Caring for transgender patients with epilepsy

Summary

Objective

Approximately 25 million individuals older than age 15 identify as transgender, representing about 0.3–0.9% of the world's population. The aim of this paper is to identify and describe important medical and social considerations facing transgender persons with epilepsy.

Methods

We performed literature searches on the following terms: transgender AND epilepsy, transgender AND neurology, gender dysphoria AND epilepsy, gender dysphoria AND neurology. We also performed literature searches for common feminizing or masculinizing treatment regimens, and searched for interactions of those treatment regimens with antiepileptic drugs (AEDs) and with seizures.

Results

There are multiple bidirectional interactions between AEDs and the commonly used treatments for aligning external sex characteristics with identified gender. The scope of the transgender population with epilepsy remains to be elucidated.

Significance

Transgender patients with epilepsy face significant social and medical challenges. Interactions between medical gender-affirming treatments and AEDs are common, and management must depend on knowledge of these interactions to provide appropriate treatment.

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U1 Adaptors Suppress the KRAS-MYC Oncogenic Axis in Human Pancreatic Cancer Xenografts

Targeting KRAS and MYC has been a tremendous challenge in cancer drug development. Genetic studies in mouse models have validated the efficacy of silencing expression of both KRAS and MYC in mutant KRAS-driven tumors. We investigated the therapeutic potential of a new oligonucleotide-mediated gene silencing technology (U1 Adaptor) targeting KRAS and MYC in pancreatic cancer. Nanoparticles in complex with anti-KRAS U1 Adaptors (U1-KRAS) showed remarkable inhibition of KRAS in different human pancreatic cancer cell lines in vitro and in vivo. As a nanoparticle-free approach is far easier to develop into a drug, we refined the formulation of U1 Adaptors by conjugating them to tumor-targeting peptides (iRGD and cRGD). Peptides coupled to fluorescently tagged U1 Adaptors showed selective tumor localization in vivo. Efficacy experiments in pancreatic cancer xenograft models showed highly potent (>90%) antitumor activity of both iRGD and (cRGD)₂-KRAS Adaptors. U1 Adaptors targeting MYC inhibited pancreatic cancer cell proliferation caused by apoptosis in vitro (40%–70%) and tumor regressions in vivo. Comparison of iRGD-conjugated U1 KRAS and U1 MYC Adaptors in vivo revealed a significantly greater degree of cleaved caspase-3 staining and decreased Ki67 staining as compared with controls. There was no significant difference in efficacy between the U1 KRAS and U1 MYC Adaptor groups. Our results validate the value in targeting both KRAS and MYC in pancreatic cancer therapeutics and provide evidence that the U1 Adaptor technology can be successfully translated using a nanoparticle-free delivery system to target two undruggable genes in cancer. Mol Cancer Ther; 16(8); 1445–55. ©2017 AACR.

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Local DNA Repair Inhibition for Sustained Radiosensitization of High-Grade Gliomas

High-grade gliomas, such as glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG), are characterized by an aggressive phenotype with nearly universal local disease progression despite multimodal treatment, which typically includes chemotherapy, radiotherapy, and possibly surgery. Radiosensitizers that have improved the effects of radiotherapy for extracranial tumors have been ineffective for the treatment of GBM and DIPG, in part due to poor blood–brain barrier penetration and rapid intracranial clearance of small molecules. Here, we demonstrate that nanoparticles can provide sustained drug release and minimal toxicity. When administered locally, these nanoparticles conferred radiosensitization in vitro and improved survival in rats with intracranial gliomas when delivered concurrently with a 5-day course of fractionated radiotherapy. Compared with previous work using locally delivered radiosensitizers and cranial radiation, our approach, based on the rational selection of agents and a clinically relevant radiation dosing schedule, produces the strongest synergistic effects between chemo- and radiotherapy approaches to the treatment of high-grade gliomas. Mol Cancer Ther; 16(8); 1456–69. ©2017 AACR.

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Reactivation of the p90RSK-CDC25C Pathway Leads to Bypass of the Ganetespib-Induced G2-M Arrest and Mediates Acquired Resistance to Ganetespib in KRAS-Mutant NSCLC

A subset of non–small cell lung cancers (NSCLC) are dependent upon oncogenic driver mutations, including the most frequently observed driver mutant KRAS, which is associated with a poor prognosis. As direct RAS targeting in the clinic has been unsuccessful to date, use of Hsp90 inhibitors appeared to be a promising therapy for KRAS-mutant NSCLC; however, limited clinical efficacy was observed due to rapid resistance. Furthermore, the combination of the Hsp90 inhibitor (Hsp90i), ganetespib, and docetaxel was tested in a phase III clinical trial and failed to demonstrate benefit. Here, we investigated the mechanism(s) of resistance to ganetespib and explored why the combination with docetaxel failed in the clinic. We have not only identified a critical role for the bypass of the G₂–M cell-cycle checkpoint as a mechanism of ganetespib resistance (GR) but have also found that GR leads to cross-resistance to docetaxel. Reactivation of p90RSK and its downstream target, CDC25C, was critical for GR and mediated the bypass of a G₂–M arrest. Overexpression of either p90RSK or CDC25C lead to bypass of G₂–M arrest and induced ganetespib resistance in vitro and in vivo. Moreover, resistance was dependent on p90RSK/CDC25C signaling, as synthetic lethality to ERK1/2, p90RSK, or CDC25C inhibitors was observed. Importantly, the combination of ganetespib and p90RSK or CDC25C inhibitors was highly efficacious in parental cells. These studies provide a way forward for Hsp90 inhibitors through the development of novel rationally designed Hsp90 inhibitor combinations that may prevent or overcome resistance to Hsp90i. Mol Cancer Ther; 16(8); 1658–68. ©2017 AACR.

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Tumor-targeted Nanoparticle Delivery of HuR siRNA Inhibits Lung Tumor Growth In Vitro and In Vivo By Disrupting the Oncogenic Activity of the RNA-binding Protein HuR

Selective downregulation of the human antigen R (HuR) protein by siRNA may provide a powerful approach for treating lung cancer. To this end, we investigated the efficacy of transferrin receptor-targeted liposomal nanoparticle-based HuR siRNA (HuR-TfNP) therapy and compared with control siRNA (C)-TfNP therapy both, in vitro and in vivo using lung cancer models. In vitro studies showed HuR-TfNP, but not C-TfNP, efficiently downregulated HuR and HuR-regulated proteins in A549, and HCC827 lung cancer cells, resulting in reduced cell viability, inhibition of cell migration and invasion, and induction of G₁ cell-cycle arrest culminating in apoptosis. However, HuR-TfNP activity in normal MRC-9 lung fibroblasts was negligible. In vivo biodistribution study demonstrated that fluorescently labeled HuR-siRNA or ICG dye–loaded TfNP localized in tumor tissues. Efficacy studies showed intratumoral or intravenous administration of HuR-TfNP significantly inhibited A549 (>55% inhibition) and HCC827 (>45% inhibition) subcutaneous tumor growth compared with C-TfNP. Furthermore, HuR-TfNP treatment reduced HuR, Ki67, and CD31 expression and increased caspase-9 and PARP cleavage and TUNEL-positive staining indicative of apoptotic cell death in tumor tissues compared with C-TfNP treatment. The antitumor activity of HuR-TfNP was also observed in an A549-luc lung metastatic model, as significantly fewer tumor nodules (9.5 ± 3.1; P < 0.001; 88% inhibition) were observed in HuR-TfNP–treated group compared with the C-TfNP–treated group (77.7 ± 20.1). Significant reduction in HuR, Ki67, and CD31 expression was also observed in the tumor tissues of HuR-TfNP-treatment compared with C-TfNP treatment. Our findings highlight HuR-TfNP as a promising nanotherapeutic system for lung cancer treatment. Mol Cancer Ther; 16(8); 1470–86. ©2017 AACR.

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Risk of Pneumonitis Associated with Programmed Cell Death 1 Inhibitors in Cancer Patients: A Meta-analysis

Pneumonitis, a rare but potentially life-threatening adverse event in cancer patients receiving programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitors, has been reported in case reports, clinical trials, and retrospective studies. We performed a systematic review and meta-analysis to calculate the RR of pneumonitis associated with the use of PD-1/L1 inhibitors in randomized clinical trials (RCT). We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, trial registers, conference proceedings, review articles, and reference lists of trial publications for all relevant RCTs comparing PD-1/L1 inhibitors to control with available data on pneumonitis. The pooled incidence, RR, and 95% confidence intervals (CI) were calculated using fixed effects or random effects model according to the heterogeneity of included trials. Twelve RCTs were eligible for the meta-analysis, yielding a total of 5,775 patients included in trials evaluating a PD-1 inhibitor; no eligible trials evaluated a PD-L1 inhibitor. The pooled incidence of all-grade pneumonitis for patients treated with PD-1 inhibitors was 3.2% (95% CI, 2.3–4.5), and that of high-grade pneumonitis was 1.1% (95% CI, 0.7–1.7). The RR of all-grade and high-grade pneumonitis was 4.36 (95% CI, 2.58–7.38) and 2.86 (95% CI, 1.30–6.31), respectively. In a sensitivity analysis, PD-1 inhibitors were also associated with significantly increased risk of pneumonitis per person-month (for all grade, RR = 3.37; 95% CI, 1.97–5.76; for high grade, RR = 2.25; 95% CI, 1.03–4.94). PD-1 inhibitors were associated with a significant increase of all-grade and high-grade pneumonitis both per treatment episode and per person-month. Mol Cancer Ther; 16(8); 1588–95. ©2017 AACR.

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Photodynamic Therapy Using Photosensitizer-Encapsulated Polymeric Nanoparticle to Overcome ATP-Binding Cassette Transporter Subfamily G2 Function in Pancreatic Cancer

Chlorin-based photosensitizers are commonly used in photodynamic therapy (PDT). These drugs are effluxed by cell membrane transporters, such as the ATP-binding cassette subfamily G member 2 (ABCG2). PDT efficacy is limited in tumor cells expressing high levels of these proteins. Pancreatic cancer cell lines AsPC-1 and MIA PaCa-2, which have high and low ABCG2 expression, respectively, were used, and ABCG2-overexpressing MIA PaCa-2 cells were generated. We compared PDT efficacy between chlorin e6 (Ce6) and cationic photosensitizer–encapsulated polymeric nanoparticle (PS-pNP), which is comprised with Ce6, polyethylene glycol, and polyethylenimine. The intracellular concentration of Ce6 was significantly higher in MIA PaCa-2 cells than in AsPC-1 or ABCG2-overexpressing MIA PaCa-2 cells. PS-pNP increased intracellular levels of the photosensitizer in all cell lines. The cell viability experiments indicated increased Ce6 resistance in ABCG2-overexpressing cells. In contrast, PS-pNP produced similar levels of cytotoxicity in each of the cancer cell lines tested. Singlet oxygen production was higher in cells treated with PS-pNP than in those treated with Ce6. Furthermore, in heterotopic and orthotopic AsPC-1 xenograft mouse models, PDT using PS-pNP significantly reduced tumor volume in comparison with that of Ce6 treatment. PS-pNP could increase intracellular Ce6 concentration, which was related with reduced ABCG2-mediated efflux of Ce6, thereby enhancing the effects of PDT in pancreatic cancer cells. Mol Cancer Ther; 16(8); 1487–96. ©2017 AACR.

