Can molecular profiling enhance radiotherapy? Impact of personalized targeted gold nanoparticles on radiosensitivity and imaging of adenoid cystic carcinoma.

Personalized molecular profiling has an established role in selection of treatment for metastatic disease; however, its role in improving radiosensitivity and functional imaging has not been evaluated. In the current study, we examined molecular profiling as a tool for designing personalized targeted gold nanoparticles (GNP) to serve as dual-modal tumor radiosensitizers and functional imaging enhancers. To this end, molecular profiling of a patient's salivary gland adenoid cystic carcinoma (ACC) was performed, and anaplastic lymphoma kinase (ALK) mutation was detected. The extracted tumor was subcutaneously injected into mice, which were then treated either with radiation, the specific ALK inhibitor crizotinib, or a combination of therapies. One of these combinations, namely, ALK-targeted GNP (via crizotinib coating), was found to enhance radiation treatment, as demonstrated by a significant decrease in tumor volume over 24 days. In parallel, ALK-targeted GNP substantially augmented tumor visualization via computed tomography. The mechanism of radiosensitivity enhancement was mostly related to a diminished cell repair mechanism in tumors, as demonstrated by proliferating cell nuclear antigen staining. These findings indicate that personalized molecular profiling is an effective technique for enhancing cancer theranostics.

Heat shock proteins HSP90, HSP70 and GRP78 expression in medullary thyroid carcinoma.

BACKGROUND: Medullary thyroid carcinoma management consists mainly of surgical resection and is largely chemoresistant. There is ongoing effort to discover novel therapies for medullary thyroid carcinoma. Increased levels of heat shock proteins have been associated with multiple cancers and are being studied as potential therapeutic targets. The purpose of this study was to determine the expression levels of heat shock proteins 90 and 70 and of glucose related protein 78 in medullary thyroid carcinoma tissues compared with normal thyroid tissues. METHODS: 20 tissue specimens of medullary thyroid carcinoma and 10 specimens of thyroids without malignancy were analyzed by immunohistochemistry. RESULTS: Medullary thyroid carcinoma specimens showed 27% higher expression level of heat shock protein 90 immunostaining, and a 43% higher expression level of heat shock protein 70 immunostaining versus normal controls. These differences, however, were not statistically significant. A significantly higher expression level was noted for glucose related protein 78 in the medullary thyroid carcinoma specimens than in the controls. CONCLUSION: This study indicates increased expression levels of heat shock proteins 90 and 70 and glucose related protein 78 levels in medullary thyroid carcinoma. These findings, though preliminary imply that these proteins may have a role in medullary thyroid carcinoma's tumor biology and may have and future therapeutic options. Larger cohorts are needed to corroborate these results.

Acute Rhinosinusitis in Immunosuppressed Children: Diagnostic and Therapeutic Management.

BACKGROUND: Immunosuppressive therapy places pediatric patients at risk of developing life-threatening sinonasal infections. Diagnosis and treatment are challenging owing to nonspecific signs and symptoms. The aim of this study was to present our department's experience with the surgical management of acute rhinosinusitis in immunosuppressed children. METHODS: The records of all children with a hematologic or oncologic disease who underwent endoscopic sinus surgery (ESS) for acute rhinosinusitis from January 2005 to May 2014 were reviewed. Data were retrospectively collected on demographics, clinical and imaging characteristics, microbiology, pathology, treatment and outcome. RESULTS: Thirty-four-immunosuppressed children underwent ESS for acute rhinosinusitis. Most patients had a fungal infection. Nineteen patients died at the end of follow-up; 10 deaths were infection-related. Facial swelling was the only symptom that correlated with death of infection. Relapse of the underlying disease, bone marrow transplantation, and long duration of neutropenia correlated with infection-related mortality. Fungal infection, and specifically Aspergillus, correlated with death from infection. CONCLUSIONS: ESS is a safe and efficient procedure for diagnosing and treating immunosuppressed pediatric patients with acute rhinosinusitis. Early detection and aggressive medical and surgical treatment, with control of underlying risk factors, are crucial to improve outcome.

Repair of caudal septal deviation: the fishing line technique.

