Does Reinke's Edema Grade Determine Premalignant Potential?

OBJECTIVE: Reinke's edema (RE) is a benign disease of the vocal folds with a wide spectrum of clinical severity. We aim to evaluate the clinical impact of RE grade and determine if RE grade correlates with severity of dysplasia and tobacco exposure. METHODS: Patients with isolated RE who underwent surgical excision between December 2010 and December 2014 were retrospectively reviewed. The RE grade was determined from archived laryngeal videostroboscopy exams. Pathologic severity of dysplasia, categorized by squamous intraepithelial neoplasia (SIN) classification, and tobacco history were extracted from medical records. RESULTS: Of 95 lesions, 3 (3.16%) were RE grade 1, 33 (34.74%) were RE grade 2, 24 (25.26%) were RE grade 3, and 35 (36.84%) were RE grade 4. Fifty-nine lesions (62.11%) had no dysplasia (SIN0), 19 (20.00%) had mild dysplasia (SIN1), 15 (15.79%) had moderate dysplasia (SIN 2), and 2 (2.11%) had severe dysplasia (SIN3). The 2 patients with severe dysplasia had grade 4 lesions. No statistical correlation was identified between RE grade and the severity of dysplasia. Furthermore, no statistical correlation was seen between tobacco exposure and the severity of dysplasia or the RE grade. CONCLUSIONS: Size of RE lesion does not reflect premalignancy. The majority of RE lesions, regardless of size, have little to no premalignant potential. Severe dysplasia/carcinoma in situ may be more likely seen in grade 4 lesions; however, the paucity of severe dysplasia published in RE data and in this cohort preclude any formal inference. Further study of grade 4 lesions is warranted.

Pressure and Flow Comparisons Across Vocal Pathologies.

OBJECTIVE: The aim of this study was to aid in the distinction among hyperadductive dysphonias by evaluating peak glottal pressure, release burst, and mid and final airflow values across repeated /pa/ syllable trains. METHODS: Sixty subjects were assessed for aerodynamic patterns during onset-offset for the /papapapapa/ task in modal voice. Subject groups included adductory spasmodic dysphonia (AdSD), benign vocal fold lesion, primary muscle tension dysphonia (MTD-1), secondary muscle tension dysphonia with an identifiable primary benign vocal fold lesion (MTD-2), vocal fold paresis or paralysis, and normal controls. RESULTS: Increased peak pressure (PP) was found for AdSD and MTD-2 subjects compared with controls. Release burst and mid airflow were not significantly different among groups. Final airflow was significantly higher for AdSD compared with the other groups. Final airflow was significantly lower for MTD-1. CONCLUSIONS: Significant differences in aerodynamics are seen in subjects with AdSD compared to MTD. AdSD was characterized by higher PP and higher final airflow. MTD-1 was characterized by lower final airflow, whereas MTD-2 was characterized by higher PP. Aerodynamic evaluation may aid in differential diagnosis for those patients in whom distinction among hyperadductive disorders is challenging.

Clinical grading of Reinke's edema.

OBJECTIVE: Reinke's edema (RE) is a pathologically benign structural change of the vocal folds with a wide spectrum of clinical severity. We aim to propose and validate a clinical grading system based on size of the lesion to facilitate effective universal communication of disease severity. STUDY DESIGN: Retrospective review. METHODS: Patients diagnosed with RE exclusive of other glottic pathology between December 2010 and December 2014 were included. Sixty laryngoscopy photographs were extracted from recorded archived laryngeal videostroboscopy exams, blinded and graded by four laryngologists with experience diagnosing RE. RESULTS: A high degree of agreement among all four raters was demonstrated by high interclass correlation coefficients with a 95% confidence interval. Similarly, high intra-rater reliability was seen across all raters. Forty-nine (33%) lesions were grade 1. Thirty-five lesions (29.17%) were grade 2; 18 (15%) lesions were grade 3; and nine (7.5%) lesions were grade 4. Contralateral vocal fold was not graded in cases of grade 4. CONCLUSION: This clinical grading for RE is a reliable tool for conveying severity of disease. High inter- and intra-rater reliability strongly suggest that RE similarly can be graded by different raters, and that a single rater is expected to grade RE similarly at different times. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:2310-2313, 2017.

