Molecular Determinants of Thyroid Nodules with Indeterminate Cytology and RAS Mutations.

Background:RAS gene family mutations are the most prevalent in thyroid nodules with indeterminate cytology and are present in a wide spectrum of histological diagnoses. We evaluated differentially expressed genes and signaling pathways across the histological/clinical spectrum of RAS-mutant nodules to determine key molecular determinants associated with a high risk of malignancy. Methods: Sixty-one thyroid nodules with RAS mutations were identified. Based on the histological diagnosis and biological behavior, the nodules were grouped into five categories indicating their degree of malignancy: non-neoplastic appearance, benign neoplasm, indeterminate malignant potential, low-risk cancer, or high-risk cancer. Gene expression profiles of these nodules were determined using the NanoString PanCancer Pathways and IO 360 Panels, and Angiopoietin-2 level was determined by immunohistochemical staining. Results: The analysis of differentially expressed genes using the five categories as supervising parameters unearthed a significant correlation between the degree of malignancy and genes involved in cell cycle and apoptosis (BAX, CCNE2, CDKN2A, CDKN2B, CHEK1, E2F1, GSK3B, NFKB1, and PRKAR2A), PI3K pathway (CCNE2, CSF3, GSKB3, NFKB1, PPP2R2C, and SGK2), and stromal factors (ANGPT2 and DLL4). The expression of Angiopoietin-2 by immunohistochemistry also showed the same trend of increasing expression from non-neoplastic appearance to high-risk cancer (p < 0.0001). Conclusions: The gene expression analysis of RAS-mutant thyroid nodules suggests increasing upregulation of key oncogenic pathways depending on their degree of malignancy and supports the concept of a stepwise progression. The utility of ANGPT2 expression as a potential diagnostic biomarker warrants further evaluation.

Patient choice for high-volume center radiation impacts head and neck cancer outcome.

BACKGROUND: Studies suggest treatment outcomes may vary between high (HVC)- and low-volume centers (LVC). Radiation therapy (RT) for head and neck cancer (HNC) requires weeks of treatment, the inconvenience of which may influence a patient's choice for treatment location. We hypothesized that receipt of RT for HNC at a HVC would influence outcomes compared to patients evaluated at a HVC, but who chose to receive RT at a LVC. METHODS: From 1998 to 2011, 1930 HNC patients were evaluated at a HVC and then treated with RT at either a HVC or LVC. Time-to-event outcomes and treatment factors were compared. RESULTS: Median follow-up was 34 months. RT was delivered at a HVC for 1368 (71%) patients and at a LVC in 562 (29%). Patients were more likely to choose HVC-RT if they resided in the HVC's county or required definitive RT (all P < 0.001). HVC-RT was associated with a significant improvement in 3-year LRC (84% vs 68%), DFS (68% vs 48%), and OS (72% vs 57%) (all P < 0.001). On multivariate analysis (MVA), HVC-RT independently predicted for improved LRC, DFS, and OS (all P < 0.05). CONCLUSIONS: In patients evaluated at a HVC, the choice of RT location was primarily influenced by their residing distance from the HVC. HVC-RT was associated with improvements in LRC, DFS, and OS in HNC. As treatment planning and delivery are technically demanding in HNC, the choice to undergo treatment at a HVC may result in more optimal delivered dose, RT duration, and outcome.

Association of Tumor Size With Histologic and Clinical Outcomes Among Patients With Cytologically Indeterminate Thyroid Nodules.