BACKGROUND: Repair of caudal septal deviation using currently described methods is challenging technically. The aim of this work is to describe a novel and simple technique for the treatment of caudal septal deviations that protects the nasal tip, by fixating of cartilage to the columella. METHODS: All patients with caudal septal deviation operated on between June 2008 to November 2013 in 2 major medical centers were operated using the "fishing line technique." Patient satisfaction was recorded by a standard questionnaire (16-item Sino-Nasal Outcome Test [SNOT-16]), before and after surgery. The fishing line technique was performed in 63 patients with a severe caudal septal deviation of which 14 also had rhinoplasty. A mucoperichondrial flap was elevated on either side of the damaged septal cartilage. The cartilage was excised and remodeled into a straight sheet, and then repositioned between the mucoperichondrial flaps, and fixed to the septal columella. RESULTS: Mean age of the study group was 36 years. Follow-up ranged from 24 to 70 months. At the last follow-up, the septum was straight in all cases, with no deviation from the nostrils to the choana. Good airway was found in 53 patients. Eight patients had partial turbinate hypertrophy with an impaired airway, and 2 had severe turbinate hypertrophy. SNOT-16 mean score improved from 27 to 10 (p < 0.001). All patients were satisfied with the aesthetic outcome. CONCLUSION: The fishing-line technique for severe caudal septum deviations is easy to perform and yields satisfactory anatomic and aesthetic results.

Prognostic factors in metastatic cutaneous squamous cell carcinoma of the head and neck.

Metastatic cutaneous squamous cell carcinoma (SCC) of the head and neck poses a significant therapeutic challenge due to its aggressive biologic behavior. We conducted a retrospective study of 71 patients-58 men and 13 women, aged 28 to 88 years (mean: 71)-who had been treated at our university-affiliated tertiary care medical center for metastatic cutaneous SCC over a 15-year period. In addition to demographic data, we compiled and analyzed information on tumor characteristics, the site and extent of metastasis, treatment, follow-up, and outcome. Among the tumor factors, poorly differentiated carcinoma was an independent predictor of poorer disease-free survival, and older age was found to be an independent predictor of poorer overall survival. We found no significant difference in disease-free or disease-specific survival among patients with parotid involvement, neck involvement, or both. In our series, the site of nodal involvement appeared to have no prognostic significance in patients with metastatic cutaneous SCC of the head and neck.

Bacteriology of the Middle Meatus in Chronic Rhinosinusitis with and without Polyposis.

There are only limited data in the literature, and none specifically from the Middle East, on the pathogenic bacteria in chronic rhinosinusitis (CRS) as opposed to healthy nasal cavities and their association with disease severity. The present study was conducted in the department of head and neck surgery of a tertiary medical center. Middle meatal swabs were taken preoperatively from patients with CRS with nasal polyposis (CRSwNP) (n = 60), CRS without nasal polyposis (CRSsNP) (n = 50), and control patients with septal deviation (n = 26) or no nasal abnormalities (n = 27). Culture findings were compared among the groups and correlated with CRS severity. Positive pathogenic culture rates were 78% in the CRSwNP group and 64% in the CRSsNP group. Twenty pathogenic bacterial species were identified; the most common was Staphylococcus aureus (27%). The most common Gram-negative isolate was Citrobacter spp. (17%). Gram-negative species were significantly more prevalent in the CRSwNP group than the others. Mean Lund-Mackay scores were 12.8 in the CRSwNP group and 6.9 in the CRSsNP group, and were unrelated to the culture findings. Positive culture rates were significantly higher in the septal deviation (54%) than the nasal healthy group (26%), although both values were significantly lower than in the CRS groups. In conclusion, patients with CRS have higher rates of bacterial isolates than patients without CRS. CRSwNP is associated with more Gram-negative bacteria than CRSsNP, regardless of disease severity. The relatively high positive culture rate in patients with septal deviation merits investigation.

Brachytherapy for radiotherapy-resistant head and neck cancer: A review of a single center experience.

