Layered gadolinium-based nanoparticle as a novel delivery platform for microRNA therapeutics.

Specific expression patterns of microRNA (miRNA) molecules have been linked to cancer initiation, progression, and metastasis. The accumulating evidence for the role of oncogenic or tumor-suppressing miRNAs identified the need for nano-scaled platform that can help deliver nucleotides to modulate miRNAs. Here we report the synthesis of novel layered gadolinium hydroxychloride (LGdH) nanoparticles, a member of the layered double hydroxide (LDH) family, with physiochemical properties suitable for cell uptake and tracing via magnetic resonance (MR) imaging. As a proof of concept, we demonstrate the inhibition of mature miRNA-10b in metastatic breast cancer cell line using LGdH nanoparticle as a delivery platform. Through characterization analysis, we show that nanoparticles are easily and stably loaded with anti-miRNA oligonucleotides (AMO) and efficiently penetrate cell membranes. We demonstrate that AMOs delivered by LGdH nanoparticles remain functional by inducing changes in the expression of its downstream effector and by curbing the invasive properties. Furthermore, we demonstrate the traceability of LGdH nanoparticles via T1 weighted MR imaging. LGdH nanoparticles, which are biocompatible with cells in vitro, provide a promising multifunctional platform for microRNA therapeutics through their diagnostic, imaging, and therapeutic potentials.

The biodistribution and pharmacokinetic evaluation of choline-bound gold nanoparticles in a human prostate tumor xenograft model.

PURPOSE: Gold nanoparticles (GNPs) have attracted significant attention in the treatment of cancer due to their potential as novel radiation enhancers, particularly when functionalized with various targeting ligands. The aim of this study was to assess the biodistribution and pharmacokinetic characteristics of a novel choline-bound GNP (choline-GNP) stabilized with polyethelenimine (PEI). METHODS: Choline bound to 27 nm diameter GNPs was characterized using transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR). Toxicity of choline-GNPs was examined on DU-145 prostate cancer cells using an MTT assay. Using balb/c mice bearing flank DU-145 prostate tumors, choline-GNPs bio-distribution was measured using inductively coupled mass spectroscopy (ICP-MS). Blood, heart, lung, liver, spleen, brain, kidney and tumor gold content were examined at multiple time points over a 24-hour period after tail vein injection. RESULTS: An MTT assay using DU-145 prostate cancer cells yielded a 95% cell viability 72 hours after choline-GNP administration. The tumor GNP area under the concentration-time curve during the first 4 hours (AUC0-4) was 2.2 µg/ml h, representing 13% of the circulating blood GNP concentration over the same time period. The maximum intra-tumor GNP concentration observed was 1.4% of the injected dose per gram of tumor tissue (%ID/g) one hour post injection. CONCLUSIONS: GNPs functionalized with choline demonstrates a viable future nanoparticle platform with increased intra-tumor uptake as compared to unconjugated GNPs. Decreased intra-hepatic accumulation appears to be the reason for the improved systemic bioavailability. The next logical translational investigation will incorporate external beam radiation with the observed maximum intra-tumor uptake.

Sputum microRNA profiling: a novel approach for the early detection of non-small cell lung cancer.

PURPOSE: MicroRNAs (miRNAs) post-transcriptionally regulate hundreds of gene targets involved in tumorigenesis thereby controlling vital biological processes, including cellular proliferation, differentiation and apoptosis. MiRNA profiling is an emerging tool for the potential early detection of a variety of malignancies. This study was conducyed to assess the feasibility and methodological robustness of quantifying sputum miRNAs, employing quantitative real-time polymerase chain reaction (RT-qPCR) and cluster analysis on an optimized miRNA profile as a novel approach for the early detection of non-small cell lung cancer (NSCLC). METHODS: The relative expressions of 11 miRNAs in sputum (miR-21, miR-145, miR-155, miR-205, miR-210, miR-92, miR-17-5p, miR-143, miR-182, miR-372, and let-7a) in addition to U6 were retrospectively assessed in four NSCLC-positive and four negative controls. Subsequently, a set of five miRNAs (miR-21, miR-143, miR-155, miR-210, miR-372) was selected because of degree of relatedness observed in the cluster analysis and tested in the same sputum sample set. The five optimized miRNAs accurately clustered these eight retrospective patients into NSCLC positive cases and negative controls. The five miRNA panel was then prospectively quantified in the sputum of 30 study patients (24 NSCLC cases and six negative controls) in a double-blind fashion to validate a five miRNA panel using hierarchical cluster analysis. RESULTS: The optimized five miRNA panel detected NSCLC (83.3% sensitivity and 100% specificity) in 30 prospectively accrued study patients. CONCLUSION: Sputum miRNA profiling using cluster analysis is a promising approach for the early detection of non-small cell lung cancer. Further investigation using this approach is warranted.