Swallowing function in pediatric patients with bilateral vocal fold immobility.

INTRODUCTION: Infants with bilateral vocal fold immobility (BVFI) often have poor swallow function in addition to potential airway compromise. While there are several reports on BVFI and its effect on patients' airway status, little is known about long term swallow function. OBJECTIVES: We aim to characterize the swallowing function over time in pediatric patients with bilateral vocal fold immobility. METHODS: A retrospective review of medical records of infants diagnosed with BVFI at a tertiary care children's hospital between 2005 and 2014 was conducted. Patient demographics, nature and etiology of immobility, laryngoscopy findings, comorbidities, and swallow outcomes at diagnosis and follow-up were recorded. Swallowing outcomes as measured by presence or absence of a gastrostomy tube were compared by etiology, vocal fold status, and normal or developmentally delay using the Fisher's exact test. RESULTS: 110 patients with a diagnosis of vocal fold immobility were identified. Twenty-nine (26%) had BVFI and twenty-three had complete medical records. Etiologies of vocal fold immobility include cardiac related in 13% (3/23), idiopathic in 30% (7/23) prolonged intubation in 26% (6/23) central neurologic in 22% (5/23), trauma in 4% (1/23), and infection in 4% (1/23). Average follow-up time was 44 months (range 5-94 months). Ten patients (56.5%) required a gastrostomy tube at time of diagnosis. Of this cohort who received gastrostomy tubes, three (30%) ultimately transitioned to complete oral feeds. Return of vocal fold mobility did not correlate with swallow function. In those with non-neurologic etiologies, the need for gastrostomy tube at end of follow up was unlikely. There was a statistically significant difference in the percentage of gastrostomy tube-free children at most recent follow up in patients who were normally developed (86%) versus those who were developmentally delayed (33%) (p = 0.02). CONCLUSION: We characterized the swallowing function of 23 pediatric patients with BVFI. Comorbidities are significant predictors of long term swallow function in patients with BVFI while return of vocal fold function is not.

Etiology and long-term functional swallow outcomes in pediatric unilateral vocal fold immobility.

OBJECTIVE: Unilateral vocal fold immobility (UVFI) results in deficits in phonatory, respiratory, and swallow function of the pediatric patient. Little is known about long-term functional swallow outcomes. METHODS: Medical records of children diagnosed with UVFI between 2005 and 2014 at a tertiary children's hospital were retrospectively reviewed. Etiology, laryngoscopy findings, and swallow status at diagnosis and follow-up were recorded. Swallow outcomes were compared by etiology using Fisher's exact test. McNemar's test was used to identify correlations between return of mobility and swallow recovery. Rates of pneumonia were compared with initial swallow evaluation results using a two-tailed t-test. RESULTS: Eighty-eight patients with UVFI were identified and 73 patients (47% female, mean age 14.4 months, standard deviation (SD) 26.7 months) had complete medical records. Mean follow up time was 52.7 months (SD 36.8 months). Etiologies included cardiothoracic surgery (68.5%), idiopathic (12.3%), prolonged intubation (11.0%), central nervous system (CNS) abnormality (5.5%), and non-cardiac iatrogenic injury to the recurrent laryngeal nerve (2.7%). Forty-seven patients underwent a follow up laryngoscopy, and recovery of vocal fold (VF) mobility was documented in 42.6% (20/47). At diagnosis, 31.5% fed orally, compared with 79.5% at follow-up. Direct correlation between recovery of VF mobility and swallow recovery was not demonstrated. Cardiac etiologies demonstrated higher rates of swallow recovery than CNS abnormalities (p = 0.0393). Twenty-five children aspirated on initial modified barium swallow (MBS) and 10 children developed pneumonias at some point during the follow up period. There was no significant difference in rates of pneumonia in patients with and without aspiration on MBS. CONCLUSION: Recovery of swallow in children with UVFI does not directly parallel return of VF mobility. Long-term swallow outcome is favorable in this population. Initial MBS does not indicate ultimate swallow outcome.

