99mTc-Tilmanocept vs. Sulfur Colloid for Sentinel Node Biopsy for Melanoma in the Head and Neck.

The objective of the study is to compare sentinel lymph node (SLN) identification rates and performance characteristics of lymphoscintigraphy using 99mTc-sulfur colloid (SC) and 99mTc-tilmanocept (TL) for head and neck cutaneous melanoma. This study is a retrospective study, conducted at a single, tertiary care cancer center. Patients underwent sentinel lymph node biopsy (SLNB) for head and neck cutaneous melanoma, using SC or TL, between October 2014 and February 2019. Differences in SLN identification rates and performance characteristics between the groups were examined using the Mann-Whitney, or Fisher's exact test. Sixty patients underwent SLNB, of which 19 employed TL. There were no significant differences between SC vs. TL in operative duration (116 vs. 127 min, P = 0.97), radiation dose (530 vs. 547 µCi, P = 0.27), median number of SLNs removed (3 vs. 2, P = 0.32), or median follow-up (46.3 vs. 38.4 months, P = 0.11). The rates of positive SLNs (17% vs. 37%, P = 0.11), intraoperative non-localization (12% vs. 16%, P = 0.70), and false-negative SLNB (5% each, P = 1.00) were not significantly different between groups. In patients with head and neck melanoma undergoing SLNB, 99mTc-tilmanocept may not differ from 99mTc-sulfur colloid in identifying SLNs or other performance characteristics. The added expense related to 99mTc-tilmanocept and lack of favorable performance data should urge caution in its adoption and promote further examination of its value in similar patient cohorts.

Ultrasound Versus Fluoroscopy for Stellate Ganglion Block: A Cadaveric Study.

OBJECTIVE: Post-Traumatic Stress Disorder (PTSD) is a common psychiatric disorder. Recent investigations have demonstrated effectiveness of Stellate Ganglion Blocks (SGB) for reducing symptoms associated with PTSD. Both fluoroscopic guided and ultrasound guided SGB have been described and are regularly used in clinical practice. This study sought to evaluate differences in block performance when comparing fluoroscopic versus ultrasound guided SGB. DESIGN: Cadaveric Pilot Study. SETTING: Academic Research Laboratory. SUBJECTS: Ten Soft-Cured Human Cadavers. METHODS: Ten soft-cured human cadavers were used after being at room temperature for 3 hours. Fluoroscopic and ultrasound guided injections were both performed on each cadaver, randomized to left or right sidedness. In total, 7 mL of omnipaque and methylene blue (5:1) was injected in each side. Injectate spread was assessed by measuring vertebral body spread under fluoroscopy. Successful staining of the sympathetic trunk was assessed under cadaveric dissection, with visualization of the sympathetic trunk stained with methylene blue. RESULTS: Ultrasound guided injections resulted in successful staining in 9 of 10 injections, while 6 of 10 for fluoroscopic guidance (P = .3034). The average spread in the ultrasound group was 4.0 compared with 5.2 for the fluoroscopic group (P =.088). In the four fluoroscopic guided injections which failed to stain, the injection occurred posterior to the prevertebral fascia. In the single ultrasound guided block that failed to stain, the injection was in the carotid sheath. CONCLUSIONS: While there appeared to be a trend favoring ultrasound guidance, no statistical significance was achieved. This was likely due to this being a limited pilot study. Numerous limitations exist in cadaveric studies, and future investigations should be completed to further study this comparison. That said, the use of the SGB may provide significant relief for patients suffering with PTSD.

The Impact on Nasal Septal Anatomy and Physiology Following Le Fort I Osteotomy for Orthognathic Surgery.

