was 0.46 ± 0.12 liters (15 ± 3% of predicted), mean forced vital capacity (FVC) was 1.61 ± 0.62 liters (42 ± 13% of predicted), mean residual volume (RV) was 6.03 ± 0.81 liters (275 ± 51% of predicted) and 6-minute walk distance was 229 ± 102 m. Bilateral LVRC treatment was completed in 21 of these patients (63.6%). Bilateral LVRC treatment led to significant improvements in functional parameters with an increase in mean FEV1 from 0.44 ± 0.11 liters to 0.54 ± 0.12 liters ( p = 0.001), equivalent to a relative improvement of 24.5 ± 26.9%, an increase in mean FVC from 1.49 ± 0.54 liters to 1.84 ± 0.49 liters ( p = 0.001), a decrease in mean RV from 6.27 ± 0.83 liters to 5.83 ± 1.09 liters ( p = 0.004) and an improvement in 6-minute walk distance from 218 ± 91 m to 266 ± 96 m ( p = 0.01). There were no cases of respiratory failure requiring mechanical ventilation and no deaths. Conclusions: LVRC treatment was effective and safe in patients with very low FEV1.
Topical Anesthesia in 27-Gauge Pars Plana Vitrectomy
Authors: Jeroudi Abdallah M. , Shieh Wen-Shi , Chen Yicheng , Connors Daniel B. , Blinder Kevin J. , Shah Gaurav K. 
Published: February 2018

Purpose: To explore the safety, comfort, and feasibility of topical anesthesia in 27-gauge pars plana vitrectomy surgery. Methods: A prospective, observational case series of 37 nonconsecutive patients undergoing 3-port, 27-gauge pars plana vitrectomy under topical anesthesia with lid block from July 2016 to March 2017 with a single surgeon was performed. Topical anesthesia was achieved with proparacaine 0.5% drops and 2% lidocaine gel. Surgery was performed for select indications with carefully selected patients amenable to topical anesthesia. Patients were queried and observed to identify the most painful steps of the case and to rate their intraoperative and postoperative pain scores on a 1- to 10-point pain scale. Results: The mean intraoperative pain score was 2.1 with the most painful steps rated as scleral depression (37.8%), trocar/cannula insertion (24.3%), and conjunctival coaptation (24.3%). When correlating the overall intraoperative pain score with the self-identified most painful step, the mean pain scores were highest for endolaser (2.6), scleral depression (2.1), conjunctival coaptation (2.1), and trocar/cannula insertion (1.6). Supplemental intravenous anesthesia was requested once by the surgeon in 54% of the cases. No rescue with local infiltrative anesthesia was required. The mean pain scores were 0.7 and 0 at postoperative day 1 and week 1. No intraoperative or postoperative complications were encountered. Conclusions: Topical anesthesia for 27-gauge pars plana vitrectomy is a safe and feasible anesthesia option for carefully selected patients for certain surgical indications.
Effective Treatment of Choroidal Metastasis With ALK Inhibitor Chemotherapy That Crosses the Blood–Brain Barrier
Authors: Possin Michael , Altaweel Michael 
Published: February 2018

Purpose: We report a case of metastatic non-small cell lung cancer (NSCLC) with choroidal metastasis, which responded to oral ensartinib. Methods: Retrospective case report on a 44-year-old male with a past medical history significant for metastatic NSCLC with a positive anaplastic lymphoma kinase (ALK) translocation that was treated for 4 years with oral crizotinib systemically, and bevacizumab intravitreal injections for management of subretinal fluid associated with a left macular choroidal metastasis. The vision was maintained at 20/25 to 20/40, but there was steady growth in the breadth and thickness of the choroidal lesion. Results: Two months after starting daily oral ensartinib, his vision improved from 20/40 to 20/20. His lesion decreased significantly in size, with resolution of his subretinal fluid, and has not required any additional bevacizumab intravitreal injections in the 8 months since starting ensartinib. Conclusion: Ensartinib may be beneficial in the treatment of choroidal metastases in patients with NSCLC with ALK mutations.
Depth and durability of response to ibrutinib in CLL: 5-year follow-up of a phase 2 study
Authors: Ahn Inhye E. , Farooqui Mohammed Z. H. , Tian Xin , Valdez Janet , Sun Clare , Soto Susan , Lotter Jennifer , Housel Stephanie , Stetler-Stevenson Maryalice , Yuan Constance M. , Maric Irina , Calvo Katherine R. , Nierman Pia , Hughes Thomas E. , Saba Nakhle S. , Marti Gerald E. , Pittaluga Stefania , Herman Sarah E. M. , Niemann Carsten U. , Pedersen Lone B. , Geisler Christian H. , Childs Richard , Aue Georg , Wiestner Adrian 
Published: February 2018

