Darshni Vira

Cancer stem cells, microRNAs, and therapeutic strategies including natural products

Embryonic stem cells divide continuously and differentiate into organs through the expression of specific transcription factors at specific time periods. Differentiated adult stem cells on the other hand remain in quiescent state and divide by receiving cues from the environment (extracellular matrix or niche), as in the case of wound healing from tissue injury or inflammation. Similarly, it is believed that cancer stem cells (CSCs), forming a smaller fraction of the tumor bulk, also remain in a quiescent state. These cells are capable of initiating and propagating neoplastic growth upon receiving environmental cues, such as overexpression of growth factors, cytokines, and chemokines. Candidate CSCs express distinct biomarkers that can be utilized for their identification and isolation. This review focuses on the known and candidate cancer stem cell markers identified in various solid tumors and the promising future of disease management and therapy targeted at these markers. The review also provides details on the differential expression of microRNAs (miRNAs), and the miRNA- and natural product-based therapies that could be applied for the treatment of cancer stem cells.

Schneiderian papillomas: comparative review of exophytic, oncocytic, and inverted types.

Background Sinonasal papillomas are benign epithelial neoplasms arising from Schneiderian mucosa. The three subtypes, exophytic, oncocytic, and inverted (inverted papilloma [IP]), should be distinguished from one another histopathologically. This study (1) highlight the histopathological and clinical differences between the Schneiderian papilloma subtypes and (2) identifies clinical features that potentially predict papilloma subtypes. Methods A retrospective review was performed of patients with Schneiderian papillomas over an 11-year period. Results Seventy patients with sinonasal papillomas who underwent sinus surgery were identified. There were 50 (71%) male and 20 (29%) female subjects diagnosed at an average age of 53 years (range, 13–80 years). Exophytic (n = 25), oncocytic (n = 9), and IP (n = 37) were identified. IP was associated with transformation into squamous cell carcinoma in three (8%) cases and dysplasia in three (8%) cases. Neither oncocytic nor exophytic subtypes were associated with dysplasia or malignancy. On multivariate analysis of potential predictors of papilloma subtype, history of chronic rhinosinusitis (CRS) and location of papilloma were significantly associated with papilloma subtype. Using classification and regression tree model, papilloma subtypes can be predicted based on presence or absence of CRS and papilloma location with nominal 82.4% accuracy. Conclusion The inverted and exophytic type are the most common sinonasal papillomas, with the inverted type having an 8% rate of malignant transformation in this study. In contrast, the oncocytic type was not associated with dysplasia or malignancy in our series despite reports in the literature indicating malignant potential. History of CRS and papilloma location can provide clues to the histological subtype, which is important for surgical planning and patient counseling.

Respiratory epithelial adenomatoid hamartomas

The aim of this study was to understand the definition of respiratory epithelial adenomatoid hamartoma (REAH) and the association between REAH and chronic sinusitis and nasal polyposis, and to describe the histology and management of REAH.

Adenoviral-encoded antigens are presented efficiently by a subset of dendritic cells expressing high levels of αvβ3 integrins

Dendritic cells (DC) play a central role in antigen presentation and are often targeted by adenoviral (Ad)‐based gene therapy. However, DC lack the coxsackie‐Ad receptor, and little is known about the process by which they acquire and present Ad‐encoded antigens. We examined the expression of ανβ3 integrins (CD51/CD61) on mouse bone marrow‐derived DC (BM‐DC) and their susceptibility to transduction by Ad vectors. Less than 10% of BM‐DC precursors expressed CD51, but expression increased over time in culture with granulocyte macrophage‐colony stimulating factor (GM‐CSF)/interleukin (IL)‐4. After 7 days, 28 ± 1.7% of CD11c+ DC expressed high levels of CD51 (CD51hi), and the remaining DC expressed low levels of CD51 (CD51lo). CD51hi CD express higher major histocompatibility complex type 1 (MHC I); however, both of the DC subsets expressed similar levels of MHC II and costimulatory molecules. When exposed to a first‐generation Ad vector, transgene expression was restricted to the CD51hi DC subset and blocked by soluble peptides expressing an arginine, glycine, aspartic acid (RGD) sequence, confirming the role of integrins in viral entry. Consistent with this, a modified Ad expressing an RGD‐binding sequence in its fiber knob (Ad‐RGD) transduced the CD51hi DC subset with significantly higher efficiency. When BM‐DC were transduced with an Ad‐expressing ovalbumin (Ad‐OVA), the CD51hi subset proved superior in activating OT‐I (T cell receptor‐OVA) T cells. Similar to in vitro effects, systemic administration of GM‐CSF/IL‐4 increased the expression of CD51 on splenic DC and rendered these cells susceptible to Ad transduction. These results suggest that a limited subset of DC expressing high levels of ανβ3 integrins is preferentially transduced by Ad vectors and activates CD8+ T cell responses against Ad‐encoded antigens.

Airway Management and Endoscopic Treatment of Subglottic and Tracheal Stenosis The Laryngeal Mask Airway Technique

Objectives: The objective is to present clinical outcomes of subglottic and tracheal stenosis treated by flexible bronchoscopic delivery of carbon dioxide (CO2) laser via laryngeal mask airway (LMA). Methods: All consecutive, nontracheotomy dependent cases of subglottic and tracheal stenosis treated endoscopically over a 4-year period were retrospectively reviewed. The surgical approach consisted of radial incisions using a flexible fiber-based CO2 laser, balloon dilation, and topical application of mitomycin C. Ventilation during the procedure occurred through the LMA, and the CO2 laser fiber was delivered through the working channel of a flexible bronchoscope passed through the LMA. Number of dilations, period between dilations, and operative times were reviewed. Results: Eleven patients who underwent airway intervention during the study period were identified. Average follow-up was 28 months. Etiologies of airway stenosis included intubation injury (6), idiopathic (4), or autoimmune disease (1), requiring an average of 1.3, 1.5, and 3 dilations, respectively. Average operative time was 67 minutes. Autoimmune etiology correlated with more frequent dilations. Conclusion: LMA is an effective way to manage ventilation while simultaneously allowing unencumbered flexible bronchoscopic access for laser surgery, balloon dilation, and mitomycin C application for airway stenosis. Long-term success in treating stenosis is achievable using this technique.

p16 Protein and gigaxonin are associated with the ubiquitination of NFκB in cisplatin-induced senescence of cancer cells.