Importance: Tens of thousands of unnecessary operations are performed each year for diagnostic purposes among patients with cytologically indeterminate thyroid nodules. Whereas a diagnostic lobectomy is recommended for most patients with solitary indeterminate thyroid nodules, a total thyroidectomy is preferred for nodules larger than 4 cm. Objective: To determine whether histologic or clinical outcomes of indeterminate thyroid nodules 4 cm or larger are worse than those for nodules smaller than 4 cm, thus justifying a more aggressive initial surgical approach. Design, Setting, and Participants: In this retrospective cohort study, 652 indeterminate thyroid nodules (546 nodules <4 cm and 106 nodules ≥4 cm) with surgical follow-up were consecutively evaluated at an academic cancer center from October 1, 2008, through April 30, 2016. Exposure: Tumor size. Main Outcomes and Measures: Differences in cancer rates, rates of invasive features, cancer aggressiveness, and response to therapy between indeterminate thyroid nodules smaller than 4 cm and 4 cm or larger. Results: A total of 652 indeterminate thyroid nodules (546 nodules <4 cm and 106 nodules ≥4 cm) from 589 patients (mean [SD] age, 53.1 [13.8] years; 453 [76.9%] female) were studied. No differences were found in the baseline characteristics of patients or nodules between the 2 size groups. Tumor size was not associated with the cancer rate as a categorical (140 of 546 [25.6%] for nodules <4 cm and 33 of 106 [31.1%] for nodules ≥4 cm; effect size, 0.05; 95% CI, 0.002-0.12) or continuous (odds ratio [OR], 1.03; 95% CI, 0.92-1.15) variable. No association was found between nodule size and prevalence of extrathyroidal extension, positive margins, lymphovascular invasion, lymph node metastasis, or distant metastasis. Most malignant tumors were low risk in both size groups (70% in the nodules <4 cm and 72% in the nodules ≥4 cm), and tumor size was not associated with tumor aggressiveness as a categorical (effect size, 0.10; 95% CI, 0.03-0.31) or continuous variable (OR for intermediate-risk cancer, 0.91; 95% CI, 0.72-1.14; OR for high-risk cancer, 1.43; 95% CI, 0.96-2.15). At the last follow-up visit, 88 of 105 patients (83.8%) with malignant tumors in the smaller than 4 cm group and 21 of 25 (84.0%) in the 4 cm or greater group had no evidence of disease, and tumor size was not associated with response to therapy (effect size, 0.13; 95% CI, 0.07-0.33). Conclusions and Relevance: Most indeterminate thyroid nodules are benign or low-risk malignant tumors regardless of tumor size. In the absence of other indications for total thyroidectomy, this study suggests that a thyroid lobectomy is sufficient initial treatment for most solitary cytologically indeterminate thyroid nodules independent of the tumor size.

Impact of oncogene panel results on surgical management of cytologically indeterminate thyroid nodules.

BACKGROUND: The impact of oncogene panel results on the surgical management of indeterminate thyroid nodules (ITNs) is currently unknown. METHODS: Surgical management of 649 patients consecutively evaluated from October 2008 to April 2016 with a single nodule biopsied and indeterminate cytology (193 evaluated with and 456 without oncogene panels) was assessed and compared. Histological features of 629 consecutively resected ITNs (164 evaluated with and 465 without oncogene panels) were also characterized and compared. RESULTS: Oncogene panel evaluation was associated with higher rates of total thyroidectomy (45% vs 28%; P = .006), and central lymph node dissection (19% vs 12%; P = .03) without increasing the yield of malignancy or decreasing the rate of completion thyroidectomy. Most malignancies (64%), including 83% of those with driver mutation identified, were low-risk cancers for which a lobectomy could have been sufficient initial treatment. CONCLUSION: Current oncogene panel results seem insufficient to guide the surgical extent of solitary ITNs.

Cancer Risk Associated with Nuclear Atypia in Cytologically Indeterminate Thyroid Nodules: A Systematic Review and Meta-Analysis.

