Clinicopathological Characteristics of High-grade Squamous Intraepithelial Lesions Involving Condyloma Acuminatum

Background/Aim: Severe nuclear atypia can be associated with condyloma acuminatum. In this study, we investigated nine cases of perianal condyloma acuminatum with severe nuclear atypia and determined whether severe nuclear atypia is sufficient for the diagnosis of high-grade squamous intraepithelial lesion (HSIL). Materials and Methods: The clinical data and pathological features of the nine patients were collected. p16 Immunostaining and human papillomavirus genotyping were also performed. Results: The resected specimens of six men infected with human immunodeficiency virus showed features suggestive of HSIL, including the expansion of basaloid cells, severe nuclear pleomorphism in the lower one-third, bizarre nuclei, mitotic figure in the upper two-thirds, atypical mitosis, block positivity for p16, and high-risk human papillomavirus infection. In contrast, the resected specimens of the remaining three patients did not show any of those HSIL features, even though there were several microscopic foci showing severe nuclear atypia in the upper two-thirds of the papillomatous epithelium. Conclusion: Our observation regarding the occurrence of HSIL involving perianal condyloma acuminatum in human immunodeficiency virus-infected patients suggests that active, complete surgical excision of perianal condyloma acuminatum and a thorough histopathological examination are necessary. The diagnosis of severe nuclear atypia involving the upper two-thirds of the epithelium should be made with great caution.

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Is Adjuvant Endocrine Therapy Indicated for DCIS Patients After Complete Surgical Excision?

Data derived from pathological analysis, natural history, radiological characteristics, genomic profiling, and clinical outcome indicate that ductal carcinoma in situ (DCIS) is a heterogeneous disease; meaning that no single therapeutic strategy is best, but rather that treatment should be personalised and entail a rigorous multidisciplinary approach. The role of adjuvant endocrine therapy after surgical excision has been the subject of scientific debate in view of the in situ nature of this neoplasm. We reviewed the literature and summarised the evidence regarding the need for adjuvant endocrine therapy following complete surgical excision of DCIS through the identification of the most important outcomes, evaluation of quality of evidence, and assessment of the trade-offs involved. There is no scientific evidence that adjuvant endocrine therapy reduces the incidence of ipsilateral breast invasive recurrence or breast cancer mortality in the context of adequate local treatment of DCIS in the form of breast conserving surgery with clear surgical margins plus adjuvant radiotherapy or total mastectomy. Therefore, its routine use is not indicated. However, adjuvant endocrine therapy can be considered after a rigorous multidisciplinary discussion and patient counselling in a carefully selected subgroup of patients with high-risk estrogen receptor-positive DCIS.

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Number of Resected Lymph Nodes and Survival of Patients with Locally Advanced Esophageal Squamous Cell Carcinoma Receiving Preoperative Chemoradiotherapy

Background: The association of extended lymph node (LN) dissection with improved outcomes in patients with locally advanced esophageal squamous cell carcinoma (ESCC) who received preoperative chemoradiotherapy (CRT) followed by surgery is debatable. Patients and Methods: We reviewed data from patients with esophageal cancer enrolled in three phase II clinical trials of preoperative paclitaxel and cisplatin-based CRT during 2000-2012. Patients with ESCC who underwent planned esophagectomy were enrolled. The number of resected LNs and other clinicopathological factors were analyzed regarding their impact on progression-free (PFS) and overall (OS) survival using Cox proportional hazards model. Results: In total, 139 patients were included. The median PFS and OS were 24.4 and 31.8 months, respectively. The median number of resected and positive LNs were 19 (range=2-96) and 0 (range=0-9), respectively. The mean number of positive LNs did not differ significantly among quartile groups of total resected LNs (quartile 1: 2-12, 2: 13-19, 3: 20-29, and 4: 30-96). The resected LN number analyzed as dichotomies divided by the median or as continuous variables was not associated with PFS or OS. However, in an exploratory analysis, patients of quartiles 2 and 3 had longer PFS and OS than those with quartiles of 1 and 4 in multivariate analysis (p=0.019 and 0.005, respectively). Conclusion: Although extensive LN dissection was not associated with improved survival, resection of 13-29 LNs was associated with improved survival in patients with locally advanced ESCC receiving preoperative paclitaxel and cisplatin-based CRT.

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Update on Surgical Management of Small Bowel Neuroendocrine Tumors

The widespread use of endoscopy and imaging in combination with the continuous update of the staging systems for neuroendocrine tumors has led to an increase in the incidence of small intestinal neuroendocrine tumors (si-NENs) globally. Despite high survival rates, severe complications may occur even in early stages due to the anatomic location of the primary site and the desmoplastic reaction. Surgery plays a central role in the management of patients with si-NENs. Excision of locoregional disease along with extensive lymph node dissection should be performed in fit patients, even in the presence of metastases. Multimodality treatment of liver metastases includes hepatectomy, ablative techniques and liver transplantation. Hormone therapy with somatostatine analogs is of high importance for symptomatic control; special caution should be exercised both pre- and intra-operatively. A multidisciplinary approach is essential in order to provide personalized therapeutics for patients with si-NENs. Clinical research and specialization in this field should be further encouraged.

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Expression of Class III Beta-tubulin Predicts Prognosis in Patients with Cisplatin-resistant Bladder Cancer Receiving Paclitaxel-based Second-line Chemotherapy

Background/Aim: Class III beta-tubulin (TUBB3) expression is recognized as a predictive marker for chemosensitivity to cisplatin- and taxane-based chemotherapies in various malignancies. The aim of this study was to clarify the predictive value of TUBB3 expression for the anticancer effects of first-line cisplatin-based chemotherapy and second-line paclitaxel-based chemotherapy in patients with urothelial cancer (UC). Patients and Methods: We reviewed 116 patients with UC (90 with bladder cancer and 27 with upper urinary tract cancer) treated with first-line cisplatin-based chemotherapy. Among them, 42 patients received a paclitaxel-based regimen as second-line chemotherapy for advanced cisplatin-resistant UC. TUBB3 expression was evaluated using immunohistochemistry, and survival analyses were performed using Kaplan–Meier survival curves and multivariate Cox proportional hazard analysis. Results: TUBB3 was mainly detected in the cytoplasm of cancer cells, and 64 patients (55.2%) were judged as having positive TUBB3 expression. TUBB3 expression was significantly associated with tumour grade (p<0.001). TUBB3 expression was not associated with time to progression after first-line cisplatin-based chemotherapy. However, positive expression of TUBB3 was significantly associated with unfavourable overall survival in patients receiving second-line paclitaxel-based chemotherapy (p=0.021). In addition, a multivariate analysis model including T-stage and metastasis at the beginning of second-line therapy and regimen showed that TUBB3 expression was an independent predictor of poorer survival (hazard ratio(HR)=3.44, 95% confidential interval(CI)=1.15-10.33, p=0.027). Conclusion: TUBB3 expression was identified as a useful predictive factor for survival after second-line paclitaxel-based therapy in patients with cisplatin-resistant UC. Our results are useful for determining treatment strategies for such patients

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Detection of Distinct Changes in Gene-expression Profiles in Specimens of Tumors and Transition Zones of Tenascin-positive/-negative Head and Neck Squamous Cell Carcinoma

Background/Aim: Having previously initiated genome-wide expression profiling in head and neck squamous cell carcinoma (HNSCC) for regions of the tumor, the margin of surgical resecate (MSR) and normal mucosa (NM), we here proceed with respective analysis of cases after stratification according to the expression status of tenascin (Ten). Materials and Methods: Tissue specimens of each anatomical site were analyzed by immunofluorescent detection of Ten, fibronectin (Fn) and galectin-1 (Gal-1) as well as by microarrays. Results: Histopathological examination demonstrated that Ten⁺Fn⁺Gal-1⁺ co-expression occurs more frequently in samples of HNSCC (55%) than in NM (9%; p<0.01). Contrary, the Ten^–Fn⁺Gal-1^– (45%) and Ten^–Fn^–Gal-1^– (39%) status occurred with significantly (p<0.01) higher frequency than in HNSCC (3% and 4%, respectively). In MSRs, different immunophenotypes were distributed rather equally (Ten⁺Fn⁺Gal-1⁺=24%; Ten^–Fn⁺Gal-1^–=36%; Ten^–Fn^–Gal-1^–=33%), differing to the results in tumors (p<0.05). Absence/presence of Ten was used for stratification of patients into cohorts without a difference in prognosis, to comparatively examine gene-activity signatures. Microarray analysis revealed i) expression of several tumor progression-associated genes in Ten⁺ HNSCC tumors and ii) a strong up-regulation of gene expression assigned to lipid metabolism in MSRs of Ten^– tumors, while NM profiles remained similar. Conclusion: The presented data reveal marked and specific changes in tumors and MSR specimens of HNSCC without a separation based on prognosis.

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Prognostic Significance of High EphA1-4 Expression Levels in Locally Advanced Gastric Cancer

Background/Aim: Erythropoietin-producing hepatocellular carcinoma receptor A (EphA) is associated with angiogenesis and invasive tumor progression. In this study, we evaluated the EphA1-4 expression levels in advanced gastric cancer. Patients and Methods: Tumor tissues obtained from 114 patients with advanced gastric adenocarcinoma who underwent gastrectomy were analyzed. In addition, the impact of EPHA 1-4 mRNA expression on survival was analyzed using the Kaplan-Meier plotter database on the website. Results: High EphA 1, 2, and 4 expression levels were significantly related to recurrence (p<0.01, p=0.04, and p<0.01). Both high EphA 1 and 4 expression levels were independent predictors of relapse-free interval (hazard ratio [HR]=2.0, p=0.03; HR=2.4, p=0.03) and disease-specific survival (HR=2.0, 95% p=0.03; HR=2.5, p=0.02) on multivariate analysis. In the Kaplan-Meier plotter database, high EPHA2 mRNA expression was significantly associated with poor survival in patients with gastric cancer (p=0.0098), and high expression levels of EPHA1 and 4 tended to be associated with poor survival (p=0.050, p=0.052). Conclusion: EphA 1, 2, and 4 may play key roles in recurrence and survival in patients with advanced gastric cancer.