ABSTRACT: Orthognathic surgery utilizing a Le Fort I osteotomy is performed by oral and maxillofacial surgeons to correct midface and dental occlusal abnormalities. However, the potential sequelae on sinonasal function have had minimal discussion in the literature. The objective of this study was to assess the impact on nasal septum anatomy and physiology following Le Fort I osteotomy for maxillary repositioning surgery. Thirty patients who previously underwent elective orthognathic surgery with Le Fort I osteotomy were enrolled retrospectively to assess the change in their nasal septal anatomy and nasal breathing. Pre- and postoperative computed tomography (CT) scans were used to determine axial displacement of the septum, in both degrees and millimeters, at 4 different standardized anatomic sites following the surgery. These objective anatomic measurements were then compared to the patient's perception of nasal congestion and difficulty breathing via the validated Chronic Sinusitis Survey-Duration Based (CSS-D). Comparison of the CTs before and after surgery demonstrated a new deviation of the nasal septum in all 30 patients, with maximal axial displacements up to 7.22 mm and a mean of 2.64 mm. Postoperative angular displacement changes ranged from minimal to 24°. The CTs showed persistence of a new septal perforation in 20% (6 of 30 patients) following surgery. The CSS-D results demonstrated a mean worsening of nasal breathing and congestion scores from 1.4 before surgery to 3.0 at least 8 weeks after surgery (P < 0.001). Orthognathic surgery utilizing Le Fort I osteotomy may result in persistent nasal septal perforations, new displacement of the nasal septum, and increased perception of nasal dyspnea not previously reported. Further understanding of anatomic changes and nasal airway obstruction that may be caused following such operations warrants further study in order to improve surgical technique and postoperative outcomes.

The protease inhibitor HAI-2, but not HAI-1, regulates matriptase activation and shedding through prostasin.

The membrane-anchored serine proteases, matriptase and prostasin, and the membrane-anchored serine protease inhibitors, hepatocyte growth factor activator inhibitor (HAI)-1 and HAI-2, are critical effectors of epithelial development and postnatal epithelial homeostasis. Matriptase and prostasin form a reciprocal zymogen activation complex that results in the formation of active matriptase and prostasin that are targets for inhibition by HAI-1 and HAI-2. Conflicting data, however, have accumulated as to the existence of auxiliary functions for both HAI-1 and HAI-2 in regulating the intracellular trafficking and activation of matriptase. In this study, we, therefore, used genetically engineered mice to determine the effect of ablation of endogenous HAI-1 and endogenous HAI-2 on endogenous matriptase expression, subcellular localization, and activation in polarized intestinal epithelial cells. Whereas ablation of HAI-1 did not affect matriptase in epithelial cells of the small or large intestine, ablation of HAI-2 resulted in the loss of matriptase from both tissues. Gene silencing studies in intestinal Caco-2 cell monolayers revealed that this loss of cell-associated matriptase was mechanistically linked to accelerated activation and shedding of the protease caused by loss of prostasin regulation by HAI-2. Taken together, these data indicate that HAI-1 regulates the activity of activated matriptase, whereas HAI-2 has an essential role in regulating prostasin-dependent matriptase zymogen activation.

Efficient targeting of head and neck squamous cell carcinoma by systemic administration of a dual uPA and MMP-activated engineered anthrax toxin.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. Although considerable progress has been made in elucidating the etiology of the disease, the prognosis for individuals diagnosed with HNSCC remains poor, underscoring the need for development of additional treatment modalities. HNSCC is characterized by the upregulation of a large number of proteolytic enzymes, including urokinase plasminogen activator (uPA) and an assortment of matrix metalloproteinases (MMPs) that may be expressed by tumor cells, by tumor-supporting stromal cells or by both. Here we explored the use of an intercomplementing anthrax toxin that requires combined cell surface uPA and MMP activities for cellular intoxication and specifically targets the ERK/MAPK pathway for the treatment of HNSCC. We found that this toxin displayed strong systemic anti-tumor activity towards a variety of xenografted human HNSCC cell lines by inducing apoptotic and necrotic tumor cell death, and by impairing tumor cell proliferation and angiogenesis. Interestingly, the human HNSCC cell lines were insensitive to the intercomplementing toxin when cultured ex vivo, suggesting that either the toxin targets the tumor-supporting stromal cell compartment or that the tumor cell requirement for ERK/MAPK signaling differs in vivo and ex vivo. This intercomplementing toxin warrants further investigation as an anti-HNSCC agent.

