Natural killer (NK) cells are innate lymphoid cells, and their presence within human tumors correlates with better prognosis. However, the mechanisms by which NK cells control tumors in vivo are ...unclear. Here, we used reflectance confocal microscopy (RCM) imaging in humans and in mice to visualize tumor architecture in vivo. We demonstrated that signaling via the NK cell receptor NKp46 (human) and Ncr1 (mouse) induced interferon-γ (IFN-γ) secretion from intratumoral NK cells. NKp46- and Ncr1-mediated IFN-γ production led to the increased expression of the extracellular matrix protein fibronectin 1 (FN1) in the tumors, which altered primary tumor architecture and resulted in decreased metastases formation. Injection of IFN-γ into tumor-bearing mice or transgenic overexpression of Ncr1 in NK cells in mice resulted in decreased metastasis formation. Thus, we have defined a mechanism of NK cell-mediated control of metastases in vivo that may help develop NK cell-dependent cancer therapies.
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•NKp46 expression on NK cells controls growth of melanoma and carcinoma metastases•In the absence of NKp46, tumor architectural properties indicate an aggressive phenotype•NK cell NKp46-mediated IFN-γ production controls tumor structure via FN1 induction•IFN-γ treatment or Ncr1 overexpression in tumor-bearing mice decreases tumor metastases
NK cells defend against various pathogens and tumors, but the mechanisms by which they control tumor metastases are not clear. Here, Glasner et al. show that NK cells prevent tumor metastases in vivo by editing tumor architecture via NKp46-mediated IFN-γ production that leads to upregulation of extracellular matrix protein FN1 in the tumor.
Dermoscopy is a noninvasive technique for the diagnosis of skin lesions. Its accuracy for basal cell carcinoma (BCC) has not been systematically studied.
We sought to systematically investigate the ...accuracy of dermoscopy for the diagnosis of BCC compared with examination with the naked eye.
A systematic review of studies reporting the accuracy of naked eye examination and dermoscopy for the diagnosis of BCC was conducted. A meta-analysis for sensitivity and specificity was performed using a bivariate mixed-effects logistic regression modeling framework.
Seventeen studies were identified. The pooled sensitivity and specificity of dermoscopy for the diagnosis of BCC were 91.2% and 95%, respectively. In studies comparing test performance, adding dermoscopy to naked eye examination improved sensitivity from 66.9% to 85% (P = .0001) and specificity from 97.2% to 98.2% (P = .006). The sensitivity and specificity of dermoscopy were higher for pigmented than nonpigmented BCC. Sensitivity increased when dermoscopy was performed by experts and when the diagnosis was based on in-person dermoscopy as opposed to dermoscopic photographs.
Significant heterogeneity among studies with a medium-to-high risk of bias.
Dermoscopy is a sensitive and specific add-on tool for the diagnosis of BCC. It is especially valuable for pigmented BCC.
Bullous pemphigoid (BP) is the most common autoimmune blistering skin disease worldwide. Systemic corticosteroids are considered the mainstay of therapy; however, they may cause significant adverse ...effects and treatment failures, so additional therapeutic modalities with better safety profiles are required. Rituximab and omalizumab are novel biologic agents administered in recent years for the treatment of BP, yet data regarding their use in the disease are limited.
Our objective was to systematically review the current literature regarding the use of rituximab and omalizumab for the treatment of BP to evaluate their safety and efficacy.
A systematic review of all publications evaluating patients with BP treated with rituximab or omalizumab was performed. The primary outcome was clinical response; secondary outcomes were adverse events and recurrence rate.
The systematic review included 35 publications (84 patients: 62 receiving rituximab and 22 receiving omalizumab). In total, 61 of 63 patients had not experienced disease control with systemic corticosteroids before receiving the biologic treatment. Complete response rates were 85% and 84% for rituximab and omalizumab, respectively. The recurrence rate was considerably lower with rituximab (29%) than with omalizumab (80%). Mean time to recurrence was 10.2 and 3.4 months, and adverse effects occurred in 24% and 20% of the patients, respectively.
Available data, although potentially limited because of publication bias, suggest that rituximab and omalizumab have similar safety profiles and provide clinical benefit for patients with BP. The reviewed data indicated that rituximab resulted in lower recurrence rates and a longer time until recurrence than omalizumab.