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Modulation of Tumor Cell Metabolism by Laser Photochemotherapy with Cisplatin or Zoledronic Acid In Vitro

Background/Aim: Laser photochemotherapy is a new approach in cancer treatment using low-level laser therapy (LLLT) to enhance the effect of chemotherapy. Materials and Methods: In order to evaluate the effect of LLLT on tumor cells, HeLa cells were treated with cisplatin or zoledronic acid (ZA) followed by LLLT. Cell viability was evaluated with 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide assay. Oxidative phosphorylation and glycolysis were measured using extracellular flux analysis. Immunocytochemistry of heat-shock protein 70 (HSP70) and western blot analysis were performed. Results: LLLT alone increased viability and was associated with lower oxidative phosphorylation but higher glycolysis rates. Cisplatin and ZA alone lowered cell viability, glycolysis and oxidative phosphorylation. This effect was significantly enhanced in conjunction with LLLT and was accompanied by reduced oxidative phosphorylation and collapse of glycolysis. Conclusion: Our observations indicate that LLLT may raise the cytotoxicity of cisplatin and ZA by modulating cellular metabolism, pointing to a possible application in cancer treatment.

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A Feasibility Study of Capecitabine and Oxaliplatin for Patients with Stage II/III Colon Cancer -ACTOR Study-

Background/Aim: Past studies have suggested that adjuvant capecitabine and oxaliplatin (CAPOX) provides decreased tumor relapse and longer survival in patients with curatively resected colon cancer. We report the first evidence of the feasibility of adjuvant CAPOX in Japanese patients with early colon cancer. Patients and Methods: Eligible patients had histologically-confirmed stage II/III colon cancer and received curative resection. The primary endpoint was completion rate of treatment after 8 cycles of adjuvant CAPOX. Results: Thirty-six patients were enrolled in this study. The completion rate of CAPOX and oxaliplatin were 77.8% and 61.1%, respectively. The incidence of grade ≥3 adverse events was neutropenia (n=6), thrombocytopenia (n=3), nausea (n=5), hand-foot syndrome (n=1) and peripheral sensory neuropathy (n=1). Three-year disease-free survival for stage II patients and stage III patients were 100% and 79.3%, respectively. Conclusion: Adjuvant CAPOX can be safely administered to Japanese patients with stage II/III colon cancer.

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Combination Treatment of Polo-Like Kinase 1 and Tankyrase-1 Inhibitors Enhances Anticancer Effect in Triple-negative Breast Cancer Cells

Background/Aim: Breast cancer is the most common malignant cancer type in women, and triple-negative breast cancer (TNBC) is an extremely aggressive subtype of breast cancer with poor prognosis rates. The present study investigated the antitumor effect of polo-like kinase 1 (PLK1) inhibitor in combination with the tankyrase-1 (TNKS1) inhibitor on TNBC cells. Materials and Methods: We evaluated the antitumor effects of combination therapy with PLK1 and TNKS1 inhibitor using cell viability analysis, apoptosis assay and transwell assay for cell invasion and migration in TNBC cells. Results: Combination treatment with PLK1 and TNKS1 inhibitors not only inhibited the invasion and migration capacity of TNBC cells, but also increased the apoptosis and cell death of TNBC cells. The viability of TNBC cells with low expression of β-catenin and high expression of PLK1 was not affected by treatment with PLK1 inhibitor. However, the combination treatment with the TNKS1 inhibitor significantly decreased cell invasion and migration and increased apoptosis. Conclusion: Combination therapy of PLK1 and TNKS1 inhibitors may improve the therapeutic efficacy of the current treatment for TNBC.

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Spatiotemporal Analysis of Breast Cancer Incidence: A Study in Southern Portugal Between 2005 and 2012

Aim: To characterize the spatiotemporal patterns of breast cancer (BC) incidence in females in the area with the highest incidence rate (IR) of the country in 2005-2012. Materials and Methods: The BC-IR was studied using mapping techniques, analysis of spatiotemporal clusters and analysis of spatial variations in temporal trends. Results: The overall BC-IR was 119.13/10⁵ inhabitants. The annual BC-IRs were 17.7, 156.9, 213.3 and 232.9/10⁵ inhabitants for women diagnosed at <40, 40-49, 50-64 and ≥65 years of age. This IR increased overall (by 4.113%/year) and for the four age groups (by 5.935, 3.833, 4.114 and 2.194%/year, respectively). In patients with locoregional and metastatic disease, the IRs were 93.6 and 7.4/10⁵ inhabitants, increasing by 6.976 and 0.303%/year, respectively. Several spatiotemporal clusters and two spatial-variations in temporal trends were detected. The Lisbon region showed high IR clusters for most groups. Conclusion: This study identified critical areas of high IR and increasing trends for female BC-IR, providing evidence of heterogeneities in this area.

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Chemotherapeutic Effect of CD147 Antibody-labeled Micelles Encapsulating Doxorubicin Conjugate Targeting CD147-Expressing Carcinoma Cells

Background: CD147 (basigin/emmprin) is expressed on the surface of carcinoma cells. Materials and Methods: For studying the efficacy of CD147-targeting medicine on CD147-expressing cells, we studied the effect of anti-CD147-labeled polymeric micelles (CD147ab micelles) that encapsulated a conjugate of doxorubicin with glutathione (GSH-DXR), with specific accumulation and cytotoxicity against CD147-expressing A431 human epidermoid carcinoma cells, Ishikawa human endometrial adenocarcinoma cells, and PC3 human prostate carcinoma cells. Results: By treatment of each cell type with CD147ab micelles for 1 h, a specific accumulation of CD147ab micelles in CD147-expressing cells was observed. In addition, the cytotoxicity of GSH-DXR-encapsulated micelles against each cell type was measured by treatment of the micelles for 1 h. The cytotoxic effect of CD147ab micelles carrying GSH-DXR was 3- to 10-fold higher for these cells than that of micelles without GSH-DXR. Conclusion: These results suggest that GSH-DXR-encapsulated CD147ab micelles could serve as an effective drug delivery system to CD147-expressing carcinoma cells.

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Development of allergic sensitization and its relevance to paediatric asthma

Purpose of review The purpose of this review is to summarize the recent evidence on the distinct atopic phenotypes and their relationship with childhood asthma. We start by considering definitions and phenotypic classification of atopy and then review evidence on its association with asthma in children. Recent findings It is now well recognized that both asthma and atopy are complex entities encompassing various different sub-groups that also differ in the way they interconnect. The lack of gold standards for diagnostic markers of atopy and asthma further adds to the existing complexity over diagnostic accuracy and definitions. Although recent statistical phenotyping studies contributed significantly to our understanding of these heterogeneous disorders, translating these findings into meaningful information and effective therapies requires further work on understanding underpinning biological mechanisms. Summary The disaggregation of allergic sensitization may help predict how the allergic disease is likely to progress. One of the important questions is how best to incorporate tests for the assessment of allergic sensitization into diagnostic algorithms for asthma, both in terms of confirming asthma diagnosis, and the assessment of future risk.

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DNA methylation of imprinted gene control regions in the regression of low-grade cervical lesions

Abstract

The role of host epigenetic mechanisms in the natural history of low-grade cervical intraepithelial neoplasia (CIN1) is not well characterized. We explored differential methylation of imprinted gene regulatory regions as predictors of the risk of CIN1 regression.

A total of 164 patients with CIN1 were recruited from 10 Duke University clinics for the CIN Cohort Study. Participants had colposcopies at enrollment and up to five follow-up visits over three years. DNA was extracted from exfoliated cervical cells for methylation quantitation at CpG (cytosine-phosphate-guanine) sites and human papillomavirus (HPV) genotyping. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression to quantify the effect of methylation on CIN1 regression over two consecutive visits, compared to non-regression (persistent CIN1; progression to CIN2+; or CIN1 regression at a single time-point), adjusting for age, race, high-risk HPV (hrHPV), parity, oral contraceptive and smoking status.

Median participant age was 26.6 years (range: 21-64.4 years), 39.0% were African-American, and 11% were current smokers. Most participants were hrHPV-positive at enrollment (80.5%). Over one-third of cases regressed (n=53, 35.1%). Median time-to-regression was 12.6 months (range: 4.5-24.0 months). Probability of CIN1 regression was negatively correlated to methylation at IGF2AS CpG 5 (HR=0.41; 95% CI=0.23-0.77) and PEG10 DMR (HR=0.80; 95% CI=0.65-0.98).

Altered methylation of imprinted IGF2AS and PEG10 DMRs may play a role in the natural history of CIN1. If confirmed in larger studies, further research on imprinted gene DMR methylation is warranted to determine its efficacy as a biomarker for cervical cancer screening. This article is protected by copyright. All rights reserved.

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Endothelial progenitor cells contribute to neovascularization of non-small cell lung cancer via HDAC7 mediated cytoskeleton regulation and angiogenic genes transcription

Abstract

To supply tumor tissues with nutrients and oxygen, endothelial progenitor cells (EPCs) home to tumor sites and contribute to neovascularization. Although the precise mechanism of EPCs-induced neovascularization remains poorly understood in non-small cell lung cancer (NSCLC), histone deacetylase 7 (HDAC7) is considered as a critical regulator. To explore the function of HDAC7 in neovascularization induced by EPCs, tube formation assay, immunofluorescence, microarray, Western blot analysis and animal models were performed. In vitro, HDAC7 abrogation led to the activation of ROCK/MLC2 pathway concomitant with ERK dephosphorylation, causing the instability of cytoskeleton and collapse of tube formation. In vivo, absence of HDAC7 impaired the vascular lumen integrity and decreased the functional blood perfusion, inhibiting the growth of tumor. At the level of transcription, HDAC7 silencing upregulated antiangiogenic genes and suppressed proangiogenic genes collectively, turning off the angiogenic switch during vessel formation. Taken together, HDAC7 plays a dual role in maintaining the structural and non-structural functions of EPCs. Our work demonstrates the molecular mechanism by which HDAC7 contributes to the angiogenic property of EPCs and provides a rational basis for specific targeting of antiangiogenic strategies in lung cancer. This article is protected by copyright. All rights reserved.

