Discovery of MK-4688: an Efficient Inhibitor of the HDM2-p53 Protein-Protein Interaction.

Identification of low-dose, low-molecular-weight, drug-like inhibitors of protein-protein interactions (PPIs) is a challenging area of research. Despite the challenges, the therapeutic potential of PPI inhibition has driven significant efforts toward this goal. Adding to recent success in this area, we describe herein our efforts to optimize a novel purine carboxylic acid-derived inhibitor of the HDM2-p53 PPI into a series of low-projected dose inhibitors with overall favorable pharmacokinetic and physical properties. Ultimately, a strategy focused on leveraging known binding hot spots coupled with biostructural information to guide the design of conformationally constrained analogs and a focus on efficiency metrics led to the discovery of MK-4688 (compound 56), a highly potent, selective, and low-molecular-weight inhibitor suitable for clinical investigation.

Sinonasal quality of life outcomes following laser treatment of epistaxis related to hereditary hemorrhagic telangiectasia.

Hereditary hemorrhagic telangiectasia (HHT) is an inherited vascular disorder which manifests as recurrent, episodic, and potentially debilitating epistaxis. In this study, we aim to (1) characterize baseline sinonasal symptoms for HHT patients and to (2) analyze changes in sinonasal symptoms before and after laser surgical treatment for HHT. We performed a retrospective chart review of sinonasal outcome test-22 (SNOT-22) scores before and after one or more laser surgical treatments for HHT-related epistaxis between January 1, 2010 and December 1, 2015 at a tertiary academic medical center with an HHT Foundation-approved Center of Excellence. Preoperative and all subsequent postoperative SNOT-22 scores (short-term, <45 days and long-term, ≥45 days) were compared. Twenty consecutive HHT patients underwent 51 laser surgeries for recurrent epistaxis. Mean preoperative, short-term postoperative, and long-term postoperative SNOT-22 scores were 34.6 ± 5.4, 33.9 ± 5.5, and 18.8 ± 4.6, respectively. When analyzing subcategory scores, there was a significant improvement in the rhinologic domain from short-term to long-term postoperatively (13.5 vs. 7.3; p = 0.004), in the non-rhinologic otolaryngic domain from short-term to long-term postoperatively (2.8 vs. 1.7; p = 0.014), and in the psychological domain from preoperative and short-term postoperative to long-term postoperatively (12.2 and 10.0 vs. 6.0; p = 0.015 and 0.01, respectively). Following laser surgery for HHT-related epistaxis, patients' rhinologic symptoms worsened on the short run postoperatively but improved over time. The main benefit of laser treatment appears to be long-term improvement in psychological factors. This study once again underscores the important role of the otolaryngologist in managing sinonasal manifestations of HHT.

Nasoorbital Osteoma Presenting as Valsalva-Induced Orbital Emphysema.

An 18-year-old female athlete with a history of multiple traumatic concussions presented with complaints of recurrent bouts of right periorbital swelling that arose with Valsalva maneuvers such as nose-blowing or sneezing. The swelling resolved over hours to days. A CT scan of the sinuses revealed an osteoma originating from the right ethmoid roof involving the frontal recess and projecting into the orbit. She underwent excision of the osteoma via endoscopic transnasal and transcaruncular anterior orbitotomy approaches without complication.

Proton pump inhibitors decrease eotaxin-3/CCL26 expression in patients with chronic rhinosinusitis with nasal polyps: Possible role of the nongastric H,K-ATPase.

BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is often characterized by tissue eosinophilia that is associated with poor prognosis. Recent findings that proton pump inhibitors (PPIs) directly modulate the expression of eotaxin-3, an eosinophil chemoattractant, in patients with eosinophilic diseases suggest therapeutic potential for PPIs in those with CRSwNP. OBJECTIVE: We assessed the effect of type 2 mediators, particularly IL-13 and eotaxin-3, on tissue eosinophilia and disease severity in patients with chronic rhinosinusitis (CRS). Further investigation focused on PPI suppression of eotaxin-3 expression in vivo and in vitro, with exploration of underlying mechanisms. METHODS: Type 2 mediator levels in nasal tissues and secretions were measured by using a multiplex immunoassay. Eotaxin-3 and other chemokines expressed in IL-13-stimulated human sinonasal epithelial cells (HNECs) and BEAS-2B cells with or without PPIs were assessed by using ELISA, Western blotting, real-time PCR, and intracellular pH imaging. RESULTS: Nasal tissues and secretions from patients with CRSwNP had increased IL-13, eotaxin-2, and eotaxin-3 levels, and these were positively correlated with tissue eosinophil cationic protein levels and radiographic scores in patients with CRS (P < .05). IL-13 stimulation of HNECs and BEAS-2B cells dominantly induced eotaxin-3 expression, which was significantly inhibited by PPIs (P < .05). Patients with CRS taking PPIs also showed lower in vivo eotaxin-3 levels compared with those without PPIs (P < .05). Using intracellular pH imaging and altering extracellular K+, we found that IL-13 enhanced H+,K+-exchange, which was blocked by PPIs and the mechanistically unrelated H,K-ATPase inhibitor, SCH-28080. Furthermore, knockdown of ATP12A (gene for the nongastric H,K-ATPase) significantly attenuated IL-13-induced eotaxin-3 expression in HNECs. PPIs also had effects on accelerating IL-13-induced eotaxin-3 mRNA decay. CONCLUSION: Our results demonstrated that PPIs reduce IL-13-induced eotaxin-3 expression by airway epithelial cells. Furthermore, mechanistic studies suggest that the nongastric H,K-ATPase is necessary for IL-13-mediated epithelial responses, and its inhibitors, including PPIs, might be of therapeutic value in patients with CRSwNP by reducing epithelial production of eotaxin-3.

