Variability of pulsed energy outputs from three dermatology lasers during multiple simulated treatments

Abstract

Background

Dermatology laser treatments are undertaken at regional departments using lasers of different powers and wavelengths. In order to achieve good outcomes there need to be good consistency of laser output across different weeks as it is custom and practice to break down the treatments into individual fractions. Departments will also collect information from test patches to help decide on the most appropriate treatment parameters for individual patients.

Objectives

The objective of these experiments is to assess the variability of the energy outputs from a small number of lasers across multiple weeks at realistic parameters.

Methods

The energy outputs from 3 lasers were measured at realistic treatment parameters using a thermopile device across a period of 6 weeks.

Results

All lasers fired in single pulse mode demonstrated good repeatability of energy output. In spite of one of the lasers being scheduled for a dye canister change in the next two weeks there was good energy matching between the two devices with only a 4 -5% variation in measured energies.

Conclusions

Based on the results presented, clinical outcomes should not be influenced by variability in the energy outputs of the Dermatology lasers used as part of the treatment procedure.

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Aprepitant did not modify global disease activity in cutaneous T cell lymphomas

Abstract

Recent investigations are focused on the potential antitumor effect of neurokinin-1 receptor (NK1R) antagonists in different neoplastic diseases¹. Consequently, Kwatra et al. raised an interesting observation about the possible influence of aprepitant on CTCL outcome².

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Effects of neuroimmune axis modulation by aprepitant on anti-pruritic and global disease severity in patients with cutaneous T-cell lymphoma

Abstract

Itch pathogenesis involves modulation of the neuroimmune axis, with several immunosuppressants such as azathioprine¹ and mycophenolate mofetil² demonstrating significant anti-pruritic activity in subsets of patients with pruritus. These immunosuppressive agents are contraindicated in patients with malignancy, and thus there is a need for novel anti-pruritic agents without significant immunosuppressive effects in neoplastic conditions such as cutaneous T cell lymphoma (CTCL).

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Characterization of skin blister fluids from children with Epstein–Barr virus-associated lymphoproliferative disease

Abstract

Epstein–Barr virus (EBV)-associated T- or natural killer (NK)-cell lymphoproliferative disease (LPD) is a heterogeneous group of disorders characterized by chronic proliferation of EBV-infected lymphocytes. Patients may present with severe skin manifestations, including hypersensitivity to mosquito bites (HMB) and hydroa vacciniforme (HV)-like eruption, which are characterized by blister formation and necrotic ulceration. Skin biopsy specimens show inflammatory reactions comprising EBV-infected lymphocytes. However, blister fluids have not been fully assessed in patients with this disease. Blister fluids were collected from three patients with EBV-associated LPD: two with HMB and one with HV. Immunophenotyping of blister lymphocytes and measurement of tumor necrosis factor (TNF)-α in blister fluids were performed. The patients with HMB and HV exhibited markedly increased percentages of NK and γδ T cells, respectively, in both peripheral blood and blister fluids. These NK and γδ T cells strongly expressed the activation marker human leukocyte antigen-DR and were considered to be cellular targets of EBV infections. TNF-α was highly elevated in all blister fluids. Severe local skin reactions of EBV-associated LPD may be associated with infiltrating EBV-infected lymphocytes and a high TNF-α concentration in blister fluids.

2016 measles outbreak in Japan: A report of two cases with reappraisal of histological features

Epidermal aspects of type VII collagen: Implications for dystrophic epidermolysis bullosa and epidermolysis bullosa acquisita

Abstract

Type VII collagen (COL7), a major component of anchoring fibrils in the epidermal basement membrane zone, has been characterized as a defective protein in dystrophic epidermolysis bullosa and as an autoantigen in epidermolysis bullosa acquisita. Although COL7 is produced and secreted by both epidermal keratinocytes and dermal fibroblasts, the role of COL7 with regard to the epidermis is rarely discussed. This review focuses on COL7 physiology and pathology as it pertains to epidermal keratinocytes. We summarize the current knowledge of COL7 production and trafficking, its involvement in keratinocyte dynamics, and epidermal carcinogenesis in COL7 deficiency and propose possible solutions to unsolved issues in this field.

Case of relapsing remitting neuro-Sweet disease mimicking immunoglobulin G4-related disease

Oral lichenoid reaction showing multiple ulcers associated with anti-programmed death cell receptor-1 treatment: A report of two cases and published work review

Abstract

Anti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment opinion for advanced melanoma and non-small-cell lung cancer, as well as other cancerous entities. Immune checkpoint inhibitors such as anti-PD-1 antibody result in a unique side-effect profile, commonly described as immune-related adverse events (irAE). These irAE affect the skin, gastrointestinal tract, liver, endocrine system and other organ systems. We report two cases of oral lichenoid reaction showing multiple ulcers associated with nivolumab treatment. Both patients presented with multiple ulcers covered with fibrinous plaque over the entire oral mucosa, lips and tongue. Histopathological examination of ulceration showed epithelial necrosis and subepidermal clefts with dense band-like layers of lymphohistiocytic infiltrate within the upper dermis. Nivolumab was interrupted in both cases. Case 1 responded well to topical corticosteroids. Case 2 required oral corticosteroids, however, nivolumab could be restarted without recurrence of oral ulcers. We provide a comprehensive review of reported cases of lichenoid reaction showing multiple oral ulcers associated with anti-PD-1 therapy to date. Early recognition and management may improve treatment, avoid discontinuation of life-saving therapy and maintain quality of life in these patients.

Who Are the Online Extremists Among Us? Sociodemographic Characteristics, Social Networking, and Online Experiences of Those Who Produce Online Hate Materials

Violence and Gender , Vol. 0, No. 0.

Skin Testing for Suspected Iodinated Contrast Media Hypersensitivity

Publication date: Available online 19 January 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Rik Schrijvers, Christine Breynaert, Yazid Ahmedali, Jean-Luc Bourrain, Pascal Demoly, Anca Mirela Chiriac
BackgroundThe management of iodinated contrast medium (ICM) hypersensitivity has been a matter of debate. Skin testing to identify a subgroup of ICM allergic patients has been proposed, in addition to complete avoidance, provocation testing, or premedication.Objective: The objective of this study was to assess the negative predictive value (NPV) of skin testing for ICM.MethodsPatients with a hypersensitivity reaction to ICM who underwent skin testing during a 13.5-year period at a single center were evaluated for re-exposure to a negatively skin-tested ICM. Premedication, consisting of second-generation H1-antihistamines twice a day 48 hours before the examination, was advised only for patients with mast cell disorder or chronic urticaria who had negative skin tests.ResultsA total of 597 patients tested for 423 (70.9%) immediate, 118 (19.7%) nonimmediate, and 56 (9.4%) hypersensitivity reactions with undetermined chronology were included. Eighty (13.4%) patients were skin test positive. Re-exposure to ICM occurred in 233 (39.0%) patients and was tolerated in 16 of 17 (94.1%) with at least 1 positive skin test and 201 of 216 (93.1%) with all negative skin tests. Reaction intensity was similar in 4, milder in 10, unknown in 1, and worse in 1 patient although this reaction was deemed to be nonallergic in hindsight. Premedication was administered in 20.7% of patients and associated with more reactions (19.4% vs 5.7%, P = .01). The overall NPV of skin testing for ICM was 93.1% (95% confidence interval [CI] 89.1% to 96.0%), and for immediate and nonimmediate hypersensitivity reactions 94.2% (95% CI 89.6% to 97.2%) and 86.1% (95% CI 72.1% to 94.7%), respectively. We cannot exclude some challenges occurred with a different than the initial culprit ICM, possibly overestimating the NPV.ConclusionsSkin testing for potential ICM hypersensitivity can identify safe alternative(s) for ICM re-exposure especially in patients with an immediate hypersensitivity reaction and/or skin test-proven ICM drug allergy. Reactions on re-exposure were infrequent, mostly milder, and occurred in some patients despite premedication.

Apixaban Causing Leukocytoclastic Vasculitis

Publication date: Available online 19 January 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Usama Bin Nasir, Aswini Kumar, Arti Easwar

Behavioral risks associated with food allergy management in an urban pediatric population

Publication date: Available online 19 January 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Tukisa D. Smith, Jennifer Camacho, Julie Wang

Survival of LA-MRSA in Dust from Swine Farms

Abstract

Dust is suspected to be an important factor in transmission of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) between pigs and pig farmers and their families. The aim of this study was to determine the rate of decay for Staphylococcus aureus and LA-MRSA in dust from swine farms. Electrostatic dust fall collectors (EDCs) were used for passive sampling of settling airborne dust in 11 stable sections from six swine farms. Extraction, plating, identification, and enumeration of cultivable S. aureus and LA-MRSA from the EDCs were performed after storage for 0–30 days postsampling. The survival of S. aureus was measured in 196 dust samples from all farms, and data were used to estimate the decay constant λ according to a model for exponential decay: N(t) = N₀ × e^−λt. The number of S. aureus colonies was up to 600-fold higher than the number of LA-MRSA colonies on MRSA selective agar. The data showed a good fit to the model (λ = 0.13, r² = 0.86) even with a large difference in initial concentrations of S. aureus between stables. The loads of S. aureus and LA-MRSA in the dust were significantly reduced by storage time, and the half-life was 5 days for both S. aureus and LA-MRSA. In dust samples with high initial concentrations, LA-MRSA and S. aureus could still be cultivated 30 days after sampling. On all farms MRSA isolates belonged to the clonal complex (CC) 398, and at one farm some isolates also belonged to CC30. A screening for other Staphylococcus species in the farm dust revealed 13 different species numerically dominated by Staphylococcus equorum. Based on the exponential decay model, S. equorum had a half-life of 4 days. In conclusion, the presence of MRSA in airborne dust from five of six farms indicates that dust might be an important vehicle for transmission of LA-MRSA. LA-MRSA and S. aureus was found to survive well in farm dust with half-lives of 5 days, and dependent on the initial concentration they could be found in farm dust for weeks. The 99.9% die-off rate was 66 days for LA-MRSA. Thus, farm dust can pose an exposure risk for humans in the farm environment, but also when transported to other environments. On the other hand, the risk will decrease by time. These results provide important knowledge to diminish spread from farm environments to other environments on, e.g., tools or clothing, and in relation to cleaning of emptied LA-MRSA-positive stables.

