Initial Safety and Tumor Control Results From a "First-in-Human" Multicenter Prospective Trial Evaluating a Novel Alpha-Emitting Radionuclide for the Treatment of Locally Advanced Recurrent Squamous Cell Carcinomas of the Skin and Head and Neck.

PURPOSE: Our purpose was to report the feasibility and safety of diffusing alpha-emitter radiation therapy (DaRT), which entails the interstitial implantation of a novel alpha-emitting brachytherapy source, for the treatment of locally advanced and recurrent squamous cancers of the skin and head and neck. METHODS AND MATERIALS: This prospective first-in-human, multicenter clinical study evaluated 31 lesions in 28 patients. The primary objective was to determine the feasibility and safety of this approach, and the secondary objectives were to evaluate the initial tumor response and local progression-free survival. Eligibility criteria included all patients with biopsy-proven squamous cancers of the skin and head and neck with either primary tumors or recurrent/previously treated disease by either surgery or prior external beam radiation therapy; 13 of 31 lesions (42%) had received prior radiation therapy. Toxicity was evaluated according to the Common Terminology Criteria for Adverse Events version 4.03. Tumor response was assessed at 30 to 45 days at a follow-up visit using the Response Evaluation Criteria in Solid Tumors, version 1.1. Median follow-up time was 6.7 months. RESULTS: Acute toxicity included mostly local pain and erythema at the implantation site followed by swelling and mild skin ulceration. For pain and grade 2 skin ulcerations, 90% of patients had resolution within 3 to 5 weeks. Complete response to the Ra-224 DaRT treatment was observed in 22 lesions (22/28; 78.6%); 6 lesions (6/28, 21.4%) manifested a partial response (>30% tumor reduction). Among the 22 lesions with a complete response, 5 (22%) developed a subsequent local relapse at the site of DaRT implantation at a median time of 4.9 months (range, 2.43-5.52 months). The 1-year local progression-free survival probability at the implanted site was 44% overall (confidence interval [CI], 20.3%-64.3%) and 60% (95% CI, 28.61%-81.35%) for complete responders. Overall survival rates at 12 months post-DaRT implantation were 75% (95% CI, 46.14%-89.99%) among all patients and 93% (95% CI, 59.08%-98.96%) among complete responders. CONCLUSIONS: Alpha-emitter brachytherapy using DaRT achieved significant tumor responses without grade 3 or higher toxicities observed. Longer follow-up observations and larger studies are underway to validate these findings.

Sildenafil Protects Endothelial Cells From Radiation-Induced Oxidative Stress.

INTRODUCTION: The etiology of radiation-induced erectile dysfunction (ED) is complex and multifactorial, and it appears to be mainly atherogenic. AIM: To focus on vascular aspects of radiation-induced ED and to elucidate whether the protective effects of sildenafil are mediated by attenuation of oxidative stress and apoptosis in the endothelial cells. METHODS: Bovine aortic endothelial cells (BAECs), with or without pretreatment of sildenafil (5 µM at 5 minutes before radiation), were used to test endothelial dysfunction in response to external beam radiation at 10-15 Gy. Generation of reactive oxygen species (ROS) was studied. Extracellular hydrogen peroxide (H2O2) was measured using the Amplex Red assay and intracellular H2O2 using a fluorescent sensor. In addition, ROS superoxide (O2•-) was measured using a O2•- chemiluminescence enhancer. Both H2O2 and O2•- are known to reduce the bioavailability of nitric oxide, which is the most significant chemical mediator of penile erection. Generation of cellular peroxynitrite (ONOO-) was measured using a chemiluminescence assay with the PNCL probe. Subsequently, we measured the activation of acid sphingomyelinase (ASMase) enzyme by radioenzymatic assay using [14C-methylcholine] sphingomyelin as substrate, and the generation of the proapoptotic C16-ceramide was assessed using the diacylglycerol kinase assay. Endothelial cells apoptosis was measured as a readout of these cells' dysfunction. MAIN OUTCOME MEASURES: Single high-dose radiation therapy induced NADPH oxidases (NOXs) activation and ROS generation via the proapoptotic ASMase/ceramide pathway. The radio-protective effect of sildenafil on BAECs was due to inhibition of this pathway. RESULTS: Here, we demonstrate for the first time that radiation activated NOXs and induced generation of ROS in BAECs. In addition, we showed that sildenafil significantly reduced radiation-induced O2•- and as a result there was reduction in the generation of peroxynitrite in these cells. Subsequently, sildenafil protected the endothelial cells from radiation therapy-induced apoptosis. STRENGTHS AND LIMITATIONS: This is the first study demonstrating that single high-dose radiation therapy induced NOXs activation, resulting in the generation of O2•- and peroxynitrite in endothelial cells. Sildenafil reduced ROS generation by inhibiting the ASMase/ceramide pathway. These studies should be followed in an animal model of ED. CONCLUSIONS: This study demonstrated that sildenafil protects BAECs from radiation-induced oxidative stress by reducing NOX-induced ROS generation, thus resulting in decreased endothelial dysfunction. Therefore, it provides a potential mechanism to better understand the atherogenic etiology of postradiation ED. Wortel RC, Mizrachi A, Li H, et al. Sildenafil Protects Endothelial Cells From Radiation-Induced Oxidative Stress. J Sex Med 2019;16:1721-1733.