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Sensitization of EGFR Wild-Type Non-Small Cell Lung Cancer Cells to EGFR-Tyrosine Kinase Inhibitor Erlotinib

The benefit of EGFR–TKI in non–small cell lung cancer has been demonstrated in mutant EGFR tumors as first-line treatment but the benefit in wild-type EGFR tumors is marginal as well as restricted to maintenance therapy in pretreated patients. This work aimed at questioning the effects of cisplatin initial treatment on the EGFR pathway in non–small cell lung cancer and the functional consequences in vitro and in in vivo animal models of patient-derived xenografts (PDX). We establish here that cisplatin pretreatment specifically sensitizes wild-type EGFR-expressing cells to erlotinib, contrary to what happens in mutant EGFR cells and with a blocking EGFR antibody, both in vitro and in vivo. The sensitization entails the activation of the kinase Src upstream of EGFR, thereafter transactivating EGFR through a ligand-independent activation. We propose a combination of markers that enable to discriminate between the tumors sensitized to erlotinib or not in PDX models, which should be worth testing in patients. These markers might be useful for the selection of patients who would benefit from erlotinib as a maintenance therapy. Mol Cancer Ther; 16(8); 1634–44. ©2017 AACR.

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Selective Glucocorticoid Receptor Modulators (SGRMs) Delay Castrate-Resistant Prostate Cancer Growth

Increased glucocorticoid receptor (GR) expression and activity following androgen blockade can contribute to castration-resistant prostate cancer (CRPC) progression. Therefore, we hypothesized that GR antagonism will have therapeutic benefit in CRPC. However, the FDA-approved nonselective, steroidal GR antagonist, mifepristone, lacks GR specificity, reducing its therapeutic potential. Here, we report that two novel nonsteroidal and highly selective GR modulators (SGRM), CORT118335 and CORT108297, have the ability to block GR activity in prostate cancer and slow CRPC progression. In contrast to mifepristone, these novel SGRMs did not affect androgen receptor (AR) signaling, but potently inhibited GR transcriptional activity. Importantly, SGRMs decreased GR-mediated tumor cell viability following AR blockade. In vivo, SGRMs significantly inhibited CRPC progression in high GR–expressing, but not in low GR–expressing xenograft models. Transcriptome analysis following AR blockade and GR activation revealed that these SGRMs block GR-mediated proliferative gene expression pathways. Furthermore, GR-regulated proliferation-associated genes AKAP12, FKBP5, SGK1, CEBPD, and ZBTB16 are inhibited by CORT108297 treatment in vivo. Together, these data suggest that GR-selective nonsteroidal SGRMs potently inhibit GR activity and prostate cancer growth despite AR pathway inhibition, demonstrating the therapeutic potential of SGRMs in GR-expressing CRPC. Mol Cancer Ther; 16(8); 1680–92. ©2017 AACR.

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Vulnerability of Small-Cell Lung Cancer to Apoptosis Induced by the Combination of BET Bromodomain Proteins and BCL2 Inhibitors

Ten percent to 15% of all lung cancers are small-cell lung cancer (SCLC). SCLC usually grows and metastasizes before it is diagnosed and relapses rapidly upon treatment. Unfortunately, no new targeted agent has been approved in the past 30 years for patients with SCLC. The BET (bromodomain and extraterminal) proteins bind acetylated histones and recruit protein complexes to promote transcription initiation and elongation. BET proteins have been shown to regulate expression of key genes in oncogenesis, such as MYC, CCND2, and BCL2L1. Here, we demonstrate that approximately 50% of SCLC cell lines are exquisitely sensitive to growth inhibition by the BET inhibitor, ABBV-075. The majority of these SCLC cell lines underwent apoptosis in response to ABBV-075 treatment via induction of caspase-3/7 activity. ABBV-075 enhanced the expression of proapoptotic protein BIM and downregulated antiapoptotic proteins BCL2 and BCLxl to a lesser extent. Furthermore, BET inhibition increased BCL2–BIM complex, thus priming the cells for apoptosis. Indeed, strong synergy was observed both in vitro and in vivo when cotreating the cells with BET inhibitor and the BH3-mimetic, BCL2 inhibitor venetoclax (ABT-199). ABBV-075 interaction with venetoclax positively correlated with BCL2 expression. Taken together, our studies provide a rationale for treating SCLC with BET and BCL2 inhibitors in tumors with high BCL2 protein expression. Mol Cancer Ther; 16(8); 1511–20. ©2017 AACR.

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Highlights of This Issue

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Niclosamide and Bicalutamide Combination Treatment Overcomes Enzalutamide- and Bicalutamide-Resistant Prostate Cancer

Activation of the androgen receptor (AR) and its splice variants is linked to advanced prostate cancer and drives resistance to antiandrogens. The roles of AR and AR variants in the development of resistance to androgen deprivation therapy (ADT) and bicalutamide treatment, however, are still incompletely understood. To determine whether AR variants play a role in bicalutamide resistance, we developed bicalutamide-resistant LNCaP cells (LNCaP-BicR) and found that these resistant cells express significantly increased levels of AR variants, particularly AR-V7, both at the mRNA and protein levels. Exogenous expression of AR-V7 in bicalutamide-sensitive LNCaP cells confers resistance to bicalutamide treatment. Knockdown of AR-V7 in bicalutamide- and enzalutamide-resistant CWR22Rv1, enzalutamide-resistant C4-2B (C4-2B MDVR), and LNCaP-BicR cells reversed bicalutamide resistance. Niclosamide, a potent inhibitor of AR variants, significantly enhanced bicalutamide treatment. Niclosamide and bicalutamide combination treatment not only suppressed AR and AR variants expression and inhibited their recruitment to the PSA promoter, but also significantly induced apoptosis in bicalutamide- and enzalutamide-resistant CWR22Rv1 and C4-2B MDVR cells. In addition, combination of niclosamide with bicalutamide inhibited the growth of enzalutamide-resistant tumors. In summary, our results demonstrate that AR variants, particularly AR-V7, drive bicalutamide resistance and that targeting AR-V7 with niclosamide can resensitize bicalutamide-resistant cells to bicalutamide treatment. Furthermore, combination of niclosamide with bicalutamide inhibits enzalutamide resistant tumor growth, suggesting that the combination of niclosamide and bicalutamide could be a potential cost-effective strategy to treat advanced prostate cancer in patients, including those who fail to respond to enzalutamide therapy. Mol Cancer Ther; 16(8); 1521–30. ©2017 AACR.

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Identification of the Serine Biosynthesis Pathway as a Critical Component of BRAF Inhibitor Resistance of Melanoma, Pancreatic, and Non-Small Cell Lung Cancer Cells

Metastatic melanoma cells commonly acquire resistance to BRAF V600E inhibitors (BRAFi). In this study, we identified serine biosynthesis as a critical mechanism of resistance. Proteomic assays revealed differential protein expression of serine biosynthetic enzymes PHGDH, PSPH, and PSAT1 following vemurafenib (BRAFi) treatment in sensitive versus acquired resistant melanoma cells. Ablation of PHGDH via siRNA sensitized acquired resistant cells to vemurafenib. Inhibiting the folate cycle, directly downstream of serine synthesis, with methotrexate also displayed similar sensitization. Using the DNA-damaging drug gemcitabine, we show that gemcitabine pretreatment sensitized resistant melanoma cells to BRAFis vemurafenib and dabrafenib. We extended our findings to BRAF WT tumor cell lines that are intrinsically resistant to vemurafenib and dabrafenib. Pretreatment of pancreatic cancer and non–small cell lung cancer cell lines with sublethal doses of 50 and 5 nmol/L of gemcitabine, respectively, enhanced killing by both vemurafenib and dabrafenib. The novel aspects of this study are the direct identification of serine biosynthesis as a critical mechanism of BRAF V600E inhibitor resistance and the first successful example of using gemcitabine + BRAFis in combination to kill previously drug-resistant cancer cells, creating the translational potential of pretreatment with gemcitabine prior to BRAFi treatment of tumor cells to reverse resistance within the mutational profile and the WT. Mol Cancer Ther; 16(8); 1596–609. ©2017 AACR.

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Notch Inhibitor PF-03084014 Inhibits Hepatocellular Carcinoma Growth and Metastasis via Suppression of Cancer Stemness due to Reduced Activation of Notch1-Stat3

Aberrant activation of the Notch signaling pathway is implicated in many solid tumors, including hepatocellular carcinoma, indicating a potential use of Notch inhibitors for treatment. In this study, we investigated the antitumor and antimetastasis efficacy of the novel Notch inhibitor (-secretase inhibitor) PF-03084014 in hepatocellular carcinoma. Hepatocellular carcinoma spherical cells (stem-like cancer cells), a sphere-derived orthotopic tumor model and one patient-derived xenograft (PDX) model were used in our experiment. We demonstrated that PF-03084014 inhibited the self-renewal and proliferation of cancer stem cells. PF-03084014 reduced the hepatocellular carcinoma sphere-derived orthotopic tumor and blocked the hepatocellular carcinoma tumor liver to lung metastasis. We further tested the PF-03084014 in PDX models and confirmed the inhibition tumor growth effect. In addition, a low dose of PF-03084014 induced hepatocellular carcinoma sphere differentiation, resulting in chemosensitization. Antitumor activity was associated with PF-03084014-induced suppression of Notch1 activity, decreased Stat3 activation and phosphorylation of the Akt signaling pathway, and reduced epithelial–mesenchymal transition. These are the key contributors to the maintenance of cancer stemness and the promotion of cancer metastasis. Moreover, the Notch–Stat3 association was implicated in the clinical hepatocellular carcinoma prognosis. Collectively, PF-03084014 revealed antitumor and antimetastatic effects in hepatocellular carcinoma, providing evidence for the potential use of gamma-secretase inhibitors as a therapeutic option for the treatment of hepatocellular carcinoma. Mol Cancer Ther; 16(8); 1531–43. ©2017 AACR.