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Response to Czarnecki

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Immigration is the most likely reason for the generational change in melanoma incidence in Queensland, Australia

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Asthma exacerbation prediction: recent insights

Purpose of review Asthma attacks are frequent in children with asthma and can lead to significant adverse outcomes including time off school, hospital admission and death. Identifying children at risk of an asthma attack affords the opportunity to prevent attacks and improve outcomes. Recent findings Clinical features, patient behaviours and characteristics, physiological factors, environmental data and biomarkers are all associated with asthma attacks and can be used in asthma exacerbation prediction models. Recent studies have better characterized children at risk of an attack: history of a severe exacerbation in the previous 12 months, poor adherence and current poor control are important features which should alert healthcare professionals to the need for remedial action. There is increasing interest in the use of biomarkers. A number of novel biomarkers, including patterns of volatile organic compounds in exhaled breath, show promise. Biomarkers are likely to be of greatest utility if measured frequently and combined with other measures. To date, most prediction models are based on epidemiological data and population-based risk. The use of digital technology affords the opportunity to collect large amounts of real-time data, including clinical and physiological measurements and combine these with environmental data to develop personal risk scores. These developments need to be matched by changes in clinical guidelines away from a focus on current asthma control and stepwise escalation in drug therapy towards inclusion of personal risk scores and tailored management strategies including nonpharmacological approaches. Summary There have been significant steps towards personalized prediction models of asthma attacks. The utility of such models needs to be tested in the ability not only to predict attacks but also to reduce them.

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‘Hidden’ occupational allergens such as additives

Purpose of review With the development of innovative technologies, new agents are continually introduced to the workplace. Some of these agents can act as hidden allergens whenever they are not declared in the product labels or whenever their health hazards are unknown. This review article focuses on the identification and description of unusual and/or hidden allergens recently incriminated in occupational diseases. Recent findings Occupational exposure is an important global health issue that can induce respiratory and cutaneous disorders, as well as life-threatening anaphylaxis. Apart from the classic forms of occupational exposure, reports have emerged from nonconventional or newly identified allergens or additives. These compounds are substances added to another in order to alter or improve the general quality or to counteract undesirable properties, and some of them may behave as potent and frequently hidden allergens. These highly uncommon and/or hidden allergens belong to several categories: foods, spices, cosmetics, insects, enzymes, chemicals, drugs, preservatives, and coloring agents, among others. Summary A high level of suspicion and awareness about the potential hidden allergens is necessary to ascertain the allergens implicated. It is of utmost importance to identify the specific eliciting agents of the occupational diseases in order to avoid strictly further exposure to them.

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Evidence establishing a link between prenatal and early-life stress and asthma development

Purpose of review The objective of this review is to provide an update on our evolving understanding of the effects of stress in pregnancy and during early development on the onset of asthma-related phenotypes across childhood, adolescence, and into early adulthood. Recent findings Accumulating evidence over the past 2 decades has established that prenatal and early-life psychological stress and stress correlates (e.g., maternal anxiety or depression) increase the risk for childhood respiratory disorders. Recent systematic reviews and meta-analyses including numerous prospective epidemiological and case–control studies substantiate a significant effect of prenatal stress and stress in early childhood on the development of wheeze, asthma, and other atopic-related disorders (eczema and allergic rhinitis), with many studies showing an exposure–response relationship. Offspring of both sexes are susceptible to perinatal stress, but effects differ. The impact of stress on child wheeze/asthma can also be modified by exposure timing. Moreover, coexposure to prenatal stress can enhance the effect of chemical stressors, such as prenatal traffic-related air pollution, on childhood respiratory disease risk. Understanding complex interactions among exposure dose, timing, child sex, and concurrent environmental exposures promises to more fully characterize stress effects and identify susceptible subgroups. Although the link between perinatal stress and childhood asthma-related phenotypes is now well established, pathways by which stress predisposes children to chronic respiratory disorders are not as well delineated. Mechanisms central to the pathophysiology of wheeze/asthma and lung growth and development overlap and involve a cascade of events that include disrupted immune, neuroendocrine, and autonomic function as well as oxidative stress. Altered homeostatic functioning of these integrated systems during development can enhance vulnerability to asthma and altered lung development. Summary Mechanistic studies that more comprehensively assess biomarkers reflecting alterations across interrelated stress response systems and associated regulatory processes, in both pregnant women and young children, could be highly informative. Leveraging high-throughput systems-wide technologies to include epigenomics (e.g., DNA methylation, microRNAs), transcriptomics, and microbiomics as well as integrated multiomics are needed to advance this field of science. Understanding stress-induced physiological changes occurring during vulnerable life periods that contribute to chronic respiratory disease risk could lead to the development of preventive strategies and novel therapeutic interventions.

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Update on metal-induced occupational lung disease

Purpose of review Occupational and environmental exposures to metals can result in multiple pulmonary conditions. This article will review recent epidemiologic and mechanistic studies that have enhanced our understanding of the association between particular lung diseases and exposure to specific metals. Recent findings Recent studies have broadened our understanding of the mechanisms of lung diseases such as CBD in established industries and drawn attention to conditions that may arise from exposure to metals such as indium in developing technologies. New diagnostic techniques such as elemental tissue analysis may help establish a diagnosis of metal-induced occupational lung disease. Electronic cigarette devices, environmental pollutants, and the growing use of nanoparticle-sized metals pose additional risks to workers and consumers. Summary Recognizing the risks of pulmonary disease in workers exposed to metals and performing a thorough occupational history and diagnostic work-up in patients with unexplained respiratory findings is necessary to promote understanding and prevention of metal-induced lung disease.

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Role of epigenetics in the development of childhood asthma

Purpose of review Epigenetic marks are emerging as mediators of genetics and the environment on complex disease phenotypes, including childhood asthma and allergy. Recent findings Epigenome-wide association studies over the past year have added to the growing body of evidence supporting significant associations of epigenetic regulation of gene expression and asthma and allergy. Studies in children have identified signatures of eosinophils in peripheral blood, Th2 cell transcription factors and cytokines in peripheral blood mononuclear cells, and epithelial dysfunction in the respiratory epithelium. Importantly, studies at birth have begun to decipher the contribution of epigenetic marks to asthma inception. Few studies have also begun to address the contribution of genetics and the environment to these associations. Summary Next generation of epigenome-wide association studies that will deal with confounders, study the influence of the genetics and environment, and incorporate multiple datasets to provide better interpretation of the findings are on the horizon. Identification of key epigenetic marks that are shaped by genetics and the environment, and impact transcription of specific genes will help us have a better understanding of etiology, heterogeneity and severity of asthma, and will also empower us to develop biologically driven therapeutics and biomarkers for secondary prevention of this disease.

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Health surveillance for occupational asthma

Purpose of review The outcome for workers with occupational asthma is improved for those with an earlier diagnosis. Health surveillance at work is in principle designed to identify such cases, so that the risks to the individual worker, and coworkers, can be reduced. There is recent evidence to suggest that the uptake and quality of such surveillance could be improved. This review has assessed current approaches to health surveillance for occupational asthma. Recent findings The article covers a review of the utility of questionnaires, lung function testing, immunological investigations, and other tests, including exhaled nitric oxide, sputum eosinophilia, and exhaled breath condensate specifically in the context of workplace-based health surveillance. Summary Questionnaires remain a key component of respiratory health surveillance, although maybe limited by both sensitivity and specificity for early occupational asthma. The role of lung function testing is debated, although is recommended for higher level health surveillance. Various examples of immunological testing in health surveillance are discussed, but more evidence is needed in many specific areas before more general recommendations can be made. Evidence is discussed in relation to the utility of newer approaches such as exhaled nitric oxide, sputum eosinophilia, and exhaled breath condensate.

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Editorial introductions

No abstract available

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The emerging spectrum of exposure-related bronchiolitis

Purpose of review Exposure-related bronchiolitis is increasingly recognized as an important but challenging clinical diagnosis. Acute and chronic inhalational exposures are associated with variable clinical presentations and a spectrum of histopathologic abnormalities affecting the small airways. This review provides an overview of the histologic patterns and occupational settings for exposure-related bronchiolitis, along with recent advances in disease diagnosis and management. Recent findings The entire histopathologic spectrum of bronchiolitis (constrictive, obliterative, proliferative, lymphocytic, respiratory) has been reported in exposure-related bronchiolitis. Recent studies have shown that lung clearance index testing and impulse oscillometry are more sensitive than spirometry in detecting small airways abnormalities and may augment the diagnosis of occupational bronchiolitis. Prognosis in indolent occupational bronchiolitis appears more favorable than some other types of bronchiolitis but is variable depending on the extent of bronchiolar inflammation and the stage of disease at which exposure removal occurs. Summary No specific histopathologic pattern of bronchiolitis is pathognomonic for occupational bronchiolitis as one or more histologic patterns may be present. A high index of suspicion is needed for exposure and disease recognition. Recent advances that may aid in diagnosis include transbronchial cryobiopsy, lung clearance index testing, and impulse oscillometry, although further research is needed.

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Assessing the impact of air pollution on childhood asthma morbidity: how, when, and what to do

Purpose of review Exposure to air pollutants is linked with poor asthma control in children and represents a potentially modifiable risk factor for impaired lung function, rescue medication use, and increased asthma-related healthcare utilization. Identification of the most relevant pollutants to asthma as well as susceptibility factors and strategies to reduce exposure are needed to improve child health. Recent findings The current available literature supports the association between pollutants and negative asthma outcomes. Ethnicity, socioeconomic status, and presence of certain gene polymorphisms may impact susceptibility to the negative health effects of air pollution. Improved air quality standards were associated with better asthma outcomes. Summary The link between air pollution and pediatric asthma morbidity is supported by the recent relevant literature. Continued efforts are needed to identify the most vulnerable populations and develop strategies to reduce exposures and improve air quality.

