bluuebunny/crossref_metadata_2025_split huggingface dataset:
Autologous Chondrocyte Implantation “Segmental-Sandwich” Technique for Deep Osteochondral Defects in the Knee: Clinical Outcomes and Correlation With Magnetic Resonance Imaging Findings
Authors: Ogura Takahiro , Merkely Gergo , Bryant Tim , Winalski Carl S. , Minas Tom 
Published: May 2019

Background: Symptomatic osteochondral defects are difficult to manage, especially in patients with deep (>8-10 mm) empty defects. The restoration of articular congruence is crucial to avoid the progression to osteoarthritis (OA). Purpose: To describe the autologous chondrocyte implantation (ACI) “segmental-sandwich” technique for restoration of the osteochondral unit and to evaluate midterm outcomes in patients treated with this procedure. Correlations between magnetic resonance imaging (MRI) and radiographic findings with outcomes were assessed. Study Design: Case series; Level of evidence, 4. Methods: Outcomes were evaluated for a consecutive cohort of 15 patients with symptomatic deep (>8 mm) osteochondral lesions who underwent autologous bone grafting plus the ACI segmental-sandwich technique performed by a single surgeon between 2003 and 2011. Patients with a minimum 2-year follow-up were included. All patients completed validated clinical outcome scales and a patient satisfaction survey. The Kellgren-Lawrence (K-L) grade was assessed for the progression to OA. The repair site was evaluated with the MOCART (magnetic resonance observation of cartilage repair tissue) score. Filling and tissue characteristics of the bone defect were analyzed with MRI. Results: All patients (mean age at surgery, 31.0 ± 9.1 years) were available for follow-up (mean follow-up, 7.8 ± 3.0 years; range, 2-15 years). The mean chondral lesion size was 6.0 ± 3.5 cm2 (range, 1.5-13.5 cm2), with a mean bone defect area of 1.7 cm2 (27%-40% of overall surface area treated by ACI) and depth of 1.0 cm. All patients had successful clinical outcomes, and all functional scores improved significantly ( P < .05). Patients reported a very high satisfaction rate (93%). The K-L grade demonstrated no significant progression to OA over a mean follow-up of 4.7 years. For 12 patients with MRI results available, the mean MOCART score at a mean of 3.3 years was 64.2 ± 19.9, with complete or near-complete (≥75% of defect volume) chondral defect filling (83%) and complete integration to adjacent cartilage (83%). Bone defects were completely filled in 83% of patients. Conclusion: The ACI segmental-sandwich technique provides significant functional improvements at midterm follow-up and excellent survival rates. This unique treatment allows for the resurfacing of cartilage defects and the repair of underlying segmental bone lesions.
Plasma metabolomic profiling of proliferative diabetic retinopathy
Authors: Zhu Xiao-Rong , Yang Fang-yuan , Lu Jing , Zhang Hui-rong , Sun Ran , Zhou Jian-Bo , Yang Jin-Kui 
Published: May 2019

Abstract
Background
Proliferative diabetic retinopathy (PDR), a sight-threatening retinopathy, is the leading cause of irreversible blindness in adults. Despite strict control of systemic risk factors, a fraction of patients with diabetes develop PDR, suggesting the existence of other potential pathogenic factors underlying PDR. This study aimed to investigate the plasma metabotype of patients with PDR and to identify novel metabolite markers for PDR. Biomarkers identified from this study will provide scientific insight and new strategies for the early diagnosis and intervention of diabetic retinopathy.

Methods
A total of 1024 patients with type 2 diabetes were screened. To match clinical parameters between case and control subjects, patients with PDR (PDR, n = 21) or those with a duration of diabetes of ≥10 years but without diabetic retinopathy (NDR, n = 21) were assigned to the present case-control study. Distinct metabolite profiles of serum were examined using liquid chromatography-mass spectrometry (LC-MS).

Results
The distinct metabolites between PDR and NDR groups were significantly enriched in 9 KEGG pathways (P < 0.05, impact > 0.1), namely, alanine, aspartate and glutamate metabolism, caffeine metabolism, beta-alanine metabolism, purine metabolism, cysteine and methionine metabolism, sulfur metabolism, sphingosine metabolism, and arginine and proline metabolism. A total of 63 altered metabolites played important roles in these pathways. Finally, 4 metabolites were selected as candidate biomarkers for PDR, namely, fumaric acid, uridine, acetic acid, and cytidine. The area under the curve for these biomarkers were 0.96, 0.95, 1.0, and 0.95, respectively.