Using fixed anatomical landmarks to avoid medial rectus injury: a radiographic analysis in patients with and without Graves' disease.

BACKGROUND: Injury to the medial rectus (MR) is a potentially devastating complication of orbital and sinus surgery. Precise knowledge of the MR relative to the lamina papyracea (LP) is important during endoscopic surgery for both Graves' ophthalmopathy and inflammatory disease. The objective of this study is to determine the location of the MR in relation to easily identified and frequently encountered intranasal landmarks in patients with and without Graves' disease. METHODS: High-resolution computed tomography scans were analyzed in 100 controls and 63 patients with Graves' disease. The MR position was recorded relative to the maxillary sinus ostium (MSO), anterior ethmoid artery (AEA), and posterior ethmoid artery (PEA)/horizontal basal lamella (BL). Clinically relevant variables recorded at each level included the Keros stage, AEA position, MR height, and distance of the MR to orbital floor, skull base, and LP. RESULTS: The mean distances between the MR and LP were statistically different for both groups. Controls at the MSO, AEA, and PEA/BL were 2.92, 1.69, and 1.06mm; for Graves' patients measurements at these sites were 2.12, 1.20, and 0.029mm. When comparing the two groups, each of these distances were statistically significant (p<0.02). There was no difference in ethmoid cavity width (p>0.05) between controls (9.66mm) and Graves' patients (9.70mm). Sex, age, and skull base depth were not statistically significant factors. CONCLUSION: This study illustrates the position of the MR from the perspective of an endoscopic surgeon utilizing fixed intranasal landmarks. Knowledge of the position of MR is critical to safely perform decompression surgery and when operating adjacent to the LP during endoscopic surgery.

A pilot study of symptom profiles from a polyp vs an eosinophilic-based classification of chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis (CRS) is likely a biologically heterogeneous disease process. Current guidelines propose subclassification using polyp status while others propose using mucosal eosinophilia. We hypothesized that appropriate CRS subclassification would increase homogeneity of baseline symptoms, and identify characteristic symptoms of each subtype. METHODS: A total of 57 CRS patients undergoing surgery prospectively completed a preoperative battery of 73 questions relating to symptoms including the 22-item Sino-Nasal Outcome Test (SNOT-22) and 29-item Patient-Reported Outcomes Measurement Information System (PROMIS-29) general quality of life (QOL) measures. Eosinophilic cationic protein (ECP) levels were determined from ethmoid, uncinate, and polyp tissue homogenates using enzyme-linked immunosorbent assay (ELISA) and normalized to total protein. Patients were classified as eosinophilic (eCRS) or non-eosinophilic (neCRS) using a 95th percentile threshold established from control tissue from 82 patients without CRS. Separate pairwise comparisons were performed on patient-reported symptoms using polyp and eosinophilic status. RESULTS: Of the 57 patients, 28 had CRS with nasal polyps (CRSwNP); 27 of 57 patients had eCRS (CRSwNP, n = 21; CRS without nasal polyps [CRSsNP], n = 6). CRSwNP patients had increased need to blow nose, frequency of nasal congestion, more severe difficulty breathing through nose, more severe nasal discharge, but less cough (p < 0.05). eCRS patients had more bothersome loss of taste/smell, ear pain, sneezing, severe difficulty breathing through nose, and severe nasal congestion compared to neCRS patients (p < 0.05). CONCLUSION: Subclassifying CRS with symptoms alone is difficult with neither polyp status nor eosinophilia giving a distinctive clinical symptom profile. However, certain symptoms may help otolaryngologists identify CRS subtypes, which may help guide future treatments. Further validation and evaluation of prognosis following treatment is required to evaluate appropriate means of subclassifying CRS.