Case-control study evaluating competing risk factors for angioedema in a high-risk population.

OBJECTIVES/HYPOTHESIS: Black race is a risk factor for angioedema. The primary aim was to examine the relationship between race-ethnicity and risk factors for angioedema. STUDY DESIGN: Using a retrospective case-control study design, data was extracted with the Clinical Looking Glass utility, a data collection and management tool that captures data from electronic medical record systems within the Montefiore Healthcare System. Cases were emergency department (ED) visits with primary or secondary International Classification of Diseases, Ninth Revision, code diagnoses of angioedema in adults aged ≥ 18 years from January 2008 to December 2013 at three Montefiore centers in Bronx, New York. Controls were a random sampling of adult ED visits during the same period. METHODS: In primary analyses, angiotensin-converting enzyme inhibitor (ACE-I) and black race were evaluated for synergy. The influence of different risk factors in the development of angioedema was evaluated using logistic regression models. Finally, race-ethnicity was further explored by evaluating for effect modification by stratification of models by race-ethnicity categories. RESULTS: There were 1,247 cases and 6,500 controls randomly selected from a larger control pool. ACE-I use (odds ratio [OR] 3.70, 95% confidence interval [CI] 2.98, 4.60), hypertension (OR 1.88, 95% CI 1.55, 2.29), and black race (OR 2.25, 95% CI 1.86, 2.72) were the strongest risk factors. ACE-I use and black race were not synergistic (OR 1.10, 95% CI 0.80, 1.51). Race-ethnicity was an effect modifier for certain risk factors. CONCLUSION: Race-ethnicity acts as an effect modifier for particular angioedema risk factors. The two strongest risk factors, ACE-I use and black race, were not synergistic. LEVEL OF EVIDENCE: 3b. Laryngoscope, 126:1823-1830, 2016.

Role of Advanced Laryngeal Imaging in Glottic Cancer: Early Detection and Evaluation of Glottic Neoplasms.

Laryngeal cancer accounts for approximately 2.4% of new malignancies worldwide each year. Early identification of laryngeal neoplasms results in improved prognosis and functional outcomes. Imaging plays an integral role in the diagnosis, staging, and long-term follow-up of laryngeal cancer. This article highlights advanced laryngeal imaging techniques and their application to early glottic neoplasms.

Aerodynamic measures and biofeedback as management in persistent paradoxical vocal fold motion and reverse phonation.

OBJECTIVES: Paradoxical vocal fold motion (PVFM) and reverse phonation are characterized by aberrant vocal fold adduction. To date, there have been no studies examining the aerodynamic events during reverse phonation. We present an unusual case of persistent reverse phonation secondary to respiratory distress associated with PVFM. STUDY DESIGN: Case report. METHODS: We present the case of a 42-year-old female with sudden onset of respiratory distress associated with PVFM and persistent reverse phonation. She underwent baseline aerodynamic measurements followed by trial therapy. Through the use of instrumental and tactile aerodynamic biofeedback, the patient was able to coordinate exhalatory breath pressure flow during phonation, which resulted in immediately improved voice quality from highly dysphonic to nearly normal voice quality. CONCLUSIONS: Patients with reverse phonation seldom undergo aerodynamic testing as part of the initial diagnostic and management program. Our case study demonstrates the effectiveness of aerodynamic technology to enable a patient with aberrant glottic function to recognize inspiratory phonation events and to reestablish consistent expiratory flow/pressure egress in speech tasks. Instrumental and tactile biofeedback is effective for reinforcement of normal flow patterns during speech tasks.

Risk factors associated with severe and recurrent angioedema: an epidemic linked to ACE-inhibitors.