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Resistance to RET-Inhibition in RET-Rearranged NSCLC Is Mediated By Reactivation of RAS/MAPK Signaling

Oncogenic rearrangements in RET are present in 1%–2% of lung adenocarcinoma patients. Ponatinib is a multi-kinase inhibitor with low-nanomolar potency against the RET kinase domain. Here, we demonstrate that ponatinib exhibits potent antiproliferative activity in RET fusion–positive LC-2/ad lung adenocarcinoma cells and inhibits phosphorylation of the RET fusion protein and signaling through ERK1/2 and AKT. Using distinct dose escalation strategies, two ponatinib-resistant LC-2/ad cell lines, PR1 and PR2, were derived. PR1 and PR2 cell lines retained expression, but not phosphorylation of the RET fusion and lacked evidence of a resistance mutation in the RET kinase domain. Both resistant lines retained activation of the MAPK pathway. Next-generation RNA sequencing revealed an oncogenic NRAS p.Q61K mutation in the PR1 cell. PR1 cell proliferation was preferentially sensitive to siRNA knockdown of NRAS compared with knockdown of RET, more sensitive to MEK inhibition than the parental line, and NRAS dependence was maintained in the absence of chronic RET inhibition. Expression of NRAS p.Q61K in RET fusion expressing TPC1 cells conferred resistance to ponatinib. PR2 cells exhibited increased expression of EGFR and AXL. EGFR inhibition decreased cell proliferation and phosphorylation of ERK1/2 and AKT in PR2 cells, but not LC-2/ad cells. Although AXL inhibition enhanced PR2 sensitivity to afatinib, it was unable to decrease cell proliferation by itself. Thus, EGFR and AXL cooperatively rescued signaling from RET inhibition in the PR2 cells. Collectively, these findings demonstrate that resistance to ponatinib in RET-rearranged lung adenocarcinoma is mediated by bypass signaling mechanisms that result in restored RAS/MAPK activation. Mol Cancer Ther; 16(8); 1623–33. ©2017 AACR.

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Colony-Stimulating Factor 1 Receptor Blockade Inhibits Tumor Growth by Altering the Polarization of Tumor-Associated Macrophages in Hepatocellular Carcinoma

Colony-stimulating factor-1 (CSF-1) and its receptor, CSF-1R, regulate the differentiation and function of macrophages and play an important role in macrophage infiltration in the context of hepatocellular carcinoma. The therapeutic effects of CSF-1R blockade in hepatocellular carcinoma remain unclear. In this study, we found that CSF-1R blockade by PLX3397, a competitive inhibitor with high specificity for CSF-1R tyrosine kinase, significantly delayed tumor growth in mouse models. PLX3397 inhibited the proliferation of macrophages in vitro, but intratumoral macrophage infiltration was not decreased by PLX3397 in vivo. Gene expression profiling of tumor-associated macrophages (TAM) showed that TAMs from the PLX3397-treated tumors were polarized toward an M1-like phenotype compared with those from vehicle-treated tumors. In addition, PLX3397 treatment increased CD8⁺ T-cell infiltration, whereas CD4⁺ T-cell infiltration was decreased. Further study revealed that tumor cell–derived CSF-2 protected TAMs from being depleted by PLX3397. In conclusion, CSF-1R blockade delayed tumor growth by shifting the polarization rather than the depletion of TAMs. CSF-1R blockade warrants further investigation in the treatment of hepatocellular carcinoma. Mol Cancer Ther; 16(8); 1544–54. ©2017 AACR.

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JUN-Mediated Downregulation of EGFR Signaling Is Associated with Resistance to Gefitinib in EGFR-mutant NSCLC Cell Lines

Mutations or deletions in exons 18–21 in the EGFR) are present in approximately 15% of tumors in patients with non–small cell lung cancer (NSCLC). They lead to activation of the EGFR kinase domain and sensitivity to molecularly targeted therapeutics aimed at this domain (gefitinib or erlotinib). These drugs have demonstrated objective clinical response in many of these patients; however, invariably, all patients acquire resistance. To examine the molecular origins of resistance, we derived a set of gefitinib-resistant cells by exposing lung adenocarcinoma cell line, HCC827, with an activating mutation in the EGFR tyrosine kinase domain, to increasing gefitinib concentrations. Gefitinib-resistant cells acquired an increased expression and activation of JUN, a known oncogene involved in cancer progression. Ectopic overexpression of JUN in HCC827 cells increased gefitinib IC₅₀ from 49 nmol/L to 8 μmol/L (P < 0.001). Downregulation of JUN expression through shRNA resensitized HCC827 cells to gefitinib (IC₅₀ from 49 nmol/L to 2 nmol/L; P < 0.01). Inhibitors targeting JUN were 3-fold more effective in the gefitinib-resistant cells than in the parental cell line (P < 0.01). Analysis of gene expression in patient tumors with EGFR-activating mutations and poor response to erlotinib revealed a similar pattern as the top 260 differentially expressed genes in the gefitinib-resistant cells (Spearman correlation coefficient of 0.78, P < 0.01). These findings suggest that increased JUN expression and activity may contribute to gefitinib resistance in NSCLC and that JUN pathway therapeutics merit investigation as an alternate treatment strategy. Mol Cancer Ther; 16(8); 1645–57. ©2017 AACR.

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Identification of Cancer-Targeted Tropomyosin Inhibitors and Their Synergy with Microtubule Drugs

Actin filaments, with their associated tropomyosin polymers, and microtubules are dynamic cytoskeletal systems regulating numerous cell functions. While antimicrotubule drugs are well-established, antiactin drugs have been more elusive. We previously targeted actin in cancer cells by inhibiting the function of a tropomyosin isoform enriched in cancer cells, Tpm3.1, using a first-in-class compound, TR100. Here, we screened over 200 other antitropomyosin analogues for anticancer and on-target activity using a series of in vitro cell-based and biochemical assays. ATM-3507 was selected as the new lead based on its ability to disable Tpm3.1-containing filaments, its cytotoxicity potency, and more favorable drug-like characteristics. We tested ATM-3507 and TR100 alone and in combination with antimicrotubule agents against neuroblastoma models in vitro and in vivo. Both ATM-3507 and TR100 showed a high degree of synergy in vitro with vinca alkaloid and taxane antimicrotubule agents. In vivo, combination-treated animals bearing human neuroblastoma xenografts treated with antitropomyosin combined with vincristine showed minimal weight loss, a significant and profound regression of tumor growth and improved survival compared with control and either drug alone. Antitropomyosin combined with vincristine resulted in G₂–M phase arrest, disruption of mitotic spindle formation, and cellular apoptosis. Our data suggest that small molecules targeting the actin cytoskeleton via tropomyosin sensitize cancer cells to antimicrotubule agents and are tolerated together in vivo. This combination warrants further study. Mol Cancer Ther; 16(8); 1555–65. ©2017 AACR.

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Erratum to: Changes in dural sac caliber with standing MRI improve correlation with symptoms of lumbar spinal stenosis

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Corrigendum to “Measuring satisfaction with appearance: Validation of the FACE-Q scales for double-eyelid blepharoplasty with minor incision in young Asians- retrospective study of 200 cases” [J Plast Reconstr Aesthet Surg 70 (2017) 1129–1135]

The authors regret that the authorship of the original article was incorrect and should be cited as per the authorship of this corrigendum. To confirm, the order of authors should be as follows: Baoguo Chen, Huifeng Song, Quanwen Gao, Minghuo Xu, Jue Wang, Fang Wang, Shuai Chen, Jiang Wu, Huichao Li.

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Frequency of self-reported drug allergy

Patients reporting drug allergy are treated with second-line therapies, with possible negative clinical and health consequences.

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Palmar Eccrine Hidradenitis Secondary to Trauma from Computer Gaming in an Adolescent After Bone Marrow Transplantation

Abstract

A 14-year-old boy who had undergone a matched sibling bone marrow transplant for acute lymphoblastic leukemia presented with painful nodules on his palms after prolonged gaming on his computer and mobile phone. Histology showed a neutrophilic inflammatory infiltrate surrounding the acrosyringium and eccrine sweat coils in the deep dermis. The lesions resolved spontaneously with conservative management.

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Tuberous Sclerosis Complex in 29 Children: Clinical and Genetic Analysis and Facial Angiofibroma Responses to Topical Sirolimus

Abstract

Background/Objectives

Tuberous sclerosis complex (TSC) is a genetic disorder and facial angiofibromas are disfiguring facial lesions. The aim of this study was to analyze the clinical and genetic features of TSC and to assess the treatment of facial angiofibromas using topical sirolimus in Chinese children.

Methods

Information was collected on 29 patients with TSC. Genetic analyses were performed in 12 children and their parents. Children were treated with 0.1% sirolimus ointment for 36 weeks. Clinical efficacy and plasma sirolimus concentrations were evaluated at baseline and 12, 24, and 36 weeks.

Results

Twenty-seven (93%) of the 29 patients had hypomelanotic macules and 15 (52%) had shagreen patch; 11 of the 12 (92%) who underwent genetic analysis had gene mutations in the TSC1 or TSC2 gene. Twenty-four children completed 36 weeks of treatment with topical sirolimus; facial angiofibromas were clinically undetectable in four (17%). The mean decrease in the Facial Angiofibroma Severity Index (FASI) score at 36 weeks was 47.6 ± 30.4%. There was no significant difference in the FASI score between weeks 24 and 36 (F = 1.00, p = 0.33). There was no detectable systemic absorption of sirolimus.

Conclusion

Hypomelanotic macules are often the first sign of TSC. Genetic testing has a high detection rate in patients with a clinical diagnosis of TSC. Topical sirolimus appears to be both effective and well-tolerated as a treatment of facial angiofibromas in children with TSC. The response typically plateaus after 12 to 24 weeks of treatment.

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Can You See Me Now? Video Supplementation for Pediatric Teledermatology Cases

Abstract

Background/Objectives

Digital video is widely available and is used sporadically in clinical settings to evaluate patients, but whether it helps improve clinical management has not been determined. The aim of this study was to assess whether recorded video in addition to still images can improve residents' diagnostic and management accuracy and confidence with pediatric teledermatology cases.

Methods

Dermatology residents from three programs were assigned alternately to an online survey with 15 pediatric teledermatology cases presented with still images only (still) or still images plus recorded video (mixed). Participants provided free-text diagnoses and management recommendations and rated their confidence and image quality. Responses were scored using a modified script concordance grading key based on reference panelists' responses.

Results

Thirty-one residents participated (response rate 57%). Participants in the mixed group scored significantly higher on management accuracy (87.6 ± 12.9 vs 71.7 ± 14.2; p = 0.003). Both groups performed better on more common conditions than less common conditions. The mixed group outperformed the still group on less common conditions with respect to management recommendations.

Conclusion

This novel study suggests that supplemental recorded video may improve the management accuracy of pediatric teledermatology consultations, particularly for complex cases. Residents may benefit from training in recording and interpreting video.

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HOXA13 is associated with unfavorable survival and acts as a novel oncogene in prostate carcinoma

Future Oncology, Ahead of Print.


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Boosting anti-HER2 CD4 T-helper responses in HER2 expressing ductal carcinoma in situ

Future Oncology, Ahead of Print.


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Meta-analysis of clinical significance of p53 protein expression in patients with osteosarcoma

Future Oncology, Ahead of Print.


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Regorafenib as treatment for patients with advanced hepatocellular cancer

Future Oncology, Ahead of Print.


