Citations

A 72‐year‐old female with a history of idiopathic subglottic tracheal stenosis suffered tracheal rupture during endoscopic balloon dilation. The defect measured 7.5 cm in length, through which the mediastinum was visualized. An 80 × 20‐mm silicone‐covered tracheobronchial stent was deployed over the defect. The patient was extubated subsequent to intraoperative computed tomography demonstrating minimal air escape. Postoperatively, the patient saw no further complications and was discharged 3 days later. The stent was removed 80 days postoperatively revealing healed trachea. Tracheal rupture is a potential risk of balloon dilation, and the list of possible complications is extensive and morbid. Although traditional repair requires an open approach, endoscopic techniques are growing in description, and tracheal stenting was successful in this case. Laryngoscope, 126:2774–2777, 2016

Abstract Background. The salivary gland is one of the most common sites involved by nongastric, extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT). A large series of patients with long-term follow-up has not been documented. This multicenter, international study sought to characterize the clinical characteristics, treatment, and natural history of salivary gland MALT lymphoma. Methods. Patients with biopsy-confirmed salivary gland MALT lymphoma were identified from multiple international sites. Risk factors, treatment, and long-term outcomes were evaluated. Results. A total of 247 patients were evaluated; 76% presented with limited-stage disease. There was a history of autoimmune disorder in 41%, with Sjögren disease being the most common (83%). Fifty-seven percent of patients were initially treated with local therapy with surgery, radiation, or both; 37 of patients were treated with systemic therapy initially, with 47% of those receiving rituximab; and 6% of patients were observed. The median overall survival (OS) was 18.3 years. The median progression-free survival (PFS) following primary therapy was 9.3 years. There was no difference in the outcomes between patients receiving local or systemic therapy in first-line management. On multivariate analysis, age <60 years and low to intermediate international prognostic index were associated with improved OS and PFS; Sjögren disease was associated with improved OS. Conclusion. Salivary gland MALT lymphoma has an excellent prognosis regardless of initial treatment, and patients with Sjögren disease have improved survival. Risks for long-term complications must be weighed when determining initial therapy. Implications for Practice: Patients with salivary gland extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) have an excellent prognosis, particularly those with associated Sjögren's disease. A wide range of available therapies may provide similar durable rates of disease control and survival. Therefore, an important goal in selection of therapy should be to minimize morbidity from treatment. When determining initial therapy for these patients, practitioners should consider the potential side effects and long-term toxicities of treatment.

The gene product affected in cystic fibrosis, the cystic fibrosis transmembrane conductance regulator (CFTR), is a chloride-selective ion channel that is regulated by cAMP-dependent protein kinase-mediated phosphorylation, ATP binding and ATP hydrolysis. Mutations in the CFTR gene may result in cystic fibrosis characterized by severe pathology (e.g. recurrent pulmonary infection, male infertility and pancreatic insufficiency) involving organs expressing the CFTR. Interestingly, in the kidney, where expression of the CFTR has been reported, impaired ion transport in patients suffering from cystic fibrosis could not be observed. To understand the role of the CFTR in chloride transport in the kidney, we attempted to identify an epithelial cell line that can serve as a model. We demonstrate that the CFTR is expressed constitutively in MadineŐDarby canine kidney (MDCK) type I cells, which are thought to have originated from the distal tubule of the dog nephron. We show expression at the mRNA level, using reverse transcriptase-PCR, and at the protein level, using Western blot analysis with three different monoclonal antibodies. Iodide efflux measurements indicate that CFTR expression confers a plasma membrane anion conductance that is responsive to stimulation by cAMP. The cAMP-stimulated iodide release is sensitive to glybenclamide, diphenylamine carboxylic acid and 5-nitro-2-(3-phenylpropylamino)benzoic acid, but not to 4,4ƀ-di-isothiocyanostilbene-2,2ƀ-disulphonic acid, an inhibitor profile characteristic of the CFTR chloride channel. Finally, the polarized localization of the CFTR to the apical plasma membrane was established by iodide efflux measurements and cell-surface biotinylation on MDCK I monolayers. Interestingly, MDCK type II cells, which are thought to have originated from the proximal tubule of the kidney, lack CFTR protein expression and cAMP-stimulated chloride conductance. In conclusion, we propose that MDCK type I and II cells can serve as convenient model systems to study the physiological role and differential expression of CFTR in the distal and proximal tubule respectively.