Detection of microRNA expression in human peripheral blood microvesicles.

BACKGROUND: MicroRNAs (miRNA) are small non-coding RNAs that regulate translation of mRNA and protein. Loss or enhanced expression of miRNAs is associated with several diseases, including cancer. However, the identification of circulating miRNA in healthy donors is not well characterized. Microvesicles, also known as exosomes or microparticles, circulate in the peripheral blood and can stimulate cellular signaling. In this study, we hypothesized that under normal healthy conditions, microvesicles contain miRNAs, contributing to biological homeostasis. METHODOLOGY/PRINCIPAL FINDINGS: Microvesicles were isolated from the plasma of normal healthy individuals. RNA was isolated from both the microvesicles and matched mononuclear cells and profiled for 420 known mature miRNAs by real-time PCR. Hierarchical clustering of the data sets indicated significant differences in miRNA expression between peripheral blood mononuclear cells (PBMC) and plasma microvesicles. We observed 71 miRNAs co-expressed between microvesicles and PBMC. Notably, we found 33 and 4 significantly differentially expressed miRNAs in the plasma microvesicles and mononuclear cells, respectively. Prediction of the gene targets and associated biological pathways regulated by the detected miRNAs was performed. The majority of the miRNAs expressed in the microvesicles from the blood were predicted to regulate cellular differentiation of blood cells and metabolic pathways. Interestingly, a select few miRNAs were also predicted to be important modulators of immune function. CONCLUSIONS: This study is the first to identify and define miRNA expression in circulating plasma microvesicles of normal subjects. The data generated from this study provides a basis for future studies to determine the predictive role of peripheral blood miRNA signatures in human disease and will enable the definition of the biological processes regulated by these miRNA.

The stability of dryness symptoms after refitting with silicone hydrogel contact lenses over 3 years.

PURPOSE: To assess the stability of dryness symptoms after refitting patients wearing low-Dk/t hydrogel contact lenses with high-Dk/t silicone hydrogel contact lenses and to determine whether early dryness symptoms were predictive of discontinuation in the 3-year study. METHODS: Two hundred seventy-eight hydrogel lens wearers were refitted with lotrafilcon A silicone hydrogel contact lenses for continuous wear of up to 30 nights. Self-administered questionnaires at baseline, 1 week, and 3 years captured the frequency and intensity of dryness symptoms during the day and at the end of the day. One-week and 3-year responses were compared to baseline by a Bowker test of symmetry and median change in response with Wilcoxon signed rank test. RESULTS: Frequency of during-the-day and end-of-day dryness decreased from baseline to 1 week and 3 years (during the day, frequency > or = "sometimes" 57.1% vs. 33.1% after 1 week and 58.5% vs. 28.8% after 3 years; end of day, 61.1% vs. 41.0% after 1 week and 64.0% vs. 35.9% after 3 years [P<0.0001 for all comparisons]). After refitting, the proportion of subjects with dryness symptoms was stable. After 1 week, the presence of frequency of at least "sometimes" and severity of at least "moderate" during-the-day and end-of-day dryness were significantly associated with study discontinuation (during-the-day frequency [P=0.007] and severity [P=0.017]; end-of-day frequency [P=0.002] and severity [P=0.003]). CONCLUSIONS: Dryness symptoms improved after 1 week of refitting with lotrafilcon A and remained stable through 3 years. The presence of dryness after 1 week was associated with discontinuation from contact lens wear. Refitting with silicone hydrogel lenses reduced the frequency and severity of dryness symptoms seen with hydrogel lens wear for many subjects.