Key Points
With 5-year median follow-up, continuous single-agent ibrutinib therapy was well tolerated with deepening of response. Previously untreated patients, even those with TP53 aberration, achieved durable responses.
Cyber-physical-system-based smart water system to prevent flood hazards
Authors: Yang Tsun-Hua , Yang Sheng-Chi , Kao Hong-Ming , Wu Ming-Chang , Hsu Hao-Ming 
Published: February 2018

Abstract
Background
Extreme weather and climate events such as super typhoons and unprecedented recorded high intensity rainfall events have increased in recent years due to climate change. Such extreme weather events generate floods and cause loss of life and property. Therefore, efficient strategies and measures for flood mitigation and prevention are essential. Computer-aided techniques can increase the speed of emergency response and reduce the impacts of a flood.

Methods
This study applied the cyber-physical system concept to develop a smart flood information system, called Dayu Smart Water System. The system includes an on-site monitoring network and software for rapid flood modeling to provide updated information. With the utilization of Internet of Things and artificial intelligence, the system not only provides forecast information but also plays an active role by enabling users to take emergency response measures before, during, and after a flood. The system is aimed at accelerating emergency responses during a flood without requiring any human intervention.

Results
The system was deployed in a high-tech industrial park in central Taiwan. Experimental results revealed that the system could increase the response efficiency of the emergency operations center during a few extreme events in 2017. To enable the system to respond to a wide range of flood induced threats in a more effective manner, a few advanced functions are under development and discussed in this paper.

Conclusions
This study utilized Dayu Smart Water System that integrates on-site monitoring sensors and advanced modeling tools to provide optimal flood forecasts. However, the proposed system has implemented only the first three levels—connection, conversion, and cyber levels. The higher the number of levels is, the more added value is the system provides. The fourth and fifth levels, namely the cognition and configuration levels, were not discussed in the study. Further developments in these two levels will be conducted.
Phenotypic differences in tumor-associated macrophages between metastatic and primary sites of clear cell renal cell carcinoma.
Authors: Miura Yuji , Motoshima Takanobu , Wakigami Nanako , Kusada Natsuki , Okaneya Toshikazu , Inoshita Naoko , Takano Toshimi , Kamba Tomomi , Komohara Yoshihiro 
Published: February 2018

105 Background: Tumor-associated macrophages (TAMs) are one of the key contributors to the tumor microenvironment and are phenotypically differentiated into M1 and M2 macrophages. M1 macrophages stimulate anti-tumor immune responses, whereas M2 macrophages promote immunosuppression and are associated with tumor progression in clear cell renal cell carcinoma (ccRCC). However, little information is available regarding the difference in TAM polarization between primary and metastatic lesions of ccRCC. Methods: We collected paired samples of primary and matched metastatic sites from the first recurrence in 41 metastatic ccRCC patients. Immunohistochemistry (IHC) for Iba1, which is a common pan-macrophage marker, and CD163 and CD204, which are considered to be M2 macrophage markers, was performed on all paired samples. Results: Thirty-three paired primary and metastatic samples were available for IHC assessment in this analysis. The most common metastatic sites were lung (N = 26, 78.8 %) and lymph node (N = 3, 9.1 %). The mean (± standard deviation) cell density of Iba1+ TAMs was higher in metastatic lesions than in primary lesions (756 ± 267 mm2 vs. 581 ± 155 mm2, P = 0.0012). By contrast, the ratio of CD163+ and CD204+ to Iba1+ TAMs was significantly lower in metastatic lesions than in primary lesions (0.76 ± 0.30 vs. 0.90 ± 0.24, P = 0.0067 and 0.39 ± 0.27 vs. 0.67 ± 0.29, P = 0.0001, respectively). The median overall survival of patients with high- vs. low-density Iba1+, CD163+, and CD204+ TAMs in metastatic lesions was 120 vs. 92 months (log-rank P = 0.67), 120 vs. 58 months (log-rank P = 0.056), and 120 vs. 92 months (log-rank P = 0.35), respectively. Conclusions: TAMs in the metastatic lesions of ccRCC polarized towards an M1-like phenotype, although the total number of TAMs was greater in metastatic compared with primary lesions. The cell density of Iba1+, CD163+, and CD204+ TAMs in metastatic sites was not associated with overall survival in patients with ccRCC.
Serial changes in PD1/PDL1 expression in metastatic urothelial carcinoma (mUC) patients (pts) treated with immune checkpoint blockade (CPB).
Authors: Tzeng Alice , Diaz-Montero C. Marcela , Rayman Patricia A. , Kim Jin Sub , Pavicic Paul G , Finke James , Barata Pedro C. , Lamenza Marcelo , Devonshire Sarah , Schach Kim , Emamekhoo Hamid , Ernstoff Marc S. , Hoimes Christopher J. , Rini Brian I. , Garcia Jorge A. , Gilligan Timothy D. , Ornstein Moshe Chaim , Grivas Petros 
Published: February 2018