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Biomarkers and asthma management: analysis and potential applications

Purpose of review Asthma features a high degree of heterogeneity in both pathophysiology and therapeutic response, resulting in many asthma patients being treated inadequately. Biomarkers indicative of underlying pathological processes could be used to identify disease subtypes, determine prognosis and to predict or monitor treatment response. However, the newly identified as well as more established biomarkers have different applications and limitations. Recent findings Conventional markers for type 2-high asthma, such as blood eosinophils, fraction of exhaled nitric oxide, serum IgE and periostin, feature limited sensitivity and specificity despite their significant correlations. More distinctive models have been developed by combining biomarkers and/or using omics techniques. Recently, a model with a positive predictive value of 100% for identification of type 2-high asthma based on a combination of minimally invasive biomarkers was developed. Summary Individualisation of asthma treatment regimens on the basis of biomarkers is necessary to improve asthma control. However, the suboptimal properties of currently available conventional biomarkers limit its clinical utility. Newly identified biomarkers and models based on combinations and/or omics analysis must be validated and standardised before they can be routinely applied in clinical practice. The development of robust biomarkers will allow development of more efficacious precision medicine-based treatment approaches for asthma.

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Asthma in inner city children: recent insights United States

Purpose of review Children living in US inner cities experience disparate burdens of asthma, especially in severity, impairment, exacerbations, and morbidity. Investigations seeking to better understand the factors and mechanisms underlying asthma prevalence, severity, and exacerbation in children living in these communities can lead to interventions that can narrow asthma disparities and potentially benefit all children with asthma. This update will focus on recent (i.e. late 2016–2017) advances in the understanding of asthma in US inner city children. Recent findings Studies published in the past year expand understanding of asthma prevalence, severity, exacerbation, and the outcomes of guidelines-based management of these at-risk children, including: asthma phenotypes in US inner city children that are severe and difficult-to-control; key environmental determinants and mechanisms underlying asthma severity and exacerbations (e.g. allergy-mediated exacerbation susceptibility to rhinovirus); the importance of schools as a place for provocative exposures (e.g. mouse allergen, nitrogen dioxide) as well as a place where asthma care and outcomes can be improved; and the development and validation of clinically useful indices for gauging asthma severity and predicting exacerbations. Summary These recent studies provide a trove of actionable findings that can improve asthma care and outcomes for these at-risk children.

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Precision medicine in the treatment of primary immunodeficiency diseases

Purpose of the review Since the 1990s with the advances in molecular biology, a number of genetic defects have been described. The International Union of Immunological Sciences has recently updated the classification of genetic defects associated with primary immune deficiencies that now number 354. With the ever-expanding list of new monogenic disorders and a better understanding of the immunobiology and function of these defective genes, new therapies have emerged particularly aimed at the autoimmune and inflammatory conditions that plague these patients. Recent findings Immune deficiencies associated with gain-of-function (GOF) mutations are a potential category for targeted therapies to control the GOF activities of the mutated gene. In addition to the increased susceptibility to infections these patients have autoimmune and inflammatory diseases that are difficult to control with conventional therapies. The dysregulated immune functions of the activated phospholipase-3-kinase δ syndrome, cytotoxic T lymphocyte-associated antigen-4 haploinsufficiency, lipopolysaccharide-responsive beige-like anchor deficiency, the GOF mutations of signal transducer and activator of transcription 1 and 3 immune deficiencies will be reviewed. The targeted therapies for each of these immune deficiencies using small molecule kinase inhibitors and fusion protein biologic modifiers will be described. Summary In this review, we explore the recent advances in precision medicine treatment of several primary immunodeficiency syndromes in which immune dysregulation is a key feature. Understanding the immunobiology associated with these GOF mutations has led to the use of biologic therapies to better control the associated autoimmune and inflammatory manifestations.

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Endoscopic Endonasal Transplanum Transtuberculum Approach for the Resection of a Large Suprasellar Craniopharyngioma

J Neurol Surg B
DOI: 10.1055/s-0038-1625940

Objectives To demonstrate an endoscopic endonasal transplanum transtuberculum approach for the resection of a large suprasellar craniopharyngioma. Design Single-case-based operative video. Setting Tertiary center with dedicated skull base team. Participants A 72-year-old male patient diagnosed with a suprasellar craniopharyngioma. Main Outcomes Measured Surgical resection of the tumor and preservation of the normal surrounding neurovascular structures. Results A 72-year-old male patient presented with a 1-year history of progressive bitemporal visual loss. He also referred symptoms suggestive of hypogonadism. Neurological examination was unremarkable and endocrine workup demonstrated mildly elevated prolactin levels. Magnetic resonance images demonstrated a large solid-cystic suprasellar lesion, consistent with the diagnosis of craniopharyngioma. The lesion was retrochiasmatic, compressed the optic chiasm, and extended into the interpeduncular cistern (Fig. 1). Because of that, the patient underwent an endoscopic endonasal transplanum transtuberculum approach.1 2 3 The nasal stage consisted of a transnasal transseptal approach, with complete preservation of the patient's left nasal cavity.4 The cystic component of the tumor was decompressed and its solid part was resected. It was possible to preserve the surrounding normal neurovascular structures (Fig. 2). Skull base reconstruction was performed with a dural substitute, a fascia lata graft, and a right nasoseptal flap (Video 1). The patient did well after surgery and referred complete visual improvement. However, he also presented pan-hypopituitarism on long-term follow-up. Conclusions The endoscopic endonasal route is a good alternative for the resection of suprasellar lesions. It permits tumor resection and preservation of the surrounding neurovascular structures while avoiding external incisions and brain retraction.The link to the video can be found at: https://youtu.be/zmgxQe8w-JQ.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text

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Resection of a Retrochiasmatic Craniopharyngioma by Combined Modified Orbital Craniotomy and Transnasal Endoscopic Techniques

J Neurol Surg B
DOI: 10.1055/s-0038-1623519

A 20-year-old patient presented with hydrocephalus but intact vision and hormone function. The MRI showed a large seller, suprasellar and third ventricular mass. We chose a combined approach utilizing the translyvian, lamina terminals route, with a possible interhemispheric approach. But, we also utilized a transnasal endoscopic approach for the tumor that remained below the diaphragma sellae. The patient did well, with complete tumor resection via a staged approach, but did require hormone replacement.The link to the video can be found at: https://youtu.be/yzpfOxzI4cQ.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  open access Full text

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Hypereosinophilic syndrome presenting acutely with neurologic signs

A 70-year-old white male with a longstanding history of allergic rhinitis and nasal polyposis, and relatively recent onset of chronic cough one year prior, presented to the hospital for one-week duration of neurologic complaints including chronic and worsening neck pain, bilateral upper extremity weakness, difficulty gripping objects, blurry vision, confusion, change in gait, and difficulty with initiation of urination. His medical history also included essential hypertension, dyslipidemia, gastroesophageal reflux, and shingles.

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Displacement of the Recurrent Laryngeal Nerve in Patients with Recurrent Goiter Undergoing Redo Thyroid Surgery

Thyroid reoperations are surgically challenging because of scarring and disturbances in the anatomy of the recurrent laryngeal nerve (RLN). This study was conducted on 49 patients who underwent redo surgery. 61 RLNs were identified and completely exposed. Their functional integrity was evaluated using intraoperative nerve monitoring (IONM). Indications for secondary surgery, anatomical changes secondary to recurrent goiter mass and prior surgery, and results of IONM were studied. Frequent indications for redo surgery were multinodular goiter (MNG) in 19 (38.8%) and results of cytology in 14 (28.5%) patients. The mean time interval between primary and redo thyroid surgery was 23.4 years. We laterally approached 41 (67.2%) thyroid lobes between the sternocleidomastoid and sternohyoid muscles. 16 (26.2%) RLNs were found to be adherent to the lateral surface of the corresponding thyroid lobe. The functional integrity of all RLNs was confirmed by IONM. The remnant thyroid tissue can then lead to goiter recurrence requiring secondary surgery after a long period of time. The indications for redo surgery were similar to primary cases. Lateral displacement of the RLN which is adherent to the lateral surface of recurrent goiter mass is common anatomic variation. Thyroid reoperations based on awareness of anatomical disturbances can be performed safely by an experienced surgeon with support of ancillary electrophysiological technology.

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3 tesla MRI assisted detection of compression points in ulnar neuropathy at the elbow in correlation with intraoperative findings

Releasing the ulnar nerve from all entrapments is the primary objective of every surgical method in ulnar neuropathy at the elbow (UNE). The aim of this retrospective diagnostic study was to validate preoperative 3 Tesla MRI results by comparing the MRI findings with the intraoperative aspects during endoscopic-assisted or open surgery.

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‘Investigation of the activation of temporalis and masseter muscles in voluntary and spontaneous smile production.’

Masticatory muscles or their nerve supply are options for facial reanimation surgery but their ability to create spontaneous smile has been questioned. This study assessed the percentage of healthy adults who activate temporalis and masseter during voluntary and spontaneous smile.

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Orthotopic transfer of vascularized groin lymph node flap in the treatment of breast cancer-related lymphedema: clinical results, lymphoscintigraphy findings and proposed mechanism

Vascularized lymph node transfer (VLNT) has become more popular in treating secondary lymphedema. However, the mechanism has not been clearly elucidated.The purpose of this study were (1) to evaluate the outcome of vascularized groin lymph node (VGLN) transfer using axilla as a recipient site in patients with breast cancer-related lymphedema (BCRL) and (2) to provide radiological evidence of lymphangiogenesis in VLNT.

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Are oral mucosal nevi potential precursors for oral mucosal melanoma?