A lamellar body mimetic system for the treatment of oxazolone-induced atopic dermatitis in hairless mice

Atopic dermatitis is a common skin disease characterized by inflammatory, pruritic eczema. It is a multifactorial disease which involves a complex interplay of environmental and genetic factors. Atopic dermatitis shows a Th2 cell-dominant inflammatory infiltrate, elevated serum IgE levels and impaired epidermal barrier function [1], indicated by an increased transepidermal water loss (TEWL) [2] and decreased water-holding capacity [3].

Age-dependent trigeminal and female-specific lumbosacral increase in herpes zoster distribution in the elderly

Varicella-zoster virus (VZV) infection causes varicella and results in latent infection of the sensory ganglia, and its reactivation causes herpes zoster (HZ) along specific dermatomes. The incidence of HZ increases with age [1], and HZ occurs more commonly in female patients than in male patients [2–7]. We previously reported that HZ was observed in all age groups, especially in the elderly, at rates of 3–8 per 1,000 person-years in a study of 48,388 patients with HZ [4]. Among 16,784 patients in Miyazaki prefecture, recurrent episode were observed in 1,076 (6.4%) patients, three episodes were observed in 49 patients, and four episodes were observed in three patients [7].

Scarce evidence of ozone effect on recent health and productivity of alpine forests—a case study in Trentino, N. Italy

Abstract

We investigated the significance of tropospheric ozone as a factor explaining recent tree health (in terms of defoliation) and productivity (in terms of basal area increment, BAI) in 15 ICP Forests level I and one level II plots in alpine forests in Trentino (N. Italy). Mean daily ozone summer concentrations varied between 30 and 72 parts per billion (ppb) leading to large exceedance of concentration-based critical levels set to protect forest trees. Phytoxic ozone dose (POD₀) estimated at the level II plot over the period 1996–2009 was 31–61 mmol m⁻² projected leaf area (PLA). The role of ozone was investigated taking into account other site and environmental factors. Simple linear regression, multiple linear regression (MLR, to study mean periodical defoliation and mean periodical BAI), and linear mixed models (LMM, to study annual defoliation data) were used. Our findings suggest that—regardless of the metric adopted—tropospheric ozone is not a significant factor in explaining recent status and trends of defoliation and BAI in the alpine region examined. Both defoliation and BAI are in turn driven by biotic/abiotic damage, nutritional status, DBH (assumed as a proxy for age), and site characteristics. These results contrast with available ozone-growth dose response relationships (DRRs) and other observational studies. This may be due to a variety of concurrent reasons: (i) DRRs developed for individual saplings under controlled condition are not necessarily valid for population of mature trees into real forest ecosystems; (ii) some observational studies may have suffered from biased design; and (iii) since alpine forests have been exposed to high ozone levels (and other oxidative stress) over decades, possible acclimation mechanisms cannot be excluded.

Eco-friendly pheromone dispensers—a green route to manage the European grapevine moth?

Abstract

The development of environmentally sustainable control strategies to fight insect pests is a key challenge nowadays. Pheromone-mediated mating disruption (MD) is based on the release of synthetic sex attractants into a crop, interfering with mate finding of a given pest species. However, a limited number of research items have been published on the optimization of MD strategies against the European grapevine moth, Lobesia botrana, as well as on the use of biodegradable dispensers to reduce waste production in vineyards, despite the high economic importance of this pest. Therefore, the present study evaluated the efficacy of the MD products Isonet® L TT and the biodegradable Isonet® L TT BIO, applied at various densities, in reducing L. botrana damage on grapevine in comparison to an untreated control and the reference MD product Isonet® L. Experiments were conducted in three different areas of grapevine cultivation, located in Central and Northern Italy, over three different years. Our MD approach allowed a reliable control of the three generations of L. botrana during the whole grape growing season, leading to a significant reduction in the infested flower clusters and bunches, as well as in the number of nests per flower cluster and bunch, if compared to the untreated control. The performances of Isonet® L TT BIO, Isonet® LTT, and Isonet® L did not differ in terms of infested flower clusters/bunches, as well as nests per flower cluster/bunch. This was confirmed in all experimental sites over 3 years of field experiments. Overall, the present research provides useful information for the optimization of MD programs against L. botrana, highlighting the interesting potential of biodegradable pheromone dispensers that can be easily applied at low densities in vineyards, reducing the use of chemical pesticides to control moth pests.

The Evolution of Breast Reduction Publications: A Bibliometric Analysis

Abstract

Objective

This study aims to make a bibliometric analysis of the studies on breast reduction (BR) between the years 1980 and 2016 and identify important studies through trend topics as well as active authors, countries, universities, scientific journals, and citation and co-citation analyses about BR.

Background

Although BR looks like one of the cosmetic surgeries performed in order to restore the woman's appearance, in fact it is a reconstructive surgery that eliminates back pain, stance disorder, headache, shoulder pain, back and cervical disk hernia, difficulty in breathing, hollowness caused by bra straps, hygiene problems under breasts (e.g., rash or fungal infections), and limitations in some daily activities. However, the related literature has little information about the publications on this issue.

Methods

Bibliometric analysis was performed by downloading all the documents published between 1980 and 2016 from Thomson Reuters Web of Science (WoS; Thomson Reuters, New York, NY, USA), using the keywords including "breast reduction", "gigantomastia", "reduction mammaplasty", and "reduction mammoplasty".

Results

There was a total of 1427 publications in the WoS database. Of these publications, 869 (60.90%) were research articles. The top three research areas of these publications were surgery with 1178 (82.55%) publications, oncology with 78 (5.47%) publications, and obstetrics gynecology with 67 (4.70%) publications. The top three countries that contributed to the literature most were the USA (515), England (147), and Turkey (83), respectively; the top university that contributed most was Harvard University, and the top two authors who contributed most were Drew PJ and Iwuagwu OC (13; 0.91%). The top-cited publication was "A Simplified Vertical Reduction Mammaplasty: Shortening the Learning Curve" written by Hall-Findlay, EJ in 1999. The journals with top numbers of publications were Plastic and Reconstructive Surgery (483; 33.85%), Annals of Plastic Surgery (164; 11.50%) and Aesthetic Plastic Surgery (147; 10.30%) respectively.

Conclusion

Despite the fact that the BR literature is contributed by developed countries, developing countries, particularly Turkey and Brazil, also had significant contributions to the literature.

Level of Evidence V

This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Up-regulated expression of CD86 on circulating intermediate monocytes correlated with disease severity in psoriasis

Monocytes are the cornerstones of the immune system and critical drivers of inflammatory reactions [1]. The monocyte family has been classified into three subsets according to the expression of CD14 and CD16. Based on this nomenclature, approximately 90% of human monocytes express high levels of CD14, but not CD16, and have been categorized as "classical monocytes" (CD14++CD16−). Two minor populations constitute the remaining 10%, and include "intermediate monocytes" (CD14++CD16+) and "non-classical monocytes" (CD14+CD16++) [2].

Epistemic innocence and the production of false memory beliefs

Abstract

Findings from the cognitive sciences suggest that the cognitive mechanisms responsible for some memory errors are adaptive, bringing benefits to the organism. In this paper we argue that the same cognitive mechanisms also bring a suite of significant epistemic benefits, increasing the chance of an agent obtaining epistemic goods like true belief and knowledge. This result provides a significant challenge to the folk conception of memory beliefs that are false, according to which they are a sign of cognitive frailty, indicating that a person is less reliable than others or their former self. Evidence of memory errors can undermine a person's view of themselves as a competent epistemic agent, but we show that false memory beliefs can be the result of the ordinary operation of cognitive mechanisms found across the species, which bring substantial epistemic benefits. This challenge to the folk conception is not adequately captured by existing epistemological theories. However, it can be captured by the notion of epistemic innocence, which has previously been deployed to highlight how beliefs which have epistemic costs can also bring significant epistemic benefits. We therefore argue that the notion of epistemic innocence should be expanded so that it applies not just to beliefs but also to cognitive mechanisms.

Unexpected impact of esterification on the antioxidant activity and (photo)stability of a eumelanin from 5,6-dihydroxyindole-2-carboxylic acid

Summary

To inquire into the role of the carboxyl group as determinant of the properties of 5,6-dihydroxyindole melanins, melanins from aerial oxidation of 5,6-dihydroxyindole (DHICA) and its methyl ester MeDHICA were comparatively tested for their antioxidant activity. MALDI MS spectrometry analysis of MeDHICA melanin provided evidence for a collection of intact oligomers. EPR analysis showed g-values almost identical and signal amplitudes (ΔB) comparable to those of DHICA melanin, but spin density was one order of magnitude higher, with a different response to pH changes. Antioxidant assays were performed and a model of lipid peroxidation was used to compare the protective effects of the melanins. In all cases MeDHICA melanin performed better than DHICA melanin. This capacity was substantially maintained following exposure to air in aqueous buffer over one week or to solar simulator over 3 h. Differently from DHICA melanin, MeDHICA melanin proved fairly soluble in different water miscible organic solvents, suggesting its use in dermocosmetic applications.

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Review of the Comparative Susceptibility of Microbial Species to Photoinactivation Using 380-480 nm Violet-blue Light

Abstract

Antimicrobial violet-blue light is an emerging technology designed for enhanced clinical decontamination and treatment applications, due to its safety, efficacy and ease of use. This systematised review was designed to compile the current knowledge on the antimicrobial efficacy of 380-480 nm light on a range of healthcare and food related pathogens including vegetative bacteria, bacterial endospores, fungi and viruses. Data was compiled from 79 studies, with the majority focussing on wavelengths in the region of 405 nm. Analysis indicated that Gram positive and negative vegetative bacteria are the most susceptible organisms, whilst bacterial endospores, viruses and bacteriophage are the least. Evaluation of the dose required for a 1 log₁₀ reduction of key bacteria compared to population, irradiance and wavelength indicated that microbial titre and light intensity had little effect on the dose of 405 nm light required, however linear analysis indicated organisms exposed to longer wavelengths of violet-blue light, may require greater doses for inactivation. Additional research is required to ensure this technology can be used effectively, including: investigating inactivation of multidrug-resistant organisms, fungi, viruses and protozoa; further knowledge about the photodynamic inactivation mechanism of action; the potential for microbial resistance; and the establishment of a standardised exposure methodology.