Impact of pulmonary function on pulmonary complications after robotic-assisted thoracoscopic lobectomy.

OBJECTIVES: Percentage-predicted forced expiratory volume in 1 s (FEV1) and diffusing capacity for carbon monoxide (DLCO), and their predicted postoperative (ppo) values are established prognostic factors for postoperative pulmonary complications after thoracotomy. However, their predictive value for minimally invasive pulmonary resections remains controversial. This study assessed the incidence of pulmonary complications after robotic lobectomy for primary lung cancer and analysed the predictive significance of FEV1 and DLCO. METHODS: This was a retrospective analysis of patients who underwent robotic lobectomy from 4 institutions. Descriptive and comparative analyses were performed for patients who experienced pulmonary complications versus patients who did not, in relation to FEV1 and DLCO values. To identify thresholds for increased complications, patients were categorized into groups of 10% incremental increases in FEV1 and DLCO, and their ppo values. RESULTS: From November 2002 to April 2018, 1088 patients underwent robotic lobectomy. Overall, 169 postoperative pulmonary complications occurred in 141 patients. Male gender and Eastern Cooperative Oncology Group grade ≥1 were associated with increased pulmonary complications on univariable analysis. Patients who experienced pulmonary complications had increased mortality (2.1% vs 0.2%, P = 0.017) and longer hospitalizations (9 vs 4 days, P < 0.001). Pulmonary complications were associated when FEV1 ≤60% and DLCO ≤50%, and when ppo FEV1 or DLCO was ≤50%; ppo FEV1 ≤50% (P < 0.001) and ppo DLCO ≤50% (P = 0.031) remained statistically significant on multivariable analysis. CONCLUSIONS: Both FEV1 and DLCO were shown to be significant predictors of pulmonary complications. Furthermore, thresholds of percentage-predicted and ppo FEV1 and DLCO values were identified, below which pulmonary complications occurred significantly more frequently, suggesting their predictive values are particularly useful in patients with poorer pulmonary function.

Outcomes of major complications after robotic anatomic pulmonary resection.

BACKGROUND: There is a paucity of robust clinical data on major postoperative complications following robotic-assisted resection for primary lung cancer. This study assessed the incidence and outcomes of patients who experienced major complications after robotic anatomic pulmonary resection. METHODS: This was a multicenter, retrospective review of patients who underwent robotic anatomic pulmonary resection between 2002 and 2018. Major complications were defined as grade III or higher complications according to the Clavien-Dindo classification. Statistical analysis was performed based on patient-, surgeon-, and treatment-related factors. RESULTS: During the study period, 1264 patients underwent robotic anatomic pulmonary resections, and 64 major complications occurred in 54 patients (4.3%). Univariate analysis identified male sex, forced expiratory volume in 1 second, diffusion capacity of the lung for carbon monoxide, neoadjuvant therapy, and extent of resection as associated with increased likelihood of a major postoperative complication. Patient age, performance status, body mass index, reoperation status, and surgeon experience did not have a significant impact on major complications. Patients who experienced at least 1 major complication were at higher risk for an intensive care unit stay of >24 hours (17.0% vs 1.4%; P < .001) and prolonged hospitalization (8.5 days vs 4 days; P < .001). Patients who experienced a major postoperative complication had a 14.8% risk of postoperative death. CONCLUSIONS: In this series, the major complication rate during the postoperative period was 4.3%. A number of identified patient- and treatment-related factors were associated with an increased risk of major complications. Major complications had a significant impact on mortality and duration of stay.