OBJECTIVES/HYPOTHESIS: To evaluate the etiology and risk factors for severe manifestation and recurrent episodes of angioedema; to evaluate efficacy of short-term and long-term management strategies for angioedema among a high-risk population. STUDY DESIGN: Institutional review board-approved retrospective review of a large, urban population. METHODS: Data from 875 adult patients treated from January 2008 to December 2013 with the diagnosis of angioedema were obtained using the Clinical Looking Glass utility and review of medical records. Demographic and clinicopathologic risk factors were recorded. The major outcomes evaluated were hospital admission, need for airway intervention, and recurrent episodes of angioedema following the first presentation. Initial treatment strategy and follow-up recommendations were also recorded. RESULTS: The most common cause of angioedema was angiotensin converting enzyme inhibitor (ACEi)-induced (496 [56.6%]). Significant risk factors for severe cases of angioedema included older age, Hispanic race, ACEi-induced angioedema type, American Society of Anesthesiologists class III or above, coexistent cardiopulmonary disease, and a positive smoking history. A total of 17.2% of patients experienced recurrent attacks of angioedema; of those patients, 25.9% were still taking an ACEi at subsequent presentation. Risk factors for recurrent episodes included older age, idiopathic angioedema type, and coexistent cardiopulmonary disease. Only 54.1% of patients who experienced ACEi-induced angioedema had electronic medical record documentation of these allergies. CONCLUSIONS: Knowledge of risk factors for severe and recurrent episodes of angioedema and improved education for both healthcare providers and patients, specifically related to ACEi use and allergy documentation, may significantly decrease the burden and morbidity of angioedema among high risk populations. LEVEL OF EVIDENCE: 2b.

Distribution, clinical characteristics, and surgical treatment of lip infantile hemangiomas.

IMPORTANCE: Infantile hemangiomas (IHs) are the most common tumors of infancy. OBJECTIVES: To describe the patterns of occurrence of lip IHs and correlate these findings with patterns of anatomical distortion and predictable clinical outcomes and to describe the surgical management of these lesions. DESIGN: A retrospective medical record review of patients diagnosed as having facial IH of the upper or lower lips during an 8-year period (January 1, 2004, through December 31, 2011). Using clinical photographs and patient records, we mapped the 360 IHs of 342 patients on a lip schematic. Each lesion was encoded with a number reflective of its location, and this number was shared by other lesions found at the same site. Frequencies of lesion characteristics, complicating functional and aesthetic factors, and airway obstruction were documented. The treatment course was noted. SETTING: Tertiary care hospital and practice specializing in the care of congenital pediatric vascular anomalies of the head and neck. PARTICIPANTS: Three hundred forty-two patients with 360 IHs. RESULTS: A total of 1916 IHs were diagnosed. Of these, lip IHs were found in 342 patients. We reviewed those patients' medical records. Of the lesions, 59.2% were focal and 40.8% were segmental. A nonrandom distribution of lip IHs was found. The most common focal lesion occurred at the lower lip (98 of 213 lesions [46.0%]). The most common segmental lesion involved the mandibular segment (75 of 147 [51.0%]). Of the 75 patients, 30 (40.0%) had airway involvement. The most common anatomical distortions of the lip involved the vermiliocutaneous junction in 216 (61.5%). Horizontal and vertical lengthening of the lip was evident in 28.7% and 31.0% of patients, respectively. Ulceration and scarring were common findings in 137 patients overall (38.1%), with segmental mandibular IHs associated with the highest percentage (46 of 137 [33.6%]), followed by focal IHs of the lower lip (35 of 137 [25.5%]). Using previously described surgical procedures, we developed a problem-oriented solution for each of these zones. CONCLUSIONS AND RELEVANCE: The nonrandom distribution of facial hemangiomas has been documented with focal and segmental patterns of growth. Distinct anatomical patterns of occurrence for lip IHs are described. The distribution seems to be related to the embryologic development of the upper and lower lips. These anatomical patterns allow for the prediction of anatomical location, structural distortion, and possible clinical outcomes. This information is relevant when planning medical and surgical treatment for these children. LEVEL OF EVIDENCE: NA.

Application of natural orifice transluminal endoscopic surgery (NOTES) instrumentation to the endolarynx.