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Co-administration of a tumor-penetrating peptide improves the therapeutic efficacy of paclitaxel in a novel air-grown lung cancer 3D spheroid model

Abstract

Three-dimensional (3D) cell culture platforms are increasingly being used in cancer research and drug development since they mimic avascular tumors in vitro. In the present study, we focused on the development of a novel air-grown multicellular spheroid (MCS) model to mimic in vivo tumors for understanding lung cancer biology and improvement in the evaluation of aerosol anticancer therapeutics. 3D MCS were formed using A549 lung adenocarcinoma cells, comprising cellular heterogeneity with respect to different proliferative and metabolic gradients. The growth kinetics, morphology, and 3D structure of air-grown MCS were characterized by brightfield, fluorescent, and scanning electron microscopy. MCS demonstrated a significant decrease in growth when the tumor-penetrating peptide iRGD and paclitaxel (PTX) were co-administered as compared to PTX alone. It was also found that when treated with both iRGD and PTX, A549 MCS exhibited an increase in apoptosis and decrease in clonogenic survival capacity in contrast to PTX treatment alone. This study demonstrated that co-administration of iRGD resulted in the improvement of the tumor penetration ability of PTX in an in vitro A549 3D MCS model. In addition, this is the first time a high-throughput air-grown lung cancer tumor spheroid model has been developed and evaluated. This article is protected by copyright. All rights reserved.

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Cancers, Vol. 9, Pages 100: Crosstalk between microRNA and DNA Methylation Offers Potential Biomarkers and Targeted Therapies in ALK-Positive Lymphomas

Cancers, Vol. 9, Pages 100: Crosstalk between microRNA and DNA Methylation Offers Potential Biomarkers and Targeted Therapies in ALK-Positive Lymphomas

Cancers doi: 10.3390/cancers9080100

Authors: Coralie Hoareau-Aveilla Fabienne Meggetto

The discovery of microRNA (miRNA) has provided new and powerful tools for studying the mechanism, diagnosis and treatment of human cancers. The down-regulation of tumor suppressive miRNA by hypermethylation of CpG island (CpG is shorthand for 5′-C-phosphate-G-3′, that is, cytosine and guanine separated by only one phosphate) is emerging as a common hallmark of cancer and appears to be involved in drug resistance. This review discusses the role of miRNA and DNA methylation in drug resistance mechanisms and highlights their potential as anti-cancer therapies in Anaplastic Lymphoma Kinase (ALK)-positive lymphomas. These are a sub-type of non-Hodgkin's lymphomas that predominantly affect children and young adults and are characterized by the expression of the nucleophosmin (NPM)/ALK chimeric oncoprotein. Dysregulation of miRNA expression and regulation has been shown to affect several signaling pathways in ALK carcinogenesis and control tumor growth, both in cell lines and mouse models. These data suggest that the modulation of DNA methylation and/or the expression of these miRNA could serve as new biomarkers and have potential therapeutic applications for ALK-positive malignancies.

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See One, Do One, Teach One: No More

Anatomic dissection prior to examining and treating a living person dates back to Alexandria, Greece in the third century bc.1 For Otolaryngologist-Head and Neck Surgeons, anatomic dissections, the original "simulators," have served to prepare them for open approaches to the face, head, and neck, for temporal bone surgery, and for paranasal sinus procedures. But, as with diagnostic and surgical methods and tools, simulation tools and techniques have evolved, most rapidly over the past several years.

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Simulation in Otolaryngology

At present, simulation is widely accepted as a means of providing surgical education outside of the clinical environment. Recent advances in simulation technology and medical education reform coupled with political and societal demands have provided the impetus toward the exponential growth of this field. Research in this area supports the use of simulation to train and assess individuals in both psychomotor and team-based skills. Further benefits include translation of these improved skills to patient care practices with better patient outcomes and reduced health care costs.

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Monitoring of Optimal Cerebral Perfusion Pressure in Traumatic Brain Injured Patients Using a Multi-Window Weighting Algorithm

Journal of Neurotrauma , Vol. 0, No. 0.


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Using Evidence To Inform Practice and Policy To Enhance the Quality of Care for Persons with Traumatic Spinal Cord Injury

Journal of Neurotrauma , Vol. 0, No. 0.


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Boosting anti-HER2 CD4 T-helper responses in HER2 expressing ductal carcinoma in situ

Future Oncology, Ahead of Print.


from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2u2fYxf

Meta-analysis of clinical significance of p53 protein expression in patients with osteosarcoma

Future Oncology, Ahead of Print.


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Regorafenib as treatment for patients with advanced hepatocellular cancer

Future Oncology, Ahead of Print.


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Detection of Maltodextrin and Its Discrimination from Sucrose are Independent of the T1R2+T1R3 Heterodimer

Maltodextrins, such as Maltrin and Polycose, are glucose polymer mixtures of varying chain lengths that are palatable to rodents. Although glucose and other sugars activate the T1R2+T1R3 "sweet" taste receptor, recent evidence from T1R2 or T1R3 knockout (KO) mice suggests that maltodextrins, despite their glucose polymer composition, activate a separate receptor mechanism to generate a taste percept qualitatively distinguishable from that of sweeteners. However, explicit discrimination of maltodextrins from prototypical sweeteners has not yet been psychophysically tested in any murine model. Therefore, mice lacking T1R2+T1R3 and wild-type controls were tested in a two-response taste discrimination task to determine if maltodextrins are 1) detectable when both receptor subunits are absent, and 2) perceptually distinct from that of sucrose irrespective of viscosity, intensity, and hedonics. Most KO mice displayed similar Polycose sensitivity as controls. However, some KO mice were only sensitive to the higher Polycose concentrations, implicating potential allelic variation in the putative polysaccharide receptor or downstream pathways unmasked by the absence of T1R2+T1R3. Varied Maltrin and sucrose concentrations of approximately matched viscosities were then presented to render the oral somatosensory features, intensity, and hedonic value of the solutions irrelevant. While both genotypes competently discriminated Maltrin from sucrose, performance was apparently driven by the different orosensory percepts of the two stimuli in control mice and the presence of a Maltrin but not sucrose orosensory cue in KO mice. These data support the proposed presence of an orosensory receptor mechanism that gives rise to a qualitatively distinguishable sensation from that of sucrose.

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Energy homeostasis in apolipoprotein AIV and cholecystokinin-deficient mice

Apolipoprotein AIV (ApoAIV) and cholecystokinin (CCK) are well-known satiating signals that are stimulated by fat consumption. Peripheral ApoAIV and CCK interact to prolong satiating signals. In the present study, we hypothesized that ApoAIV and CCK control energy homeostasis in response to high-fat diet feeding. To test this hypothesis, energy homeostasis in ApoAIV and CCK double knockout (ApoAIV/CCK-KO), ApoAIV knockout (ApoAIV-KO), and CCK knockout (CCK-KO) mice were monitored. When animals were maintained on a low-fat diet, ApoAIV/CCK-KO, ApoAIV-KO, and CCK-KO mice had comparable energy intake and expenditure, body weight, fat mass, fat absorption, and plasma parameters relative to the controls. In contrast, these KO mice exhibited impaired lipid transport to epididymal fat pads in response to intraduodenal infusion of dietary lipids. Furthermore, ApoAIV-KO mice had upregulated levels of CCK receptor 2 (CCK2R) in the small intestine while ApoAIV/CCK-KO mice had upregulated levels of CCK2R in the brown adipose tissue. After 20 weeks of a high-fat diet, ApoAIV-KO and CCK-KO mice had comparable body weight and fat mass, as well as lower energy expenditure at some time points. However, ApoAIV/CCK-KO mice exhibited reduced body weight and adiposity relative to wild-type mice, despite having normal food intake. Furthermore, ApoAIV/CCK-KO mice displayed normal fat absorption and locomotor activity, as well as enhanced energy expenditure. These observations suggest that mice lacking ApoAIV and CCK have reduced body weight and adiposity, possibly due to impaired lipid transport and elevated energy expenditure.

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In vitro studies to evaluate the effect of varying culture conditions and IPL fluencies on tenocyte activities

Abstract

Tendons are dense, fibrous connective tissues which carry out the essential physiological role of transmitting mechanical forces from skeletal muscle to bone. From a clinical perspective, tendinopathy is very common, both within the sporting arena and amongst the sedentary population. Studies have shown that light therapy may stimulate tendon healing, and more recently, intense pulsed light (IPL) has attracted attention as a potential treatment modality for tendinopathy; however, its mechanism of action and effect on the tendon cells (tenocytes) is poorly understood. The present study therefore investigates the influence of IPL on an in vitro bovine tendon model. Tenocytes were irradiated with IPL at different devise settings and under variable culture conditions (e.g. utilising cell culture media with or without the pH indicator dye phenol red), and changes in tenocyte viability and migration were subsequently investigated using Alamar blue and scratch assays, respectively. Our data demonstrated that IPL fluencies of up to 15.9 J/cm² proved harmless to the tenocyte cultures (this was the case using culture media with or without phenol red) and resulted in a significant increase in cell viability under certain culture conditions. Furthermore, IPL treatment of tenocytes did not affect the rate of cell migration. This study demonstrates that irradiation with IPL is not detrimental to the tenocytes and may increase their viability under certain conditions, thus validating our in vitro model. Further studies are required to elucidate the effects of IPL application in the clinical situation.

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Monitoring of Optimal Cerebral Perfusion Pressure in Traumatic Brain Injured Patients Using a Multi-Window Weighting Algorithm

Journal of Neurotrauma , Vol. 0, No. 0.


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Using Evidence To Inform Practice and Policy To Enhance the Quality of Care for Persons with Traumatic Spinal Cord Injury

Journal of Neurotrauma , Vol. 0, No. 0.


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The Temporal Stability of Visuomotor Adaptation Generalization

Movement adaptation in response to systematic motor perturbations exhibits distinct spatial and temporal properties. These characteristics are typically studied in isolation, leaving the interaction largely unknown. Here, we examined how the temporal decay of visuomotor adaptation influences the spatial generalization of the motor recalibration. First, we quantified the extent adaptation decayed over time. Subjects reached to a peripheral target and a rotation was applied to the visual feedback of the unseen motion. The retention of this adaptation over different delays (0 to 120 seconds) (1) decreased by 29.0 ± 6.8% at the longest delay, and (2) was represented by a simple exponential, with a time constant of 22.5 ± 5.6 seconds. Based on this relationship we simulated how the spatial generalization of adaptation would change with delay. To test this directly, we trained additional subjects with the same perturbation and assessed transfer to 19 different locations (spaced 15 degrees apart, symmetric around the trained location) and examined three delays (approximately 4, 12 and 25 sec). Consistent with the simulation, we found that generalization around the trained direction (± 15 degrees) significantly decreased with delay and distance, while locations > 60 degrees displayed near constant spatiotemporal transfer. Intermediate distances (30 and 45 degrees) showed a difference in transfer across space, but this amount was approximately constant across time. Interestingly, the decay at the trained direction was faster than that based purely on time suggesting that the spatial transfer of adaptation is modified by concurrent passive (time-dependent) and active (movement-dependent) processes.