This article is protected by copyright. All rights reserved.

Laser Scanning Microscopic Investigations of the Decontamination of Soot Nanoparticles from the Skin

Background/Aims: Airborne pollutants, such as nano-sized soot particles, are increasingly being released into the environment as a result of growing population densities and industrialization. They can absorb organic and metal compounds with potential biological activity, such as polycyclic aromatic hydrocarbons and airborne pollen allergens. Local and systemic toxicities may be induced in the skin if the particulates release their harmful components upon dermal contact. Methods: In the present study, skin pretreatments with serum and/or shield as barrier formulations prior to exposure and washing with a cleanser subsequent to exposure were evaluated as a protection and decontamination strategy using laser scanning microscopy. Results: The results indicate that while the application of serum and a cleanser was insufficient for decontamination, the pretreatment with shield prior to nanoparticle exposure followed by washing led to the removal of a considerable amount of the carbon black particles. The combined application of serum and shield before the administration of carbon black particles and subsequent washing led to their elimination from the skin samples. Conclusion: The application of barrier-enhancing formulations in combination with a cleanser may reduce the penetration of harmful airborne particulates by preventing their adhesion to the skin and facilitating their removal by subsequent washing with the cleanser.
Skin Pharmacol Physiol 2018;31:87-94

Comparison of lesional skin c-KIT mutations with clinical phenotype in patients with mastocytosis

Summary

Background

Activating c-KIT mutations cause abnormal mast cell growth and appear to play a role in mastocytosis. However, the correlation of c-KIT mutations with disease phenotypes is poorly characterized.

Aim

To evaluate the correlation of c-KIT mutations with clinical presentations and laboratory findings.

Methods

Total cellular RNA was isolated from the skin lesions of 43 adults and 7 children with mastocytosis, and PCR amplicons of cDNA were sequenced for c-KIT mutations.

Results

The most common activating mutation, KIT-D816V, was identified in 72% of adults and 57% of children. Additional activating mutations, namely, V560G and the internal tandem duplications (ITDs) 502-503dupAY, were detected in 12% of adults and 8% of children. V560G occurred more commonly in our patients than previously reported, and it appeared to be associated with more advanced disease. Otherwise, the presence or absence of activating mutations did not correlate with skin lesion morphology, disease extent or total serum tryptase levels. Four adults had expression only of wild-type KIT, while two others had expression of a truncated KIT lacking tyrosine kinase activity; yet these patients were clinically indistinguishable from those patients with activating c-KIT mutations.

Conclusions

Activating c-KIT mutations exist in a significant portion of patients with mastocytosis, but not all patients showed expression of these mutations. Except for V560G, the presence or absence of activating c-KIT mutations did not predict the extent of disease. These observations suggest that although activating c-KIT mutations are associated with mast cell growth, other genes probably play a role in the cause of mastocytosis.

Tobacco regulation as a paradigm for advancing regulatory science in dermatology

Cutaneous hyperpigmentation induced by apremilast

Acute hemorrhagic lesions in an immunosuppressed patient

Cleft palate repair: description of an approach, its evolution, and analysis of post-operative fistulas

Background: Fistulas following cleft palate repair impair speech, health, and hygiene and occur in up to 35% cases. The purpose of this study was to (1) describe the evolution of a surgical approach to cleft palate repair; (2) assess the rates, causes, and predictive factors of fistulas; (3) assess the temporal association of modifications to fistula rates during six years of a single surgeon experience. Methods: Consecutive patients (N=146) undergoing cleft palate repair were included. The technique of repair was based on cleft type and a common surgical approach was used for all repairs. Modifications to the approach were made around specific anatomic features including peri-articular bony hillocks, maxilla-palatine suture, velopalatine pits, and tensor insertion. Results: Fistula rate after primary repair was 2.4% (N=125) and after secondary repair was 0% (N=22). All complications occurred in patients with Type 3 or 4 clefts. Cleft width and cleft:total palatal width were associated with fistulas whereas syndromes, age, and adoption were not. Traumatic dissection and inadequate release were suspected in cases of delayed healing and flap necrosis during the first 2 years. Modifications were introduced following these complications. The fistula rate declined by one half in subsequent years. Conclusions: We describe a surgical approach to cleft palate repair and its evolution. Fistulas were rare but associated with increasing cleft severity (type, width). A reduction in frequency and severity of fistulas was consistent with a learning curve and may in part be associated with modifications to the surgical approach. Funding support: None Commercial associations and financial disclosures: None Conflicts of interest: None Acknowledgements: Thanks to Jemère Ruby for illustrating the figures; to Erik Stuhaug for intra-operative photography; to Joseph Gruss, Richard Hopper, and Craig Birgfeld for their mentorship, feedback, and assistance with this manuscript; to David Fisher for the training in cleft palate repair; to Shane Morrison for assistance in revision; and to the residents and fellows for suggesting this study. Corresponding author: Raymond Tse, Seattle Children's Hospital, M/S OB.9.527, 4800 Sand Point Way NE , Seattle, WA,98105 ©2018American Society of Plastic Surgeons

The management of partial zone II intrasynovial flexor tendon lacerations: A literature review of biomechanics, clinical outcomes and complications

Background. Penetrating trauma or lacerations within zone II of the flexor sheath may result in partial tendon injury. The proper management of this injury is controversial; the literature contains differing indications for surgical treatment and post-operative rehabilitation. Methods. A literature review of the Cochrane, Medline and Pubmed databases was performed using the following search criteria: partial, flexor, tendon, laceration. All English language studies that evaluated biomechanical strength, complications, and outcomes after partial tendon injury in human and animal studies were included and reviewed by two of the authors. Results. Animal and cadaveric biomechanical studies have demonstrated that partial lacerations involving up to 95% of the tendon cross-sectional area can safely tolerate loads generated through unresisted, active finger flexion. Suture tenorraphy of partial tendon injury is associated with decreased tendon tensile strength, increased resistance, and decreased tendon gliding. Complications of non-surgical management include triggering and entrapment, which can be managed by tendon beveling or pulley release. Late rupture is extremely uncommon (one report). Conclusions. Partial tendon lacerations involving 90% of the cross-sectional area can be safely treated without surgical repair and immediate protected active motion. Indications for exploration and treatment include concern for complete injury, triggering of the involved digit, or entrapment of the tendon. Surgical treatment for tendon triggering or entrapment with less than 75% cross-sectional injury is beveling of the tendon edges and injuries greater than 75% should be repaired with a non-, simple epitendinous suture. All patients should be allowed to perform early protected active motion after surgery. No authors have a conflict of interest to report No funding was provided for this study No IRB approval was necessary for this literature review None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this manuscript Corresponding author: Kyle J. Chepla MD, 2500 MetroHealth Drive Cleveland OH 44109, Phone: 216-778-4450, Email: kchepla@metrohealth.org ©2018American Society of Plastic Surgeons

The effect of impactful papers on clinical practice in the US: Corticosteroid injection for patients with lateral epicondylitis

Background: Following the publication of high level evidence demonstrating that corticosteroid inject is not an effective treatment for lateral epicondylitis, a reduction in the rate of corticosteroid injection would be expected. We aimed to clarify the current clinical practice pattern for lateral epicondylitis and to identify which factors hinder or encourage the introduction of evidence into clinical practice. Methods: In this administrative claims analysis, we used the 2009 to 2015 Truven MarketScan databases. We extracted claims for corticosteroid injection, physiotherapy, platelet-rich-plasma injection, and surgery for lateral epicondylitis. We performed multivariable analysis using generalized estimating equation model to identify the variables that potentially affect the odds of receiving a given treatment. Results: We included a total of 711,726 claims. The odds of receiving a corticosteroid injection slightly increased after publication of these impactful papers (OR: 1.7 95% CI: 1.04-1.11 in 2015). Patient-related factors such as male sex (OR: 1.21 95% CI: 1.19-1.23), older age (OR: 1.16 95% CI: 1.13-1.19), and managed care insurance (OR: 1.15 95% CI: 1.13-1.18) significantly contributed to increased odds of receiving corticosteroid injections. Patients seen at facilities in the South (OR: 1.33 95% CI: 1.30-1.36 compared with Northeast) and by plastic or orthopaedic surgeons (OR: 2.48 95% CI: 2.43-2.52) also had increased odds of receiving corticosteroid injection. Conclusions: Corticosteroid injection use did not decrease after publication of impactful papers, regardless of provider specialty or other patient-related factors. This finding implies that there are various barriers for even high level evidence to overcome the inertia of current practice. Funding Sources: Though our study was supported by a Midcareer Investigator Award in Patient-Oriented Research (2K24AR053120-06) to Kevin C. Chung, Principal Investigator, the National Institutes of Health did not have any role in preparation of the manuscript or in the decision to submit it for publication. This work was also funded by the Chang Gung Memorial Hospital (project CORPG3G0111 and CORPG3G0161) to Ting-Ting Chung. Corresponding author: Kevin C. Chung, MD, MS Section of Plastic Surgery, University of Michigan Health System,, 2130 Taubman Center, SPC 5340, 1500 East Medical Center Drive, Ann Arbor, Mich. 48109-5340, kecchung@med.umich.edu Phone: 734-998-6022 ©2018American Society of Plastic Surgeons

Cleft-Palate Repair: Does Hospital Case-Volume Impact Outcomes or Cost?

