Comparative Treatment Outcomes for Patients With Idiopathic Subglottic Stenosis.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadImportance: Surgical treatment comparisons in rare diseases are difficult secondary to the geographic distribution of patients. Fortunately, emerging technologies offer promise to reduce these barriers for research. Objective: To prospectively compare the outcomes of the 3 most common surgical approaches for idiopathic subglottic stenosis (iSGS), a rare airway disease. Design, setting, and participants: In this international, prospective, 3-year multicenter cohort study, 810 patients with untreated, newly diagnosed, or previously treated iSGS were enrolled after undergoing a surgical procedure (endoscopic dilation [ED], endoscopic resection with adjuvant medical therapy [ERMT], or cricotracheal resection [CTR]). Patients were recruited from clinician practices in the North American Airway Collaborative and an online iSGS community on Facebook. Main outcomes and measures: The primary end point was days from initial surgical procedure to recurrent surgical procedure. Secondary end points included quality of life using the Clinical COPD (chronic obstructive pulmonary disease) Questionnaire (CCQ), Voice Handicap Index-10 (VHI-10), Eating Assessment Test-10 (EAT-10), the 12-Item Short-Form Version 2 (SF-12v2), and postoperative complications. Results: Of 810 patients in this cohort, 798 (98.5%) were female and 787 (97.2%) were white, with a median age of 50 years (interquartile range, 43-58 years). Index surgical procedures were ED (n = 603; 74.4%), ERMT (n = 121; 14.9%), and CTR (n = 86; 10.6%). Overall, 185 patients (22.8%) had a recurrent surgical procedure during the 3-year study, but recurrence differed by modality (CTR, 1 patient [1.2%]; ERMT, 15 [12.4%]; and ED, 169 [28.0%]). Weighted, propensity score-matched, Cox proportional hazards regression models showed ED was inferior to ERMT (hazard ratio [HR], 3.16; 95% CI, 1.8-5.5). Among successfully treated patients without recurrence, those treated with CTR had the best CCQ (0.75 points) and SF-12v2 (54 points) scores and worst VHI-10 score (13 points) 360 days after enrollment as well as the greatest perioperative risk. Conclusions and relevance: In this cohort study of 810 patients with iSGS, endoscopic dilation, the most popular surgical approach for iSGS, was associated with a higher recurrence rate compared with other procedures. Cricotracheal resection offered the most durable results but showed the greatest perioperative risk and the worst long-term voice outcomes. Endoscopic resection with medical therapy was associated with better disease control compared with ED and had minimal association with vocal function. These results may be used to inform individual patient treatment decision-making.Patient-Centered Outcomes Research Institute - PCOR

Weighted Moments Estimators of the Parameters for the Extreme Value Distribution Based on the Multiply Type II Censored Sample

We propose the weighted moments estimators (WMEs) of the location and scale parameters for the extreme value distribution based on the multiply type II censored sample. Simulated mean squared errors (MSEs) of best linear unbiased estimator (BLUE) and exact MSEs of WMEs are compared to study the behavior of different estimation methods. The results show the best estimator among the WMEs and BLUE under different combinations of censoring schemes

Randomized controlled study of ECP with methoxsalen as first-line treatment of patients with moderate to severe cGVHD

The investigation of extracorporeal photopheresis (ECP) plus standard of care (SoC) (SoC+ECP) in chronic graft-versus-host disease (cGVHD) within prospective, randomized clinical studies is limited, despite its frequent clinical use. This phase 1/pilot study was the first randomized, prospective study to investigate ECP use as first-line therapy in cGVHD, based on the 2015 National Institutes of Health (NIH) consensus criteria for diagnosis and response assessment. Adult patients with new-onset (<= 3 years of hematopoietic stem cell transplantation) moderate or severe cGVHD were randomized 1:1 to 26 weeks of SoC+ECP vs SoC (corticosteroids and cyclosporine A/tacrolimus) between 2011 and 2015. The primary endpoint was overall response rate (ORR), defined as complete or partial response, at week 28 in the intention-to-treat population (ITT). Other outcomes included quality of life (QoL) measures and safety. Sixty patients were randomized; ITT included 53 patients (SoC+ECP: 29; SoC: 24). Week 28 ORR was 74.1% (SoC+ECP) and 60.9% (SoC). Investigator-assessed ORR was 56.0% (SoC+ECP) and 66.7% (SoC). Patients treated with SoC experienced a decline in QoL over the 28-week study period; QoL remained unchanged in SoC+ECP patients. Most frequent treatment-emergent adverse events (TEAEs) in SoC+ECP patients were hypertension (31.0%), cough (20.7%), dyspnea (17.2%), and fatigue (17.2%). Seventeen patients (SoC+ECP: 8; SoC: 9) experienced 35 serious adverse events (SAEs). No TEAEs or SAEs were considered related to the ECP instrument or methoxsalen. The encouraging short-term results of this study could inform the design of subsequent studies

Additional file 1: Figure S1. of The Yin/Yan of CCL2: a minor role in neutrophil anti-tumor activity in vitro but a major role on the outgrowth of metastatic breast cancer lesions in the lung in vivo