OBJECTIVES: RealHand instruments are high-dexterity instruments that have been designed for natural orifice transluminal endoscopic surgery applications. They provide dexterity by offering a full range of motion to endoscopic instruments. We hypothesize that RealHand instruments will resolve some of the limitations encountered in traditional endolaryngeal surgery. They have the potential to do so in the following ways: (1) they negate the limitation of mobility of traditional laryngoscopy instrumentation, which is rigid and fixed; (2) they maintain the ability of direct visualization through a telescope while precluding the need for an operating microscope; (3) they provide the dexterity to perform tasks that are otherwise not possible with traditional instrumentation; and (4) they provide flexibility that can be advantageous in difficult foreign body retrieval from distal airways. METHODS: To test this hypothesis, we developed and optimized a cadaveric lamb larynx model for endolaryngeal microsurgery. To evaluate the feasibility of the RealHand instruments in their application to laryngeal surgery, we had 2 otolaryngology senior residents and 2 laryngology fellows-in-training perform 5 different endoscopic tasks: (1) foreign body removal; (2) arytenoidectomy; (3) microflap elevation; (4) cricopharyngeal myotomy; and (5) endoknot suture tying. RESULTS: Experience with RealHand instruments demonstrated that although they are limited in application to phonosurgery, they have the potential for more facile tissue manipulation in the supraglottic and hypopharyngeal structures. Endoscopic suturing ability is enhanced. CONCLUSIONS: RealHand high-dexterity instrumentation allows for full range-of-motion instrumentation and, with modification, has potential for wider application in endoscopic laryngeal surgery.

Obstacles to communication in children with cri du chat syndrome.

BACKGROUND: Cri du chat syndrome (CCS) is a genetic disorder resulting from the deletion of the short arm of chromosome 5. Perhaps the most distinctive characteristic of this syndrome is the congenital high-pitched cry, which frequently brings these patients to the attention of an otolaryngologist. Speech and language development in children with CCS is notable for a reduced receptive vocabulary and a profound deficit in expressive language. Currently, no clear guidelines have been established for the treatment of the speech and language difficulties exhibited by these patients. In this article, we present a case report and discuss the current literature regarding the challenges to effective communication in CCS. METHODS: Case report. CASE: We present a 7-year-old girl with CCS who sought help to improve her ability to communicate. The patient presented with a persistent high-pitched voice unchanged since birth and a breathy dysphonia. Findings on examination were significant for an abnormally oriented larynx with atrophic vocal folds. She continues to undertake intensive speech therapy to assist in her language development. CONCLUSION: CCS is a genetic disorder that universally results in profound deficits in expressive speech. Although patients with CCS commonly present with a high-pitched voice and marked laryngeal abnormalities, they are unlikely to benefit from surgical intervention. Speech and language therapy, including augmentative communication devices, may enhance effective communication and improve the quality of life of these patients.

Western blot confirmation of the H+/K+-ATPase proton pump in the human larynx and submandibular gland.

OBJECTIVE: The authors have previously demonstrated the H(+)/K(+)-ATPase (proton pump) in human larynx and lung glands via immunohistochemistry (IHC). The present hypothesis is that the proton pump is expressed in other seromucinous glands of the digestive tract that can be confirmed by IHC and Western blot analysis. STUDY DESIGN: Prospective controlled tissue analysis study. SETTING: Academic medical institution. METHODS: Ten anonymous fresh-frozen donor specimens were obtained, comprising 3 submandibular glands, 4 larynges, and 3 normal stomach specimens for control. Submandibular gland sections were immunostained with 2 monoclonal antibodies selectively reactive with α or ß subunits of the H(+)/K(+)-ATPase. Western blot analysis was performed on all specimens. RESULTS: Consistent IHC staining was observed in the submandibular gland specimens for both α and ß subunits. Western blot analysis revealed very strong expression for the stomach at 100 kDa, corresponding to the α protein, and weak but notable banding for all larynx and submandibular gland specimens. Similar findings were noted for the 60- to 80-kDa glycosylated ß subunit protein, as well as the 52-kDa ß subunit precursor for all specimens. CONCLUSION: The H(+)/K(+)-ATPase (proton) pump is present in the human larynx and submandibular gland although in much lower concentrations than in the stomach. Proton pump involvement in human aerodigestive seromucinous glands may have a role in protecting mucosa from acid environments (local or systemic), explain heightened laryngeal sensitivity in those patients with laryngopharyngeal reflux, and be a site of action for proton pump inhibitor pharmacotherapy.