Background: How hospital case-volume affects operative outcomes and cost continues to grow in importance. The purpose of this study is to examine the relationship of case volume with operative outcomes and cost in cleft palate repair. Methods: Subjects undergoing cleft palate repair between 2004 and 2015 were identified in the Pediatric Health Information System (PHIS). Outcomes were compared between two exposure groups, those undergoing treatment at a high-volume institution (>85th percentile; >60 cases per year), and those undergoing treatment at a low-volume institution. Primary outcomes were: any complication, prolonged length of stay, and increased total cost. Results: Over twenty thousand patients (N=20,320) from 49 institutions met inclusion criteria. Over one third of subjects underwent palate repair at a high-volume institution (N=7,813, 38.4%). On univariate analysis, these subjects who underwent treatment at a high-volume institution had a lower rate of overall complications (3.4% vs. 5.1%; P

One-Stage vs. Two-Stage Repair of Asymmetric Bilateral Cleft Lip: A 20-Year Retrospective Study of Clinical Outcome

Background: The one-stage or two-stage approaches have been a widely used technique for patients with an asymmetric bilateral cleft lip (ABCL). There is insufficient long-term outcome data between these two methods. The purpose of this retrospective study is to compare the clinical outcome over the last 20 years. Methods: The senior author's database was searched for patients with ABCL from 1995 to 2015. Qualified patients were divided into two groups: one-stage vs. two-stage. The postoperative photographs of patients were subjectively evaluated by surgical professionals and the laypersons. Ratios of the nasolabial region calculated for objective analysis. Finally, the revision procedures in the nasolabial area were reviewed. Statistical analyses were performed. Results: A total of 95 consecutive patients were qualified for evaluation. Average follow-up was 13.1 years. 35% of the patients had a two-stage method, and 65% had a one-stage approach. All received primary nasal reconstruction. Among the satisfaction rating scores, the one-stage repair was significantly higher than two-stage reconstruction (p= 0.0001). Long-term outcomes of the two-stage patients and the unrepaired mini-microform deformities were unsatisfying in both professional and non-professional evaluators. Revision rate was higher in patients with a greater-side complete cleft lip and palate as compared with those without palatal involvement. Conclusion: The results suggested that one-stage repair provided better results to achieve more symmetric and smooth lip and nose after primary reconstructions. The revision rate is slightly higher in the two-stage patient group. The long-term outcome of unrepaired mini-microform cleft lip remains unsatisfactory. Conflicts of interest statement: No conflicting relationship exists for all authors Meeting presentation: Asian Pacific Craniofacial Association Meeting, December 2016, Nara, Japan; American Cleft Palate- Craniofacial Association Meeting, March 2017, Colorado Springs, USA Financial Disclosure: None of the authors have any source of financial or other support or any financial or professional relationship that may pose a competing interest. Author's role/participation: KHC was responsible for data collection, analysis, and writing manuscript. LJL was responsible for analysis and editing of manuscript. Acknowledgement: Special thanks to Miss Yi-Tan Hung for data collections, measurement and analysis. * Corresponding author: Lun-Jou Lo, M.D. Plastic & Reconstructive Surgery, Chang Gung Memorial Hospital. 5 Fu-Shin Street, Kwei Shan, Taoyuan, Taiwan 333. Tel: 886-3- 3281200, ext. 2430. Fax: 886-3-3271029. Email: lunjoulo@cgmh.org.tw ©2018American Society of Plastic Surgeons

Arterial Vascularization of the Mandibular Condyle and Fractures of the Condyle

Background: Despite substantial displacements, fractures of the mandibular condyle rarely lead to necrosis. This illustrates the negligible role of the inferior alveolar artery in intraosseous supply to the condyle, and led to this systematization of its arterial vascularization. Methods: Forty-two temporomandibular joints (TMJ) from non-embalmed cadaveric specimens were studied following injection of latex (32 TMJ) or India ink (10 TMJ). Results: The intraosseous branches of the inferior alveolar artery that lead to the condyle were inconstant and often rudimentary. In this study, the arteries that consistently led to the condyle were: the superficial temporal artery, the deep posterior temporal artery, and arterial branches leading to the lateral pterygoid muscle emanating directly from the maxillary artery. These arteries, along with the transverse facial artery and the masseteric artery (when they participated in condoyle vascularization) formed a quadrangle around the mandibular condyle. Following India ink injection, the pterygoid muscle was the most strongly colored muscle, thus indicating substantial vascularization. Conclusions: While there is a lack of consensus in the literature regarding the constancy and proportions of the arteries participating in vascularization of the condyle, the superficial temporal artery, the maxillary arterial branches leading to the lateral pterygoid muscle, and the deep posterior temporal artery were constant in this study. This study shows the important role of the lateral pterygoid in the vascularization of the condyle. In case of a fracture with substantial displacement, the vascularization emanating from the superficial temporal artery and the lower alveolar artery is ruptured or compromised. Financial Disclosure Statement: The author has no funding to declare Acknowledgments: The author would like to thank the administrative and technical staff of the anatomy laboratory, URDIA and ANCRE, from Paris Descartes University for their help. The author would also like to thank the donors. Corresponding author: Gaoussou Toure, MD, PhD, FEBOMFS , Centre Hospitalier Intercommunal Lucie & Raymond Aubrac, 40 allée de la source, 94195 Villeneuve Saint-Georges Cedex, France; Tel: +33 143 862 247; +33 143 862 128, Email: gaoussou.toure@chiv.fr; gtoure1@gmail.com ©2018American Society of Plastic Surgeons

The Skoog Lip Repair for Unilateral Cleft Lip Deformity – the Uppsala Experience

Background: Uppsala Craniofacial Center has been treating patients with unilateral cleft lip deformity using the lip repair technique described by Tord Skoog. The aim of this study was to determine complications after lip surgery and the incidence and indications for lip revisions in all patients born with unilateral cleft lip 1960-2004. Methods: All patients who were born 1960-2004 with unilateral cleft lip, cleft lip and alveolus, or cleft lip and palate and underwent lip repair were retrospectively studied. The timing, indication, complications of the primary procedure, and type of secondary surgery were recorded. Kruskal-Wallis and Fisher's exact tests were used, with Bonferroni correction. Results: The study included 443 patients. The total rate of early surgical complications was 6% (n=26). Secondary surgery for short upper lip was performed in 3.8% (n=17); 8.4% (n=37) had reduction of excess vermillion, 8.6% (n=38) underwent scar revision, incongruent vermillion–cutaneous border in 11% (n=51) and other indications in 10 % (n=45). Altogether, 45% had no secondary revisions. Conclusions: In conclusion the Skoog lip repair is associated with a low total revision rate and a short lip deformity is rare. Financial disclosure and products page: Alberto Falk-Delgado has a research residency funded by Uppsala University Hospital. We report no conflicts of interest. Corresponding author: Alberto.falk-delgado@surgsci.uu.se, Department of Surgical Sciences, Plastic Surgery, Uppsala University, Ing. 78/79, Akademiska Sjukhuset, 75185, Uppsala, Sweden, Phone: +46 186110000 ©2018American Society of Plastic Surgeons

Vascular Anomalies: From A Clinicohistologic to a Genetic Framework

BACKGROUND: Vascular anomalies currently are classified according to their clinical and histological characteristics. Recent advances in molecular genetics have enabled the identification of somatic mutations in most types of vascular anomalies. The purpose of this study was to collate information regarding the genetic basis of vascular anomalies. METHODS: The PubMed literature was reviewed for all citations that identified a mutation in a vascular anomaly between 1994-2017. Search words included "vascular anomaly", "mutation", "gene", "hemangioma", "pyogenic granuloma", "kaposiform hemangioendothelioma", "capillary malformation", "venous malformation", lymphatic malformation", "arteriovenous malformation", and "syndrome". Articles that identified both germline as well as somatic mutations in vascular anomalies were analyzed. Mutations were categorized by type (germline or somatic), gene, signaling pathway, and cell(s) enriched for the mutation. RESULTS: The majority of vascular anomalies had associated mutations that commonly affected tyrosine kinase receptor signaling through the RAS or PIK3CA pathways. Mutations in PIK3CA and G-protein coupled receptors were most frequently identified. Specific types of vascular anomalies usually were associated with a single gene. However, mutations in the same gene occasionally were found in different vascular lesions, and some anomalies had a mutation in >1 gene. Mutations were most commonly enriched in endothelial cells. CONCLUSIONS: Identification of somatic mutations in vascular anomalies is changing the paradigm by which lesions are diagnosed and understood. Mutations and their pathways are providing potential targets for the development of novel pharmacotherapy. In the future, vascular anomalies will be managed based on clinical characteristics as well as molecular pathophysiology. Presented at: 2017 New England Society for Plastic and Reconstructive Surgery (NESPRS) meeting in Falmouth, MA. Disclosures: None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this manuscript. AUTHOR ROLE AND PARTICIPATION: AKG and J.A.G. contributed to overall design, data analysis, writing manuscript, and revising manuscript. Both authors gave final approval. ACKNOWLEDGEMENTS: This manuscript was supported by the National Institutes of Health Awards NICHD-081004 (AKG), NICHD-082606 (AKG), NHLBI-127030 (AKG), and the Translational Research Program Boston Children's Hospital (AKG). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Corresponding Author: Arin K. Greene MD, MMSc, Department of Plastic and Oral Surgery, Boston Children's Hospital, 300 Longwood Ave., Boston, MA 02115, Phone: 617.355.2306, Fax: 617.738.1657, arin.greene@childrens.harvard.edu ©2018American Society of Plastic Surgeons

Facial reanimation in the 7th and 8th decade of life

Background: Treatment of facial paralysis in the older population is often relegated to static rather than dynamic reanimation for fear of poor outcomes. This pervasive approach lacks physiologic foundation nor is evidence based. Hence, the authors present an extensive literature review demonstrating weak evidence supporting this misguided concept, followed by detailed outcomes from three centers of the largest reported series to date of patients over 60 years after reanimation performed in three techniques - lengthening temporalis myoplasty, free functional muscle, and nerve transfers. Methods: PubMed search spanning over 40 years identified all reports on reanimation in patients over 60. Additionally, detailed demographics, surgical techniques, and outcomes of 30 patients over 60 were analyzed. Results: Of 629 articles, only 45 patients were identified, describing case reports or small series, lacking details or consistent long-term follow-up. In the clinical series, average age, preoperative House- Brackman score, and comorbidities was similar among the groups. Highest excursion was observed in the free functional muscle group, followed by the nerve transfer, and temporalis myoplasty, averaging 10.4, 6.8, and 3.1 mm respectively. The most notable philtral deviation correction was in the LTM group, followed by the free muscle, and nerve transfer, averaging 5.6, 2.2, and 1.13 mm respectively. Complication rates were highest in the free muscle group. Conclusion: Facial palsy patients shouldn't be denied dynamic restoration based on age alone. Although surgical technique may vary based on duration of palsy, surgeon experience and preference, each presenting advantages and disadvantages, dynamic restoration is feasible regardless of age. Financial Disclosure and Products: The authors have no commercial or financial associations related to the submitted manuscript, and no commercial or financial conflicts of interest. No funding was received for the performance of this research of production of the manuscript. Corresponding author: Shai Rozen, MD., UT Southwestern Medical Center, 1801 Inwood Rd., Dallas, TX 75390, Phone: 214-645-3117, Email: shai.rozen@utsouthwestern.edu ©2018American Society of Plastic Surgeons