Olfaction in Endoscopic Sinus and Skull Base Surgery.

Olfactory dysfunction is a common complaint for patients with chronic rhinosinusitis, because smell loss decreases a patient's quality of life. Smell loss is caused by obstruction from polyps, nasal discharge, and mucosal edema, as well as inflammatory changes within the olfactory epithelium. Addressing olfaction before endoscopic sinus and skull base surgery is important in order to set postoperative expectations, because an improvement in smell is difficult to predict. Several commercially available olfactory testing measures are available and can easily be administered in clinic. During surgery, careful dissection within the olfactory cleft is recommended in order to optimize postoperative olfactory function.

Inverted papilloma of the sphenoid sinus: risk factors for disease recurrence.

OBJECTIVES/HYPOTHESIS: Surgical treatment of inverted papilloma (IP) of the sphenoid sinus is complicated by close proximity to vital structures of the skull base. Identifying the site of tumor attachment and achieving complete removal can be challenging compared to IP at other sites. The objective of this study is to illustrate the clinical presentation, management, and risk factors for tumor recurrence for sphenoid IP. STUDY DESIGN: Retrospective study. METHODS: A multi-institutional, retrospective review of endoscopic resections of IP based within the sphenoid sinus was performed from 1996 to 2014. Demographic and tumor data, operative notes, complications, and recurrence rates were collected. Statistical analysis was performed to identify risk factors for tumor recurrence. RESULTS: Forty-eight patients (31 males, 17 females) were identified. Mean age was 57 years, with a median follow-up of 13.6 months (range 6.8-36). Rate of tumor recurrence was 14.6%, with median time to recurrence of 13.1 months. Patients with dysplasia/carcinoma in situ (CIS) had a 3.6 greater rate of recurrence (RR) compared to patients with no dysplasia, approaching significance (RR = 3.6; P = 0.08). Patients with IP attachment sites overlying the optic nerve or carotid artery had a 4.76 greater rate of recurrence compared to other sites (RR = 4.76; P = 0.073). CONCLUSION: Sphenoid sinus IP is associated with a 14.6% rate of recurrence after surgery. Potential risk factors for tumor recurrence identified in this study include attachment sites over the optic nerve and carotid artery or evidence of dysplasia or CIS. Close follow-up in the postoperative period is essential for these patients to monitor for tumor recurrence.

What is the optimal maxillary antrostomy size during sinus surgery?

PURPOSE OF REVIEW: To review all the journal articles relevant to chronic maxillary sinusitis in order to discuss the optimal size of maxillary antrostomy during endoscopic sinus surgery. RECENT FINDINGS: Although endoscopic maxillary antrostomy is a longstanding and frequently performed procedure, there is limited evidence about the optimal size of the antrostomy. Commonly employed surgical options include dilation via balloon sinuplasty, traditional antrostomy with uncinectomy using forceps and powered microdebriders, enlargement of the natural ostium, and the mega-antrostomy or modified medial maxillectomy. Historically, inferior antrostomies or nasal-antral windows were commonly utilized in the preendoscopic era, although this procedure is less commonly used today. SUMMARY: Balloon sinuplasty can be effective in dilating the ethmoid infundibulum and natural ostium for select patients with isolated maxillary sinusitis or mild disease. A standard antrostomy using biting forceps and powered instrumentation is more appropriate for advanced disease such as severe mucosal hyperplasia or nasal polyps, as it allows for visualization of the maxillary sinus cavity and more effective topical delivery of saline irrigations and medications. For recalcitrant maxillary sinusitis, the mega-antrostomy allows for gravity-dependent drainage and is most appropriate for patients with inherent mucociliary defects.

Single Diastereomer of a Macrolactam Core Binds Specifically to Myeloid Cell Leukemia 1 (MCL1).

A direct binding screen of 100 000 sp(3)-rich molecules identified a single diastereomer of a macrolactam core that binds specifically to myeloid cell leukemia 1 (MCL1). A comprehensive toolbox of biophysical methods was applied to validate the original hit and subsequent analogues and also established a binding mode competitive with NOXA BH3 peptide. X-ray crystallography of ligand bound to MCL1 reveals a remarkable ligand/protein shape complementarity that diverges from previously disclosed MCL1 inhibitor costructures.

Oncologic validity of recipient vessel preservation in microvascular free-flap reconstruction.