Allograft (Alloderm) and autograft (temporalis fascia) implantation for glottic insufficiency: a novel approach.

OBJECTIVE: Traditionally, glottic insufficiency because of scar, atrophy, and sulcus has been treated by injection or medialization laryngoplasty. These procedures do not reestablish the vertical height of the vocal fold margin. We propose soft tissue augmentation laryngoplasty with allograft (sheet Alloderm; LifeCell Corporation, Branchburg, NJ) or autograft (temporalis fascia) via a minithyrotomy or a transoral approach. STUDY DESIGN: A retrospective case series analysis of 21 patients treated by sheet Alloderm or temporalis fascia for correction of glottic insufficiency. METHODS: Twenty-one patients with glottic insufficiency secondary to scar, atrophy, or sulcus were treated. Ten failed prior techniques. Seventeen had minithyrotomy by a small fenestration in the thyroid cartilage. Exploration of scar or lamina propria through the fenestration allowed for the creation of a pocket for Alloderm implantation within the intermediate layer of the lamina propria. Four patients underwent a transoral approach by cordotomy with either Alloderm or temporalis fascia implantation, which also allowed for exploration of scar but required repair using sutures. These implantation approaches allowed for both restoration of the layered structure and augmentation of the middle third of the musculomembranous vocal fold. Preoperative and postoperative videostroboscopic examinations were reviewed with review of clinical outcome. RESULTS: With a median follow-up time of 12 months, patients demonstrated excellent long-term vocal fold augmentation and minimal absorption of the implant in 19 out of 21 patients. There is improved pliability of the vocal fold with good oscillation in scar patients. CONCLUSION: Minithyrotomy with soft tissue augmentation is a novel approach for soft tissue augmentation of glottic insufficiency. It has the advantage of augmentation of the medial edge of the vocal fold with a soft tissue implant that has long-term viability. Its role should be explored further in patients with atrophy and scar.

A case of bilateral vocal fold mucosal bridges, bilateral trans-vocal fold type III sulci vocales, and an intracordal polyp.

INTRODUCTION: We present a patient with a novel finding of bilateral mucosal bridges, bilateral type III trans-vocal fold sulci vocales, and a vocal fold polyp. Although sulci and mucosal bridges occur in the vocal folds, it is rare to find multiples of these lesions in a single patient, and it is even more uncommon when they occur in conjunction with a vocal fold polyp. To our knowledge, this is the first description of a vocal fold polyp in combination with multiple vocal fold bridges and multiple type III sulci vocales in a single patient. OBJECTIVE: To describe and visually present the diagnosis and treatment of a patient with an intracordal polyp, bilateral mucosal bridges, as well as bilateral type III trans-vocal fold sulci vocales. METHODS: Presentation of a set of high definition intraoperative photos displaying the extent of the vocal fold lesions and the resection of the intracordal polyp. RESULTS: This patient presented with only 6 months of significant dysphonia. It was felt that the recent change in voice was because of the polyp and not the bridges or sulci vocales. Considering the patient's presentation and the possible morbidity of resection of mucosal bridges and sulci, only the polyp was excised. Postoperatively, the patient's voice returned to his acceptable mild baseline dysphonia, and the benefit has persisted 6 months postoperatively. CONCLUSION: The combination of bilateral mucosal bridges, bilateral type III sulcus vocalis, and an intracordal polyp in one patient is rare if not novel. Treatment of the polyp alone returned the patient's voice to his lifelong baseline of mild dysphonia.

Injection laryngoplasty with micronized dermis: a 10-year experience with 381 injections in 344 patients.