Outpatient Versus Inpatient Primary Cleft Lip and Palate Surgery: Analysis of Early Complications

Background: Fiscal constraints are directing healthcare systems towards shorter patient hospital lengths of stay. Outpatient primary cleft lip surgery (PCLS) has been shown to be safe but outpatient primary cleft palate surgery (PCPS) remains controversial. This study evaluates 30-day postoperative complications associated with PCLS and PCPS. Methods: The American College of Surgeons National Surgical Quality Improvement Program Pediatric (ACS NSQIP-Pediatric) database was used to identify patients undergoing PCLS and PCPS between 2012 and 2015. Patient demographic and clinical factors, as well as 30-day complications were compared between outpatient versus inpatient PCLS and PCPS. Chi-square, t-tests and multivariate regression were performed. Results: 3,142 patients were included in the PCLS group and 4,191 in the PCPS group. Patients in the PCLS group with underlying structural pulmonary abnormality had significantly longer hospital lengths of stay (B = 4.94; 95% CI: 2.21-7.66; p=0.001). In the PCPS group, patients undergoing outpatient surgery has a significantly higher risk of superficial wound dehiscence (OR = 1.99; 95% CI: 1.22-3.24; p=0.01), deep wound dehiscence (OR = 2.22; 95% CI: 1.25-3.95; p=0.01) and at a significantly lower risk of reoperation (OR = 0.36; 95% CI: 0.14-0.96; p=0.04) and readmission (OR = 0.52; 95% CI: 0.31-0.88; p=0.02). Conclusions: Outpatient PCLS is safe and has a similar perioperative complication profile as inpatient surgery. Outpatient PCPS is a common practice in many US hospitals and has a significantly higher rate of wound complications and lower rates of reoperation as well as readmission. In properly selected patients, outpatient palatoplasty can be safely performed. We have no financial relationships to disclose. Primary Cleft Lip and Palate Surgery Outcomes Disclaimer The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) and the hospitals participating in the ACS NSQIP are the source of the data used herein; they have not verified and are not responsible for the statistical validity of the data analysis or the conclusions derived by the authors. Corresponding author: Roberto L. Flores, MD, Director of Cleft Lip & Palate Program, Hansjörg Wyss Department of Plastic Surgery, NYU Langone Medical Center, 305 E 33rd Street, New York City, NY, 10016, U.S.A., Roberto.Flores2@nyumc.org, T: (212) 263-3704, F: (212) 263-8494 ©2018American Society of Plastic Surgeons

“Morphometric Evaluation of the Frontal Migraine Trigger Site”

Background: Migraine headache has been attributed to specific craniofacial peripheral nerve trigger sites. Some have postulated that hypertrophy of the corrugator muscles causes compression of the supraorbital and supratrochlear nerves resulting in migraine headache. This study uses morphometric evaluation to determine if corrugator anatomy differs between patients with migraine headache and control subjects. Methods: A retrospective review identified patients with and without migraine headache who had a recent computed tomography (CT) scan. Morphometric evaluation of the corrugator supercilii muscles was performed in a randomized and blinded fashion on 63 migraine headache and 63 gender-matched control patients using a three-dimensional image-processing program. These images were analyzed to determine if corrugator size differed between migraine and control patients. Results: There was no difference in mean corrugator volume or thickness between migraine and control patients. The mean corrugator volume was 1.01 ± 0.26 cm3 compared to 1.06 ± 0.27 cm3 in control patients (p = 0.258) and the mean maximum thickness was 5.36 ± 0.86 mm in migraine patients compared to 5.50 ± 0.91 mm in controls (p = 0.359). Similarly, subgroup analysis of 38 patients with frontal migraine and 38 control subjects demonstrated no difference in corrugator size. Further subgroup analysis of nine patients with unilateral frontal migraine showed no difference in corrugator size between the symptomatic side compared to the contralateral side. Conclusion: Muscle hypertrophy itself does not play a major role in triggering migraine headache. Instead, factors such as muscle hyperactivity or peripheral nerve sensitization may be more causative. Financial Disclosure Statement: The authors have nothing to disclose. No funding was received for this article. Presented at: American Society for Peripheral Nerve 2016 in Scottsdale, Arizona and Plastic Surgery Research Council 2016 in New York City, New York. ACKNOWLEDGMENTS:The authors thank Eric Wizauer for his time and assistance with VitreaCore and the University of Michigan Consulting for Statistics, Computing, and Analytics Research as well as Niki Matusko for their guidance with statistical analysis. Corresponding author: Theodore A Kung, MD, University of Michigan Health System, 1500 E Medical Center Drive, Ann Arbor, Michigan 48109 USA, thekung@med.umich.edu ©2018American Society of Plastic Surgeons

Accessory Nerves of the Forehead. A Newly Discovered Frontotemporal Neurovascular Bundle and its Implications in the Treatment of Migraine Headache, Migraine Surgery, and Cosmetic Temple Filler Injection

Background: Surgical decompression of peripheral cranial and spinal nerves at several anatomically studied trigger sites has demonstrated significant efficacy in bringing permanent relief to migraine sufferers. In our experience doing frontal nerve decompression on migraine patients, we noticed a previously undescribed accessory nerve and vessel in the frontotemporal area, and report its implication in migraine surgery and cosmetic filler injection. Methods: A retrospective review of 113 patients who underwent frontal migraine decompression surgery at UT Southwestern from July 2011 to May 2016 was done. For the included 76 patients, measurements of this nerve had been taken intraoperatively using high-definition endoscopic assistance and topographic measurements where correlated with endoscopic location of the nerve. Results: This frontotemporal nerve was present in 55%, and bilateral incidence was 57% of those. An accompanying vessel was also present in 81% of nerve complexes. Both nerve and vessel varied in size. A large vessel was present in 8% of all patients, and a medium vessel in 20%. Consistently, the nerve exited a foramen in the frontal bone on average 3.4 cm (SD = 0.47 cm) superior to the lateral canthus. Conclusion: The identification and proper avulsion neurectomy of this newly described sensory frontotemporal nerve may lead to better surgical response rate during migraine surgery. Additionally, this nerve should be considered during nerve block and botulinum toxin injections in migraine treatment. The existence of the accompanying vessel could have significant implications in the safety of filler and fat injections to this area. Financial Disclosure Statement: The authors have no financial interests in this research project or in any of the techniques or equipment used in this study. Presented at : 1- 55th Annual Medical Student Research Forum: 2017 Jan 17; Dallas, TX Corresponding author: Bardia Amirlak, M.D.F.A.C.S,, Department of Plastic Surgery, University of Texas Southwestern Medical Center, 1801 Inwood Road, Dallas, TX 75390-9132, E-mail: Bardia.Amirlak@UTSouthwestern.edu ©2018American Society of Plastic Surgeons

Trends in ACGME Accreditation for Subspecialty Fellowship Training in Plastic Surgery

Background: Increasingly, surgical residents in the U.S. pursue subspecialty fellowship training. The purpose of this study was to 1) determine the proportion of plastic surgery residents pursuing subspecialty training relative to other surgical specialties, and 2) analyze trends in ACGME accreditation of plastic surgery subspecialty fellowship programs. Methods: The American Medical Association provided data on career intentions of surgical chief residents graduating from 2014 to 2016. The percentage of residents pursuing fellowship training was compared by specialty. Trends in the proportion of accredited fellowship programs in craniofacial, hand, and microsurgery were analyzed. The percentage of accredited programs was compared between subspecialties with added-certification options (hand surgery) and subspecialties without added-certification options (craniofacial surgery and microsurgery). Results: Most integrated and independent plastic surgery residents pursued fellowship training (61.8% vs 49.6%, p = 0.014). Differences existed by specialty from a high in orthopaedic surgery (90.8%) to a low in colon & rectal surgery (3.2%). From 2005 to 2015, the percentage of accredited craniofacial fellowship programs increased, but was not significant (27.8% to 33.3%, p = 0.386). Accredited programs were not found for microsurgery. For hand surgery, the proportion of accredited programs that were plastic surgery (p = 0.755) and orthopaedic surgery (p = 0.253) was stable while general surgery decreased (p = 0.010). Subspecialty areas with added-certification options had more accredited fellowships than those without (100% vs 19.2%, p

Evaluating the July Phenomenon in Plastic Surgery: a NSQIP Analysis

Background: The perception that complications are more frequent during the early months of the medical academic year, known as the "July Phenomenon," has been studied in several specialties with conflicting results. This phenomenon has yet to be studied in plastic surgery; therefore, the purpose of this study was to evaluate the presence of the July Phenomenon within plastic surgery. Methods: The ACS-NSQIP database was accessed and cases from 2005-2014 where "Plastic Surgery" was listed as the surgical specialty were identified. Cases with trainee involvement were included for analysis and stratified into two groups based on calendar-year quarter of admission. The Q3 group included 2,451 cases performed during July-September of each calendar year and the RQ group included 7,131 cases performed in the remaining quarters of each calendar year within the study period. Complication rates for 24 complications of interest for Q3 and RQ cases with trainee involvement were calculated, Chi-square analysis was used to compare complication rates between Q3 and RQ groups. Multivariate regression analysis was performed to control for potential confounders. Results: Comparison of complication rates within operations with trainee involvement showed a statistically significant increase in Q3 vs RQ for superficial wound infection (0.032 vs. 0.023, p=0.046) and wound dehiscence (0.010 vs. 0.006, p =0.034). No significant difference was found for the remaining 22 complications evaluated. Conclusion: This study of a nationwide surgical database found that for the vast majority of complications coded in the NSQIP database, rates do not increase in the beginning of the academic year * These authors contributed equally to this work. Financial Disclosures: None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this manuscript. Accepted for presentation at Plastic Surgery, The Meeting: 2017. Corresponding author: Eduardo D. Rodriguez, MD, DDS, Chair, Hansjörg Wyss Department of Plastic Surgery, New York University Langone Medical Center, 305 East 33rd Street, New York, New York, 10016. Phone: (212) 263-8745, Fax: (212) 263-8492, Email: eduardo.rodriguez@nyumc.org ©2018American Society of Plastic Surgeons

Book Review Plastic Surgery Emergencies: Principles and Techniques.