Fine-needle aspiration cytology for parotid lesions, can we avoid surgery?

OBJECTIVE: Salivary gland neoplasms are rare tumours, with most arising in the parotid gland. Fine-needle aspiration cytology (FNAC) is a common method for preoperative evaluation of parotid masses, although its usefulness is controversial. This study was designed to evaluate the accuracy of FNAC in a large cohort of patients, with emphasis on diagnosis of benign tumours and especially Warthin tumour which can be managed conservatively. STUDY DESIGN: Retrospective case series with chart review. SETTING: Tertiary medical centre. SUBJECTS AND METHODS: From 1991 to 2014, all patients 18 or older with both preoperative FNAC and postoperative pathology report were included. Patients with a history of head and neck malignancy or chronic sialoadenitis and patients who had undergone prior oncological treatment were excluded. RESULTS: 470 patients were available for analysis. Overall accuracy was 82.6%. Positive predictive value (PPV) varied between 88.6% and 94.3% for pleomorphic adenoma and 77.1%-100% for Warthin tumour, with values varying depending on different characteristics of patients (eg age, smoking status). For pathologically proven malignant tumours, the FNAC diagnosis was benign or non-diagnostic in 26% of the cases. CONCLUSION: Fine-needle aspiration cytology has limited utility in confirming a benign diagnosis of a parotid mass for most patients, although for some subpopulations, the PPV may be high enough to defer surgery.

Inflammation following invasive procedures for Warthin's tumour: A retrospective case series.

OBJECTIVE: To determine the risk of inflammation associated with fine-needle aspiration during evaluation of Warthin's tumour. DESIGN: Retrospective case series. SETTING: Tertiary medical centre. PARTICIPANTS: All patients who underwent fine-needle aspiration followed by parotidectomy between 1992 and 2009 for the diagnosis/evaluation of a parotid gland tumour. MAIN OUTCOME MEASURE: Rate of fine-needle-aspiration-related parotitis in patients with Warthin's tumour or other parotid pathologies. RESULTS: A total of 593 parotidectomies were performed in 553 patients during the study period, 96 (16.2%) for Warthin's tumour (study group) and 497 for other parotid-related pathologies (control group). Parotid gland inflammation following fine-needle aspiration was observed in 16 cases in the study group (16.7%) and eight (1.6%) in the control group (P<.001). On multivariate regression analysis, parotitis following fine-needle aspiration was more common in patients with Warthin's tumour than other parotid-related pathologies even after adjustment for possible confounders (P<.007). Signs of inflammation were noted during surgery in six cases in the study group (6.3%) and none in the control group (P<.001); respective rates of postoperative inflammation (wound infection) were 1.04% and 3.3% (P=NS). Management of parotitis consisted of hospitalisation and systemic antibiotic therapy. CONCLUSIONS: Warthin's tumour is associated with a tenfold higher risk of inflammation compared to other parotid tumours following invasive procedures. Clinicians should be alert to this complication in order to initiate proper treatment and patients must be properly counselled.

Parathyroid adenoma: a comprehensive biochemical and histological correlative study.

OBJECTIVE: To investigate the controversial relationship between preoperative calcium and parathyroid hormone levels and the dimensions and histological features of parathyroid adenoma in patients with primary hyperparathyroidism. STUDY DESIGN: Historical cohort. SETTING: Tertiary medical centre. SUBJECTS AND METHODS: Clinical and tumour-related data were collected from the medical files of all patients who underwent parathyroidectomy for primary hyperparathyroidism in 1996-2012. Preoperative blood parathyroid hormone and calcium levels and urine calcium levels were correlated with the size, weight and volume of the parathyroid adenoma. Pathohistological features were determined in a representative sample of archived paraffin-embedded sections and analysed by calcium or parathyroid hormone level (high/low) and adenoma weight (high/low). RESULTS: A total of 378 patients were included. There was a statistically significant direct correlation of preoperative calcium and parathyroid hormone levels with tumour dimensions and of tumour weight and chief-cell percentage. At a preoperative calcium level >11.5 mg/dL and parathyroid hormone (PTH) level >165 mg/dL, we predict that the adenoma would measure more than 2.7 g, 2.18 cm and volume of 3.59 cm3 . CONCLUSIONS: In patients with primary hyperparathyroidism, preoperative calcium and PTH levels may be predictive of parathyroid adenoma dimensions.

Noninvasive positive pressure ventilation in acute asthmatic attack.