109 Background: Since CPB may alter immune marker expression in key immunomodulatory populations such as myeloid-derived suppressor cells (MDSC) and CD8+ cytotoxic T lymphocytes (CTL), we evaluated PD1/PDL1 expression in longitudinal samples from mUC pts treated with CPB. Methods: Serial peripheral blood samples were collected from mUC pts who received CPB. PD1/PDL1 and VISTA expression was measured in MDSC (CD33+HLADR−) and CTL (CD8+CD4−) from live peripheral blood mononuclear cells using flow cytometry. MDSC subsets were further defined as (G)ranulocytic (CD15+CD14−), (M)onocytic (CD15−CD14+), and (I)mmature (CD15−CD14−). PD1/PDL1 and VISTA expression was presented as % of each MDSC subset or CTL. Wilcoxon signed-rank tests and mixed-model regression analyses were performed to assess changes in immune marker expression after CPB. Results: Of 30 CPB-treated pts with ≥ 2 blood samples for analysis, 21 received anti-PDL1 (20 atezolizumab/1 avelumab; [A]) and 9 received anti-PD1 (pembrolizumab [P]). Median age at diagnosis was 69.5 (4681), 77% men, 33% never smokers, 63% pure UC, 70% bladder primary, 20% prior intravesical BCG, 37% prior neoadjuvant chemotherapy, 63% prior cystectomy. Best overall responses to CPB were 3 PR/13 SD/5 PD (A) and 1 CR/1 PR/4 SD/3 PD (P). Successive doses of A correlated with decreased %PDL1+ M-MDSC, while those of P correlated with decreased %PD1+ M- and I- MDSC (Table). No significant changes in VISTA expression were detected. In 11 A-treated pts with samples before/after the 1st dose, %PDL1+ M- and I- MDSC decreased (median change −25.5 and −5.7; p = 0.02 and 0.03) and %PD1+ CTL increased (median change +2.4; p = 0.02) between 1st and 2nd samples. Conclusions: In this mUC pt cohort, distinct post-tx changes in %PD1/PDL1 in MDSC subsets and CTL occurred based on CPB (anti-PD1 vs anti-PDL1). Further analysis of correlations between CPB, immune marker expression, clinicopathologic factors, and outcomes is ongoing in a larger cohort. Mean absolute change in marker expression per dose in pts treated with CPB. [Table: see text]
RNAScope as a platform to detect IDO1 expression in tumor tissue sections.
Authors: Pratta Michael 
Published: February 2018