OBJECTIVE: Micronized Dermis (MD) has been used for injection laryngoplasty for correction of glottic insufficiency since 2000. There is controversy whether the material is temporary or permanent. This is a retrospective review of 381 injections in 344 patients. From this review, we hope to better define the role of MD in injection laryngoplasty. METHOD: Retrospective chart review from a single surgeon (2000-2010) RESULTS: The indications for MD were for both temporary and permanent correction of glottic insufficiency. The diagnoses were: vocal fold paralysis (n = 216), scar (n = 51), atrophy (n = 42), sulcus (n = 22), and others (n = 13). The material has the best effect when placed into the membranous vocal fold just lateral to the vocal ligament. The operative and postoperative complication was 1.05%. Twenty-nine percent of all injections resulted in unwanted absorption. Overinjection was needed and transcervical approach was preferred to prevent implant extrusion with overinjection. The median volume of injected material has increased from 0.8 cc to 1.0 cc over the decade. In 159 patients with long-term follow-up (>1 year), there was a 14% incidence of reinjection. Despite this, the overall need for open procedures in patients with long-term follow-up was 20%. CONCLUSIONS: Despite the problems of inconsistency in preparation, slow absorption and need for overinjection, micronized dermis is a safe allograft material that has long-term (>1 year) stability. The material may reduce the need for open surgery. It can be used for both temporary and permanent vocal fold augmentation.

Differential expression of SKI oncogene protein in hemangiomas.

OBJECTIVE: The pathogenesis for benign tumorigenesis in hemangiomas is unknown. Oncogene proteins may be influential in this process. SKI proteins have been previously described in various malignancies. We investigated the differential expression of the SKI (sarcoma viral oncogene) protein in hemangiomas. STUDY DESIGN: Prospective basic science study. SUBJECTS AND METHODS: Paraffin-embedded hemangioma tissues were obtained from the senior author from 2005 to 2006. We created the first vascular tissue array composed of 12 hemangioma specimens at various stages of growth and anatomic location. Two cores were taken from each sample. Controls were also included. Immunohistochemical studies were performed using SKI, CD31, and Ki67. RESULTS: All 12 hemangioma tissues overexpressed the SKI protein. The staining pattern was perinuclear within the endothelial cells. The intensity of staining was inversely proportional to the growth stage. The endothelial cells that were SKI-positive were involved in active cell division. CONCLUSION: SKI oncogene protein is differentially and specifically expressed in hemangioma tissues. SKI acts as a transcriptional co-repressor and inhibits the TGF-beta pathway, thus leading to uncontrolled cellular proliferation and transformation. All vascular controls were negative for SKI staining. CLINICAL SIGNIFICANCE OF STUDY: The SKI oncogene protein is upregulated by hemangiomas and may play a role in hemangioma tumorigenesis.

In vitro effects of dentin matrix protein-1 on hydroxyapatite formation provide insights into in vivo functions.

Dentin matrix protein-1 (DMP1) is a mineralized tissue matrix protein synthesized by osteoblasts, hypertrophic chondrocytes, and ameloblasts as well as odontoblasts. DMP1 is believed to have multiple in vivo functions, acting both as a signaling molecule and a regulator of biomineralization. Using a cell-free system in vitro, we evaluated the action of DMP1 in the regulation of hydroxylapatite (HA) formation and crystal growth. The non-phosphorylated recombinant protein acted as an HA nucleator, increasing the amount of mineral formed in a gelatin gel HA growth system relative to protein-free controls. The recombinant protein phosphorylated in vitro had no detectable effect on HA formation and growth. In contrast, phosphorylated bovine DMP1 expressed in marrow stromal cells with an adenovirus vector containing 29.7 phosphates/mol was an effective inhibitor of HA formation and growth. The native full-length protein appeared to be absent or present in only small amounts in the extracellular matrix of bones and teeth. However, two highly phosphorylated fragments representing the N- and C-terminal portions of DMP1 have been identified, apparently arising from proteolytic cleavage of four X-Asp bonds. The highly phosphorylated C-terminal 57-kDa fragment (containing 42 phosphates/mol), like the non-phosphorylated DMP1, was an HA nucleator. These data suggest that, in its native form, DMP1 inhibits mineralization, but when cleaved or dephosphorylated, it initiates mineralization. These in vitro data are consistent with the findings in the DMP1 knockout mouse.