Conclusions
This study suggested that impairment in the metabolism of pyrimidines, arginine and proline were identified as metabolic dysregulation associated with PDR. And fumaric acid, uridine, acetic acid, and cytidine might be potential biomarkers for PDR. Fumaric acid was firstly reported as a novel metabolite marker with no prior reports of association with diabetes or diabetic retinopathy, which might provide insights into potential new pathogenic pathways for diabetic retinopathy.
RETRACTED ARTICLE: Exosomes from the tumour-adipocyte interplay stimulate beige/brown differentiation and reprogram metabolism in stromal adipocytes to promote tumour progression
Authors: Wu Qi , Li Juanjuan , Li Zhiyu , Sun Si , Zhu Shan , Wang Lijun , Wu Juan , Yuan Jingping , Zhang Yimin , Sun Shengrong , Wang Changhua 
Published: May 2019

AbstractBackgroundEmerging evidence supports the pivotal roles of adipocytes in breast cancer progression. Tumour induced beige/brown adipose tissue differentiation contributes to the hypermetabolic state of the breast cancer. However, the mediators and mechanisms remain unclear.MethodsSurvival probabilities were estimated using the Kaplan–Meier method based on immunohistochemistry results. Biochemical studies were performed to characterize the novel interrelation between breast cancer cells and adipocytes.ResultsWe show that tumour-surrounding adipocytes exhibit an altered phenotype in terms of upregulated beige/brown characteristics and increased catabolism associated with an activated state characterized by the release of metabolites, including free fatty acids, pyruvate, lactate and ketone bodies. Likewise, tumour cells cocultivated with mature adipocytes exhibit metabolic adaptation and an aggressive phenotype in vitro and in vivo. Mechanistically, we show that tumour cells induce beige/brown differentiation and remodel metabolism in resident adipocytes by exosomes from the co-culture system that carry high levels of miRNA-144 and miRNA-126. miRNA-144 promotes beige/brown adipocyte characteristics by downregulating the MAP3K8/ERK1/2/PPARγ axis, and exosomal miRNA-126 remodels metabolism by disrupting IRS/Glut-4 signalling, activating the AMPK/autophagy pathway and stabilizing HIF1α expression in imminent adipocytes. In vivo inhibition of miRNA-144 or miRNA-126 decreases adipocyte–induced tumour growth.ConclusionsThese results demonstrate that by inducing beige/brown differentiation and enhancing catabolism in recipient adipocytes, exosomal miRNA-144 and miRNA-126 from the tumour-adipocyte interaction reprogram systemic energy metabolism to facilitate tumour progression.
3D vs. 4K Display System - Influence of “State-of-the-art”-Display Technique On Surgical Performance (IDOSP-Study) in minimally invasive surgery: protocol for a randomized cross-over trial
Authors: Wahba Roger , Datta Rabi Raj , Hedergott Andrea , Bußhoff Jana , Bruns Thomas , Kleinert Robert , Dieplinger Georg , Fuchs Hans , Giezelt Caroline , Möller Desdemona , Hellmich Martin , Bruns Christiane J. , Stippel Dirk L. 
Published: May 2019

Abstract

Background
Three-dimensional (3D) stereoscopic vision is crucial to perform any kind of manual task. The reduction from real life 3D to virtual two-dimensional (2D) sight is a major challenge in minimally invasive surgery (MIS). A 3D display technique has been shown to reduce operation time and mistakes and to improve the learning curve. Therefore, the use of a3D display technique seems to optimize surgical performance for novice and experienced surgeons. Inspired by consumer electronics, a 4K display technique was recently introduced to MIS. Due to its high resolution and zoom effect, surgeons should benefit from it. The aim of this study is to evaluate if “state-of-the-art” 3D- vs. 4K-display techniques could influence surgical performance.

Methods
A randomized, cross-over, single-institution, single-blinded trial is designed. It compares the primary outcome parameter “surgical performance”, represented by “performance time ”and “number of mistakes”, using a passive polarizing 3D and a 4K display system (two arms) to perform different tasks in a minimally invasive/laparoscopic training parkour. Secondary outcome parameters are the mental stress load (National Aeronautics and Space Administration (NASA) Task Load Index) and the learning curve. Unexperienced novices (medical students), non-board-certified, and board-certified abdominal surgeons participate in the trial (i.e., level of experience, 3 strata). The parkour consists of seven tasks (for novices, five tasks), which will be repeated three times. The 1st run of the parkour will be performed with the randomized display system, the 2nd run with the other one. After each run, the mental stress load is measured. After completion of the parkour, all participants are evaluated by an ophthalmologist for visual acuity and stereoscopic vision with five tests. Assuming a correlation of 0.5 between measurements per subject, a sample size of 36 per stratum is required to detect a standardized effect of 0.5 (including an additional 5% for a non-parametric approach) with a power of 80% at a two-sided type I error of 5%. Thus, altogether 108 subjects need to be enrolled.