OBJECTIVES/HYPOTHESIS: Despite advances in radiotherapy and chemotherapy treatments for head and neck cancers, the local failure rate is high. In most radiotherapy-resistant cases, surgery is performed; however, some cases are considered unresectable. No standard treatment for these situations has been established. In this study, we review our experience with brachytherapy (BT), which has a different biological mechanism than standard radiotherapy. METHODS: All patients received prior radiation to the recurrence area. Median high-dose radiation BT dose was 50 Gy, administered in 5 to 10 Gy fractions twice daily for 5 days. High-dose radiation was given via four to 10 catheters inserted under local anesthesia (3 patients) or general anesthesia with preventive tracheostomy (10 patients). RESULTS: Thirteen patients received BT from 2010 to 2014. Male:female ratio was 1.6:1, and median age was 66 years (range 23-89). Of those 13 patients, 10 patients were diagnosed with squamous cell carcinoma (SCC) of the oral cavity, two patients with SCC of the nasal mucosa, and one patient with eccrine duct carcinoma. Prior radiation dose ranged from 60 to 70 Gy. Local control was achieved in 11 of 13 patients; only 15.3% (2 of 13) had in-field recurrence. Five patients developed local out-of-field recurrence, and two developed distant metastases. Five patients are alive with no evidence of disease. No major toxicities were encountered. Two patients had severe mucositis and recovered within several weeks. CONCLUSION: Brachytherapy for radiotherapy-resistant head and neck cancers is feasible with minor adverse events, which enables good local control. However, many advanced head and neck cancers develop regional or distant metastases; therefore, additional treatment should be suggested. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2246-2251, 2016.

Cancer of the head and neck region in solid organ transplant recipients.

BACKGROUND: Solid organ recipients are at an increased risk of developing various malignancies. We investigated the incidence, clinical features, and outcome of patients diagnosed with head and neck cancer after organ transplantation. METHODS: A retrospective analysis was undertaken of patients who underwent solid organ transplantation (kidney, liver, lung, heart) treated at our institution from 1992 to 2010. RESULTS: Of 2817 organ recipients, 175 patients (6.1%) developed 391 head and neck malignancies. Cutaneous malignancies were the most common (93%): squamous cell carcinoma (SCC; 51%) and basal cell carcinoma (BCC; 42%). The average interval from transplantation to diagnosis of head and neck malignancy was 7.3 years, with liver recipients diagnosed earlier. Eighteen percent of patients presented with an aggressive pattern of head and neck cancer, including 24% of patients with cutaneous SCC. CONCLUSION: Organ transplantation recipients are at a higher risk to develop head and neck cancer with an aggressive behavior characterized by multiple recurrences and decreased survival.

Post-laryngectomy voice rehabilitation: comparison of primary and secondary tracheoesophageal puncture.

BACKGROUND: Voice restoration following total laryngectomy is an important part of patients' rehabilitation and long-term quality of life. OBJECTIVES: To evaluate the long-term outcome of indwelling voice prostheses inserted during (primary procedure) or after (secondary procedure) total laryngectomy. METHODS: The study group included 90 patients who underwent total laryngectomy and tracheoesophageal puncture (TEP) with placement of voice prosthesis at a tertiary medical center during the period 1990-2008. Background, clinical and outcome data were collected by medical file review. Findings were compared between patients in whom TEP was performed as a primary or a secondary procedure. RESULTS: TEP was performed as a primary procedure in 64 patients and a secondary procedure in 26. Corresponding rates of satisfactory voice rehabilitation were 84.4% and 88.5% respectively. There was no association of voice quality with either receipt of adjuvant radiation/chemoradiation or patient age. The average lifetime of the voice prosthesis was 4.2 months for primary TEP and 9.06 months for secondary TEP (P= 0.025). CONCLUSIONS: Primary TEP provides almost immediate and satisfactory voice rehabilitation. However, it is associated with a significantly shorter average prosthesis lifetime than secondary TEP. Chemoradiotherapy and patient age do not affect voice quality with either procedure.

Size discrepancy between sonographic and pathological evaluation of solitary papillary thyroid carcinoma.