Background: Molecular mechanism of p16-mediated cellular senescence in cisplatin-treated cells is not known. Results: Cisplatin treatment leads to p16 nuclear transport and association with gigaxonin for the ubiquitination of NFκB. Conclusion: A protein associated with neural diseases is involved in cisplatin-mediated cellular senescence. Significance: Nuclear expression of p16 and gigaxonin is a useful marker of cancer cell chemosensitivity. The molecular mechanism of p16-mediated senescence in cisplatin-treated cancer cells is not fully understood. Here we show that cisplatin treatment of head and neck cancer cells results in nuclear transport of p16 leading to a molecular modification of NFκB. Chromatin immunoprecipitation assays show that this modification is associated with the inhibition of NFκB interacting with its DNA binding sequences, leading to decreased expression of NFκB-transcribed proteins. LCMS proteomic analysis of LAP-TAP-purified proteins from HeLa cells containing a tetracycline-inducible GFP-S peptide-NFκB expression system identified gigaxonin, an ubiquitin E3 ligase adaptor, as an NFκB-interacting protein. Immunoblotting and siRNA studies confirmed the NFκB-gigaxonin interaction and the dependence of this binding on p16-NFκB binding. Using gel shift assays, we have confirmed p16-NFκB and gigaxonin-NFκB interactions. Furthermore, we have observed increased NFκB ubiquitination with cisplatin treatment that is abolished in the absence of p16 and gigaxonin expression. Analysis of 103 primary tumors has shown that increased nuclear p16 expression correlates with enhanced survival of head and neck cancer patients (p < 0.0000542), indicating the importance of nuclear p16 expression in prognosis. Finally, p16 expression is associated with reduced cytokine expression and the presence of human papilloma virus in chemoradiation-sensitive basaloid tumors. However, the absence of p16 expression is associated with enhanced cytokine expression and the absence of human papilloma virus in aggressive tumors. These results clearly demonstrate that nuclear p16 and gigaxonin play an important role in chemosensitivity of head and neck cancers through ubiquitination of NFκB.

Endoscopic management of supraglottic laryngopharyngeal stenosis.

S tenosis of the supraglottic larynx and pharynx is an uncommon and difficult condition to treat. The most common etiologies include iatrogenic injury from oropharyngeal and supraglottic surgery, radiation therapy, prolonged intubation, trauma, caustic ingestion, and inflammatory diseases. Presenting symptoms are a function of stenosis severity and can range from dysphagia and dysphonia to potentially life-threatening airway obstruction. The optimal treatment of supraglottic laryngopharyngeal stenosis remains unclear. Historically, supraglottic stenosis was treated with open supraglottic laryngectomy. However, this was accompanied by high morbidity related to chronic aspiration and poor wound healing. More conservative techniques with reduced morbidity have recently gained favor, especially for subglottic and tracheal stenosis.We have adapted these endoscopic techniques to manage supraglottic laryngopharyngeal stenosis to provide long-term airway patency. In this report, we present our management of a series of patients using scar-releasing CO2 laser incisions of the lateral supraglottic laryngopharynx, combined with controlled radial balloon dilation and mitomycin C application as adjunctive treatment.

Neck mass due to pedicle ossification after oromandibular reconstruction

To determine the radiographic incidence of heterotopic ossification and the clinical incidence of neck masses secondary to heterotopic ossification in a series of patients who underwent fibula free flap oromandibular reconstruction.

Radiologic Assessment of the Paranasal Sinuses after Endoscopic Skull Base Surgery

Objectives To identify sinuses demonstrating postoperative radiographic mucosal thickening after endoscopic exposure of the cranial base through the transsphenoidal corridor. Design Retrospective review. Setting University-based medical center. Participants Patients undergoing endoscopic transnasal transsphenoidal approaches to the skull base who had both preoperative and postoperative imaging. Main Outcome Measures Change in preoperative and postoperative imaging scores for each sinus and side at 3 and 6 months. The left-sided undissected sinuses served as internal controls for comparison. Results Fifty-one patients were identified with the aforementioned inclusion and exclusion criteria. The mean difference in preoperative and postoperative imaging scores for the right anterior ethmoid sinus was significantly different from the left-sided equivalents (p = 0.0020). The difference in the frontal sinuses approached significance (p = 0.0625). Conclusions Resection of the lower half of the middle turbinate and maxillary antrostomy and harvest of a nasoseptal flap are associated with an increased radiographic incidence of mucosal thickening of the ipsilateral anterior ethmoids compared with the undissected contralateral side. When accessing the transnasal transsphenoidal corridor for skull base surgery, preservation of native anatomy is associated with a lower incidence of mucosal thickening on postoperative imaging.

Parotidectomy and neck dissection in the management of conjunctival melanoma: Are they necessary?†‡

The objectives of this study were to review traditional techniques for the management of conjunctival melanoma and assess the need for parotidectomy and neck dissection in the management of conjunctival melanoma.