Discussion
Complex surgical procedures are performed in a minimally invasive/laparoscopic technique. This study should provide some evidence to decide which display technique a surgeon could choose to optimize his performance.

Trial registration
ClinicalTrials.gov, NCT03445429. Registered on 7 February 2018.
Model-driven metronomic vinorelbine in heavily pre-treated metastatic NSCLC and PM patients: Results of a phase I/II study.
Authors: Ciccolini Joseph , Cousin Elissa , Deyme Laure , Imbs Diane-Charlotte , Bonnet Sylvanie , Serre Raphael , Barbolosi Matthieu , Greiller Laurent , Tomasini Pascale , Galloux Melissa , Lacarelle Bruno , Barbolosi Dominique , Barlesi Fabrice 
Published: May 2019

e20505 Background: A phase I/II trial (NCT02555007) of oral metronomic Vinorelbine derived from a mathematical model was performed in heavily pretreated metastatic Non-Small Cell Lung Cancer or Pleural Mesothelioma patients. Progression free survival, toxicity and PK/PD endpoints were the main objectives. Methods: Metronomic scheduling was selected using a simplified phenomenological model to identify the best continuous scheduling and dosing of oral vinorelbine with a total dose of 150 mg QW. Patients were monitored on a weekly basis, efficacy was evaluated by CT scans (RECIST). Toxicity was monitored using standard CTCAE criteria. Total tumor size (TTS) was the sum of diamaters of all lesions. Computation of individual PK parameters was done with Monolix software using population approach. Results: The PK/PD model proposed the following schedule: 60 mg D1, 30 mg D2, 60 mg D4. A total of 36 patients (30 evaluable) were enrolled (22M, 13F, 24 NSCLC, 11 mesothelium, median age 69.5, range 33-85.2). Patients were all heavily pre-treated (median 3 lines, range 1-9). Grade 3+ Neutropenia was observed in 30% patients. Median PFS was 11 weeks (range: 6-16.9). Best responses included 4 PR (13%) and 18 SD (60%). Baseline total tumor size was associated with reduced PFS (HR: 1.09, p = 0.026). A large variability in drug exposure (AUC 53 %, range 26 – 501 ng.h/ml) and PK parameters (Cl 82 %, range 45-605 l/h) was observed among patients. Exposure was not associated with efficacy, apart in patients with larger TTS (i.e., > 70 mm) who seemed to have longer PFS (125 days VS. 40 days, p = 0.057). Vinorelbine exposure tended to be associated with higher risk for grade 2+ neutropenia, especially in patients with BSA < 1.8 m² (60% VS. 25.5%, p = 0.055). A non-significant trend towards baseline NLR and PFS was observed (i.e., NLR < 4: 80 days, NLR > 4: 60 days, p = 0.077). Conclusions: Metronomic vinorelbine was characterized by huge variability in drug exposure among patients. However and despite being all heavily pre-treated, 60% of stable disease and 13% of PR were achieved in these patients. Plasma exposure yielded conflicting results depending on the initial tumor burden, suggesting that patients should be carefully selected prior to be scheduled for metronomic regimen. Possible role NLR could play as a predictive marker is intriguing and should be confirmed in larger cohort.
Costs and hazard ratios of commonly used drugs in advanced/metastatic lung cancer at Cancer Free Foundation, Dana Point, California.
Authors: Guirgis Helmy M. 
Published: May 2019