BACKGROUND: Sonographic size of suspicious thyroid lesions is an essential parameter in the evaluation of thyroid nodules, determining the need for needle biopsy and has impact on the extent of surgery. Limited data is available on the correlation between the size of the thyroid nodule on sonography and the actual size measured during histological examination. The aim of the present study was to compare these two modalities and to discuss the potential clinical implications of the findings in the study population. METHODS: The database of Rabin Medical Center was reviewed for all patients with histologically proven papillary carcinoma of the thyroid treated by thyroid surgery between 2005 and 2010. RESULTS: 292 patients with papillary thyroid carcinoma were included. The mean sonographic size of the nodule was 2.19 ± 1.15 cm. The mean pathological diameter was 1.69 ± 1.09 cm. Discrepancies between tumor histological diameter and the sonographically measurement were more prominent in tumors larger than 1.5 cm. Nonetheless, 18.8% of thyroid nodules that were measured by US as larger than 1cm, were found to be smaller than 1cm on final pathology. Similarly, 7.2% of nodules evaluated by sonography were determined as being larger than 4 cm, while their definitive size was smaller than 4 cm. CONCLUSIONS: We noted a significant discrepancy between the preoperative sonographic and the pathologic size measurements for papillary thyroid carcinoma. The sonographic evaluation misclassifies both patients with small and large thyroid tumors, and consequently exposes them to unnecessary workup and more extensive operation. This discrepancy between the ultrasound findings and actual tumor size should be taken into account in clinical practice and help guide the evaluation and treatment of patients with thyroid nodules.

Prognostic significance of nodal ratio in cutaneous squamous cell carcinoma of the head and neck.

The TNM classification is not specific for head and neck skin cancer and makes no allowance for disease extent. Studies have shown that the relative number of metastatic-to-examined lymph nodes, termed the Nodal ratio, is a reliable independent prognosticator in several types of cancer. The study was designed as a retrospective analysis in a university affiliated tertiary care center setting. The files of all patients (n = 71) with cutaneous head and neck squamous cell carcinoma and regional lymph node metastasis who attended a tertiary medical center between 1990 and 2008 were reviewed for clinical variables and outcome, and Nodal ratio was calculated. Data were analyzed for impact on survival. On multivariate analysis Nodal ratio and age were found to be significant predictors of overall survival. The N-ratio was the only significant predictor of disease-specific survival. Age, type of treatment (selective/modified neck dissection), pathologic N stage, and radiotherapy had no effect. The Nodal ratio is a potentially valuable prognostic index in cutaneous squamous cell carcinoma. The minimal number of nodes that need to be excised has to be determined.

Effect of intranasal steroids on glucose and hemoglobin A1c levels in diabetic patients.

BACKGROUND: Intranasal steroids are widely used for the treatment of inflammatory diseases of the nose and sinuses such as rhinosinusitis, allergic rhinitis, and nonallergic rhinitis. Along with the general otherwise healthy population, many diabetic patients use intranasal steroids as well. This study was designed to evaluate the adverse effects of long-term treatment with intranasal corticosteroid preparations in diabetic patients. METHODS: The study group included all diabetic patients treated with intranasal steroids for at least 3 months at primary care clinics in Clalit Health Services Central District in Israel in 2002-2007. The central database had been reviewed for demographic data, medical history, medications, and laboratory test results. RESULTS: A total of 1768 diabetic patients were treated with topical nasal steroid sprays during the study period. Data on hemoglobin A1c (HbA1c) levels both before and during steroid treatment was available for 245 patients, and data on fasting serum glucose levels at both time points was available for 163 patients. On statistical analysis, there was no change in either measure from baseline to 3 months after starting treatment (p = 0.104 and p = 0.101, respectively). Treatment with triamcinolone acetonide was associated with a significantly greater increase in fasting serum glucose levels than other preparations (p = 0.006). CONCLUSION: Intranasal corticosteroids seem to have no adverse effects on HbA1c and serum glucose levels in diabetic patients. Their long-term use appears to be safe, provided that the patients are carefully monitored, especially those receiving triamcinolone acetonide.

Novel grading system for quantifying upper-airway obstruction on sleep endoscopy.