The sequential application of fractional ablative/10,600 nm/CO
2
followed by 1570 nm non-ablative laser treatment might produce better results than applying either laser treatment alone. However, ...histological data regarding the safety of this combination is lacking. This study aimed to assess and compare clinical effects, histological tissue damage, and wound healing after monochromatic and sequential fractional laser treatments. In this prospective porcine model study, three adult female pigs were each irradiated using three different wavelengths: (a) monochromatic fractional ablative CO
2
laser; (b) monochromatic fractional non-ablative 1570 nm laser; (c) sequential fractional 10,600 nm/CO
2
followed by 1570 nm laser treatment. There were six power levels in the monochromatic 1570 nm laser, five in the 10,600 nm/CO
2
, and five in the sequential treatment. The immediate skin reaction (ISR), crusting and adverse effects, was evaluated across different time points throughout the healing process. Wound biopsies were taken at immediately after (0) and at 3, 7, and 14 days after irradiation. Depth and width of craters, and width of coagulation zone were measured and compared. Similar ISR and crusting score values were obtained following the monochromatic and sequential irradiation in a similar dose–response manner. During 14 days of follow-up, the skin looked intact and non-infected with no signs of necrosis. The mean depth and width of craters were comparable only at the maximal energy level (240 mJ) of CO
2
laser, with the coagulation size greater after the sequential treatment. In histology, a similar wound healing was evident. On day 3, crusts were observed above all lesions as was epithelial regeneration. The sequential irradiation with 10,600 nm/CO
2
and 1570 nm lasers did not pose any additional risk compared to the risk of each laser alone.
(Immunity 48, 107-119; January 16, 2018) In the version of this article originally published online on January 9, Figure 3 was printed twice, once correctly and once wrongly in place of Figure 4. The ...authors regret the error and the publisher apologies for the oversight.
Acute hepatic porphyria (AHP) attacks begin with abdominal pain and can progress to severe life-threatening conditions. Early diagnosis and treatment may prevent these complications. We investigated ...the difference between the severity of porphyria attacks before and after porphyria diagnosis. A retrospective study including AHP patients hospitalized for an acute attack in Israel during a 15-year period. Diagnosis of an attack was based on typical clinical symptoms accompanied by at least one documented elevated urinary porphobilinogen above fourfold of normal values. The primary outcome was intensive care unit (ICU) admissions. Secondary outcomes included the length of hospital stay, severe hyponatremia, seizures, and psychiatric symptoms. 42 attacks in 9 patients were included. Most attacks occurred in women (78.6%) and in acute intermittent porphyria patients (76.2%). The mean age of attack was 26.5 (± 6.3) years. Attacks following porphyria diagnosis had a lower prevalence of ICU admission (3.3% versus 75.0%,
p
< 0.001), seizures (0% versus 50.0%,
p
< 0.001), psychiatric symptoms (23.3% versus 66.7%,
p
= 0.01), severe hyponatremia (16.7% versus 83.3%,
p
< 0.001), and median length of hospital stay (5 versus 11.0 days,
p
< 0.001). These results remained significant after simple univariate logistic regression for ICU admission odds ratio (OR) 0.01, 95% confidence interval (CI) 0.00–0.12, prolonged hospital stay (OR 0.08, 95% CI 0.01–0.41), seizures or neurological symptoms (OR 0.06, 95% CI 0.01–0.30), and severe hyponatremia (OR 0.02, 95% CI 0.00–0.20). Previously diagnosed AHP patients have a significantly milder attack course as compared to previously undiagnosed patients. Family screening following sentinel cases might prevent severe AHP attacks.
Café-au-lait macules (CALMs) present as benign hyperpigmented, well-circumscribed spots on the skin for which many patients seek treatment for aesthetic reasons. The objective of this study is to ...report our experience in treating CALMs using a picosecond 532-nm neodymium-doped yttrium aluminium garnet (PS 532 nm) laser. This is a retrospective case series of 16 patients with CALMs who were treated by a PS 532-nm laser (1–4 treatments, 4–8 weeks apart). Response as seen on clinical photographs was assessed by two independent dermatologists and graded on a scale of 0 (exacerbation) to 5 (95–100% improvement). Patient satisfaction and tolerance were documented at final visit. The results of 15 patients demonstrated significant improvement (average 3.43), and their satisfaction and tolerance levels were high. One patient had no response whatsoever to treatment. The PS 532-nm laser is a promising novel modality for the treatment of CALMs.