The origin of oral mucosal melanoma remains controversial with oral mucosal nevi being hypothesized to be a possible precursor. The hypotheses can be supported by the characteristics shared by the nevus cells and the melanoma cells including spindle-shaped, lack of dendritic processes, lack of contact inhibition and inability to transfer the melanosomes to the keratinocytes [1].

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Endoscopic fistulotomy in inflammatory bowel disease (with video)

Fistulas in patients with inflammatory bowel disease (IBD) poses a key challenge in the management of the IBD patients. We aimed to describe a novel endoscopic method to treat the IBD patients who have fistulas.

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Outcome of Head and Neck Squamous Cell Cancers in Low-Resource Settings

Head and neck squamous cell carcinomas (HNSCCs) are amongst the most common cancers in certain parts of the world. Low-income and low middle- income countries make up 65% of newly diagnosed HNSCC cases annually and account for about 75% of HNSCC global mortality. These countries also suffer from a significant shortage of skilled labor, equipment, and health facilities. This article discusses the burden of HNSCCs in developing countries and the differences in outcomes compared with developed countries.

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Multiple primary malignancies and prolonged survival in a patient with widespread metastatic cutaneous melanoma

No abstract available

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Nicotinamide N-methyltransferase: potential involvement in cutaneous malignant melanoma

Nicotinamide N-methyltransferase (NNMT) is an enzyme that catalyzes the N-methylation of nicotinamide and pyridine compounds, participating in xenobiotic and drug metabolism. Data on literature have evidenced a possible role of NNMT in many solid cancers, but no data are currently available in cutaneous melanoma. Recent important advances have been achieved in the treatment of advanced melanoma with targeted therapy and immunotherapy. However, the identification of biomarkers that can be used for the detection of early stage disease as well as for monitoring the therapeutic response during treatment is of utmost importance. The aim of this study was to study the possible role of NNMT in melanoma. In the present study, we carried out immunohistochemical analyses to evaluate the expression of the enzyme NNMT in 34 melanomas and 34 nevi. Moreover, we explored the relationship between NNMT levels and the prognostic parameters of patients with melanoma. The results obtained showed significantly (P

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Success of rechallenging dabrafenib and trametinib combination therapy after trametinib-induced rhabdomyolysis: a case report

The mitogen-activated protein kinase pathway regulates cell growth and differentiation and is activated by BRAF mutations. BRAF mutations are present in about 40–50% of cutaneous melanomas. More than 90% of BRAF mutations are the V600E type. BRAF inhibitor (dabrafenib or vemurafenib) and MEK inhibitor (trametinib or cobimetinib) combination therapies are effective for BRAF-mutant advanced melanomas. A variety of side effects have been observed with combination therapy including pyrexia, fatigue, nausea, and vomiting. Rhabdomyolysis is one of the most severe adverse events, but it is very rare. Only two cases of rhabdomyolysis have been reported in clinical trials. A 41-year-old Japanese woman with cutaneous melanoma was started on a combination of dabrafenib and trametinib therapy after failure of immune checkpoint therapy. One month later, she complained of myalgia and fatigue and was shifted to our hospital. She was diagnosed with trametinib-induced rhabdomyolysis and showed improvement only with a high volume of fluid infusion. We stopped combination therapy, but there were no useful treatment options for her. After resuming dabrafenib, followed by trametinib, she did not have any problems. This is the first case of a patient with metastatic cutaneous melanoma who could recommence combination therapy after trametinib-associated rhabdomyolysis. We assume that not all patients experience recurrence of rhabdomyolysis in trametinib-induced rhabdomyolysis. As few cases have been reported, more information is needed. We have to evaluate safety carefully if rechallenging combination therapy.

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Isolation and characterization of circulating melanoma cells by size filtration and fluorescent in-situ hybridization

Isolation of circulating tumor cells (CTCs) from blood of melanoma patients has been difficult owing to inconsistent expression of surface antigens. Here we report on the isolation, detection, and characterization of CTCs from blood of melanoma patients using microfiltration and fluorescent in-situ hybridization (FISH). Two tubes of blood from 15 patients with advanced melanoma were collected. These two tubes subsequently underwent filtration through a membrane with pore sizes of 7.5 μm. Isolated cells from one tube were analyzed by FISH for RREB1 (6p24), MYB (6q32), SE6 (D6Z1), and CCND1 (11q13) and the other paired specimen was analyzed by immunofluorescence for HMB45, melanoma-associated antigen recognized by T cells-1, tyrosinase and melanogenesis associated transcription factor. We identified CTCs in 10 out of 13 melanoma samples by immunofluorescence (2.5–99 CTCs/3 ml of blood) and in 13 specimens by FISH (7.2–76 CTCs/3 ml of blood) with more CTCs identified by FISH in 10 out 13 samples. Two filters failed. Our results show that CTCs are detectable in the majority of patients with advanced melanoma. These tools will be useful in characterizing treatment related changes of melanoma in CTCs.

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BRAF-inhibitors can exert control of disease in BRAF T599I mutated melanoma: a case report

BRAF signaling is involved in melanoma growth in more than half of metastatic patients. In the last few years, new drugs that block this pathway have significantly improved the outcomes of patients with metastatic melanoma. Ninety percent of BRAF mutations involve exon 15, and the most frequent, V600E, results from the amino acid change from valine (V) to glutamic acid (E). BRAFV600 inhibitor treatments have shown a notable overall response rate and improvements in progression-free and overall survival. Rare BRAF mutations of codon 599 have been also described in a few patients with papillary thyroid cancer and melanoma. Nowadays, no evidence is available in the literature, describing the role of target therapies as treatment in patients with this specific codon mutation. We describe the case of a young woman with metastatic melanoma with a particular BRAF mutation, T599I, who has benefited from treatment with a BRAF inhibitor, vemurafenib.

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Rapid BRAF mutation tests in patients with advanced melanoma: comparison of immunohistochemistry, Droplet Digital PCR, and the Idylla Mutation Platform

BRAF mutational testing has become a common practice in the diagnostic process of patients with advanced melanoma. Although time-consuming, DNA sequencing techniques are the current gold standard for mutational testing. However, in certain clinical situations, a rapid test result is required. In this study, the performance of three rapid BRAF mutation tests was compared. Thirty-nine formalin-fixed paraffin-embedded melanoma tissue samples collected between 2007 and 2014 at a single center were included. These samples were analyzed by immunohistochemistry using the anti-BRAF-V600E (VE1) mouse monocolonal antibody (BRAF-VE1 IHC), a V600E-specific Droplet Digital PCR Test, and the Idylla BRAF- Mutation Test (Idylla). Results were compared with the results of conventional BRAF mutation testing, performed using high-resolution melting analysis followed by Sanger sequencing. Next-generation sequencing was performed on samples with discordant results. The Idylla test and Droplet Digital PCR Test correctly identified all mutated and wild-type samples. BRAF-VE1 IHC showed one discordant result. The Idylla test could identify BRAF-V600 mutations other than BRAF-V600E and was the fastest and least laborious test. The Idylla Mutation Test is the most suitable test for rapid BRAF testing in clinical situations on the basis of the broad coverage of treatment-responsive mutations and the fast procedure without the need to perform a DNA isolation step.

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Fulminant type 1 diabetes associated with nivolumab in a patient with metastatic melanoma

No abstract available

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Expressions and clinical significance of HER4 and CD44 in sinonasal mucosal malignant melanoma

Sinonasal mucosal malignant melanoma (SNMMM) is a rare disease. The aim of this study was to investigate the expressions of HER4 and CD44 in human SNMMM tissues and their relationship with the clinicopathological features and prognosis of patients. In total, 64 paraffin-embedded samples of SNMMM treated in our hospital from 29 December 1999 to 24 June 2011 were collected. HER4 and CD44 were detected in the tissues of SNMMM by immunohistochemistry. The differences in the HER4 and CD44 expressions in the tissues were evaluated and matched with clinicopathological parameters and the survival rate, respectively. The positive rates of the HER4 and CD44 expressions were 70.3 and 65.6%, respectively; the positive expression of HER4 was correlated with a positive expression of CD44 (P0.05). The expressions of HER4 and CD44 were not significantly correlated with sex, age, pigment, tumor site, etc. (P>0.05). Our results further emphasize a correlation between HER4 and CD44 expressions in SNMMM tissues and point out that a positive HER4 expression might be an important factor in valuing the prognosis of patients with SNMMM.

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A novel KRAS mutation in metastasic conjunctival melanoma: a case report and literature review

Conjunctival melanoma is a rare disease, and little is known about its molecular background. Here, we present the case of a 48-year-old patient with conjunctival melanoma and metachronic lymph node and skin metastasis with KRAS p.K117Y mutation in exon 4 in all the lesions. The cancer genome interpreter predicted this mutation to have driver function. To our knowledge, this is the first time this mutation is found in conjunctival melanoma. An important role in the disease development is suggested.