BACKGROUND: Indeterminate categories of thyroid cytopathology (categories B-III and B-IV of the Bethesda system) are integrated by a heterogeneous spectrum of cytological scenarios that are generally clustered for analysis and management recommendations. It has been suggested that aspirates exhibiting nuclear atypia have a higher risk of malignancy. This study aimed to assess whether cytologically indeterminate thyroid nodules with nuclear atypia have a significantly higher cancer risk than those without nuclear atypia. METHODS: On June 30, 2016, PubMed and EMBASE were searched for articles in English or Spanish using a search strategy developed by an endocrinologist and a librarian. Case reports were excluded, and no date limits were used. The references of all included studies were also screened for relevant missing studies. Studies were included if the prevalences of malignancy of cytologically indeterminate thyroid nodules with histological confirmation with and without nuclear atypia were reported. Studies were excluded if they had: (i) nodules suspicious for malignancy; (ii) nodules with non-indeterminate (B-III or B-IV) cytology on repeated biopsy, if performed; (iii) nodules not consecutively evaluated; or (iv) cohorts overlapping with another larger series. Two investigators independently assessed the eligibility and risk of bias of the studies. PRISMA and MOOSE guidelines were followed. Summary data were extracted from published reports by one investigator and independently reviewed by another. Data were pooled using a random-effects model. Heterogeneity was explored using subgroup analysis and mixed-effect model meta-regression. The odds ratio for malignancy of cytologically indeterminate thyroid nodules with nuclear atypia over cytologically indeterminate thyroid nodules without nuclear atypia was calculated. RESULTS: Of 2571 retrieved studies, 20 were eligible. The meta-analysis was conducted on summary data of 3532 cytologically indeterminate thyroid nodules: 1162 with and 2370 without nuclear atypia. The odds ratio for malignancy in cytologically indeterminate thyroid nodules with nuclear atypia was 3.63 [confidence interval 3.06-4.35]. There was no evidence of publication bias, and heterogeneity was insignificant (I2 < 0.01%, p = 0.40). CONCLUSIONS: Nuclear atypia is a significant indicator of malignancy in cytologically indeterminate thyroid nodules and needs to be standardized and implemented into clinical practice.

Cancer Risk Stratification of Indeterminate Thyroid Nodules: A Cytological Approach.

BACKGROUND: Management recommendations for thyroid nodules rely primarily on the cytological diagnosis. However, 25% of biopsies render an indeterminate cytology for which management decision is more challenging due to heterogeneity of the specimens. This study aimed to stratify the cancer risk through subcategorization of indeterminate cytology. METHODS: The indeterminate cytological specimens (Bethesda-III or IV) of 518 thyroid nodules consecutively evaluated at our academic cancer center between October 2008 and September 2015, blinded to the histological outcome, were retrospectively reviewed. Cytological specimens were subclassified into four groups: aspirates exhibiting nuclear atypia (n = 158; 31%); architectural atypia (n = 222; 43%); oncocytic features (n = 120; 23%); or other types of atypia (n = 18; 3%). The prevalence of malignancy and odds ratio for malignancy were calculated in 323 nodules with histological confirmation. RESULTS: The prevalence of malignancy was 26% overall (20% in Bethesda-III and 29% in Bethesda-IV; p = 0.07), and 47%, 12%, 24%, and 25% for aspirates with nuclear atypia, architectural atypia, oncocytic features, or other types of atypia, respectively. The OR of nuclear atypia over architectural atypia was 6.4 (3.4-12.2; p < 0.001), and 2.7 over oncocytic features (1.4-5.1; p = 0.01), whereas the OR of architectural atypia over oncocytic features was 0.4 (0.2-0.9; p = 0.03). Results were similar for Bethesda-III and IV aspirates when analyzed independently. Furthermore, cytological subcategories improved cytology-histology correlation, as they were associated with distinct profiles of histological diagnoses (p < 0.001). CONCLUSIONS: Cytological subcategories can effectively stratify the risk of malignancy of thyroid nodules with indeterminate cytology and improve cytology-histology correlation.

Evaluation of ThyroSeq v2 performance in thyroid nodules with indeterminate cytology.

ThyroSeq v2 claims high positive (PPV) and negative (NPV) predictive values in a wide range of pretest risks of malignancy in indeterminate thyroid nodules (ITNs) (categories B-III and B-IV of the Bethesda system). We evaluated ThyroSeq v2 performance in a cohort of patients with ITNs seen at our Academic Cancer Center from September 2014 to April 2016, in light of the new diagnostic criteria for non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). Our study included 182 patients (76% female) with 190 ITNs consecutively tested with ThyroSeq v2. Patient treatment followed our institutional thyroid nodule clinical pathway. Histologies of nodules with follicular variant papillary thyroid carcinoma or NIFTP diagnoses were reviewed, with reviewers blinded to molecular results. ThyroSeq v2 performance was calculated in nodules with histological confirmation. We identified a mutation in 24% (n = 45) of the nodules. Mutations in RAS were the most prevalent (n = 21), but the positive predictive value of this mutation was much lower (31%) than that in prior reports. In 102 resected ITNs, ThyroSeq v2 performance was as follows: sensitivity 70% (46-88), specificity 77% (66-85), PPV 42% (25-61) and NPV 91% (82-97). The performance in B-IV nodules was significantly better than that in B-III nodules (area under the curve 0.84 vs 0.57, respectively; P = 0.03), where it was uninformative. Further studies evaluating ThyroSeq v2 performance are needed, particularly in B-III.