Post-surgical facial scars are often associated with unaesthetic outcome. Treatment of these scars using various lasers could be beneficial; however, the use of the Q-switched fractional (QSF) ...1064-nm neodymium-doped yttrium aluminum garnet (Nd:YAG) laser has yet to be evaluated for this indication. Our objective was to determine the safety and efficacy of a QSF-Nd:YAG laser for the treatment of post-surgical facial scars. Eleven (5 male, 6 female) patients who underwent facial surgery with significant scarring were treated using the QSF-Nd:YAG laser. Scars were exposed to 600–1200 mJ/stacked pulses (12–24 mJ per pixel), emitted at a rate of 10 Hz for up to 2 passes per treatment session, receiving overall 3–6 treatments. Patient follow-up was 3 months. Scars’ photographs were blindly assessed by two dermatologists, who graded them on a scale of scar severity from 1 to 5 (1 = least severe, 5 = most severe) before and after treatment. A blinded before/after recognition of these photographs was also performed. Patient satisfaction was assessed 3 months post-treatment and graded on a scale of 1–5 (1 = not satisfied, 5 = very satisfied). Pain perception and adverse effects were also evaluated. Patients demonstrated a decrease in scar severity score by a mean of 1.57 points (
p
= 0.0005). A blinded before/after recognition was correct in 86.5% of the cases. Pain and adverse effects were mild and transient. Patient satisfaction was high (4.2). QSF-Nd:YAG laser is a safe and effective modality for the treatment of post-surgical facial scars.
The pulsed dye laser (PDL) is the standard treatment for port-wine stains (PWS). Maximal improvement occurs after multiple treatment sessions; however, the optimal treatment interval has yet to be ...determined. The aim of this study was to review whether there is an association between PDL treatment interval and outcome of PWS. Six databases were searched by three reviewers for publications investigating treatment of PWS with PDL. The 75% improvement rates (75IR) were extracted for quantitative analysis. Meta-regression was used to investigate the association between treatment intervals and 75IR. The systematic review included 1 RCT and 33 cohort studies (7 prospective cohorts and 26 retrospective cohorts), with a total of 3777 patients. The pooled 75IR was 37% (95% CI 29–45%;
I
2
= 95%). Light Fitzpatrick skin type (
p
= 0.04), facial anatomic location (
p
= 0.01), and young age (
p
= 0.008) were associated with 75IR. In an unadjusted (
p
= 0.42) and multivariable adjusted (
p
= 0.98) meta-regression, no association was found between time interval between treatments and 75IR. These results persisted in a sensitivity analysis of studies with a mean patient age of ≤ 1. The majority of included studies were heterogeneous and retrospective. Based on cohort studies of low-to-moderate quality, time intervals between PDL treatments are not associated with PWS outcome.
Herpes simplex virus 1 (HSV1) is a ubiquitous human pathogen that utilizes variable mechanisms to evade immune surveillance. The glycosylphosphatidylinositol (GPI) anchoring pathway is a multistep ...process in which a myriad of different proteins are covalently attached to a GPI moiety to be presented on the cell surface. Among the different GPI-anchored proteins there are many with immunological importance. We present evidence that the HSV1-encoded miR H8 directly targets PIGT, a member of the protein complex that covalently attaches proteins to GPI in the final step of GPI anchoring. This results in a membrane down-modulation of several different immune-related, GPI-anchored proteins, including ligands for natural killer-activating receptors and the prominent viral restriction factor tetherin. Thus, we suggest that by utilizing just one of dozens of miRNAs encoded by HSV1, the virus can counteract the host immune response at several key points.
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•HSV1 miR H8 targets PIGT of the GPI anchoring pathway•Expression of the anti-viral protein tetherin is reduced and viral spread enhanced•Expression of GPI-anchored activating NK cell ligands is reduced•Recognition and elimination by NK cells decrease
Herpes simplex virus 1 is a ubiquitous human pathogen and the cause of several ailments. Enk et al. found that the HSV1-encoded miR H8 targets the GPI anchoring pathway, reducing expression of several immune-modulating proteins, thus enhancing viral spread and enabling evasion of natural killer cell elimination.
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