Naïve BALB/c neutrophils can kill PyMT (FVB) tumor cells, but CCL2 does not increase killing. PyMT cells from FVB mice seeded with and without naïve BALB/c neutrophils (30 neutrophils: 1 tumor cell), in the absence and presence of CCL2. After 18-h at 37 °C, cells were lysed and luciferase was measured to determine tumor cell killing. Although from a different mouse strain, naïve BALB/c neutrophils were able to kill FVB PyMT tumor cells (p = 0.005). However, CCL2 did not enhance this effect (p = 0.347), Kruskal-Wallis test with Dunn’s test for multiple comparisons. Values are graphed as mean ± SD. Figure S2. Entrainment properties of less aggressive PyMT tumor cells on the metastatic outgrowth of more aggressive TGFβR2 knock out PyMT tumors. Female FVB mice (10 weeks old) were injected with either 15,000 PyMT breast cancer cells (MFP) or PBS (Non-tumor bearing) in the 4th mammary fat pad. Two weeks later either 1 × 106 TGFβR2 knockout PyMT (TbR2KO) breast cancer cells or PBS alone (in 200 μl) were delivered by tail vein injection to mice bearing PyMT tumors or into non-tumor bearing mice (t.v. TbR2KO). Three weeks later, mice were sacrificed and lungs were removed, fixed, H&E stained and the number of metastases counted. Analysis of variance with blocking (two experiments) was performed for an overall comparison (p < 0.001). Tukey’s honestly significant difference (HSD) for multiple comparisons among groups (adj. p = 0.009 for MFP-PBS vs. MFP + TbR2KO, adj. p < 0.001 for MFP-PBS vs. t.v. TbR2KO). NS = not significant, p < 0.1, *p < 0.05, **p < 0.01, ***p < 0.001. Values are graphed as mean ± SD. Figure S3. Intranasal delivery of CCL2 facilitates the recruitment of leukocytes into BAL fluid. 3A. BAL fluid isolated from mice receiving intranasal delivery of CCL2 showed an increase in CD8+ T cells as CCL2 delivery increased from 100 ng to 1000 ng. Data are shown as % CD45+ cells and as % total cells. 3B. BAL fluid from mice receiving intranasal delivery of CCL2 exhibited a trend toward increased numbers of neutrophils and NK cells with increasing concentrations. Data are shown as % live cells in BAL fluid. Figure S4. Blocking antibody to CCL2 reverses the neutrophil killing of 67NR cells in vitro. 67NR cells(T) expressing luciferase were seeded with and without neutrophils (E for effector cells) at a ratio of 30 neutrophils: 1 tumor cell in the presence of control IgG or blocking antibody to CCL2. After an 18-hs at 37 °C, cells were lysed and luciferase was measured to determine tumor cell killing. Anti-CCL2 (50 ng/ml BD Biosciences) reversed the 67NR tumor cell killing of BALB/c TEN, p < 0.01, Student’s t test, n = 5 per group. (PPTX 124 kb

Validation of a Proteomic Signature of Lung Cancer Risk from Bronchial Specimens of Risk-Stratified Individuals

A major challenge in lung cancer prevention and cure hinges on identifying the at-risk population that ultimately develops lung cancer. Previously, we reported proteomic alterations in the cytologically normal bronchial epithelial cells collected from the bronchial brushings of individuals at risk for lung cancer. The purpose of this study is to validate, in an independent cohort, a selected list of 55 candidate proteins associated with risk for lung cancer with sensitive targeted proteomics using selected reaction monitoring (SRM). Bronchial brushings collected from individuals at low and high risk for developing lung cancer as well as patients with lung cancer, from both a subset of the original cohort (batch 1: n = 10 per group) and an independent cohort of 149 individuals (batch 2: low risk (n = 32), high risk (n = 34), and lung cancer (n = 83)), were analyzed using multiplexed SRM assays. ALDH3A1 and AKR1B10 were found to be consistently overexpressed in the high-risk group in both batch 1 and batch 2 brushing specimens as well as in the biopsies of batch 1. Validation of highly discriminatory proteins and metabolic enzymes by SRM in a larger independent cohort supported their use to identify patients at high risk for developing lung cancer

Tumoral Densities of T-Cells and Mast Cells Are Associated With Recurrence in Early-Stage Lung Adenocarcinoma.

INTRODUCTION: Lung cancer is the deadliest cancer in the United States and worldwide, and lung adenocarcinoma (LUAD) is the most prevalent histologic subtype in the United States. LUAD exhibits a wide range of aggressiveness and risk of recurrence, but the biological underpinnings of this behavior are poorly understood. Past studies have focused on the biological characteristics of the tumor itself, but the ability of the immune response to contain tumor growth represents an alternative or complementary hypothesis. Emerging technologies enable us to investigate the spatial distribution of specific cell types within the tumor nest and characterize this immune response. This study aimed to investigate the association between immune cell density within the primary tumor and recurrence-free survival (RFS) in stage I and II LUAD. METHODS: This study is a prospective collection with retrospective evaluation. A total of 100 patients with surgically resected LUAD and at least 5-year follow-ups, including 69 stage I and 31 stages II tumors, were enrolled. Multiplexed immunohistochemistry panels for immune markers were used for measurement. RESULTS: Cox regression models adjusted for sex and EGFR mutation status revealed that the risk of recurrence was reduced by 50% for the unit of one interquartile range (IQR) change in the tumoral T-cell (adjusted hazard ratio per IQR increase&nbsp;= 0.50, 95% confidence interval: 0.27-0.93) and decreased by 64% in mast cell density (adjusted hazard ratio per IQR increase&nbsp;= 0.36, confidence interval: 0.15-0.84). The analyses were reported without the type I error correction for the multiple types of immune cell testing. CONCLUSIONS: Analysis of the density of immune cells within the tumor and surrounding stroma reveals an association between the density of T-cells and RFS and between mast cells and RFS in early-stage LUAD. This preliminary result is a limited study with a small sample size and a lack of an independent validation set