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A latent low-dimensional common input drives a pool of motor neurons: a probabilistic latent state-space model

Motor neurons appear to be activated with a common input signal that modulates the discharge activity of all neurons in the motor nucleus. It has proven difficult for neurophysiologists to quantify the variability in a common input signal, but characterization of this signal may improve our understanding of how the activation signal varies across motor tasks. Contemporary methods of quantifying the common input to motor neurons relies on compiling discrete action potentials into continuous signals, assuming the motor pool acts as a linear filter, and requiring signals to be of sufficient duration. We introduce a space-state model in which the discharge activity of motor neurons is modeled as inhomogeneous Poisson processes and propose a method to quantify a latent trajectory that represents the common input received by motor neurons. The approach also approximates the synaptic noise in the common input signal. The model is validated with four datasets: a simulation of 120 motor units, a pair of integrate-and-fire neurons with a Renshaw cell providing inhibitory feedback, the discharge activity of 10 integrate-and-fire neurons, and the discharge times of concurrently active motor units during an isometric voluntary contraction. The simulations revealed that a latent state-space model can quantify the trajectory and variability of the common input signal across all four conditions. When compared with the cumulative spike train method, the state-space approach was more sensitive and was less influenced by the duration of the signal. The state-space approach appears capable of detecting rather modest changes in common input signals across conditions.

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Multiple spatial representations interact to increase reach accuracy when coordinating a saccade with a reach

Reaching is an essential behavior that allows primates to interact with the environment. Precise reaching to visual targets depends on our ability to localize and foveate the target. Despite this, how the saccade system contributes to improvements in reach accuracy remains poorly understood. To assess spatial contributions of eye movements to reach accuracy, we performed a series of behavioral psychophysics experiments in non-human primates (M. mulatta). We found that a coordinated saccade with a reach to a remembered target location increases reach accuracy without target foveation. The improvement in reach accuracy was similar to that obtained when the subject had visual information about the current target's location in the visual periphery and executed the reach while maintaining central fixation. Moreover, we found that the increase in reach accuracy elicited by a coordinated movement involved a spatial coupling mechanism between the saccade and reach movements. We observed significant correlations between the saccade and reach errors for coordinated movements. In contrast, when the eye and arm movements were made to targets in different spatial locations, the magnitude of the error, and the degree of correlation between the saccade and reach direction was determined by the spatial location of the eye and the hand targets. Hence, we propose that coordinated movements improve reach accuracy without target foveation, due to spatial coupling between the reach and saccade systems. Spatial coupling could arise from a neural mechanism for coordinated visual behavior that involves interacting spatial representations.

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Mechanisms for shaping receptive field in monkey area TE

Visual object information is conveyed from V1 to area TE along the ventral visual pathway with increasing receptive field (RF) sizes. The RFs of TE neurons are known to be large, but it is largely unknown how large RFs are shaped along the ventral visual pathway. Here, we addressed this question in two aspects, static and dynamic mechanisms, by recording neural responses from macaque area TE and V4 to object stimuli presented at various locations in the visual field. As a component related to static mechanisms, we found that, in area TE but not in V4, response latency to objects presented at fovea were different from objects in periphery. As a component of the dynamic mechanisms, we examined effects of spatial attention on the RFs of TE neurons. Spatial attention did not affect response latency, but modulated response magnitudes depending on attended location, shifting of the longitudinal axis of RFs toward the attended locations. In standard models of large RF formation, downstream neurons pool information from nearby RFs, and this process is repeated across the visual field and at each step along the ventral visual pathway. The present study revealed that this mechanism is not that simple: (1) different circuit mechanisms for foveal and peripheral visual fields may be situated between V4 and area TE, and (2) spatial attention dynamically changes shape of RFs.

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Intercepting virtual balls approaching under different gravity conditions: evidence for spatial prediction

To accurately time motor responses when intercepting falling balls we rely on an internal model of gravity. However, whether and how such a model is also used to estimate the spatial location of interception is still an open question. Here, we addressed this issue by asking 25 participants to intercept balls projected from a fixed location 6 m in front of them and approaching along trajectories with different arrival locations, flight durations, and gravity accelerations (0g and 1g). The trajectories were displayed in an immersive virtual reality system with a wide field of view. Participants intercepted approaching balls with a racket and they were free to choose the time and place of interception. We found that participants often achieved a better performance with 1g than 0g balls. Moreover, the interception points were distributed along the direction of a 1g path for both 1g and 0g balls. In the latter case, interceptions tended to cluster on the upper half of the racket, indicating that participants aimed at a lower position than the actual 0g path. These results suggest that an internal model of gravity was probably used in predicting the interception locations. However, we found that the difference in performance between 1g and 0g balls was modulated by flight duration, the difference being larger for faster balls. In addition, the number of peaks in the hand speed profiles increased with flight duration suggesting that visual information was used to adjust the motor response, correcting the prediction to some extent.

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Altered modulation of sensorimotor rhythms with chronic paralysis

After paralysis, the disconnection between the cortex and its peripheral targets leads to neuroplasticity throughout the nervous system. However, it is unclear how chronic paralysis specifically impacts cortical oscillations associated with attempted movement of impaired limbs. We hypothesized that mu (8-13Hz) and beta (15-30Hz) event-related desynchronization (ERD) would be less modulated for individuals with hand paralysis due to cervical spinal cord injury (SCI). To test this, we compared the modulation of ERD from magnetoencephalography (MEG) during attempted and imagined grasping performed by participants with cervical SCI (n = 12) and able-bodied controls (n = 13). Seven participants with tetraplegia were able to generate some electromyography (EMG) activity during attempted grasping, while the other five were not. The peak and area of ERD were significantly decreased for individuals without volitional muscle activity when they attempted to grasp compared to able-bodied subjects and participants with SCI with some residual EMG activity. However, no significant differences were found between subject groups during mentally simulated tasks (i.e. motor imagery) where no muscle activity or somatosensory consequences were expected. These findings suggest that individuals who are unable to produce muscle activity are capable of generating ERD when attempting to move, but the characteristics of this ERD are altered. However, for people who maintain volitional muscle activity after SCI, there are no significant differences in ERD characteristics compared to able-bodied controls. These results provide evidence that ERD is dependent on the level of intact muscle activity after SCI.

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The influence of pain on motor preparation in the human brain

The protective function of pain depends on appropriate motor responses to avoid injury and promote recovery. The preparation and execution of motor responses is, thus, an essential part of pain. However, it is not yet fully understood how pain and motor processes interact in the brain. We here used electroencephalography to investigate the effects of pain on motor preparation in the human brain. 20 healthy human participants performed a motor task in which they performed button presses to stop increasingly painful thermal stimuli when they became intolerable. In another condition, participants performed button presses without concurrent stimulation. The results show that the amplitudes of preparatory event-related desynchronizations at alpha and beta frequencies did not differ between conditions. In contrast, the amplitude of the preparatory readiness potential was reduced when a button press was performed to stop a painful stimulus as compared to a button press without concomitant pain. A control experiment with non-painful thermal stimuli showed a similar reduction of the readiness potential when a button press was performed to stop a non-painful thermal stimulus. Together, these findings indicate that painful and non-painful thermal stimuli can similarly influence motor preparation in the human brain. Pain-specific effects on motor preparation in the human brain remain to be demonstrated.

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Pre-movement planning processes in people with congenital mirror movements

Congenital mirrormovements (CMM), a disorder characterised by unintentional mirroring of motor systems on the contralateral side of voluntary movements, usually of the hands and wrists, is regarded as a rare condition of human movement (Schott and Wyke, 1981); its prevalence is unknown. CMM can be difficult to detect due to its isolated occurrence in the distal portions of the upper limbs in most individuals affected, and in particular, because there are no other known comorbidities (Franz, 2003; Franz et al., 2015).

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Canalicular adenoma: a systematic review

Canalicular adenoma (CA) is an uncommon but unique benign tumor of salivary gland origin. It is the third most common benign tumor of minor salivary glands, representing less than 1% of all salivary neoplasms. A systematic review is presented of reported cases of CA, to determine trends in presentation, diagnostic features, treatment, and patient outcome.

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Aesthetic facial perception and need for intervention in laterognathism in women of different ethnicities

This study compared the perception of facial pleasantness and the need for intervention, as assessed by orthodontists, oral and maxillofacial (OMF) surgeons, and laypersons, in people of different ethnicities showing varying degrees of simulated laterognathism. Facial photographs were modified to simulate deviations in the lower face of women of African, Asian and Caucasian descent, ascending in two-degree steps from zero to eight degrees of deviation. Three groups of 20 individuals each (OMF surgeons, orthodontists, and laypersons) assessed the images and rated facial pleasantness on a numerical scale ranging from 0 to 10.

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A customised digitally engineered solution for fixed dental rehabilitation in severe bone deficiency: A new innovative line extension in implant dentistry

In the 1940s, Dahl first introduced and described subperiosteal implants that were placed onto the alveolar ridge without rigid fixation (Dahl, 1943), but due to high complication rates, including implant loss, exposure, and flap dehiscence, subperiosteal implants have not been recommended for decades. However, the principle of subperiosteal implant placement onto the alveolar ridge rather than drilling implants into the bone might prove to be both simple and innovative, and could be a potential strategy for avoiding soft tissue complications leading to peri-implantitis, and bone and implant loss in complex cases (Lin et al., 2013).

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Use of cone beam computed tomography to assess significant imaging findings related to mandibular third molar impaction

Publication date: Available online 2 August 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): LH Matzen, L Schropp, R Spin-Neto, A Wenzel
ObjectiveTo identify risk factors for pathosis related to mandibular third molars observed in CBCT.Study designCBCT-volumes of 410 mandibular third molars were assessed by three observers according to angulation and position of the third molar in relation to the second molar. Moreover, pathosis (marginal bone loss, resorption of the second molar, increased follicular and lingual bone perforation) were assessed. Logistic regression analyses tested if angulation and position of the third molar were risk factors for pathosis.ResultsOn average 41% of second molars had resorption; mesio-angulated (OR 11-107, P<.001) and horizontally positioned (OR 13-120, P<.001) third molars located cervically at the second molar (OR 2-3, P<.027) highly increased the risk. On average 49% of second molars had marginal bone loss; mesio-angulated (OR 16-85, P<.001) and horizontally positioned (OR 61-573, P<.001) third molars increased the risk. For the third molar, an increased follicular space was seen in 25% of cases, distal (OR 5-9, P<.001) and vertical positions (OR 5, P<.002) increased the risk. Lingual bone perforation was not related to a specific angulation.ConclusionSpecific angulations of the mandibular third molar are risk factors for marginal bone loss and resorption of the second molar.