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Tolerance and outcomes of stereotactic radiosurgery combined with anti-programmed cell death-1 (pembrolizumab) for melanoma brain metastases

Anti-programmed cell death-1 (anti-PD1) antibodies are currently the first-line treatment for patients with metastatic BRAF wild-type melanoma, alone or combined with the anti-CTLA4 monoclonal antibody, ipilimumab. To date, data on safety and the outcomes of patients treated with the anti-PD1 monoclonal antibodies, pembrolizumab (PB), or nivolumab, combined with stereotactic radiosurgery (SRS), for melanoma brain metastases (MBM) are scarce. We retrospectively reviewed all patients with MBM treated with PB combined with SRS between 2012 and 2015. The primary endpoint was neurotoxicity. The secondary endpoints were local, distant intracranial controls and overall survival (OS). Among 74 patients with MBM treated with SRS, 25 patients with a total of 58 MBM treated with PB combined with SRS within 6 months were included. Radiation necrosis, occurring within a median time of 6.5 months, was observed for four MBM (6.8%) in four patients. No other significant SRS-related adverse event was observed. After a median follow-up of 8.4 months, local control was achieved in 46 (80%) metastases and 17 (68%) patients. Perilesional oedema and intratumour haemorrhage appearing or increasing after SRS were associated with local progression (P

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Hemorrhage of liver and bone metastases as a result of rapid response to dual BRAF/MEK inhibition in metastatic melanoma: a case report

Combination therapy using a BRAF and MEK inhibitor significantly improves both progression-free and overall survival in patients with BRAF V600-mutated stage IV melanoma. Dual MAPK inhibition achieves an objective response in the majority of patients. We present a case of a woman with BRAF V600E-mutated malignant melanoma and rapidly progressing liver, bone, and lymph node metastases. The patient commenced dabrafenib and trametinib with clinical and biochemical signs of response after 2 days. On day 3 she developed grade 3 liver hemorrhage, which was successfully embolized. Her anemia responded appropriately to transfusions and stabilized after interventional resolution of the hemorrhagic event. Subsequently she developed a pathological fracture of the right proximal humerus. MRI showed cystic bone metastases with stigmata of bleeding. To our knowledge, this is the first case report of a patient with hemorrhage of both liver and bone metastases of a melanoma. As the patient responded rapidly to dabrafenib and trametinib we hypothesize that the hemorrhage may be due to rapid tumor necrosis and bleeding of affected tumor supplying blood vessels. Our case demonstrates the importance of considering tumoral bleeding as a side effect of BRAF and MEK inhibition in responding melanoma patients. Mechanical intervention can be effective in resolving this treatment-related adverse event.

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Comparative outcomes and toxicities for ruthenium-106 versus palladium-103 in the treatment of choroidal melanoma

For the treatment of choroidal melanoma, palladium-103 (103Pd) and ruthenium-106 (106Ru) plaque brachytherapy shows reduced toxicity compared with the historical standard iodine-125. No report has directly compared the clinical outcomes between 103Pd and 106Ru, and the reasons for the selection of one over the other remain purely theoretical. Patients with choroidal melanoma with apical tumor height up to 5 mm were included. Patients from Emory University were treated with 103Pd between 1993 and 2012. Patients from Cleveland Clinic were treated with 106Ru between 2005 and 2010. Medical records were retrospectively reviewed. We compared post-treatment visual acuity (VA), toxicity, and oncologic outcomes. 103Pd patients (n=124) and 106Ru patients (n=42) had a median follow-up of 4.2 and 5.0 years, respectively. Radiation retinopathy-free survival was similar for both radioisotopes, but 106Ru had lower grades of retinopathy (P=0.006). 103Pd was associated with worse VA preservation (≥20/40) by year 3 (odds ratio: 3.8; 95% confidence interval: 1.01–14.31, P=0.048). 103Pd was associated with higher distant metastases-free survival (DMFS) in multivariate analysis (hazard ratio: 0.10; 95% confidence interval: 0.02–0.38; P

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Safety and efficacy of anti-PD-1 therapy for metastatic melanoma and non-small-cell lung cancer in patients with viral hepatitis: a case series

Anti-PD-1 monoclonal antibodies have shown durable long-term survival benefit in patients with metastatic melanoma. Limited evidence exists on the safety and efficacy of PD-1 inhibitors in patients with hepatitis B virus (HBV) and hepatitis C virus (HCV) infections as these patients have traditionally been excluded from clinical trials because of a theoretical risk of immune reconstitution inflammatory syndrome. We aim to determine the safety and efficacy of treatment with PD-1 inhibitors in seven patients with HBV/HCV infection and concurrent metastatic melanoma or non-small-cell lung cancer (NSCLC). We describe seven patients treated with PD-1 inhibitors nivolumab and pembrolizumab for either metastatic melanoma or metastatic NSCLC in the setting of chronic or past HBV/HCV infection. The safety and efficacy of treatment were analysed retrospectively by examining response to treatment, alanine transaminase (ALT) trends and viral load trends. One patient showed an increase in ALT of Common Terminology Criteria for Adverse Events (CTCAE) grade 2 severity that returned to the normal range following treatment of his HCV infection with ledipasvir 90 mg/sofosbuvir 400 mg. An additional four patients showed an increase in ALT of CTCAE grade 1 severity. The remaining two patients experienced no hepatic toxicity, with stable disease continuing after more than 24 cycles of nivolumab. Efficacy was similar to the data of published trials. Our results indicate that patients with metastatic melanoma and NSCLC can be treated safely with PD-1 inhibitors in the context of HBV/HCV infection. However, we recommend that those with active viral hepatitis be monitored closely in consultation with a hepatologist and treated with antiviral therapy if indicated.

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Clinical and radiological response of BRAF inhibition and MEK inhibition in patients with brain metastases from BRAF-mutated melanoma

Patients with brain metastases (BM) from melanoma have an overall survival (OS) of 2–6 months after whole-brain radiotherapy. Targeted therapy (TT) is an effective treatment for BRAF-mutated metastatic melanoma. Moreover, recent studies indicate intracranial responses of TT in patients with BM. We analyzed 146 patients with BM from BRAF-mutated melanoma treated with vemurafenib, dabrafenib, or dabrafenib+trametinib between 2010 and 2016. We determined clinical and radiological response, progression-free survival (PFS), and OS. Median OS of patients treated with dabrafenib+trametinib was 11.2 months [n=30; 95% confidence interval (CI): 6.8–15.7], 8.8 months for dabrafenib alone (n=31; 95% CI: 3.9–13.7), and 5.7 months for vemurafenib (n=85; 95% CI: 4.6–6.8). A significantly longer OS was observed in the dabrafenib+trametinib group than in the vemurafenib group (hazard ratio for death, 0.52; 95% CI: 0.30–0.89; P=0.02). Median intracranial PFS of all patients was 4.1 months. Median intracranial PFS for patients treated with dabrafenib+trametinib was 5.8 months (95% CI: 3.2–8.5), 5.7 months (95% CI: 3.0–8.4) for dabrafenib, and 3.6 months (95% CI: 3.5–3.8) for vemurafenib (P=0.54). A total of 63 (43%) patients had symptomatic BM. Intracranial disease control rate at 8 weeks in these patients was 65 versus 70% extracranially. Neurological symptoms improved in 46% of patients with symptomatic BM, whereas in 21%, they remained stable. Median OS in patients with BM from BRAF-mutated melanoma treated with dabrafenib+trametinib was significantly longer than for vemurafenib. Improvement of neurological symptoms was seen in almost half of the patients with symptomatic BM treated with TT.

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Aged-looking skin and encorafenib: an adverse event of BRAF inhibitors

No abstract available

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Quality of life patient-reported outcomes for locally advanced cutaneous melanoma

Locally advanced cutaneous melanoma has marked quality-of-life implications; however, the patient experience of symptom management and subsequent impact on quality of life has not been well described. This study aims to address the impact on patients of advanced cutaneous melanoma through qualitative interviews. Adults with stage IIIB, IIIC, or IV (M1a) cutaneous melanoma were recruited from two cancer centers in the USA and one in Australia. Telephone interviews were conducted to assess how locoregionally advanced cutaneous melanoma impacted everyday life. Interviews were recorded, transcribed, and coded for qualitative analysis. Twenty-two melanoma patients were interviewed, mean age 69.7 years (range: 52–83), 64% male. The study included stage IIIB (36%), stage IIIC (59%), and stage IV M1a (5%) patients. Emotional health/self-perception issues were the most commonly identified (41% of patient impact expressions), including worry, concern, embarrassment, self-consciousness, fear, and thoughts of death. Limitations of lifestyle and activities were also identified (28% of expressions) including leisure and social activities, physical functioning, general functioning, and personal care. Coping strategies such as modified clothing choices, increased use of pain and/or anti-inflammatory medications, and avoidance/protection from the sun represented 20% of all impact expressions. Ratings of the degree of difficulty patients experienced (using an 11-point numerical rating scale) ranged from 0.0 to 10.0 (mean 5.7, SD 2.9). Condition-related and treatment-related factors were well characterized in patients with locally advanced cutaneous melanoma. This provides a strong foundation for assessment of how cutaneous melanoma impacts quality of life.

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Clinical, dermoscopic, and confocal features of nevi and melanomas in a multiple primary melanoma patient with the MITF p.E318K homozygous mutation

No abstract available

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Leadership Roles and Activities Among Alumni Receiving Postdoctoral Fellowship Training in Cancer Prevention

Abstract

This study was conducted in 2016–2017 to better understand formal and informal leadership roles and activities of alumni from postdoctoral research training programs in cancer prevention. Data were obtained from surveys of 254 employed scientists who completed cancer prevention postdoctoral training within the National Cancer Institute (NCI) Cancer Prevention Fellowship Program, or at US research institutions through NCI-sponsored National Research Service Award (NRSA) individual postdoctoral fellowship (F32) grants, from 1987 to 2011. Fifteen questions categorized under Organizational Leadership, Research Leadership, Professional Society/Conference Leadership, and Broader Scientific/Health Community Leadership domains were analyzed. About 75% of respondents had at least one organizational leadership role or activity during their careers, and 13–34% reported some type of research, professional society/conference, or broader scientific/health community leadership within the past 5 years. Characteristics independently associated with leadership from regression models were being in earlier postdoctoral cohorts (8 items, range for statistically significant ORs = 2.8 to 10.8) and employment sector (8 items, range for statistically significant ORs = 0.4 to 11.7). Scientists whose race/ethnicity was other than white were less likely to report organizational leadership or management responsibilities (OR = 0.4, 95% CI 0.2–0.9). Here, many alumni from NCI-supported cancer prevention postdoctoral programs were involved in leadership, with postdoctoral cohort and employment sector being the factors most often associated with leadership roles and activities. Currently, there is relatively little research on leadership roles of biomedical scientists in general, or in cancer prevention specifically. This study begins to address this gap and provide a basis for more extensive studies of leadership roles and training of scientists.