BACKGROUND: The aim of this study was to present a novel anatomically comprehensive and clinically applicable system for the quantification of sleep endoscopy findings in patients with obstructive sleep apnea/hypopnea syndrome (OSAHS). METHODS: Fifty-five adult patients with a polysomnographic diagnosis of OSAHS were referred for midazolam-induced sleep endoscopy following failure of continuous positive airway pressure. Five anatomical sites of possible obstruction along the upper airway were documented: nose/nasopharynx (N), uvulopalatine plane (P), tongue base (T), larynx (L), and hypopharynx (H). Each involved site was assigned a severity grade of 1 (partial obstruction) or 2 (complete obstruction). The digits representing the obstruction pattern at each level were then added to yield a severity index (SI). The SI for each patient was determined by two independent observers. Findings were correlated with the respiratory disturbance index (RDI) and body mass index (BMI). RESULTS: The SI was significantly correlated with the RDI (R=0.746, Pearson; P<0.0001) and predicted disease severity with 65% accuracy. There was no association with BMI. By site, the tongue base and hypopharynx were significantly correlated with obstruction severity; obstruction in the tongue base predicted disease severity with a sensitivity of 68.8 and sensitivity of 81.1. CONCLUSION: Our easy-to-use endoscopic grading system provides physicians with an accurate picture of the pattern of the upper-airway system obstruction in patients with obstructive sleep apnea/hypopnea syndrome. It is a promising tool for estimating the location and severity of upper airway disease and may have implications for treatment planning.

Early tongue carcinoma: analysis of failure.

BACKGROUND: Failure rate of surgery for early tongue carcinoma remains high. We sought to identify patterns of failure and recurrence risk factors. METHODS: Data review was carried out on 50 patients treated for early tongue carcinoma (T1/2N0M0); surgery was unsuccessful in 11 of these patients. All patients underwent transoral resection of the tongue tumor and prophylactic neck dissection (supraomohyoid). RESULTS: Tumor recurred within 3 to 18 months. Nine died of disease. Four had failure in neck level 4, 6 in level 1, and 1 simultaneously in level 1 and locally. Most tumors were moderately differentiated. Average depth was 6.64 mm. CONCLUSIONS: We report 11 patients with early tongue carcinoma who failed local excision with neck dissection. Failures occurred in level 4 (4 patients) and level 1 (7 patients). This group may benefit from extended neck surgery. Sex, age, stage, and depth of tumor were not significantly different in the group with treatment failure. Tumors in the group with treatment failure were more poorly differentiated.

Early death from papillary thyroid carcinoma.

PURPOSE: The natural history of papillary thyroid carcinoma (PTC) is characterized by a slow growth rate and an excellent prognosis at 20 and 30 years. However, there is a small subset of patients with poorer outcome. METHODS: Twenty patients who died of PTC within 10 years of diagnosis were studied to identify prognostic indicators and biological markers of early death. Findings were statistically compared with a previous review of all patients with PTC treated in the same institute and studies in the literature. RESULTS: The study group included 6 men and 14 women with a mean age of 65 years at diagnosis. Average tumor size was 3.6 cm; 16 patients had extracapsular extension. All tumor samples studied histologically stained poorly for p53, Ki67, and CD34. Regional metastases were present in half the patients, and distal metastases in all. All patients had an advanced disease stage (Tumor, Node, Metastases classification), and only 4 had a low score on the Metastases, Age, Completeness of resection, local Invasion, tumor Size risk stratification. Analysis of the findings against data in the literature for the whole population of patients with PTC, who had a considerably better survival (<8% mortality within 8-15 years vs 100% within 10 years in our sample), yielded significant differences for rates of extrathyroidal extension (P = .0001), regional metastases (P = .016), and distant metastases (P = .0001). CONCLUSION: Extrathyroid extension, late regional metastases, and distant metastases may be risk factors for early death from PTC.

Role of parathyroid hormone monitoring during parathyroidectomy.

BACKGROUND: The value of intraoperative parathyroid hormone (IOPTH) monitoring in parathyroidectomy has been previously debated. METHODS: This retrospective analysis was of 240 patients, operated on for primary hyperparathyroidism (PHPT) between January 2002 and January 2006 and categorized into 3 groups by preoperative and intraoperative modalities: group 1 (n = 109), technetium 99m sestamibi (MIBI), ultrasonography, and IOPTH; group 2 (n = 102), ultrasonography and MIBI; and group 3 (n = 29), ultrasonography and IOPTH. Sensitivity and specificity were calculated. RESULTS: In group 1, IOPTH increased the success rate from 97% to 99%. In group 2, ultrasonography and MIBI were concordant in 95% of cases. In group 3, IOPTH increased the sensitivity from 89% to 96%. The duration of surgery was longer (p < .0001) when IOPTH was applied. CONCLUSIONS: When ultrasonography and MIBI are used, the additional benefit of IOPTH is marginal, especially given the longer duration of surgery. Ultrasonography and additional IOPTH yield good success rates when MIBI is not available.