Abstract Cholangiocarcinoma (CCA) is a malignancy arising from the epithelial cells lining the biliary tract in the liver, the cholangiocytes. While cholangiocytes normally express cilia, we showed that they are significantly reduced in CCA by a mechanism involving overexpression of histone deacetylase 6 (HDAC6), a molecule that deacetylates the ciliary axoneme and promotes ciliary disassembly. Even though HDAC6 protein is overexpressed in CCA, we found no differences in its messenger RNA (mRNA) level, suggesting a post-transcriptional regulation, possibly involving microRNA (miRNA). Therefore, we hypothesized that decreased levels of specific miRNAs induce overexpression of HDAC6 in CCA. We compared miRNA levels between normal and CCA cholangiocyte cell lines and found that three miRNAs potentially targeting HDAC6 are downregulated (40-55% decrease) in CCA: miR-433, miR-22, and miR-200a. Experimental overexpression of miR-433, miR-22, or miR-200a in normal cholangiocytes decreased HDAC6 expression by 82%, 33%, and 39%, respectively. We selected miR-433 and miR-22 for further analysis and the downregulation of both miRNAs were confirmed by qRT-PCR on normal and six different CCA cell lines, and by in situ hybridization on control and CCA human liver samples. To further investigate the dysregulation of these miRNAs, we measured its precursor forms by qRT-PCR and, in contrast to the mature miR-433 and miR-22, the levels of the precursors were increased in malignant cells. In situ hybridization on human samples showed that the miR-433 probe was accumulated in the nucleus of malignant cholangiocytes. Taken together, these data suggested a potential impairment of nuclear export; therefore, we assessed the expression of the protein responsible for transporting microRNA precursors out of the nucleus, exportin-5. By western blotting, we found that exportin-5 is decreased by 50% in five different CCA cell lines compared to normal cholangiocyte cell lines. We confirmed the downregulation of exportin-5 protein by immunofluorescence of normal and CCA human liver samples. Finally, the experimental overexpression of exportin-5 in CCA cell lines restores the precursor and mature forms of these miRNAs to normal levels, inducing a decrease in the expression of HDAC6, and decreased proliferation and anchorage independent growth of the malignant cells. In summary, these data suggest that downregulation of exportin-5, preventing the nuclear export of the precursor forms of miR-433 and miR-22, may be the underlying mechanism explaining the decrease of miR-433 and miR-22, and the overexpression of HDAC6 in CCA. Thus, our work further clarifies the molecular mechanisms accounting for the absence of cilia in CCA and also identifies multiple potential molecules for targeted therapies like HDAC6, miR-433, miR-22, or exportin-5. Citation Format: Maria J. Lorenzo Pisarello, Brynn N. Howard, Christy E. Trussoni, Sergio Gradilone. Exportin-5 downregulation induces miRNA dysregulation and HDAC6 overexpression in cholangiocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 192. doi:10.1158/1538-7445.AM2015-192

A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT–CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in‐depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio = 0.85; 95% confidence interval = 0.80–0.90, p = 8.3 × 10−8). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r2 = 0.07, D′ = 0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p = 3.0 × 10−5), rs4583925 (p = 4.0 × 10−5) and rs2735948 (p = 5.0 × 10−5). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants.

BackgroundWe report the first report of an expansile crista galli (CG) mucocele treated surgically by an endoscopic endonasal approach. Only 1 other case of a CG mucocele has been previously reported in the literature. This was treated by a craniotomy approach.Case ReportWe describe the technique employed in endoscopic marsupialization. We also discuss relevant CG anatomy, pneumatization patterns, surgical approaches, and its potential to cause disease, including CG sinusitis and mucocele formation.ConclusionWe present this case to highlight that the growing experience with endoscopic techniques offer us less morbid and more functional alternatives to a variety of lesions that were once tackled by neurosurgical or external approaches. In the contemporary era, the indications for open approaches and craniotomy for frontal sinus and CG lesions is likely limited. We recommend these patients undergo careful evaluation by a surgeon experienced in advanced endoscopic techniques before being advised to undergo open or craniotomy techniques.

Proinflammatory cytokines differentially regulate adipocyte mitochondrial metabolism, oxidative stress, and dynamics. Macrophage infiltration of adipose tissue and the chronic low-grade production of inflammatory cytokines have been mechanistically linked to the development of insulin resistance, the forerunner of type 2 diabetes mellitus. In this study, we evaluated the chronic effects of TNFα, IL-6, and IL-1β on adipocyte mitochondrial metabolism and morphology using the 3T3-L1 model cell system. TNFα treatment of cultured adipocytes led to significant changes in mitochondrial bioenergetics, including increased proton leak, decreased ΔΨm, increased basal respiration, and decreased ATP turnover. In contrast, although IL-6 and IL-1β decreased maximal respiratory capacity, they had no effect on ΔΨm and varied effects on ATP turnover, proton leak, or basal respiration. Only TNFα treatment of 3T3-L1 cells led to an increase in oxidative stress (as measured by superoxide anion production and protein carbonylation) and C16 ceramide synthesis. Treatment of 3T3-L1 adipocytes with cytokines led to decreased mRNA expression of key transcription factors and control proteins implicated in mitochondrial biogenesis, including PGC-1α and eNOS as well as deceased expression of COX IV and Cyt C. Whereas each cytokine led to effects on expression of mitochondrial markers, TNFα exclusively led to mitochondrial fragmentation and decreased the total level of OPA1 while increasing OPA1 cleavage, without expression of levels of mitofusin 2, DRP-1, or mitofilin being affected. In summary, these results indicate that inflammatory cytokines have unique and specialized effects on adipocyte metabolism, but each leads to decreased mitochondrial function and a reprogramming of fat cell biology.