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Quantitative assessment of mandibular canal compression assessed by cone beam ct

Publication date: Available online 2 August 2017
Source:Oral Surgery, Oral Medicine, Oral Pathology and Oral Radiology
Author(s): Fatima M. Jadu, Daniah Alhazmi, Fatma F. Badr, Ahmed M. Jan
ObjectiveTo objectively quantify the topographic relation of the mandibular canals, impacted third molars, and cortical plates using cone beam CT (CBCT).Study designA retrospective chart review was conducted using the database of a university-based imaging service. Two calibrated reviewers examined the CBCT images of 100 cases scheduled for mandibular third molar removal. They characterized the position and condition of the mandibular canal and measured its dimensions at three different points relative to the third molars.ResultsThe mandibular canal is more often located buccal to the third molars but is more likely to be compressed when in a lingual position. The vertical dimensions (cephalocaudal) of the mandibular canal change significantly as the canal progresses towards the ramus. The horizontal dimensions (buccolingual) of the mandibular canal fluctuate very little but significantly narrow in proximity to the third molars. Thinning of the lingual cortical plate is common, whereas grooving of molar roots is uncommon.ConclusionsMinor variations in the horizontal dimensions of the mandibular canal close to the third molars signify an effect on the canal. This effect may indicate an increased risk of neurovascular injury. The mandibular canal can have a direct or indirect effect on the cortical plates.



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Imaging of Metastases in the Chest: Mechanisms of Spread and Potential Pitfalls

Pulmonary and pleural metastases are routinely identified on thoracic computed tomography. Pulmonary metastases are the most common pulmonary neoplasms and commonly originate from primary malignancies of the lung, breast, colon, pancreas, stomach, skin (i.e., melanoma), head and neck, and kidney. Metastatic disease to the lungs may occur via three routes of spread: hematogenous, lymphatic, and endobronchial. Pleural metastases most commonly originate from primary malignancies of the lung and breast.

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“Malignant Pleural Mesothelioma: Diagnosis, Staging, Pitfalls and Follow-up”

Malignant Pleural Mesothelioma (MPM) is the most common primary neoplasm of the pleura. Imaging evaluation is essential in diagnosis, staging and assessment of treatment response in MPM. Computed tomography is the most commonly used modality for tumor staging. Assessment of tumor extension and lymph node involvement is essential in imaging evaluation as locally advanced tumors are amenable to resection. Knowledge of the full imaging spectrum of this rare disease, differential diagnosis, staging classification and the current guidelines for diagnostic evaluation and follow-up are essential in accurate interpretation to optimize patient management.

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CT Imaging of Complications Associated with Continuous-Flow Left Ventricular Assist Devices (LVADs)

Heart failure is becoming increasingly prevalent, and more patients are being treated with left ventricular assist devices (LVADs), either as a bridge to transplant or as destination therapy. The use of continuous flow LVADs is on the rise. LVAD therapy is associated with several classes of complications, including bleeding, thrombosis, and infection. CT imaging can be used effectively to diagnose LVAD complications, including mediastinal hematomas and pericardial, abdominal wall, and retroperitoneal hemorrhage, inflow and outflow graft and aortic thrombi, and driveline and pump pocket infections.

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Gastric Medullary Carcinoma with Sporadic Mismatch Repair Deficiency and a TP53 R273C Mutation: An Unusual Case with Wild-Type BRAF

Medullary carcinoma has long been recognized as a subtype of colorectal cancer associated with microsatellite instability and Lynch syndrome. Gastric medullary carcinoma is a very rare neoplasm. We report a 67-year-old male who presented with a solitary gastric mass. Total gastrectomy revealed a well-demarcated, poorly differentiated carcinoma with an organoid growth pattern, pushing borders, and abundant peritumoral lymphocytic response. The prior cytology was cellular with immunohistochemical panel consistent with upper gastrointestinal/pancreaticobiliary origin. Overall, the histopathologic findings were consistent with gastric medullary carcinoma. A mismatch repair panel revealed a mismatch repair protein deficient tumor with loss of MLH1 and PMS2 expression. BRAF V600E immunostain (VE1) and BRAF molecular testing were negative, indicating a wild-type gene. Tumor sequencing of MLH1 demonstrated a wild-type gene, while our molecular panel identified TP53 c.817C>T (p.R273C) mutation. These findings were compatible with a sporadic tumor. Given that morphologically identical medullary tumors often occur in Lynch syndrome, it is possible that mismatch repair loss is an early event in sporadic tumors with p53 mutation being a late event. Despite having wild-type BRAF, this tumor is sporadic and unrelated to Lynch syndrome. This case report demonstrates that coordinate ancillary studies are needed to resolve sporadic versus hereditary rare tumors.

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The progression of epithelial-mesenchymal transformation in gliomas

Abstract

Epithelial-mesenchymal transformation(EMT) is a coordinated process in which polarized epithelial cells are induced to lose adhesion from the basement membrane and obtain the properties of mesenchymal cells, including invasion and metastasis. It has been proved that EMT greatly contributes to the invasion and therapeutic resistance of various solid human cancers. However, the role of EMT in brain glioma has not yet been fully clarified. So in this review, we mainly elaborate the latest progression about the related regulatory transcription factors, key signaling pathways and microRNAs (miRNAs) of EMT in gliomas.

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Copyright

Publication date: September 2017
Source:Atlas of the Oral and Maxillofacial Surgery Clinics, Volume 25, Issue 2





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Contributors

Publication date: September 2017
Source:Atlas of the Oral and Maxillofacial Surgery Clinics, Volume 25, Issue 2





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Contents

Publication date: September 2017
Source:Atlas of the Oral and Maxillofacial Surgery Clinics, Volume 25, Issue 2





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Forthcoming Issues

Publication date: September 2017
Source:Atlas of the Oral and Maxillofacial Surgery Clinics, Volume 25, Issue 2





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Oral Manifestations of Systemic Diseases

Publication date: September 2017
Source:Atlas of the Oral and Maxillofacial Surgery Clinics, Volume 25, Issue 2
Author(s): Joel J. Napeñas




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Oral Manifestations of Systemic Diseases

Publication date: September 2017
Source:Atlas of the Oral and Maxillofacial Surgery Clinics, Volume 25, Issue 2
Author(s): Joel J. Napeñas




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Oral Manifestations of Immunodeficiencies and Transplantation Medicine

Publication date: September 2017
Source:Atlas of the Oral and Maxillofacial Surgery Clinics, Volume 25, Issue 2
Author(s): Elizabeth Waring, Alessandro Villa




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Oral Manifestations of Autoimmune and Connective Tissue Disorders

Publication date: September 2017
Source:Atlas of the Oral and Maxillofacial Surgery Clinics, Volume 25, Issue 2
Author(s): Vidya Sankar, Marcel Noujeim




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Drug-Induced Oral Complications

Publication date: September 2017
Source:Atlas of the Oral and Maxillofacial Surgery Clinics, Volume 25, Issue 2
Author(s): Kentaro Ikeda




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Oral Complications of Nonsurgical Cancer Therapies

Publication date: September 2017
Source:Atlas of the Oral and Maxillofacial Surgery Clinics, Volume 25, Issue 2
Author(s): Sharon Elad, Yehuda Zadik, Noam Yarom




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Oral Complications of Multiorgan Disorders

Publication date: September 2017
Source:Atlas of the Oral and Maxillofacial Surgery Clinics, Volume 25, Issue 2
Author(s): Leah Bowers, Michael Brennan




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Head and Neck Manifestations of Endocrine Disorders

Publication date: September 2017
Source:Atlas of the Oral and Maxillofacial Surgery Clinics, Volume 25, Issue 2
Author(s): Arwa M. Farag




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Oral Complications of Systemic Bacterial and Fungal Infections

Publication date: September 2017
Source:Atlas of the Oral and Maxillofacial Surgery Clinics, Volume 25, Issue 2
Author(s): Amr Bugshan, Arwa M. Farag, Bhavik Desai




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Indicadores de calidad del Programa de Detección Precoz de Hipoacusia Permanente del Hospital Padre Hurtado

Introducción: La detección precoz de hipoacusia permanente en lactantes beneficia el desarrollo integral del paciente. Los programas cuyo objetivo es la identificación universal de hipoacusia debieran tener como meta determinados criterios de calidad en su ejecución. Objetivo: El objetivo del presente trabajo es comunicar los resultados del Programa de Detección Precoz de Hipoacusia en el Hospital Padre Hurtado. Material y método: Se incluyen los recién nacidos entre el 1 de enero de 2014 y el 31 de agosto de 2016. Los pacientes sin factores de riesgo para hipoacusia congénita se evalúan con examen de emisiones otoacústicas, y los pacientes con factores de riesgo con potenciales auditivos automatizados de tronco encefálico. Refieren aquellos pacientes con exámenes alterados en forma uní o bilateral. La etapa diagnóstica incluye potenciales auditivos evocados con tono, impedanciometría de alta frecuencia y audiometría de refuerzo visual. Los pacientes con diagnóstico de hipoacusia permanente son amplificados e inician proceso de habilitación. Resultados: En el período de estudio el universo a evaluar fue de 12.313 recién nacidos. Se completó la etapa de pesquisa en 98.4% con una tasa de referencia de 0.6%. 79 pacientes pasaron a etapa diagnóstica, completaron su evaluación antes de 3 meses en 95% de los casos. Se confirmó hipoacusia sensorioneural en 7 casos, con una tasa de 0.56 por 1.000 recién nacidos vivos. En 57% de los pacientes se amplificaron antes de los seis meses de vida. Conclusiones: El Programa de Hipoacusia Congénita del Hospital Padre Hurtado cumple con los indicadores de calidad recomendados en los ítemes de pesquisa y diagnóstico. En la etapa de habilitación con audffonos esto se realiza antes de los seis meses de vida sólo en 57% de los casos.

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Introduction: Quality indicators of the newborn hearing screening program in Hospital Padre Hurtado. Aim: Asses the accomplishment of quality indicators of the newborn hearing screening program in Hospital Padre Hurtado, Chile, as proposed by the Joint Committee on Infant Hearing Loss (JCIH). Material and method: Two stage screening protocol: otoacoustic emissions for babies in the well-infant nursery and automated auditory brainstem responses for those in the intensive care unit orwith risk factors. If they fail one or both ears they proceed to a comprehensive audiological assessment. Results: 12.313 live births between 01/01/2014 and 108/31/16, 12.103 were screened before discharge (98.4%). 79 cases proceeded to diagnostic assessment, referral rate 0.6%. 95% infants completed audiological evaluation before three months, seven cases were diagnose with permanent sensorineural hearing loss for a prevalence of 0.56 per 1000 live births. Amplification was provided before 6 months of age in 57% of deaf children. Conclusions: Quality indicators of the JCIH are met by our newborn hearing screening program with the exception of adequate timing for the provision of hearing aids: 57% before six months of age.