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Cancer survivors' understanding of the cause and cure of their illness: Religious and secular appraisals

Abstract

Objective

Little is known about survivors' understanding of the cause of their cancer and of their recovery, nor how these ways of understanding relate to their well-being. No study has examined both secular and religious appraisals of the same event. The current study aimed to examine both religious (God) and secular (self) appraisals of both the cause (attributions) and course/cure of cancer in relation to multiple aspects of adjustment.

Methods

Data were obtained from a sample of cancer survivors at Time 1 (n = 250) and one year later (Time 2, n = 167).

Results

Cancer survivors endorsed higher appraisals relating to course/cure of their cancer than those relating to cause, and they endorsed both secular and religious appraisals. Appraisals of the cause and course/cure of cancer were differentially related to adjustment, such that self-attributions of cause and God-attributions of cause were related to negative aspects of adjustment (e.g., negative affect, pessimism), while appraisals of self and God's control over the course/cure were related to positive aspects of adjustment (e.g., perceived positive life and health changes since cancer). Religiosity did not moderate most of relationships between religious appraisals and adjustment outcomes.

Conclusions

Secular and religious appraisals of cancer are not mutually exclusive, and religious appraisals are associated with adjustment regardless of survivors' religiosity. Appraisals relating to cause and course/cure have differential relationships with well-being. Addressing cancer survivors' appraisals- religious or nonreligious- in a therapeutic setting may be beneficial regardless of their reported religiosity.

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Social network, autonomy, and adherence correlates of future time perspective in patients with head and neck cancer

Abstract

Objective

Socioemotional selectivity theory (SST) proposes that with more limited future time perspective (FTP) the meaning of individual life goals shifts from instrumental and long-term goals, such as autonomy, to emotionally meaningful and short-term life goals, especially concerning meaningful social relationships. Adverse side effects of cancer therapy may conflict with the realization of emotionally meaningful goals leading to non-adherence. In line with the theoretical assumptions, this study aimed to investigate a) associations between disease symptoms, physical-, and cognitive limitations and FTP and b) between FTP, family network size, striving for autonomy, and treatment adherence.

Method

157 patients (43-90 years; 75% male) with head and/or neck cancer of a German University Medical Centre completed a questionnaire measuring FTP, age, disease symptoms, physical and cognitive functioning, family network size and treatment adherence. Autonomy was assessed with a card sort task.

Results

A structural equation model yielded an acceptable fit χ²(28) = 44.41; p = .025; χ²/df = 1.59; RMSEA = .06 [90% CI = .02, .09]; TLI =.92; CFI = .96. An increased level of disease symptoms, physical-, and cognitive limitations was related to a shorter subjective FTP. Furthermore, individuals with a limited FTP reported a smaller family network, a lowered quest for autonomy, and lower treatment adherence.

Conclusions

Hypotheses derived from SST were supported by the data. Longitudinal investigations should follow to corroborate findings and to focus on underlying mechanisms as improving patients FTP may play a crucial role in future disease management programs.

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YAP1-mediated suppression of USP31 enhances NF-{kappa}B activity to promote sarcomagenesis

To date, no consistent oncogenic driver mutations have been identified in most adult soft tissue sarcomas; these tumors are thus generally insensitive to existing targeted therapies. Here we investigated alternate mechanisms underlying sarcomagenesis to identify potential therapeutic interventions. Undifferentiated pleomorphic sarcoma (UPS) is an aggressive tumor frequently found in skeletal muscle where deregulation of the Hippo pathway and aberrant stabilization of its transcriptional effector yes-associated protein 1 (YAP1) increases proliferation and tumorigenesis. However, the downstream mechanisms driving this deregulation are incompletely understood. Using autochthonous mouse models and whole genome analyses, we found that YAP1 was constitutively active in some sarcomas due to epigenetic silencing of its inhibitor angiomotin (AMOT). Epigenetic modulators vorinostat and JQ1 restored AMOT expression and wild type Hippo pathway signaling, which induced a muscle differentiation program and inhibited sarcomagenesis. YAP1 promoted sarcomagenesis by inhibiting expression of ubiquitin-specific peptidase 31 (USP31), a newly identified upstream negative regulator of NF-κB signaling. Combined treatment with epigenetic modulators effectively restored USP31 expression, resulting in decreased NF-κB activity. Our findings highlight a key underlying molecular mechanism in UPS and demonstrate the potential impact of an epigenetic approach to sarcoma treatment.

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ER{beta}-mediated alteration of circATP2B1 and miR-204-3p signaling promotes invasion of clear cell renal cell carcinoma

Early studies have indicated that estrogen receptor beta (ERβ) can influence the progression of clear cell renal cell carcinoma (ccRCC). Here we report the mechanistic details of ERβ-mediated progression of ccRCC. ERβ increased ccRCC cell invasion via suppression of circular RNA ATP2B1 (circATP2B1) expression by binding directly to the 5' promoter region of its host gene ATPase plasma membrane Ca2+ transporting 1 (ATP2B1). ERβ-suppressed circATP2B1 then led to reduced miR-204-3p, which increased fibronectin 1 (FN1) expression and enhanced ccRCC cell invasion. Targeting ERβ with shRNA suppressed ccRCC metastasis in a murine model of RCC; adding circATP2B1 shRNA partly reversed this effect. Consistent with these experimental results, ccRCC patient survival data from TCGA indicated that higher ERβ and FN1 expression had worse overall survival and higher miR-204-3p expression had significantly better overall survival. Together, these results suggest that ERβ promotes ccRCC cell invasion by altering the ERβ/circATP2B1/miR-204-3p/FN1 axis, and that therapeutic targeting of this newly identified pathway may better prevent ccRCC progression.

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TRPM2 mediates neutrophil killing of disseminated tumor cells

Neutrophils play a critical role in cancer, with both pro- and anti-tumor neutrophil subpopulations reported. The anti-tumor neutrophil subpopulation has the capacity to kill tumor cells and limit metastatic spread, yet not all tumor cells are equally susceptible to neutrophil cytotoxicity. Since cells that evade neutrophils have greater chances of forming metastases, we explored the mechanism neutrophils employ to kill tumor cells. Neutrophil cytotoxicity was previously shown to be mediated by secretion of H2O2. We report here that neutrophil cytotoxicity is Ca2+-dependent and is mediated by TRPM2, a ubiquitously expressed H2O2-dependent Ca2+ channel. Perturbing TRPM2 expression limited tumor cell proliferation leading to attenuated tumor growth. Concomitantly, cells expressing reduced levels of TRPM2 were protected from neutrophil cytotoxicity and seeded more efficiently in the premetastatic lung.

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Metabolic determinants of sensitivity to phosphatidylinositol 3-kinase pathway inhibitor in small-cell lung carcinoma

Comprehensive genomic analysis has revealed that the PI3K/AKT/mTOR pathway is a feasible therapeutic target in small-cell lung carcinoma (SCLC). However, biomarkers to identify patients likely to benefit from inhibitors of this pathway have not been identified. Here we show that metabolic features determine sensitivity to the PI3K/mTOR dual inhibitor gedatolisib in SCLC cells. Substantial phosphatidyl lipid analysis revealed that a specific phosphatidylinositol (3,4,5)-trisphosphate (PIP3) subspecies lipid product: PIP3 (38:4) is predictive in assessing sensitivity to PI3K/mTOR dual inhibitor. Notably, we found that higher amounts of purine-related aqueous metabolites such as hypoxanthine, which are characteristic of SCLC biology, lead to resistance to PI3K pathway inhibition. In addition, the levels of the mRNA encoding hypoxanthine phosphoribosyl transferase 1 (HPRT1), a key component of the purine salvage pathway, differed significantly between SCLC cells sensitive or resistant to gedatolisib. Moreover, complementation with purine metabolites could reverse the vulnerability to targeting of the PI3K pathway in SCLC cells normally sensitive to gedatolisib. These results indicate that the resistance mechanism of PI3K pathway inhibitors is mediated by the activation of the purine salvage pathway, supplying purine resource to nucleotide biosynthesis. Metabolomics is a powerful approach for finding novel therapeutic biomarkers in SCLC treatment.

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Loss of Pax5 exploits Sca1-BCR-ABLp190 susceptibility to confer the metabolic shift essential for pB-ALL

Preleukemic clones carrying BCR-ABLp190 oncogenic lesions are found in neonatal cord blood, where the majority of preleukemic carriers do not convert into precursor B-cell acute lymphoblastic leukemia (pB-ALL). However, the critical question of how these preleukemic cells transform into pB-ALL remains undefined. Here we model a BCR-ABLp190 preleukemic state and show that limiting BCR-ABLp190 expression to hematopoietic stem/progenitor cells (HS/PC) in mice (Sca1-BCR-ABLp190) causes pB-ALL at low penetrance, which resembles the human disease. pB-ALL blast cells were BCR-ABL-negative and transcriptionally similar to pro-B/pre-B cells, suggesting disease onset upon reduced Pax5 functionality. Consistent with this, double Sca1-BCR-ABLp190+Pax5+/- mice developed pB-ALL with shorter latencies, 90% incidence, and accumulation of genomic alterations in the remaining wild-type Pax5 allele. Mechanistically, the Pax5-deficient leukemic pro-B cells exhibited a metabolic switch towards increased glucose utilization and energy metabolism. Transcriptome analysis revealed that metabolic genes (IDH1, G6PC3, GAPDH, PGK1, MYC, ENO1, ACO1) were upregulated in Pax5-deficient leukemic cells, and a similar metabolic signature could be observed in human leukemia. Our studies unveil the first in vivo evidence that the combination between Sca1-BCR-ABLp190 and metabolic reprogramming imposed by reduced Pax5 expression is sufficient for pB-ALL development. These findings might help to prevent conversion of BCR-ABLp190 preleukemic cells.