e20508 Background: The American Cancer Society of Clinical Oncology used hazard ratios (HR) in its value framework as indicators of clinical response. Bevacizumab (Bev) and Pemetrexed (Peme) were introduced for non-squamous metastatic lung cancer prior to epidermal growth factor recognition. Objective: Analyze drug costs and HR in 1st-line advanced/metastatic lung cancer. Methods: Costs of Bev, Peme, Pembrolizumab (Pembro) and Atezolizumab (Atezo) were calculated x one year. Protocols and HR at 95% confidence intervals were quoted. Results: Median drug HR was 0.73. Bev costs were $132,314 and HR 0.79 (A. Sandler, 2006). Peme costs were $97,947, HR 0.63 (M. Zuchin, 2013) and 0.78 (PARAMOUNT). Costs of Pembro 2mg/Kg x 80 Kg were $125,770 compared with $157,313, the currently used 200 mg flat dose. Proportionate savings were noted over the 90-50 Kg weight. Pembro costs x 35 cycles increased to $317,450. In tumor progression score (TPS) > 50% (KEYNOTR-24), Pembro HR was 0.60. In KEYNOTE-042, HR in > 1.0% was 0.81 and improved to 0.69 in 50% with a net benefit of 14%. In squamous cell (KEYNOTE-407), Pembro+chemo HR was 0.64. Pembro+Peme+chemo costs were $255,160. In KEYNOTE-189, irrespective of program death receptor-ligand-1 (PD-L1), HR was 0.49, < 1.0% 0.59 and > 50% 0.42. The net benefit was 28%. Atezo+Bev combination costs were $287,314 and HR 0.78 (IMPOWER 150). In extensive small-cell, Atezo+chemo costs were $150,604 and HR 0.70 (IMPOWER 133). Conclusions: Pembro weight-adjusted dose resulted in significant cost saving over the fit-all 200mg. In 1st-line advanced/metastatic lung cancer, Pembro-Peme, irrespective of PD-L1, offered incomparable 0.49 HR at yearly costs of $255,160.
Efficacy and safety of PD-1/PD-L1 inhibitors plus nab-paclitaxel with or without bevacizumab as second-line therapy or beyond for patients with metastatic non-small-cell lung cancer.
Authors: Zhang Fan , Li Tao , Zhang Yuzi , Cai Shangli , Zhao Lei , Jiao Shun Chang , Hu Yi 
Published: May 2019

e20517 Background: Immunotherapy combined with platinum-based chemotherapy is now standard first line treatment for NSCLC patients. However, limited evidence exists to show the efficacy of immunotherapy plus taxanes for patients who have progressed after platinum-based chemotherapy. Therefore, a retrospective study was conducted to assess whether immunotherapy plus nab-paclitaxel with or without bevacizumb could improve efficacy compared with immune monotherapy as second line therapy or beyond for NSCLC patients. Methods: Patients with metastatic NSCLC receiving anti-PD-1/PD-L1 monotherapy or combination therapy from 2015 to 2018 were identified in Chinese People’s Liberation Army General Hospital. Patients who received PD-1/PD-L1 inhibitors as first-line therapy or combined with therapies other than nab-paclitaxel and bevacizumab were excluded. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), disease control rate (DCR) and safety. Results: Of 59 patients, 42 were treated with anti-PD-1/PD-L1 monotherapy and 17 were treated with anti-PD-1/PD-L1 plus nab-paclitaxel with or without bevacizumab. With a median follow-up of 8.2 months, combination therapy group showed significantly longer PFS compared with monotherapy group (8.4m vs. 3.7m, P = 0.047). When adjusted by covariates in COX proportional regression model, both treatment group (P = 0.007, Hazard ration [HR] 0.32; 95%CI 0.14-0.73) and performance status (P = 0.018, HR 0.44; 95%CI 0.22-0.87) demonstrated significant contribution to longer PFS. In addition, ORR was 23.5% (4/17) in the combination therapy group versus 12.8% (5/39) in the monotherapy group (P = 0.265) and the DCR was 88.2% (15/17) in the combination therapy group versus 61.5% (24/39) in the monotherapy group (P = 0.061). The incidence of grade 3/4 adverse events were 23.5% (4/17) in the combination therapy group and 4.8% (2/42) in monotherapy group (P = 0.052). Conclusions: PD-1/PD-L1 inhibitor plus nab-paclitaxel with or without bevacizumab resulted in significantly longer PFS and higher DCR as second line therapy of beyond in metastatic NSCLC patients. These findings need to be further explored by randomized controlled studies.
Randomized phase 3 study of maintenance therapy with S-1 plus best supportive care (BSC) versus BSC alone after induction therapy with carboplatin plus S-1 for advanced or relapsed squamous cell lung carcinoma (WJOG7512L).
Authors: Tanaka Kaoru , Morita Satoshi , Ando Masahiko , Yokoyama Takuma , Nakamura Atsushi , Yoshioka Hiroshige , Ishiguro Takashi , Miura Satoru , Toyozawa Ryo , Oguri Tetsuya , Daga Haruko , Ko Ryo , Bessho Akihiro , Tachihara Motoko , Iwamoto Yasuo , Hirano Katsuya , Nakanishi Yoichi , Nakagawa Kazuhiko , Yamamoto Nobuyuki , Okamoto Isamu 
Published: May 2019