No abstract available

Preoperative and Postoperative Assessment of Rectus Abdominis Muscle Size and Function Following Deep Inferior Epigastric Perforator (DIEP) Surgery

No abstract available

“40 Years of Lower Extremity Takebacks: Flap Type Influences Salvage Outcomes”

Background: Considering muscle has higher metabolic demand than fasciocutaneous tissue and can be more difficult to monitor clinically, we compared takeback salvage rates between fasciocutaneous and muscle free flaps for lower extremity trauma reconstruction. Methods: Retrospective review of 806 free flaps (1979-2016); 481 soft tissue flaps performed for below knee trauma met inclusion criteria. Primary outcome measures were perioperative complications, specifically takebacks and flap salvage rates. Univariate and multivariate regression analysis was performed where appropriate. Results: Takebacks occurred in 71 flaps (muscle = 44, fasciocutaneous = 27); at an average of 3.7±5.4 days postoperatively. Indications were venous (48%), arterial (31%), unknown (10%), and hematoma (10%). Overall outcomes were complete salvage (37%), partial failure (25%), and total failure (38%). Takebacks occurring within 48 hours postoperatively correlated with higher salvage rates (p=0.022). Fasciocutaneous flaps demonstrated increased takeback rates compared with muscle flaps (p=0.005) which more frequently occurred within 48 hours postoperatively (RR=13.2, p=0.012). Fasciocutaneous flaps were successfully salvaged more often than muscle-based flaps (p

Book review: “Peak. How to Master Almost Anything”

No abstract available

The burden of non-melanoma skin cancers in Auckland, New Zealand

Abstract

Background/Objectives

As the New Zealand Cancer Registry does not require mandatory reporting of non-melanoma skin cancers (NMSC), basal cell carcinomas (BCC) and squamous cell carcinomas (SCC), the clinical burden of these diseases is unknown.

Methods

A retrospective review of all patients with histopathology performed allowed us to estimate invasive BCC and SCC in the Auckland region in 2008 (population 1.44 million).

Results

During this period, a total of 21 236 NMSC were diagnosed among 13 996 patients, consisting of 5611 SCC lesions (26%) and 15 525 (74%) BCC. The Auckland incidence rates per 100 000 were 425 for SCC and 1177 for BCC. The overall rate of NMSC per 100 000 was 1906.5 (standardised to the census data of Australia 2001); 1385 for BCC and 522 for SCC. Using published data on incidence trends and population growth, we estimate that 29 000–33 000 NMSC would have been excised in Auckland in 2016, and 78 000–87 000 in New Zealand.

Conclusion

Auckland has the highest reported incidence of invasive NMSC in the world. We believe that high-risk cutaneous SCC and complex BCC should be recorded. Our study provides information for clinicians and health economists on the scale of the problem.

Conjunctival Dirofilariasis Causing Symptoms for 1 Day

No abstract available

Multiple Eyelid Cysts (Apocrine and Eccrine Hidrocystomas, Trichilemmal Cyst, and Hybrid Cyst) in a Patient With a Prolactinoma

A 53-year-old man presented with smooth-domed, variegated cysts (polycystic disease) of all 4 eyelids, worse on the left side. Some of the cysts were clear, while others were creamy-white colored. In addition, multiple, very fine vesicopapules were noted along the eyelid margins. Histopathologic examination revealed a trichilemmal cyst, several pure apocrine hidrocystomas displaying multiple chambers, a hybrid cyst, and many small eccrine cysts of the deep dermis. The apocrine lesions, including the small ones at the eyelid margins, predominated. Smooth muscle actin sometimes positively stained outer myoepithelial cells in some of the apocrine cysts, which helped to distinguish them from eccrine cysts. Most noteworthy was the fact that the patient had been diagnosed with a prolactinoma 20 years earlier. There is only 1 previous report of multiple apocrine cysts and an antecedent prolactinoma in the dermatologic literature. This syndrome should be separated from that of Schöpf–Schulz–Passarge, which manifests multiple small eyelid apocrine cysts and other ectodermal dysplasias without any association with neoplasia, and from that of focal dermal hypoplasia (Goltz–Gorlin) syndrome with apocrine cysts but again without neoplasia. Accepted for publication December 20, 2017. Supported by the Heed Fellowship (to N.W.). The authors have no conflicts of interest to disclose. Address correspondence and reprint requests to Frederick A. Jakobiec, M.D., D.Sc., David G. Cogan Laboratory of Ophthalmic Pathology, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, 243 Charles Street Suite 208, Boston, MA 02114. E-mail: Fred_Jackobiec@meei.harvard.edu © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Redundant roles of Bradyrhizobium oligotrophicum Cu-type (NirK) and cd1-type (NirS) nitrite reductase genes under denitrifying conditions

Abstract

Reduction of nitrite to nitric oxide gas by respiratory nitrite reductases (NiRs) is the key step of denitrification. Denitrifiers are strictly divided into two functional groups based on whether they possess the copper-containing nitrite reductase (CuNiR) encoded by nirK or the cytochrome cd₁ nitrite reductase (cdNiR) encoded by nirS. Recently, some organisms carrying both nirK and nirS genes have been found. Bradyrhizobium oligotrophicum S58 is a nitrogen-fixing oligotrophic bacterium that carries a set of genes for complete denitrification of nitrate to dinitrogen, including nirK and nirS genes. We show that denitrification in S58 is functional under low-oxygen conditions (anaerobiosis and microaerobiosis), but not under aerobiosis. Under denitrifying conditions, the ΔnirK and ΔnirS single S58 mutants grew normally and their NiR activity was not affected. However, the ΔnirKS double mutant grew more slowly, presumably because the impaired NiR activity resulted in nitrite accumulation in the medium. These results suggest a redundant role for nirK and nirS genes in B. oligotrophicum S58 denitrification. In addition, we found that the nirS gene product, but not that of nirK, maintains swimming motility of S58 under aerobic and low-oxygen conditions in the presence of nitrate.

ABC Transporters of the Multicellular Cyanobacterium Anabaena sp. PCC 7120: a Wide Variety for a Complex Lifestyle

Abstract

Two hundred genes or 3% of the known or putative protein-coding genes of the filamentous freshwater cyanobacterium Anabaena sp. PCC 7120 encode domains of ATP-binding cassette (ABC) transporters. Detailed characterization of some of these transporters (14 - 15 importers and 5 exporters) has revealed their crucial roles in the complex lifestyle of this multicellular photoautotroph, which is able to differentiate specialized cells for nitrogen fixation. This review summarizes the characteristics of the ABC transporters of Anabaena sp. PCC 7120 known to date.

Strongyloidiasis Outside Endemic Areas: Long-term Parasitological and Clinical Follow-up After Ivermectin Treatment

Abstract

Background

Strongyloides stercoralis affects 30–100 million people worldwide. The first-line therapy is ivermectin. Cure is defined as the absence of larvae by parasitological methods 1 year after treatment. To date, no longitudinal parasitological studies for longer periods of time have been conducted to confirm its cure. Here, we evaluated treatment response in long-term follow-up patients with chronic infection using parasitological and molecular methods for larvae or DNA detection.

Methods

A prospective, descriptive, observational study was conducted between January 2009 and September 2015 in Buenos Aires, Argentina. Twenty-one patients with S. stercoralis diagnosis were evaluated 30, 60, and 90 days as well as 1, 2, 3, and/or 4 years after treatment by conventional methods (fresh stool, Ritchie method, agar plate culture), S. stercoralis–specific polymerase chain reaction (PCR) in stool DNA, and eosinophil values.

Results

During follow-up, larvae were detected by conventional methods in 14 of 21 patients. This parasitological reactivation was observed starting 30 days posttreatment (dpt) and then at different times since 90 dpt. Eosinophil values decreased (P = .001) 30 days after treatment, but their levels were neither associated with nor predicted these reactivations. However, S. stercoralis DNA was detected by PCR in all patients, both in their first and subsequent stool samples, thus reflecting the poor efficacy of ivermectin at eradicating parasite from host tissues. Asymptomatic eosinophilia was the most frequent clinical form among chronically infected patients.

Conclusions

These results suggest that the parasitological cure is unlikely. Strongyloidiasis must be considered a chronic infection and ivermectin administration schedules should be reevaluated.

Sliding to predict: vision-based beating heart motion estimation by modeling temporal interactions

Abstract

Purpose

Technical advancements have been part of modern medical solutions as they promote better surgical alternatives that serve to the benefit of patients. Particularly with cardiovascular surgeries, robotic surgical systems enable surgeons to perform delicate procedures on a beating heart, avoiding the complications of cardiac arrest. This advantage comes with the price of having to deal with a dynamic target which presents technical challenges for the surgical system. In this work, we propose a solution for cardiac motion estimation.

Methods

Our estimation approach uses a variational framework that guarantees preservation of the complex anatomy of the heart. An advantage of our approach is that it takes into account different disturbances, such as specular reflections and occlusion events. This is achieved by performing a preprocessing step that eliminates the specular highlights and a predicting step, based on a conditional restricted Boltzmann machine, that recovers missing information caused by partial occlusions.

Results

We carried out exhaustive experimentations on two datasets, one from a phantom and the other from an in vivo procedure. The results show that our visual approach reaches an average minima in the order of magnitude of \(10^{-7}\) while preserving the heart's anatomical structure and providing stable values for the Jacobian determinant ranging from 0.917 to 1.015. We also show that our specular elimination approach reaches an accuracy of 99% compared to a ground truth. In terms of prediction, our approach compared favorably against two well-known predictors, NARX and EKF, giving the lowest average RMSE of 0.071.

Conclusion

Our approach avoids the risks of using mechanical stabilizers and can also be effective for acquiring the motion of organs other than the heart, such as the lung or other deformable objects.