Asthma is characterised by reversible airway obstruction. In most patients, control of disease activity is easily achieved. However, in a small minority, asthma may be fatal. Between the two extremes lie patients with severe asthmatic attacks, refractory to standard treatment. These patients are at an increased risk of recurrent severe attacks, with respiratory failure, and mechanical ventilation. Invasive mechanical ventilation of the asthmatic patient is associated with a higher risk of complications and, therefore, is a measure of last resort. Noninvasive positive pressure ventilation (NPPV) is another treatment modality that may be beneficial in patients with severe asthmatic attack who are at an increased risk of developing respiratory failure. These patients have the potential to benefit from early respiratory support in the form of NPPV. However, reports of NPPV in asthmatic patients are scarce, and its usage in asthmatic attacks is, therefore, still controversial. Only a few reports of NPPV in asthma have been published over the last decade. These studies mostly involve small numbers of patients and those who have problematic methodology. In this article we review the available evidence for NPPV in asthma and try to formulate our recommendations for NPPV application in asthma based on the available evidence and reports.

Lack of correlation between disease activity and decreased stimulated secretion of IL-10 in lymphocytes from patients with celiac disease.

BACKGROUND: Celiac disease (CD) is commonly believed to be a predominantly Th1 disease. However, the exact balance between the Th1 and Th2 arms, as well as the correlation to clinical parameters, remains unclear. The aim was to assess the Th1/Th2 cytokine profile and its correlation to clinical parameters in active and non-active CD patients. METHODS: Peak, total secretion and secretory pattern of the Th1 cytokines (IFN-gamma and IL-2) and Th2 cytokines (IL-4 and IL-10) were determined in resting and stimulated peripheral blood mononuclear cells (PBMC) from 19 CD patients with active and non-active disease and 20 normal controls. RESULTS: Peak and total secretion of IL-10 were significantly reduced in CD patients compared with normal controls. This was due to a persistently flat secretory pattern of IL-10 over time in CD patients. In addition, IFN-gamma/IL-10 and the IL-2/IL-10 ratios of peak and total secretion were higher in patients than in controls. In contrast, peak, total secretion and secretory pattern of IL-2, IFN-gamma and IL-4 were comparable in patients and controls as well as the IL-2/IL-4 and IFN-gamma/IL-4 ratios. No difference in the cytokine secretion or Th1/Th2 ratio was found between active and non-active patients or between pediatric and adult patients. CONCLUSIONS: These data indicate that the Thl/Th2 balance in CD is shifted towards Th1 cytokines because of a down-regulated IL-10 secretion. The aberrant profile of cytokine secretion of these patients is not associated with clinical parameters and suggests an inherent defect in IL-10 secretion in CD.

Decreased expression of the p21ras stimulatory factor hSOS in PBMC from inactive SLE patients.

Expression of the p21 ras protooncogene is reported to be increased in animal models and in patients with SLE. However, the expression of p21ras regulatory elements has not been determined. We determined the expression of p21ras, and its regulatory elements p120-ras-GAP and hSOS, in PBMC of 10 patients with inactive SLE (mean SLEDAI score 1.8+/-0.53) and 10 age- and sex-matched healthy controls. No difference was found between the two groups in the levels of p21 ras (3760+/-513 and 3367+/-335, P=0.25) and ras-GAP (1048+/-261 and 1534+/-247, P=0.11) in patients and controls, respectively. In contrast, levels of hSOS were significantly decreased in patients as compared to controls: 955+/-218 and 2306+/-327, P = 0.002, respectively. The mitogen-induced proliferative response was comparable in the two groups: SI 20.8+/-4.2 and 15.03+/-4.9, P=0.135, in patients and controls, respectively. Taken together, our data demonstrate that nonactive SLE patients are characterized by reduced hSOS expression and underscore the need for a comprehensive evaluation of p21ras pathway in these patients.

Neurological involvement in a child with the wrinkly skin syndrome.

In 1973, a syndrome was reported comprising of wrinkled skin over the dorsum of hands, feet, and abdomen, reduced skin elasticity, skeletal involvement, craniofacial anomalies, mental and developmental delay, and failure to thrive. Only nine cases have been reported. Three additional cases with deletion 2q32 show some manifestations of this syndrome. We present another child with this syndrome with prominent neurological involvement manifested by mental retardation, microcephaly, and an episode of status epilepticus.

Effect of different cooling rates on fracture toughness and microhardness of a glazed alumina reinforced porcelain.

Dental porcelain has superior esthetics but may be subject to fracture during mastication. Residual compressive stresses on the porcelain surface after cooling enhance resistance of porcelain to crack initiation, as quantified by its fracture toughness (Kc). The effect of different cooling rates on Kc and hardness of a glazed porcelain reinforced with approximately 2% aluminum oxide was examined in 45 porcelain disks that were divided into three groups. After final glaze firing, one group was cooled rapidly, the second was cooled at a medium rate, and the third was cooled slowly. Fracture toughness was determined with a microindentation procedure. The mean Kc recorded for rapidly cooled porcelain (1.74 +/- 0.09 MN/m3/2), for medium-cooled porcelain (1.41 +/- 0.07 MN/m3/2), and for slow-cooled porcelain (1.29 +/- 0.07 MN/m3/2) was statistically different (p < 0.001, analysis of variance and Bonferroni post hoc test). No statistically significant differences in Vickers hardness values were recorded when porcelain was cooled at different rates (530 to 540) (analysis of variance). The faster cooling rate of a glazed alumina reinforced porcelain resulted in greater fracture toughness but had no effect on hardness.