116 RNAScope is a sensitive, specific platform to detect IDO1 expression in tumor tissue sections. M Pratta, M Rupar, P Waeltz, T Burn, G Hollis, M Covington, M Smith, and R Newton. Incyte Corp. Wilm. DE. Background: Indoleamine 2,3-Dioxygenase 1 (IDO1) catalyzes the primary and rate-limiting step in tryptophan catabolism to generate N-formyl-kynurenine (Kyn). Through a combination of local depletion of tryptophan and an increase in Kyn concentrations, IDO-1 activity can result in the suppression of antitumor immune responses. Because IDO-1 inhibitors are now in the clinic for treatment of multiple tumor types, immunohistological approaches are employed to demonstrate IDO1 expression in tumor biopsies. However, using a commercially available antibody to detect IDO1 by immunohistochemistry (IHC), the level of sensitivity was inadequate. Methods: In order to improve the sensitivity of IDO1 detection, we evaluated in situ hybridization (ISH) using RNAScope technology and digital quantitation by HALO analysis in collaboration with Advanced Cell Diagnostics (ACD). The technology was cross-validated using IDO1 qRT-PCR, Western blot, and activity analysis and compared with standard IHC. We initially evaluated IDO1 expression in HeLa cells stimulated with various concentrations of IFNγ, and then extended the observations using tissue sections from multiple tumor types. Results: In the HeLa cell model, IFNγ induced a time- and concentration-dependent increase of IDO1 at the mRNA, protein, and activity level. Although IDO1 was successfully detected in the HeLa cell samples by IHC, comparison of the platforms indicated IFNγ EC50 values were in strong agreement between RNAScope (193.8 pg/ml) and Western blot analysis (170.8 pg/ml), but was much higher by IHC analysis (2206 pg/ml). A strong positive correlation (*p < 0.0001) between RNAScope and Western blot analysis was observed, suggesting a highly coordinated induction of IDO1 by IFNγ at both the mRNA and protein levels. FFPE tumor tissue from melanoma, HNSCC, bladder, renal, ovarian, and lung cancers visualized by RNAScope all show varying levels of IDO1 expression. Conclusions: These data support the use of RNAScope for the analysis of IDO1 expression in clinical trials.
Clinical significance of PD-L1 levels in plasma-derived exosomes in head and neck cancer.
Authors: Theodoraki Marie-Nicole , Yerneni Sai Gopal Krishna , Whiteside Theresa 
Published: February 2018

117 Background: Despite the broad spectrum of available therapies, HNSCC patients have poor outcome due to locoregional recurrence. Mechanisms responsible for immune suppression include activities of checkpoint receptors/ligands. HNSCCs with high expression levels of PD-L1 have especially poor outcome. Thus, PD-1 and PD-L1 inhibitors show potential as anticancer strategies. However, many patients with PD-L1+ HNSCC don’t benefit from checkpoint inhibitor therapy, suggesting that PDL-1 expression on tumors is not the only factor predictive of response. Tumor derived exosomes carry numerous immunosuppressive molecules and deliver them to recipient immune cells. We have demonstrated that elevated levels of circulating immunosuppressive exosomes play a key role in immune suppression and disease progression. Here, we show that surface PD-L1 on exosomes is responsible for these effects. Methods: Exosomes were isolated from plasma of 40 HNSCC patients by mini size exclusion chromatography, captured on beads using anti-CD63 Abs, stained for PD-1 and PD-L1 and analyzed by flow cytometry. Percentages of PD-L1+ and PD-1+ exosome/bead complexes were correlated with clinicopathological data. PD-L1high or PD-L1low exosomes were incubated with activated human CD8 T-cells ± PD-1 inhibitor and CD69 expression levels on T-cells were measured. Patients’ plasma was tested for soluble PD-L1 by ELISA. Results: The PD-L1 surface expression on exosomes correlated with patient’s disease activity, UICC stage and lymph node status with p values ranging from 0.0008-0.013. In contrast, plasma PD-L1 levels didn't correlate with any parameters. Exosome PD-1 levels were not informative. T-cell activation was inhibited (p < 0.03) by co-incubation with PD-L1high but not PD-L1low exosomes. This inhibition was reversed by adding a PD-1 inhibitor to T-cells prior to their incubation with exosomes. Conclusions: We show that PD-L1 levels on exosomes, but not plasma levels, correlated with clinicopathological data in HNSCC patients. Blocking of PD-L1+ exosomes signaling to PD-1+ T-cells with anti-PD-1 Ab attenuated immune suppression. Altogether, PD-L1+ exosomes serve as useful metrics of disease and immune activity in HNSCC patients.
Interleukin-12 armored chimeric antigen receptor (CAR) T cells for heterogeneous antigen-expressing ovarian cancer.
Authors: Yeku Oladapo O. , Purdon Terence , Spriggs David R. , Brentjens Renier J. 
Published: February 2018