Thanks to referees 2017

Ufuk Abacioglu, Istanbul, Turkey

Inhibited, trapped or adducted: the optimal selective synthetic lethal mix for BRCAness

BRCA1 and BRCA2 proteins have important roles in DNA replication fork stabilisation and a specialised form of DNA repair termed homologous recombination (HR) [1]. They are components of the Fanconi anaemia protein network [2, 3]. A hallmark of deficiency in this network is sensitivity to DNA crosslinks induced by platinum agents and mitomycin C [4, 5]. Historically platinum chemotherapy has only shown modest activity in advanced breast cancer excepting those with chemotherapy naïve disease [6, 7] but recent uncontrolled studies have suggested significant activity for single agent platinum agents in BRCA1 and BRCA2 germline mutation carriers [8]. The TNT phase III trial has recently reported positive interaction between the presence of germline mutation but not epigenetic change in these genes and specific treatment effect; with a doubling of response to carboplatin but no effect of mutation on standard of care taxane response in advanced breast cancer [9].

Safety of an anti-PD-1 immune checkpoint inhibitor in a liver transplant recipient

Monoclonal antibodies directed against regulatory immune checkpoint molecules that inhibit T-cell activation have demonstrated great efficacy in the treatment of metastatic cancer, enhancing the antitumor immunity.

European Society for Medical Oncology (ESMO) position paper on supportive and palliative care

Abstract

Oncology has come a long way in addressing patients' quality of life, together with developing surgical, radio-oncological and medical anticancer therapies. However, the multiple and varying needs of patients are still not being met adequately as part of routine cancer care. Supportive and palliative care interventions should be integrated, dynamic, personalised and based on best evidence. They should start at the time of diagnosis and continue through to end-of-life or survivorship. ESMO is committed to excellence in all aspects of oncological care during the continuum of the cancer experience. Following the 2003 ESMO stand on supportive and palliative care (Cherny N, Catane R, Kosmidis P. ESMO takes a stand on supportive and palliative care. Ann Oncol 2003; 14(9): 1335–1337), this position paper highlights the evolving and growing gap between the needs of cancer patients and the actual provision of care. The concept of patient-centred cancer care is presented along with key requisites and areas for further work.

Comprehensive analysis of the clinical immuno-oncology landscape

Abstract

Advances from immuno-oncology (IO) are changing the standard of care of many types of cancer, and the paradigm of cancer treatments and drug development is being rewritten on a regular basis. Moreover, an unprecedented number of new investigational agents and companies are entering the field of IO. As such, it has become challenging for oncology physicians conducting clinical trials, industry veterans developing IO drugs, and even regulators reviewing novel IO agents to keep track of the rapidly evolving landscape. To help the key stake holders in the field understand the latest IO landscape, we sought to present an unbiased, neutral, scientifically curated, and timely updated analysis of all the current IO agents in clinical development and the clinical trials testing these agents. We based our analyses on information collected from numerous trusted and publicly available sources. We have developed two databases. One database tracks 2004 IO agents (940 in clinical stage and 1064 in preclinical stage) against 303 targets, from 864 companies; the other tracks 3042 active clinical trials of these agents with a target enrollment of 577 076 patients. This report provides key analyses of these data. Furthermore, we will discuss a number of important and actionable trends in the current IO landscape: a large number of companies developing agents against the same IO targets; a rapid increase in the number of anti-PD-1/L1 combination studies, many of which are testing the same combinations and following inefficient patterns; and a significant increase in the number of small, investigator-initiated studies. For each of the findings, we speculate the causes and discuss a few initiatives that aim to address some of these challenges. Finally, by making these landscape analyses available, we aspire to inform the cancer community as they seek to strive for efficiencies and innovation while avoiding duplication.

BRCA 1 and 2 mutation status: the elephant in the room during oncofertility counseling for young breast cancer patients

The impact of BRCA1 or BRCA2 germ-line mutation on women fertility and reproductive outcome has been debated for some years. The biological rationale behind this is that BRCA1/2 play critical roles in homologous repair of DNA double-strand breaks (DSB) and that DNA DSB repair is essential in maintaining ovarian reserve. Animal studies have confirmed that impairment in DNA DSB repair results in accelerated loss of primordial ovarian follicles and that a decline of function of BRCA1 is associated with ovarian ageing [1, 2].

Prevalence and clinical association of gene mutations through multiplex mutation testing in patients with NSCLC: results from the ETOP Lungscape Project

Abstract

Background

Reported prevalence of driver gene mutations in non-small-cell lung cancer (NSCLC) is highly variable and clinical correlations are emerging. Using NSCLC biomaterial and clinical data from the European Thoracic Oncology Platform Lungscape iBiobank, we explore the epidemiology of mutations and association to clinicopathologic features and patient outcome (relapse-free survival, time-to-relapse, overall survival).

Methods

Clinically annotated, resected stage I–III NSCLC FFPE tissue was assessed for gene mutation using a microfluidics-based multiplex PCR platform. Mutant-allele detection sensitivity is >1% for most of the ∼150 (13 genes) mutations covered in the multiplex test.

Results

Multiplex testing has been carried out in 2063 (76.2%) of the 2709 Lungscape cases (median follow-up 4.8 years). FFPE samples mostly date from 2005 to 2008, yet recently extracted DNA quality and quantity was generally good. Average DNA yield/case was 2.63 µg; 38 cases (1.4%) failed QC and were excluded from study; 95.1% of included cases allowed the complete panel of mutations to be tested. Most common were KRAS, MET, EGFR and PIK3CA mutations with overall prevalence of 23.0%, 6.8%, 5.4% and 4.9%, respectively. KRAS and EGFR mutations were significantly more frequent in adenocarcinomas: PIK3CA in squamous cell carcinomas. MET mutation prevalence did not differ between histology groups. EGFR mutations were found predominantly in never smokers; KRAS in current/former smokers. For all the above mutations, there was no difference in outcome between mutated and non-mutated cases.

Conclusion

Archival FFPE NSCLC material is adequate for multiplex mutation analysis. In this large, predominantly European, clinically annotated stage I–III NSCLC cohort, none of the mutations characterized showed prognostic significance.

Will liquid biopsies become our fluid transition to personalized immunotherapy?

Non-small-cell lung cancer (NSCLC) treatment has moved away from the 'same-for-all-therapy' standstill of the previous decades towards personalized therapy strategies. Improvements in molecular diagnostics have gradually increased our understanding of the genetic make-up of tumours, indeed allowing more targeted therapy. This has been the case for just over a decade now, initiated by the identification of activating EGFR driver mutations in tumours with dramatic responses to gefitinib [1, 2].

Novel treatment options for refractory Germ Cell Tumours: back to the bench!

Multi-disciplinary management of germ-cell tumours (GCT) is highly effective and associated with excellent outcomes. However, treatment of refractory GCT remains a therapeutic challenge with very limited treatment options [1]. In patients who are refractory to or recur after standard dose first-line therapy and subsequent therapies including high-dose chemotherapy, only a few systemic treatments have demonstrated activity and the prognosis of refractory patients is extremely poor with cure rates of <5% [2]. Hence, the exploration of novel treatment options for these patients remains one of the remaining priorities in management of GCT.

Annals of Oncology: factors for making a real impact

It is a great honor to have been nominated interim Editor in Chief of Annals of Oncology and to succeed Professor Jean-Charles Soria [1]. Professor Soria, the Editorial Team, and ESMO have made impact factor (IF) a key priority for the development of Annals. The aim was to use the IF, a tool that is easy to monitor, as a metric for quality. Under his leadership, the IF has risen to 11.8, and, as a consequence, the quality of papers submitted to the journal has dramatically increased [2]. We will continue to have IF as one of our main metrics to evaluate the success of the journal, with the aim to consolidate and make sustainable what has been achieved so far. In addition, another goal will be to increase the influence of the journal, which can be monitored using Altmetrics scoring. In order to maintain the success already achieved and to reach our new goals, we will fine tune the current Editorial policy.

Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO–ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS

Abstract

The most recent version of the European Society for Medical Oncology (ESMO) consensus guidelines for the treatment of patients with metastatic colorectal cancer (mCRC) was published in 2016, identifying both a more strategic approach to the administration of the available systemic therapy choices, and a greater emphasis on the use of ablative techniques, including surgery. At the 2016 ESMO Asia Meeting, in December 2016, it was decided by both ESMO and the Japanese Society of Medical Oncology (JSMO) to convene a special guidelines meeting, endorsed by both ESMO and JSMO, immediately after the JSMO 2017 Annual Meeting. The aim was to adapt the ESMO consensus guidelines to take into account the ethnic differences relating to the toxicity as well as other aspects of certain systemic treatments in patients of Asian ethnicity. These guidelines represent the consensus opinions reached by experts in the treatment of patients with mCRC identified by the Presidents of the oncological societies of Japan (JSMO), China (Chinese Society of Clinical Oncology), Korea (Korean Association for Clinical Oncology), Malaysia (Malaysian Oncological Society), Singapore (Singapore Society of Oncology) and Taiwan (Taiwan Oncology Society). The voting was based on scientific evidence and was independent of both the current treatment practices and the drug availability and reimbursement situations in the individual participating Asian countries.

Biosimilars in oncology: much ado about nothing?

Biosimilars have been the subject of an impressive amount of debate since their first introduction in oncology with the development of epoetins in 2007 and later granulocyte-colony stimulating factors. In this journal there have been authoritative reviews 10 years ago [1] and opinions [2] expressing doubts about the development process and the manner in which these agents are introduced into clinical practice. Fortunately, as of today, the manner in which the European Medicines Agency approves such agents [3] has not been found to be at fault.

The European Society for Medical Oncology (ESMO) Precision Medicine Glossary

Abstract

Background

Precision medicine is rapidly evolving within the field of oncology and has brought many new concepts and terminologies that are often poorly defined when first introduced, which may subsequently lead to miscommunication within the oncology community. The European Society for Medical Oncology (ESMO) recognises these challenges and is committed to support the adoption of precision medicine in oncology. To add clarity to the language used by oncologists and basic scientists within the context of precision medicine, the ESMO Translational Research and Personalised Medicine Working Group has developed a standardised glossary of relevant terms.

Materials and methods

Relevant terms for inclusion in the glossary were identified via an ESMO member survey conducted in Autumn 2016, and by the ESMO Translational Research and Personalised Medicine Working Group members. Each term was defined by experts in the field, discussed and, if necessary, modified by the Working Group before reaching consensus approval. A literature search was carried out to determine which of the terms, 'precision medicine' and 'personalised medicine', is most appropriate to describe this field.