Squamous cell carcinoma of the oral tongue in patients over 75 years old.

BACKGROUND AND AIMS: Squamous cell carcinoma (SCC) of the oral tongue is one of the most frequent head and neck cancers. The over-70-year age group is the fastest growing segment of the population. Age, however, is not considered a prognostic factor in oral tongue SCC. This study investigated the clinical and histopathological characteristics, disease course, and outcome of SCC of the oral tongue in patients over 75 years old compared with younger patients. METHODS: We reviewed the files of 85 patients with histologically proven SCC of the oral tongue who were treated in our department in 1992-2007 and followed for a minimum of 2 years. Findings were compared between those aged 75 years or more and younger patients. RESULTS: Twenty-eight patients (33%) were aged 75 to 94 years (average 80.5±4.5 yrs), including 14 who were over 80 years old, and 57 patients were aged 15-74 years (average 51.1±18.2 yrs). No statistically significant differences were found between the groups in clinical or histopathological characteristics or patient outcome. The 5-year disease-free survival rate was 65% for patients over 75 and 58% for younger patients. Corresponding rates for 5-year disease-specific survival were 69% and 70%. These differences were not statistically significant. CONCLUSIONS: Patients over 75 with oral tongue SCC should be managed like younger patients in terms of clinical staging and co-morbidities. They should be given a chance for treatment, as their prognosis is no different from that of younger patients.

Malignant external otitis: analysis of severe cases.

OBJECTIVE: To study the effect of specific clinical, laboratory, and imaging parameters on the course of severe (type 1) malignant external otitis (MEO). STUDY DESIGN: Case series with chart review. SETTING: Tertiary, university-affiliated medical center. SUBJECTS AND METHODS: Fifty-seven patients hospitalized with severe MEO were followed for disease course and survival in a tertiary center between 1990 and 2008. RESULTS: In 20% of patients, disease was persistent and/or aggressive despite prolonged and extensive treatment. Of this subgroup, 45% died of the disease. Prognostic factors of persistent/aggressive disease were facial nerve paralysis, bilateral disease, and significant major computed tomography findings (temporomandibular joint destruction, infratemporal fossa or nasopharyngeal soft tissue involvement). Cultures grew fungi in 5 patients, and follow-up imaging revealed disease progression. The overall 5-year survival was 55% for patients with short-term disease and 40% for patients with persistent/ aggressive disease (P = .086). By age, 5-year survival was 75% in patients younger than 70 years old and 44% in older patients (P = .029). CONCLUSIONS: A significant subset of patients with MEO has a prolonged, aggressive, and highly fatal disease that needs to be identified early. These patients more frequently have bilateral disease, cranial nerve paralysis, and positive computed tomography findings. Their follow-up should routinely include imaging studies to evaluate disease progression, and every effort should be made to identify and treat underlying fungal infection.

Fungal malignant external otitis.

OBJECTIVE: To investigate the clinical characteristics and outcome of fungal malignant external otitis (MEO). METHODS: The files of 60 patients treated for MEO in 1990-2008 at a tertiary medical center were reviewed for clinical characteristics and outcome, and findings were compared between patients with fungal and nonfungal infection. RESULTS: Mean duration of follow-up was 4 years. Nine patients (15%) had fungal disease; the main pathogen was Candida spp. Compared with the nonfungal MEO group, patients with a fungal infection were younger at diagnosis (average 68 vs. 74 years, p = 0.01) and had more facial nerve palsies (55% vs. 14%, p = 0.01), fewer positive bacterial cultures at presentation (33% vs. 75%, p = 0.02), and higher rates of surgery (78% vs. 18%, p = 0.0008) and hyperbaric treatment (78% vs. 4%, p = 0.0001). Eighty-nine percent had persistent infection (>2 courses of systemic antibiotics before antifungal treatment) compared with 12% in the nonfungal group (p = 0.0001). Fungal disease was associated with more persistently positive imaging findings (87.5% vs. 25%, p = 0.0001). There was no significant between-group difference in survival. CONCLUSION: Fungal MEO probably occurs secondary to prolonged antibiotic treatment for bacterial MEO. The fungal disease is more invasive than the bacterial disease, although survival is the same. Treatment should be aggressive and hyperbaric oxygen therapy should be considered.