OBJECTIVES: The use of free-flap reconstruction requires a more limited neck dissection to allow for microvascular anastomosis. This study seeks to determine the oncologic validity of cervical vessel preservation. MATERIALS AND METHODS: The current study is a prospective review of cervical vessel biopsies from patients undergoing resection of squamous cell carcinoma (SCCA) tumors of the head and neck with free tissue reconstruction. RESULTS: From June 2010 to March 2012, 227 recipient vessel biopsies were performed on 100 patients. Three of these patients had grossly abnormal vessels, with malignancy confirmed by frozen section analysis. One patient had a vessel positive for malignancy that was grossly normal but found to have SCCA on the final pathology. CONCLUSIONS: When the recipient vessel appears grossly suspicious, a frozen section biopsy and re-resection should be considered. Recipient vessel trimmings should routinely be sent for permanent pathology since in rare cases, they can be involved by tumor, affecting the margin status, prognosis, and indications for adjuvant therapy.

Modifications to the endoscopic approach for anterior skull base lesions improve postoperative sinonasal symptoms.

Background/Objective Our institution previously showed that patients experience significant postoperative sinonasal symptoms for the first few months after endoscopic transnasal transsphenoidal skull base surgery (eTNTS). Since our initial study we have modified our technique, discontinuing routine resection of the middle turbinate, maxillary antrostomies, and nasoseptal flaps. In this study, we analyze whether these technical modifications decrease postoperative sinonasal morbidity after eTNTS. Methods A retrospective review was performed of 93 consecutive patients who underwent eTNTS at a tertiary academic medical center from August 2011 to August 2012. Main Outcome Measures Sino-Nasal Outcome Test (SNOT)-20 and SNOT-22 scores preoperatively and after surgery. Results Compared with our previous study, our new cohort experienced a significant improvement (p < 0.05) in SNOT scores for the need to blow nose, runny nose, postnasal discharge, thick nasal discharge, wake up at night, reduced concentration, and frustrated/restless/irritable. Within the new cohort, patients who did not have a nasoseptal flap or middle turbinate resection had less worsening and faster improvement of nasal symptom scores after surgery. Conclusions Preserving normal sinonasal physiology during eTNTS by limiting middle turbinate resections, avoiding unnecessary maxillary antrostomies, and reducing the use of nasoseptal flaps when feasible results in less sinonasal morbidity and more rapid recovery during the postoperative period.

Invasive fungal sinusitis in a healthy athlete due to long-term anabolic steroid use.

Invasive fungal rhinosinusitis is a potentially fatal infection that affects immunocompromised patients. Prognosis is generally poor despite aggressive medical and surgical treatments. We present the first reported case of invasive fungal sinusitis in a healthy 18-year-old male athlete who was taking anabolic androgenic steroids (AAS). The effects of excessive AAS use on the immune system are not fully understood, but there may be consequences at supraphysiological concentrations. This case demonstrates potential immunomodulatory effects of anabolic steroids and highlights a previously unknown cause of invasive fungal sinusitis.

Solitary fibrous tumor of the hypopharynx: case report and literature review.

Solitary fibrous tumors are rare mesenchymal neoplasms that are increasingly being described in the head and neck. Clinical presentations may include compression by these tumors on vital surrounding structures. While malignant transformation is rare, treatment entails wide local excision. We present the case of a 74 year-old female with an increasingly enlarging symptomatic hypopharyngeal solitary fibrous tumor that was found on carotid duplex ultrasound. Transoral surgical excision resulted in relief of symptoms. Treatment options are discussed and a literature review of this uncommon disorder presented.

Systematic review and meta-analysis of total intravenous anesthesia and endoscopic sinus surgery.

BACKGROUND: Total intravenous anesthesia (TIVA) has been shown in some studies to impact visual field, blood loss, and cardiovascular parameters during endoscopic sinus surgery when compared to inhalational anesthesia (IA). These variables are critical in endoscopic sinus surgery. A systematic review and meta-analysis was undertaken to discern the impact of TIVA vs IA in endoscopic sinus surgery. METHODS: MEDLINE (1950 to October 20, 2012) was searched using a search strategy designed to include all randomized controlled trials (RCTs) that discussed TIVA, IA, and endoscopic sinus surgery. An abstract search was then used to identify RCTs directly comparing TIVA and IA in endoscopic sinus surgery. All articles selected then underwent full-text review. Data on visual field scores, blood loss, and cardiovascular parameters was then extracted, compared, and analyzed. RESULTS: There were 42 articles identified by the search strategy. Full-text review identified 9 articles that met eligibility criteria and contained extractable data. Although inconsistently reported, preoperative characteristics (Lund-Mackay scores and history of nasal polyps) were similar (p > 0.05) between the 2 groups. No difference was found between heart rate, mean arterial pressure, anesthesia time, operative time, or estimated blood loss. Only 7 studies reported a visibility score, but overall favored the TIVA group (p < 0.001). CONCLUSION: Current evidence supporting TIVA is limited to a handful of inconsistently controlled and reported studies. Standardized grading of visibility scores and preoperative characteristics would better establish the role of TIVA in endoscopic sinus surgery.