12 Background: Immune escape via downregulation of tumor associated antigens (TAAs) is an important mechanism of resistance to Chimeric Antigen Receptor (CAR) T cell therapy. Particularly in solid tumor malignancies where antigen expression could be heterogeneous, the risk of antigen-low or antigen-negative relapse is significantly high. One strategy to overcome this limitation is to reengineer CAR T cells to engage other arms of the immune system such as endogenous cytotoxic T cells and dendritic cells (DC) to broaden the antitumor response beyond the TAA targeted by CAR T cells. This could be achieved by co-modifying CAR T cells with Interleukin-12 (IL-12). IL-12 is a proinflammatory cytokine produced by DCs, and macrophages, and has been shown to promote maturation of DCs and increase T-cell proliferation. We hypothesized that CAR T cells genetically engineered to constitutively secrete IL-12 will be efficacious against Muc16ecto low (MLo) and Muc16ecto high (MHi) heterogeneous tumors in a syngeneic mouse model of ovarian peritoneal carcinomatosis. Methods: ID8 mouse ovarian cancer cells with either low endogenous Muc16ecto or transduced to express high levels of Muc16ecto were generated. Mouse T cells were transduced with plasmids encoding second generation Muc16 or Muc16/IL-12-directed CARs. C57BL/6 mice were inoculated i.p with tumor cells and subsequently treated with CAR T cells. Results: Second generation and IL-12 armored CAR T cells (4H1128?-IL12) were cytotoxic against both MLo and MHi cells in vitro. However, 4H1128?-IL12 were significantly more efficacious at killing both MLo and MHi cancer cells. In vivo, treatment with 4H1128?-IL12 led to significantly improved survival in mice inoculated with a 50:50 mix of MLo and MHi cells. Peritoneal washes performed on mice that succumbed to disease showed equivalent eradication of MLo and MHi. Treatment with 4H1128?-IL12 resulted in increased mature peritoneal DC’s (CD11b+ MHCII+). Finally, surviving mice from 4H1128?-IL12 cohorts were found to have increased T-cell receptor (TCR-β) productive clonality. Conclusions: IL-12-secreting CAR T cells are efficacious against tumors with low and heterogeneous antigen expression.
Patient-reported outcomes in PD-1/PD-L1 inhibitor registration trials: FDA analysis of data submitted and future directions.
Authors: Howie Lynn Jackson , Singh Harpreet , King-Kallimanis Bellinda , Roydhouse Jessica , Theoret Marc Robert , Blumenthal Gideon Michael , Kluetz Paul Gustav 
Published: February 2018

134 Background: Patient-reported outcome measures (PROs) can capture the patient’s experience with disease and treatment. Anti-PD-1/PD-L1 therapies have unique symptomatic side effects; PRO data can help to better understand the patient experience on therapy. Health-related quality of life (HRQL) components most impacted by therapy include disease symptoms, symptomatic toxicity and physical function. Methods: We reviewed FDA registration trials for 5 immunotherapy agents (anti-PD-1/PD-L1) to evaluate trial design and PRO assessment. We assessed whether the PRO strategy assessed physical function and symptomatic immune-related adverse events (irAEs) by reviewing whether trials used a well-defined physical function domain and 8 symptoms related to irAEs reported in product labels (fatigue, diarrhea, cough, shortness of breath, musculoskeletal pain, rash, pruritis and fever). Results: Data from 25 trials across 7 disease types and 1 tumor agnostic indication were evaluated. Of these, 13 were randomized and 22 were open label. Eighteen of 25 contained PRO assessments and all 18 used > 1 instrument. The most common instruments were the EQ-5D (N = 17), followed by EORTC QLQ-C30 (N = 15). Disease-specific PRO tools were included in 8 trials (5 lung, 1 head and neck, 1 melanoma and 1 renal cell), consisting of modules or scales from EORTC (N = 5), FACIT (N = 2) or the Lung Cancer Symptom Scale (N = 1). Sixty percent of the trials (15/25) used an instrument that contained a well-defined physical function (PF) domain. No trial used a PRO strategy assessing all 8 selected symptoms related to irAEs. Conclusions: Collection of PRO data in anti-PD-1/PD-L1 trials submitted to FDA was variable, and did not consistently assess treatment related symptoms and physical function. Use of a HRQL tool with well-defined functional scales supplemented by item banks or libraries to incorporate symptoms associated with irAEs may improve understanding of the patient experience while receiving anti-PD-1/PD-L1 treatment. These data, along with other important clinical data such as hospitalizations, ER visits and supportive care medications can inform the benefit risk assessment for regulatory purposes.