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Predictive gene signatures determine tumor sensitivity to MDM2 inhibition

Early clinical trials using murine double minute 2 (MDM2) inhibitors demonstrated proof-of-concept of p53-induced apoptosis by MDM2 inhibition in cancer cells, however, not all wild-type TP53 tumors are sensitive to MDM2 inhibition. Therefore, more potent inhibitors and biomarkers predictive of tumor sensitivity are needed. The novel MDM2 inhibitor DS-3032b is 10-fold more potent than the first-generation inhibitor nutlin-3a. TP53 mutations were predictive of resistance to DS-3032b, and allele frequencies of TP53 mutations were negatively correlated with sensitivity to DS-3032b. However, sensitivity to DS-3032b of TP53 wild-type tumors varied greatly. We thus used two methods to create predictive gene signatures: First, by comparing sensitivity to MDM2 inhibition with basal mRNA expression profiles in 240 cancer cell lines, a 175-gene signature was defined and validated in patient-derived tumor xenograft models and ex vivo human acute myeloid leukemia (AML) cells. Second, an AML-specific 1532-gene signature was defined by performing random forest analysis with cross validation using gene expression profiles of 41 primary AML samples. The combination of TP53 mutation status with the two gene signatures provided the best positive predictive values (81 and 82%, compared to 62% for TP53 mutation status alone). In addition, the top-ranked 50 genes selected from the AML-specific 1532-gene signature conserved high predictive performance, suggesting that a more feasible size of gene signature can be generated through this method for clinical implementation. Our model is being tested in ongoing clinical trials of MDM2 inhibitors.

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Zeb1 in stromal myofibroblasts promotes Kras-driven development of pancreatic cancer

The transcription factor Zeb1 has been identified as a crucial player in Kras-dependent oncogenesis. In pancreatic ductal adenocarcinoma (PDAC), Zeb1 is highly expressed in myofibroblasts and correlates with poor prognosis. As Kras mutations are key drivers in PDAC, we aimed here to assess the necessity of Zeb1 for Kras-driven PDAC and to define the role of Zeb1-expressing myofibroblasts in PDAC development. Genetically engineered mice with conditional pancreatic KrasG12D and Trp53 mutations (KPC) were crossed with Zeb1 haploinsufficient mice (Z+/-). Extensive PDAC was prominent in all 20-week old KPC;Z+/+ mice, whereas only low-grade precursor lesions were detected in age-matched KPC;Z+/- littermates, with PDAC developing eventually in KPC;Z+/- aged animals. Zeb1 expression in myofibroblasts occurred early in tumorigenesis and Zeb1 haploinsufficiency retarded native expansion of stromal myofibroblasts during precursor-to-cancer progression. Zeb1 downregulation in mPSC repressed their activated gene profile, impaired their migratory and proliferative activity, and attenuated their tumor-supporting features. Conditioned media from Z+/+ mouse-activated (myofibroblast-like) pancreatic stellate cells (mPSC) boosted Ras activity in pancreatic cancer cells carrying mutant Kras; this effect was not oberved when using conditioned media from Z+/- mPSC, revealing a paracrinal cooperative axis between Zeb1-expressing PSC and oncogenic Kras-bearing tumor cells. We conclude that Zeb1-expressing stromal myofibroblasts enable a heterotypic collaboration with the Kras-fated epithelial compartment, thus supporting pancreatic malignancy.

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Anti-CD137 Cancer Immunotherapy Suppresses Tumor Growth—Response

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Anti-CD137 Cancer Immunotherapy Suppresses Tumor Growth—Letter

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Microbiome and Esophageal Adenocarcinoma—Letter

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Perceptual sensitivity to spectral properties of earlier sounds during speech categorization

Abstract

Speech perception is heavily influenced by surrounding sounds. When spectral properties differ between earlier (context) and later (target) sounds, this can produce spectral contrast effects (SCEs) that bias perception of later sounds. For example, when context sounds have more energy in low-F₁ frequency regions, listeners report more high-F₁ responses to a target vowel, and vice versa. SCEs have been reported using various approaches for a wide range of stimuli, but most often, large spectral peaks were added to the context to bias speech categorization. This obscures the lower limit of perceptual sensitivity to spectral properties of earlier sounds, i.e., when SCEs begin to bias speech categorization. Listeners categorized vowels (/ɪ/-/ɛ/, Experiment 1) or consonants (/d/-/g/, Experiment 2) following a context sentence with little spectral amplification (+1 to +4 dB) in frequency regions known to produce SCEs. In both experiments, +3 and +4 dB amplification in key frequency regions of the context produced SCEs, but lesser amplification was insufficient to bias performance. This establishes a lower limit of perceptual sensitivity where spectral differences across sounds can bias subsequent speech categorization. These results are consistent with proposed adaptation-based mechanisms that potentially underlie SCEs in auditory perception.

Significance statement

Recent sounds can change what speech sounds we hear later. This can occur when the average frequency composition of earlier sounds differs from that of later sounds, biasing how they are perceived. These "spectral contrast effects" are widely observed when sounds' frequency compositions differ substantially. We reveal the lower limit of these effects, as +3 dB amplification of key frequency regions in earlier sounds was enough to bias categorization of the following vowel or consonant sound. Speech categorization being biased by very small spectral differences across sounds suggests that spectral contrast effects occur frequently in everyday speech perception.

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Commentary on “Post-carotid Endarterectomy Hypertension. Part 2: Association with Peri-operative Clinical, Anaesthetic, and Transcranial Doppler Derived Parameters”

Publication date: Available online 28 February 2018
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Leonie M.M. Fassaert, Gert J. de Borst




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Response to the Commentary on “Post-Carotid Hypertension Part 2: Association with Peri-operative Clinical, Anaesthetic, and Transcranial Doppler Derived Parameters”

Publication date: Available online 28 February 2018
Source:European Journal of Vascular and Endovascular Surgery
Author(s): Jeremy Edward Newman, A. Ross Naylor




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Lung Cancer Screening Most Beneficial for Those at Highest Risk, Analysis Suggests

An analysis of data from a demonstration project led by the Veterans Health Administration may help to better define who is most likely to benefit from lung cancer screening.

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Development of Velopharyngeal Closure for Vocalization During the First 2 Years of Life

Purpose

The vocalizations of young infants often sound nasalized, suggesting that the velopharynx is open during the 1st few months of life. Whereas acoustic and perceptual studies seemed to support the idea that the velopharynx closes for vocalization by about 4 months of age, an aeromechanical study contradicted this (Thom, Hoit, Hixon, & Smith, 2006). Thus, the current large-scale investigation was undertaken to determine when the velopharynx closes for speech production by following infants during their first 2 years of life.

Method

This longitudinal study used nasal ram pressure to determine the status of the velopharynx (open or closed) during spontaneous speech production in 92 participants (46 male, 46 female) studied monthly from age 4 to 24 months.

Results

The velopharynx was closed during at least 90% of the utterances by 19 months, though there was substantial variability across participants. When considered by sound category, the velopharynx was closed from most to least often during production of oral obstruents, approximants, vowels (only), and glottal obstruents. No sex effects were observed.

Conclusion

Velopharyngeal closure for spontaneous speech production can be considered complete by 19 months, but closure occurs earlier for speech sounds with higher oral pressure demands.

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Targeting Complex Sentences in Older School Children With Specific Language Impairment: Results From an Early-Phase Treatment Study

Purpose

This study investigated the effects of a complex sentence treatment at 2 dosage levels on language performance of 30 school-age children ages 10–14 years with specific language impairment.

Method

Three types of complex sentences (adverbial, object complement, relative) were taught in sequence in once or twice weekly dosage conditions. Outcome measures included sentence probes administered at baseline, treatment, and posttreatment phases and comparisons of pre–post performance on oral and written language tests and tasks. Relationships between pretest variables and treatment outcomes were also explored.

Results

Treatment was effective at improving performance on the sentence probes for the majority of participants; however, results differed by sentence type, with the largest effect sizes for adverbial and relative clauses. Significant and clinically meaningful pre–post treatment gains were found on a comprehensive oral language test, but not on reading and writing measures. There was no treatment advantage for the higher dosage group. Several significant correlations indicated a relationship between lower pretest scores and higher outcome measures.

Conclusions

Results suggest that a focused intervention can produce improvements in complex sentence productions of older school children with language impairment. Future research should explore ways to maximize gains and extend impact to natural language contexts.

Supplemental Material

https://doi.org/10.23641/asha.5923318

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Vocalization Subsystem Responses to a Temporarily Induced Unilateral Vocal Fold Paralysis

Purpose

The purpose of this study is to quantify the interactions of the 3 vocalization subsystems of respiration, phonation, and resonance before, during, and after a perturbation to the larynx (temporarily induced unilateral vocal fold paralysis) in 10 vocally healthy participants. Using dynamic systems theory as a guide, we hypothesized that data groupings would emerge revealing context-dependent patterns in the relationships of variables representing the 3 vocalization subsystems. We also hypothesized that group data would mask important individual variability important to understanding the relationships among the vocalization subsystems.

Method

A perturbation paradigm was used to obtain respiratory kinematic, aerodynamic, and acoustic formant measures from 10 healthy participants (8 women, 2 men) with normal voices. Group and individual data were analyzed to provide a multilevel analysis of the data. A 3-dimensional state space model was constructed to demonstrate the interactive relationships among the 3 subsystems before, during, and after perturbation.

Results

During perturbation, group data revealed that lung volume initiations and terminations were lower, with longer respiratory excursions; airflow rates increased while subglottic pressures were maintained. Acoustic formant measures indicated that the spacing between the upper formants decreased (F3–F5), whereas the spacing between F1 and F2 increased. State space modeling revealed the changing directionality and interactions among the 3 subsystems.

Conclusions

Group data alone masked important variability necessary to understand the unique relationships among the 3 subsystems. Multilevel analysis permitted a richer understanding of the individual differences in phonatory regulation and permitted subgroup analysis. Dynamic systems theory may be a useful heuristic to model the interactive relationships among vocalization subsystems.

Supplemental Material

https://doi.org/10.23641/asha.5913532

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