Mini-nasoseptal flap for recalcitrant sphenoid sinusitis.

BACKGROUND: Recalcitrant sphenoid sinusitis occurs in 27% of patients undergoing revision functional endoscopic sinus surgery. One of the main causes of disease recurrence in the sphenoid is cicatricial scarring of the ostium. Highly inflammatory lesions such as fungal balls or chronic mucoceles can predispose patients to restenosis. We present a novel use of a modified nasoseptal flap to cover exposed bone after sphenoid wide sinusotomy to prevent restenosis and expedite healing. METHODS: A case series was performed. RESULTS: The mini-nasoseptal flap was successful in preventing sphenoid ostium restenosis in nine patients undergoing endoscopic sinus surgery for highly inflammatory sphenoid sinus pathology with a mean postoperative follow-up of 8.4 months (range, 2-21 months). Patients had a mean of 2.3 prior sinus surgeries (range, 0-7 surgeries). Most common indications for the flap in this series included long-standing fungal sinusitis or fungal balls (n = 6) with or without significant sphenoid wall osteoneogenesis (n = 6). There were no significant side effects related to flap harvest or inset. CONCLUSION: The mini-nasoseptal flap decreases the risk of restenosis after sphenoid sinusotomy by preventing circumferential cicatricial scarring and offers an effective surgical option on the spectrum of sphenoid surgical interventions in select patients.

Sinonasal rhabdomyosarcoma: prognostic factors and treatment outcomes.

BACKGROUND: Despite the improvement in survival of pediatric patients with rhabdomyosarcoma, the outcome of patients with sinonasal rhabdomyosarcoma is poor and has not significantly changed. Since few institutions have extensive experience with sinonasal rhabdomyosarcoma in children and adults, our objective was to determine prognostic factors and treatment outcomes for this rare malignancy. METHODS: A retrospective review was performed of consecutive patients with sinonasal rhabdomyosarcoma treated at our institution from 1992 to 2012. Kaplan-Meier estimates and the log-rank test were performed to determine factors associated with disease recurrence and disease-specific survival. RESULTS: Initial remission was achieved in 12 of the 16 patients. Age younger than 18 years (n = 9) was a positive prognostic factor, as there were no recurrences (p < 0.01) and no deaths (p < 0.01). The alveolar subtype was a poor prognostic factor, as 4 of the 5 patients with this histology died of disease (p < 0.01), and both patients with initial remission developed recurrence (p < 0.01). Presentation with later tumor-node-metastasis classification of malignant tumors (TNM) stage was also significant for poorer survival, as 2 of the 3 patients with stage IV died of disease (p = 0.05). Patient sex and treatment modality were not significant. CONCLUSION: Although the sinonasal region is an unfavorable site for rhabdomyosarcomas, in our series patients younger than 18 years and those with embryonal or botryoid subtypes responded very well to current multimodality treatment. However, a poor prognostic trend is evident in patients with sinonasal alveolar rhabdomyosarcomas, as they appear to present more often with regional and distant metastases, have increased recurrence, and decreased survival.

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.

Incidence and management of epistaxis after endoscopic skull base surgery.

BACKGROUND/AIMS: Endonasal endoscopic surgery continues to gain acceptance as a minimally invasive, effective approach for benign and malignant pathology of the paranasal sinuses and skull base. Postoperative epistaxis could potentially result in rapid and devastating consequences due to hemorrhage. Our objective was to assess the incidence and causes of epistaxis after endoscopic skull base surgery. METHODS: Retrospective review of patients undergoing endoscopic skull base surgeries from 2007 to 2012. The main outcome measure was epistaxis requiring a visit to a hospital or clinic occurring within 30 days of surgery. RESULTS: In our cohort of 330 consecutive patients, 10 (3%) experienced postoperative epistaxis, including 3 who had multiple episodes (14 events). A majority of the patients were controlled with packing in the emergency room (8/14 events). One patient required chemical cautery and 5 required control in the operating room. The only patient characteristic that reached significance was abstinence from alcohol (p value = 0.04). However, patients with epistaxis were more likely to be male, older and have hypertension. CONCLUSION: This study confirms that the risk of epistaxis after endoscopic skull base surgery is low and similar to sinonasal surgery for inflammatory conditions.