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Análisis de tiempos de espera en pacientes con cáncer de cabeza y cuello en el Hospital San Juan de Dios

Introducción: Los cánceres de cabeza y cuello (CCyC) son reconocibles precozmente mediante la cínica y exámenes poco invasivo, sin embargo, existe importante demora entre las primeras molestias del paciente y el tratamiento. Objetivo: Describir los tiempos involucrados entre los primeros síntomas y el tratamiento. Material y método: Estudio descriptivo retrospectivo, mediante evaluación de fichas de pacientes diagnosticados y tratados por CCyC en otorrinolaringología del Hospital San Juan de Dios durante 18 meses. Resultados: Fueron elegibles 33 casos. El 93,7% correspondieron a carcinomas escamosos. Fueron comprometidos principalmente laringe (45,4%) y orofaringe (24,2%). El 90,2% se diagnosticó en estadio avanzado. Los pacientes demoraron 17 semanas en consultar desde sus primeros síntomas. Pasó una semana para ser evaluados por el especialista. Este tardó una semana en obtener una biopsia. El resultado histológico tomó tres semanas y el tratamiento se realizó a las cinco semanas. Quienes recibieron cirugía como primer tratamiento tardaron cuatro semanas en recibirla. Quienes fueron a quimiorradioterapia como coadyuvancia esperaron 11,5 semanas. Mientras, quienes recibieron quimiorradioterapia como único tratamiento, tardaron 8 semanas. Conclusión: Los principales retrasos en el manejo de estos pacientes son: la demora del paciente en consultar, el informe histológico y el acceso al tratamiento al conocerse el diagnóstico, especialmente cuando el tratamiento es la radio-quimioterapia.

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Introduction: Head and neck cancers (HNC) are recognizable by clinical and early minimally invasive tests, however, there is significant delay between the first symptoms and treatment. Aim: To describe the times involved between the first symptoms and treatment. Material and method: Descriptive and retrospective study, by evaluating records of patients diagnosed and treated for HNC in otolaryngology at the Hospital San Juan de Dios, for 18 months. Results: 33 cases were eligible. 937% corresponded to squamous cell carcinoma. The sites most committed were larynx (45.4%) and (24.2%); the diagnosis was made in advanced stages in 90.2% of the cases. The patients took 17 weeks to consult since their first symptoms. It took 1 week to be evaluated by the specialist. It took 1 week to get a biopsy. The histological result took 3 weeks and treatment was performed at 5 weeks. Who received surgery as first treatment took 4 weeks to receive it. Who went to chemo-radiotherapy as co-adjuvant waited 11.5 weeks. Those receiving chemo-radiotherapy as the only treatment, 8 weeks. Conclusion: The major delays are the patient delay in consulting, the time delay in the histological report and access to treatment when knowing the diagnosis, especially when treatment is radio-chemotherapy.

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Estimación de la incidencia del cáncer de laringe en Chile según la aplicación de un formulario de registro digital

Introducción: El cáncer de laringe es una neoplasia frecuente en otorrinolaringología. Actualmente la incidencia ajustada por edad en Chile de cáncer laríngeo se proyecta en base al Registro Poblacional de Cáncer de la provincia de Los Lagos (International Agency for Research on Cancer - WHO), siendo ésta de 1,3 x100.000 habitantes. Objetivo: Estimar la incidencia del cáncer de laringe en Chile medida mediante un formulario de registro digital en hospitales y clínicas del país que realizan diagnóstico y tratamiento a esta patología, entre septiembre de 2015 y septiembre de 2016. Material y metodo: Estudio descriptivo prospectivo. Se utilizó un formulario de registro digital. Se incluyeron pacientes con diagnóstico histológico de cáncer de laringe entre septiembre de 2015 y septiembre de 2016. Resultados: Se registraron un total de 134 carcinomas escamosos de laringe. 15 (11%) de sexo femenino y 119 (89%) de sexo masculino. La incidencia fue de 2,13 casos por cada 100.000 habitantes, al estandarizarla por edad fue de 2,12 por cada 100.000 habitantes. Conclusión: La estimación del presente estudio es más alta que la reportada en los registros nacionales. Es necesario crear un registro poblacional más representativo de la realidad nacional, y así conocer la magnitud real de los casos de cáncer en el país.

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Introduction: The squamous cell carcinoma of the larynx is a frequent neoplasms within otorhinolaryngology Currently the age standardized incidence of Chile for laryngeal cancer is based on the cancerpopulation registration of the province of Los Lagos (International Agency for Research on Cancer - WHO), which is 1.3 x 100,000 inhabitants. Aim: To estimate the incidence of laryngeal cancer in Chile using a digital registry form in hospitals and clinics of the country that diagnose and treat this condition between September 2015 and September 2016. Material and method: A descriptive prospective study was conducted. We use a digital registration form. We included patients with clinical diagnosis of laryngeal cancer between September 2015 and September 2016. Data was analyzed with descriptive statistics. Results: A total of 134 squamous cell carcinomas of the larynx were registered. 15 (11%) were female and 119 (89%) were male, with a mean age of65years. The incidence was of 2.13 cases per 100,000 inhabitants, and the age-standardized incidence was of 2.12 per 100,000 inhabitants. Conclusion: In this study the incidence is greater than the one reported in other registrations. It is necessary a more representative population registration of the national reality in order to estimate accurately the cancer cases in the country.

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Angiomiolipoma de cavidad nasal: Reporte de un caso y revisión de la literatura

El angiomiolipoma de cavidad nasal es un tumor hamartomatoso extremadamente infrecuente compuesto por adipocitos maduros, espacios vasculares con escaso tejido elástico y la presencia de haces de células musculares lisas maduras. Se manifiesta principalmente por obstrucción nasal unilateral y epistaxis recurrente. Se presenta el caso de una paciente de 73 años con historia crónica de obstrucción nasal y epistaxis recurrente izquierda asociada a rinorrea y descarga posterior intermitente. La tomografía computarizada (TC) y resonancia nuclear magnética (RNM) demuestran una lesión vascular circunscrita en fosa nasal izquierda. La angiografía demostró irrigación exclusiva de la arteria esfenopalatina izquierda. Se realizó extirpación de la lesión por abordaje endonasal endoscópico previa embolización arterial. La revisión de la literatura mundial muestra que es el duodécimo caso de angiomiolipoma de cavidad nasal reportado.

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Angiomyolipoma of nasal cavity is an extremely rare hamartoma tumor composed of mature adipocytes, vascular spaces with lack of elastic tissue, and the presence of bundles of mature smooth muscle cells. It manifests itself mainly by unilateral nasal obstruction and recurrent epistaxis. We present the case of a 73-years-old woman with chronic history of left-sided nasal obstruction and recurrent epistaxis associated with rhinorrhea and intermittent post nasal drip. Computed tomography and magnetic resonance imaging demonstrate a vascular lesion inside the left nasal cavity. Angiography showed irrigation exclusively by the left sphenopalatine artery Surgical excision was performed by endoscopic endonasal approach after arterial embolization. World literature review showed that this is the twelfth reported case of angiomyolipoma of the nasal cavity.

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Pólipo bilateral de cuerda vocal: Presentación de un caso clínico

Los pólipos de cuerda vocal son lesiones laríngeas benignas. Se asocian a micro-traumatismos por mal uso vocal que generan remodelación de la lámina propia y el epitelio. Es más frecuente en hombres entre los veinte y cuarenta años. En la gran mayoría de los casos se presenta de manera unilateral. Si bien estas lesiones están bien documentadas en la literatura, es raro encontrar presentaciones bilaterales, por lo que su enfrentamiento y manejo puede ser discutible. Se presenta el caso de una paciente de sexo femenino de 41 años, fumadora, que consulta por disfonía de larga data. Se diagnostican pólipos bilaterales de cuerda vocal, realizando una intervención quirúrgica en un tiempo, con un resultado favorable.

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Vocal cord polyps are benign Iaryngeal lesions. They are associated to micro traumatisms because ofvocal misuse, generating a remodelation of the lamina propria and the epithelium. It is more common in men between twenty and forty years of age. In the vast majority of cases it unilaterally occurs. While these are well documented injuries in the literature, it is rare to find bilateral presentations, so their confrontation and management may be debatable. We present the case of a female patient, smoker, who consulted for chronic dysphonia. Bilateral vocal cord polyps were diagnosed, performing a bilateral resection with a positive outcome.

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Condrosarcoma de la laringe: Reporte de un caso y revisión de la literatura

El cáncer de laringe es un tumor relativamente raro en Ecuador (0,5/100000 varones). Las lesiones neoplásicas de laringe son usualmente epiteliales y el tipo histológico más frecuente es el carcinoma escamocelular. El tumor mesenquimal más común es el condrosarcoma. En los 31 años de existencia del Registro Nacional de Tumores de Ecuador éste es el primer caso de condrosarcoma de laringe registrado. Por este motivo, hemos decidido reportar el manejo diagnóstico y terapéutico de este caso.

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Laryngeal cancer is a relatively uncommon tumor en Ecuador (0,5/100000 males). These neoplastic lesions usually epithelial and the most frequent histological type is squamous cell carcinoma. The most common mesenchymal tumor is chondrosarcoma. No case of this type of laryngeal tumor has been registered since the foundation of the National Cancer Registry of Ecuador thirty-one years ago. For this reason, we have decided to report the diagnostic and therapeutic management of his case.

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Estenosis de la apertura piriforme y síndrome de incisivo central único: Casos clínicos

El síndrome incisivo central único es un trastorno que involucra anomalías de la línea media. Se puede presentar con dificultad respiratoria poniendo en peligro la vida del recién nacido, debido a malformaciones nasales. Estas malformaciones incluyen atresia de coanas y la estenosis de la apertura del orificio piriforme. Debe pensarse en esta última en todo recién nacido con estridor y dificultad respiratoria de grado variable, asociado a la dificultad de pasar una sonda a través de la región anterior de las fosas nasales. El diagnóstico se confirma por tomografía computarizada del macizo craneofacial y el examen nasofibroscópico. La conducta terapéutica dependerá de la gravedad de los síntomas, pero en general si es que no hay compromiso respiratorio severo, se prefiere una conducta expectante, y esperar el crecimiento craneofacial del niño, para aumentar permeabilidad nasal. Presentamos dos casos clínicos.

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Solitary median maxillary central incisor syndrome is a rare disorder involving midline abnormalities. It may present with life threatening respiratory distress in the neonate secondary to nasal malformations. These include choanal atresia and pyriform aperture stenosis. The last to be thought in any newborn with stridor and respiratory distress associated with the difficulty of passing a tube through the anterior region of the nostrils. The diagnosis is confirmed by craniofacial CT scan and nasolaryngoscope evaluation. The therapeutic approach depends on the severity of symptoms.

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Abordaje cerrado en patología de vía aérea superior con el uso de microelectrodos: Nuestra experiencia

El láser como alternativa a la cirugía abierta de la vía aérea superior ha venido a modificar la forma de abordaje de las patologías en esta área, pero no deja de ser un procedimiento costoso que no está al alcance de todos los servicios. Por este motivo se han reinventado nuevas formas de abordaje que cumplan los mismos requisitos tanto de la cirugía abierta como con láser pero con un menor coste. Presentamos una serie de 30 casos realizados en un período de 6 años por motivos tanto tumorales como no, en los que se realizaron abordajes cerrados a través de microcirugía con disección mediante microelectrodos. Obteniendo pocas complicaciones y una disminución de la estancia hospitalaria significativa. Con lo cual nos parece una técnica eficiente para abordajes de este tipo.