Results

A total of 43 terms are included in the glossary, grouped into five main themes—(i) mechanisms of decision, (ii) characteristics of molecular alterations, (iii) tumour characteristics, (iv) clinical trials and statistics and (v) new research tools. The glossary classes 'precision medicine' or 'personalised medicine' as technically interchangeable but the term 'precision medicine' is favoured as it more accurately reflects the highly precise nature of new technologies that permit base pair resolution dissection of cancer genomes and is less likely to be misinterpreted.

Conclusions

The ESMO Precision Medicine Glossary provides a resource to facilitate consistent communication in this field by clarifying and raising awareness of the language employed in cancer research and oncology practice. The glossary will be a dynamic entity, undergoing expansion and refinement over the coming years.

Curcumin dietary supplements and everolimus-based cancer treatment

The majority of adults in the United States take one or more dietary supplements, either every day or occasionally. Curcuma-containing supplements are broadly used by cancer patients, hoping that curcumin (the main metabolite of curcuma) could exert anticancer effects [1].

Programmed death-1 inhibition and atherosclerosis: can nivolumab vanish complicated atheromatous plaques?

Atherosclerosis is considered to be a T-cell-driven disease since the interaction between resident cells, immune cells and their products has been recognized to promote the development of atheromatous plaques in the arterial walls [1]. The process of atherosclerosis evolves from a prelesional phase, which is potentially reversible, to complicated lesions characterized by the formation of a fibrous cap and vulnerable plaques, followed by possible rupture and atherothrombosis [2].

Safety and efficacy of alternating treatment with EP2006, a filgrastim biosimilar, and reference filgrastim: a phase III, randomised, double-blind clinical study in the prevention of severe neutropenia in patients with breast cancer receiving myelosuppressive chemotherapy

Abstract

Background

In 2015, the biosimilar filgrastim EP2006 became the first biosimilar approved by the US Food and Drug Administration for commercial use in the United States, marketed as Zarxio^® (Sandoz). This phase III randomised, double-blind registration study in patients with breast cancer receiving (neo)adjuvant myelosuppressive chemotherapy (TAC; docetaxel + doxorubicin + cyclophosphamide) compares reference filgrastim, Neupogen^® (Amgen), with two groups receiving alternating treatment with reference and biosimilar every other cycle.

Patients and methods

A total of 218 patients receiving 5 µg/kg/day filgrastim over six chemotherapy cycles were randomised 1: 1: 1: 1 into four arms. Two arms received only one product, biosimilar or reference (unswitched), and two arms (switched) received alternating treatments every other cycle (biosimilar then reference or vice versa over six cycles). Since the switch occurred from cycle 2 onwards, this analysis compared pooled switched groups to the unswitched reference group for efficacy during cycles 2–6. Safety was also assessed. Non-inferiority in febrile neutropenia (FN) rates between groups for cycles 2–6 was shown if 95% were within a pre-defined margin of − 15%.

Results

A total of 109 patients switched treatment, and 52 patients received reference in all cycles. Baseline characteristics were similar between groups. The incidence of FN was 0% (reference) versus 3.4% (n = 3, switched) across cycles 2–6, with a difference of − 3.4% (95% confidence interval: −9.65% to 4.96%), showing non-inferiority. Infections occurred in 9.3% (switched) versus 9.9% (reference). Hospitalisation due to FN was low (one patient in cycle 6; switched). Adverse events related to filgrastim were reported in 42.1% (switched) versus 39.2% (reference) (all cycles). Musculoskeletal/connective tissue disorders related to filgrastim occurred in 35.5% (switched) versus 39.2% (reference) (all cycles), including bone pain (30.8% versus 33.3%). No neutralising antibodies were detected.

Conclusions

There were no clinically meaningful results regarding efficacy, safety or immunogenicity when switching from reference to biosimilar filgrastim/EP2006, or vice versa.

Monitoring resistance through liquid biopsy

The clonal evolution of tumors and the development of drug resistance is arguably the most substantial hindrance in the treatment of patients with targeted therapy. In their prospective study 'Dynamic molecular analysis and clinical correlates of tumor evolution within a phase 2 trial of panitumumab-based therapy in metastatic colorectal cancer' [1], Siena et al. illustrate the value of cell-free DNA (cfDNA) in understanding the clonal evolution of colorectal cancer during anti-EGFR therapy. This study demonstrates how cfDNA may be useful in understanding mechanisms of acquired resistance to anti-EGFR therapy and how the detection of resistance mechanisms in cfDNA may correlate with clinical outcomes. In this phase II study, patients with KRAS exon 2 wild-type metastatic colorectal cancer were treated panitumumab and irinotecan. The original design of the trial was to explore the role of emergent KRAS exon 2 mutations in acquired resistance to anti-EGFR therapy. However, as the clinical importance of additional RAS family mutations became apparent, this study was expanded to explore the role of these additional RAS mutations.

A gene signature to predict high tumor-infiltrating lymphocytes after neoadjuvant chemotherapy and outcome in patients with triple-negative breast cancer

Abstract

Background

In patients with triple-negative breast cancer (TNBC), the extent of tumor-infiltrating lymphocytes (TILs) in the residual disease after neoadjuvant chemotherapy (NACT) is associated with better prognosis. Our objective was to develop a gene signature from pretreatment samples to predict the extent of TILs after NACT and then to test its prognostic value on survival.

Patients and methods

Using 99 pretreatment samples, we generated a four-gene signature associated with high post-NACT TILs. Prognostic value of the signature on distant relapse-free survival (DRFS) was first assessed on the training set (n=99) and then on an independent validation set (n=115).

Results

A four-gene signature combining the expression levels of HLF, CXCL13, SULT1E1, and GBP1 was developed in baseline samples to predict the extent of lymphocytic infiltration after NACT. In a multivariate analysis performed on the training set, this signature was associated with DRFS [hazard ratio (HR): 0.28, for a one-unit increase in the value of the four-gene signature, 95% confidence interval (CI): 0.13–0.63)]. In a multivariate analysis performed on an independent validation set, the four-gene signature was significantly associated with DRFS (HR: 0.17, 95% CI: 0.06–0.43). The four-gene signature added significant prognostic information when compared with the clinicopathologic pretreatment model (likelihood ratio test in the training set P=0.004 and in the validation set P=0.002).

Conclusions

A four-gene signature predicts high levels of TILs after anthracycline-containing NACT and outcome in patients with TNBC and adds prognostic information to a clinicopathological model at diagnosis.

Ten-year results of intense dose-dense chemotherapy show superior survival compared with a conventional schedule in high-risk primary breast cancer: final results of AGO phase III iddEPC trial

Abstract

Background

Primary breast cancer (BC) patients with extensive axillary lymph-node involvement have a limited prognosis. The Arbeitsgemeinschaft fuer Gynaekologische Onkologie (AGO) trial compared intense dose-dense (idd) adjuvant chemotherapy with conventionally scheduled chemotherapy in high-risk BC patients. Here we report the final, 10-year follow-up analysis.

Patients and methods

Enrolment took place between December 1998 and April 2003. A total of 1284 patients with 4 or more involved axillary lymph nodes were randomly assigned to receive 3 courses each of idd sequential epirubicin, paclitaxel and cyclophosphamide (iddEPC) q2w or standard epirubicin/cyclophosphamide followed by paclitaxel (EC → P) q3w. Event-free survival (EFS) was the primary end point.

Results

A total of 658 patients were assigned to receive iddEPC and 626 patients were assigned to receive EC → P. The median duration of follow-up was 122 months. EFS was 47% (95% CI 43% to 52%) in the standard group and 56% (95% CI 52% to 60%) in the iddEPC group [hazard ratio (HR) 0.74, 95% CI 0.63–0.87; log-rank P = 0.00014, one-sided]. This benefit was independent of menopausal, hormone receptor or HER2 status. Ten-year overall survival (OS) was 59% (95% CI 55% to 63%) for patients in the standard group and 69% (95% CI 65% to 73%) for patients in the iddEPC group (HR = 0.72, 95% CI 0.60–0.87; log-rank P = 0.0007, two-sided). Nine versus two cases of secondary myeloid leukemia/myelodysplastic syndrome were observed in the iddEPC and the EC → P arm, respectively.

Conclusion

The previously reported OS benefit of iddEPC in comparison to conventionally dosed EC → P has been further increased and achieved an absolute difference of 10% after 10 years of follow-up.

Sequential chemotherapy/radiotherapy was comparable with concurrent chemoradiotherapy for stage I/II NK/T-cell lymphoma

Abstract

Background

In stage I/II natural killer (NK)/T-cell lymphoma, concurrent chemoradiotherapy (CCRT) had previously been shown to result in superior outcome compared with anthracycline-containing regimens, which have since been considered ineffective. The role of CCRT in comparison with approaches employing nonanthracycline-containing chemotherapy (CT) and sequential radiotherapy (RT) in such patients remains to be defined.

Patients and methods

Three hundred and three untreated patients (207 men, 96 women; median age: 51, 18–86 years) with stage I/II NK/T-cell lymphoma who had received nonanthracycline-containing regimens were collected from an international consortium and retrospectively analyzed. Treatment included single modality (CT and RT), sequential modalities (CT + RT; RT + CT) and concurrent modalities (CCRT; CCRT + CT). The impact of clinicopathologic parameters and types of treatment on complete response (CR) rate, progression-free-survival (PFS) and overall-survival (OS) was evaluated.

Results

For CR, stage (P = 0.027), prognostic index for NK/T-cell lymphoma (PINK) (P = 0.026) and types of initial treatment (P = 0.011) were significant prognostic factors on multivariate analysis. On Cox regression analysis, ECOG performance score (P = 0.021) and PINK-EBV DNA (PINK-E) (P = 0.002) significantly impacted on PFS; whereas ECOG performance score (P = 0.008) and stage (P < 0.001) significantly impacted on OS. For comparing CCRT ± CT and sequential CT + RT, CCRT ± CT patients (n = 190) were similar to sequential CT + RT patients (n = 54) in all evaluated clinicopathologic parameters except two significantly superior features (higher proportion of undetectable circulating EBV DNA on diagnosis and lower PINK-E scores). Despite more favorable pre-treatment characteristics, CCRT ± CT patients had CR rate, PFS and OS comparable with sequential CT + RT patients on multivariate and Cox regression analyses.

Conclusions

In stage I/II NK/T-cell lymphomas, when effective chemotherapeutic regimens were used, CCRT and sequential CT + RT gave similar outcome.