Incidence, Management, and Outcomes of Intraoperative Catastrophes During Robotic Pulmonary Resection.

BACKGROUND: Intraoperative catastrophes during robotic anatomical pulmonary resections are potentially devastating events. The present study aimed to assess the incidence, management, and outcomes of these intraoperative catastrophes for patients with primary lung cancers. METHODS: This was a retrospective, multiinstitutional study that evaluated patients who underwent robotic anatomical pulmonary resections. Intraoperative catastrophes were defined as events necessitating emergency thoracotomy or requiring an additional unplanned major surgical procedure. Standardized data forms were collected from each institution, with questions on intraoperative management strategies of catastrophic events. RESULTS: Overall, 1810 patients underwent robotic anatomical pulmonary resections, including 1566 (86.5%) lobectomies. Thirty-five patients (1.9%) experienced an intraoperative catastrophe. These patients were found to have significantly higher clinical TNM stage (P = .031) and lower forced expiratory volume in 1 second (81% vs 90%; P = .004). A higher proportion of patients who had a catastrophic event underwent preoperative radiotherapy (8.6% vs 2.3%; P = .048), and the surgical procedures performed differed significantly compared with noncatastrophic patients. Patients in the catastrophic group had higher perioperative mortality (5.7% vs 0.5%; P = .018), longer operative duration (195 minutes vs 170 minutes; P = .020), and higher estimated blood loss (225 mL vs 50 mL; P < .001). The most common catastrophic event was intraoperative hemorrhage from the pulmonary artery, followed by injury to the airway, pulmonary vein, and liver. Detailed management strategies were discussed. CONCLUSIONS: The incidence of catastrophic events during robotic anatomical pulmonary resections was low, and the most common complication was pulmonary arterial injury. Awareness of potential intraoperative catastrophes and their management strategies are critical to improving clinical outcomes.

Excision of middle mediastinal parathyroid adenoma by videoscopic assisted mediastinoscopy (VAM).

We report a case involving a female patient with primary hyperparathyroidism arising from a middle mediastinal parathyroid adenoma. Initial diagnosis was made based on a history of polyuria and recurrent renal colic. At the age of 77 she underwent videoscopic assisted mediastinoscopy (VAM) for resection of the adenoma which was localized using single-photon emission computed tomography (SPECT/CT). This case illustrates the importance for accurate pre-operative localization and intra-operative monitoring to ensure complete surgical removal in order to improve postoperative normocalcemia success rates.

Non-small cell lung cancer detection using microRNA expression profiling of bronchoalveolar lavage fluid and sputum.

AIM: To assess if miRNA expression profiling of bronchoalveolar lavage (BAL) fluid and sputum could be used to detect early-stage non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Hierarchical cluster analysis was performed on the expression levels of 5 miRNAs (miR-21, miR-143, miR-155, miR-210, and miR-372) which were quantified using RNA reverse transcription and quantitative real-time polymerase chain reaction in sputum and BAL samples from NSCLC cases and cancer-free controls. RESULTS: Cluster analysis of the miRNA expression levels in BAL samples from 21 NSCLC cases and sputum samples from 10 cancer-free controls yielded a diagnostic sensitivity of 85.7% and specificity of 100%. Cluster analysis of sputum samples from the same patients yielded a diagnostic sensitivity of 67.8% and specificity of 90%. CONCLUSION: miRNA expression profiling of sputum and BAL fluids represent a potential means to detect early-stage NSCLC.

Spindle cell lipoma of the esophagus.

Esophageal lipomas are benign tumors representing less than 0.5% of all gastrointestinal lipomas. They are typically detected incidentally but occasionally present with local symptoms and rarely with life-threatening complications. We describe a case of a 60-year-old man with progressive dysphagia and weight loss, who presented with several episodes of near asphyxiation secondary to regurgitation and aspiration of the pedunculated mass. Preoperative investigations included a barium meal, esophagoscopy and computerized tomography. The pedunculated lipoma was excised via a cervical approach and found, at final pathology, to be a spindle cell lipoma, a rare variant not previously described in relation to the esophagus.