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The laser as an alternative to open surgery of the upper airway has come to change the form of approaching the disease in this area, but it is still an expensive procedure that is not available to all services. For this reason a new ways of approach to meet the same requirements both open as laser but at a lower cost surgery. We present a series of 30 cases performed over a period of 6 years for reasons as much tumor, which closed approaches through microsurgical dissection were performed using microelectrodes. Obtaining few complications and significant decreased hospital stay. Our considerations is it seems an efficient technique for such approaches.

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Presentación inusual de fracturas laríngeas: Reporte de dos casos de fracturas laríngeas no traumáticas

Las fracturas laríngeas se producen principalmente en el contexto de traumas cervicales, ahorcamiento o estrangulamiento. Las fracturas laríngeas no traumáticas son excepcionales, existiendo escasos reportes en la literatura. A continuación, presentamos dos casos de fracturas laríngeas no traumáticas evaluadas en nuestro servicio.

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Laryngeal fractures occur mainly in the context of cervical trauma, hanging or strangulation. Nontraumatic laryngeal fractures are rare and there are fewreports in the literature. We present two cases of nontraumatic laryngeal fractures evaluated in our service.

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Utilidad de imagen de banda estrecha en un caso de melanoma mucoso de septum nasal

En los últimos años, se está utilizando la fibrolaringoscopía con imagen de banda estrecha (NBI) como técnica novedosa para observar el patrón específico de microvas-cularización de una lesión concreta a evaluar. Es conocida por su utilidad en el diagnóstico de otras lesiones de vías aerodigestivas superiores, fundamentalmente laríngea y digestiva. Los melanomas mucosos son tumores infrecuentes, que suelen localizarse a nivel del área rinosinusaly que comportan un manejo y pronóstico distinto con respecto a los melanomas cutáneos. Se presenta el caso clínico de una paciente mujer con anamnesis, exploración y fibrolaringoscopía con imagen de banda estrecha, compatible con melanoma mucoso de fosa nasal izquierda. El tratamiento realizado fue quirúrgico, sin necesidad de tratamiento coadyuvante, y no presenta evidencia de enfermedad al año postseguimiento.

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In recent years, it is being used fibrolaryngoscopy with narrowband image (NBI) as a novel technique to observe the specific pattern of microvasculature of a particular lesion. NBI is known for its usefulness in the diagnosis of other lesions of the upper aerodigestive tract, (primarily laryngeal and digestive lesions). Mucosal melanomas are rare tumors, which are usually located at the level of rhino-sinusal area and involving a different prognosis and management regarding cutaneous melanomas. We report a female patient case with anamnesis, clinical examination and NBI compatible with mucosal melanoma of left nostril. Surgical treatmentwas performed without adjuvant therapy, and there is no evidence of disease at one year post-monitoring.

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Linfoma T/NK extraganglionar tipo nasal: Caso clínico

El linfoma T/NK extraganglionar tipo nasal es un linfoma extraganglionar, habitualmente expresa el fenotipo NK y VEB positivo. Cursa ocasionando necrosis y angioinvasión afectando de manera preferente estructuras mediofaciales. Característicamente es muy agresivo. Presentamos un caso con una sobrevida de siete meses a partir de los primeros síntomas y realizamos revisión de la literatura.

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Extranodal NK/T-cell lymphoma nasal type, is an extranodal lymphoma, usually with an NK-cell phenotype and EBV possitive. It causes necrosis and angioinvasion, and it is most commonly presenting in the midfacial area. Characteristically it is very aggressive. A case with survival of seven months from the first symptoms is reported and a review of the literature is made.

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Cierre de fístula oroantral con injerto de hueso vómer

Presentamos un caso de fístula oroantral y rinosinusitis maxilar, resuelto por abordaje combinado endoscópico, nasal e intraoral en el cual se utilizó colgajo de mucosa palatina y hueso vómer para el cierre de la misma. Describimos el caso de una paciente femenina de 66 años de edad, que consultó por presentar cacosmia, algia facial izquierda y rinorrea posterior purulenta, 3 semanas posterior a extracción de segundo molar superior izquierdo, la tomograffa axial computarizada (TC) de senos paranasales evidenció velamiento total maxilar izquierdo, parcial etmoidal izquierdo y defecto óseo en reborde alveolar superior izquierdo. Se realizó toma de fragmento de hueso vómer. Seguidamente abordaje de cavidad antral izquierda por vía endoscópica; e intraoral, se concluyó disección, cierre óseo y mucoso de la fístula.

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We report a case of an oroantral fistula and maxillary rhinosinusitis, that was resolved by combined approach, in which palatal mucosa flap and vomer bone was used for its closure. We describe the case of a female patient of 66 years old, who consulted for having cacosmia, left facial pain and purulent rhinorrhea, after left second molar extraction. CT-scan sinus showed the total left maxillary sinus, partial left ethmoid opacity and bone defect in left alveolar ridge. A vomer bone graft was taken from the nasal septum; left maxillary sinus surgerywas done by endoscopic approach and intraoral closure of bony and mucosa fístula was concluded.

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Carcinoma familiar de tiroides no medular: Reporte de un caso clínico y revisión de la literatura

El carcinoma tiroideo familiar no medular (CFTNM) representa aproximadamente entre el 3,2% y 9,6% de todos los cánceres de tiroides, y se define por la presencia de cáncer diferenciado de tiroides en 2 o más familiares, en ausencia de otros síndromes familiares conocidos o exposición a radiación. Si bien su fisiopatología es aún incierta, algunos investigadores postulan un patrón de herencia dominante con penetrancia incompleta, no habiendo aún un gen específico responsable. Esta entidad suele presentarse a una menor edad y con características más agresivas que en su forma esporádica. Dado el interés por conocer la presentación de esta enfermedad y las recomendaciones para su manejo, se presenta el caso de una paciente diagnosticada con cáncer papilar de tiroides con el antecedente de 4 familiares con la misma patología. Actualmente el tamizaje mediante ecografía cervical y biopsia por punción aspiración con aguja fina de los nódulos tiroideos es el examen de elección ante la presencia del antecedente de CFTNM, ya que aún no hay estudios genéticos disponibles. La tiroidectomía total más disección ganglionar es el tratamiento de elección. Debido al comportamiento más agresivo y peor pronóstico del CFTNM, es necesaria un alto índice de sospecha y una investigación completa en la presencia de un componente familiar.

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The non-familial medullary thyroid carcinoma (FNMTC) represents approximately between 3.2 and 9.6% of all thyroid cancers, and is defined by the presence of differentiated thyroid cancer in 2 or more families in the absence of other known familial syndromes or radiation exposure. Although the pathophysiology is still uncertain, some investigators posit a dominant pattern of inheritance with incomplete penetrance, but still there is no specific gene responsible. It occurs at a younger age and with more aggressive characteristics than the sporadic form. Because of the interest in learning about the presentation of this disease and its recommendations, we present the case of a patient diagnosed with papillary thyroid cancer with a history of 4 family with the same pathology. Actually cervical screening by ultrasound and the fine needle aspiration biopsy (FNAB) of thyroid nodules is the examination of choice in the presence of a history of FNMTC, since no genetic studies yet available. Total thyroidectomy with lymph node dissection is the treatment of choice. Because the more aggressive behavior and poor prognosis of FNMTC, a high index of suspicion and a full investigation is required in the presence of a familial component.

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Uso de probióticos en otorrinolaringología

En los humanos las infecciones más frecuentes son las respiratorias, siendo la principal indicación de antibióticos en niños. El uso indiscriminado de antibióticos lleva a la aparición de gérmenes multirresistentes. Uno de los objetivos actuales en salud es la prevención de las enfermedades infecciosas para disminuir el uso de antibióticos. Una estrategia postulada recientemente para prevenir infecciones respiratorias es el uso de probióticos.

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In humans, the most frequent infections are respiratory, being the main indication of antibiotics in children. The indiscriminate use of antibiotics leads to the emergence of multi-resistant germs. One of the current health objectives is the prevention of infectious diseases so we can reduce the use of antibiotics. A potential strategy for preventing respiratory infections is the use of probiotics.

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Superviviencia en cáncer de laringe: A propósito de un artículo

En los humanos las infecciones más frecuentes son las respiratorias, siendo la principal indicación de antibióticos en niños. El uso indiscriminado de antibióticos lleva a la aparición de gérmenes multirresistentes. Uno de los objetivos actuales en salud es la prevención de las enfermedades infecciosas para disminuir el uso de antibióticos. Una estrategia postulada recientemente para prevenir infecciones respiratorias es el uso de probióticos.

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In humans, the most frequent infections are respiratory, being the main indication of antibiotics in children. The indiscriminate use of antibiotics leads to the emergence of multi-resistant germs. One of the current health objectives is the prevention of infectious diseases so we can reduce the use of antibiotics. A potential strategy for preventing respiratory infections is the use of probiotics.

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A Cost Comparison for Telehealth Utilization in the Kidney Transplant Waitlist Evaluation Process.

Background: There have been limited publications on telehealth utilization in transplantation with no prior reports of telehealth-related costs for pretransplant evaluations. The aim of this study is to compare costs throughout the evaluation process for those patients assessed initially by telehealth to those seen in-person. Methods: All patients approved for kidney transplant waitlist evaluation at our center from March 2013 thru May 2016 with decisions were included in this study. Patients approved for evaluation were scheduled for either an initial telehealth or in-person visit, partly based on patient factors. Clinically-related and travel-related costs were calculated. Time estimates for patient time needed to complete visit, time from application approval to initial visit, and time from application approval to decision were obtained. Comparisons were made using t tests. Results: Thirty-nine months were included for 302 patients. All categories of clinically or travel-related costs were significantly less for the telehealth cohort (p

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Refractory Vascular Rejection in a Hand Allograft in the Presence of Antibodies Against Angiotensin II (Type 1) Receptor.

No abstract available

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Gender equity in Transplantation: A Report from the Women in Transplantation Workshop of the Transplantation Society of Australia and New Zealand.

The exponential growth of young talented females choosing science and medicine as their professional career over the past decade is substantial. Currently, more than half of the Australian medical doctoral graduates and early career researchers are comprised of women, but less than 20% of all academic professorial staff are female. The loss of female talent in the hierarchical ladder of Australian academia is a considerable waste of government investment, productivity and scientific innovation. Gender disparity in the professional workforce composition is even more striking within the field of transplantation. Women are grossly under-represented in leadership roles, with currently no female Heads of Unit in any of the Australian and New Zealand Transplanting centres. At the same time, there is also gender segregation with a greater concentration of women in lower-status academic position compared to their male counterparts. Given the extent and magnitude of the disparity, the Women In Transplantation Committee, a subcommittee of the Transplantation Society of Australia and New Zealand established a workshop comprising 8 female clinicians/scientists in transplantation. The key objectives were to i) identify potential gender equity issues within the transplantation workforce, ii) devise and implement potential strategies and interventions to address some of these challenges at a societal level, iii) set realistic and achievable goals to enhance and facility gender equality, equity and diversity in transplantation. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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