e20531 Background: Our previous phase 3 study established carboplatin plus the oral fluorinated pyrimidine formulation S-1 as a standard option for first-line treatment of advanced non–small cell lung cancer (NSCLC) (J Clin Oncol 2010; 28:5240). The importance of maintenance therapy for patients with advanced squamous NSCLC has been unknown, however. Methods: WJOG7512L was designed as a randomized phase 3 study to evaluate whether maintenance therapy with S-1 improves clinical outcome after induction therapy with carboplatin plus S-1 in such patients. Before randomization, patients received carboplatin (AUC of 5 on day 1 every 3 weeks) plus S-1 (40 mg/m2 twice per day on days 1 to 14 every 3 weeks) as induction therapy. Those who did not progress after four cycles of induction therapy were randomized to receive either S-1 plus best supportive care (BSC) or BSC alone. The primary objective was to confirm the superiority of S-1 plus BSC with regard to progression-free survival. Results: Of the 365 patients enrolled, 347 participated in the induction phase and 131 of these individuals were randomized to receive S-1 plus BSC ( n = 67) or BSC alone ( n = 64). Baseline demographics and clinical characteristics of the subjects, including the response to induction therapy, were well balanced. Patients receiving S-1 plus BSC showed a significantly reduced risk of disease progression compared with those receiving BSC alone (hazard ratio [HR], 0.548; 95% confidence interval [CI], 0.374–0.802; P = 0.0019). Median overall survival from randomization did not differ significantly between the two arms: 17.8 months for BSC alone and 16.7 months for S-1 plus BSC (HR, 0.890; 95% CI, 0.583–1.357). Time to deterioration in quality of life also showed no significant difference ( P = 0.8754 for FACT-TOI, P = 0.9016 for FACT-LCS). The incidence of adverse events during maintenance therapy was low, with neutropenia, anemia, and thrombocytopenia of grade 3 or 4 each occurring in ~1% to 4% of patients. Conclusions: Maintenance with S-1 plus BSC is an effective and well-tolerated treatment option for patients with advanced squamous NSCLC. Clinical trial information: UMIN000010396.
Comprehensive genomic profiling identifies novel genetic predictors of response to anti-PD-(L)1 therapies in NSCLC.
Authors: Fang Wenfeng , Ma Yuxiang , Yin Jiani , Hong Shaodong , Zhou Huaqiang , Wang Ao , Wang Fufeng , Bao Hua , Wu Xue , Yang Yunpeng , Huang Yan , Zhao Hongyun , Shao Yang , Zhang Li 
Published: May 2019

e20536 Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of many different cancer types, including non-small-cell lung cancer (NSCLC). However, our understandings of the molecular and immunologic determinants of response to ICIs remain incomplete. Methods: We performed whole-exon sequencing (WES) in 73 patients with advanced NSCLC who underwent anti-PD-(L)1 therapies to further explore predictive biomarkers for treatment efficacy. Novel somatic mutations and copy number alterations were identified to be predictive of response or resistance to anti-PD-(L)1 therapies. Results: We confirmed that high tumor mutation burden (TMB) was associated with improved clinical outcomes. Quantification of TMB by targeted next-generation sequencing using a customized panel including 422 cancer-relevant genes (Geneseeq) was strongly correlated with WES results (Spearman's Rho = 0.81, p < 0.001). Patients whose tumour harbored FAT1 mutant had higher durable clinical response (DCB) and objective response rate (ORR) compared with wild-type (62.5% vs 20%, p = 0.02, and 50% vs 12.3%, p = 0.02, respectively), whereas patients with activating mutations in EGFR or ERBB2 had significantly shorter mPFS compared with other patients (51 vs 70.5 days, p = 0.0037, HR = 2.47 [95% CI, 1.33-4.62]). Furthermore, We found copy number loss in specific 3p segments (mPFS, 61.5 vs 65 days; survival rates at 6 months, 0% vs 31%, p = 0.012, HR = 2.08 [95% CI, 1.09-4.00]), which contain the tumor suppressor ITGA9 (mPFS, 36.5 vs 64 days, p < 0.0001, HR = 9.09 [95% CI, 2.91-27.78]) and several chemokine receptor pathway genes, were highly predictive of poor clinical outcome. These findings were further validated in two independently published datasets comprising multiple cancer types. Conclusions: Our findings suggest that comprehensive profiling of TMB and the aforementioned novel genetic alterations could result in greater predictive power of response in NSCLC patients treated with ICI therapies.