Increased acute mortality with chemoradiotherapy for locally advanced head and neck cancer in patients ≥70years.

PURPOSE: Concurrent chemoradiotherapy (CRT) is the standard of care for many sites of locally advanced head and neck squamous cell carcinomas (LAHNC). However, on meta-analysis, the addition of chemotherapy did not improve survival for patients >70years. We hypothesized that elderly patients treated with CRT would have increased toxicity without similar improvements in survival. METHODS: A single-institution, IRB-approved retrospective study took place from 2005 to 2012 including 369 patients treated with CRT for LAHNC. Multivariate models for death at 3months and death over time were developed using logistic regression and Cox modeling, respectively. RESULTS: Patients ≥70years were treated less often with concurrent cisplatin dosed every 3weeks (25.5% vs. 71.4%, respectively) and more often with weekly carboplatin (31.9% vs. 3.4%) than patients <70years (n=322; p<0.001). Patients ≥70years experienced increased toxicity during treatment with more frequently hospitalizations (36.2% vs. 21.1%; p=0.02) and a lower rate of PEG removal at last follow-up or death (77.1% vs. 92.9%; p=0.004). A higher proportion of patients ≥70years died within 3months (12.8% vs. 2.8%; p=0.001) following CRT. Patients ≥70 had an increased risk of death at 3months following CRT (odds ratio 5.19, 95% CI 1.64-16.41; p=0.005) and worse survival over time (hazard ratio 2.30, 95% CI 1.34-3.93; p=0.002). CONCLUSIONS: Patients ≥70years were more often treated with less toxic chemotherapy, yet experienced higher rates of hospitalization during treatment and increased rates of acute mortality following CRT. The efficacy of chemoradiotherapy for elderly patients should be evaluated in a prospective setting.

Adjuvant radiotherapy versus concurrent chemoradiotherapy for the management of high-risk salivary gland carcinomas.

BACKGROUND: Given the aggressive behavior of advanced salivary malignancies, the purpose of the current study was to explore the utility of adjuvant chemoradiotherapy (CRT) in this population. METHODS: A retrospective study of salivary carcinomas treated from 1998 to 2013 with postoperative CRT (37 patients) or radiotherapy (RT; 103 patients) was completed. RESULTS: The decision to utilize adjuvant CRT versus RT was influenced by tumor grade and histology, cervical lymph node status, surgical margins, and perineural invasion. In both treatment cohorts, high locoregional control rates were obtained (79% for CRT vs 91% for RT; p = .031). Multivariate Cox regression analysis did not identify a difference in 3-year progression-free survival (PFS) with the use of CRT versus RT (hazard ratio [HR] = 0.783; 95% confidence interval [CI] = 0.396-1.549; p = .482). CONCLUSION: Until prospective evidence is available, such as from Radiation Therapy Oncology Group 1008, the standard use of CRT for advanced salivary malignancies cannot be recommended. © 2016 Wiley Periodicals, Inc. Head Neck 38: 1708-1716, 2016.

Institutional prevalence of malignancy of indeterminate thyroid cytology is necessary but insufficient to accurately interpret molecular marker tests.

OBJECTIVE: Several molecular marker tests are available to refine the diagnosis of thyroid nodules. Knowing the true prevalence of malignancy (PoM) within each cytological category is considered necessary to select the most appropriate test and to interpret results accurately. We describe our institutional PoM among cytological categories and report our experience with molecular markers. DESIGN: Single-center retrospective study. METHODS: We calculated the institutional PoM for each category of the Bethesda system (Bethesda) on all thyroid nodules with cytological evaluation from October 2008 to May 2014. We estimated the predictive values for Afirma, miRInform, and ThyroSeq v2, based on published sensitivity and specificity. Finally, we assessed our own experience with miRInform. RESULTS: The PoMs for Bethesda III and IV categories were 21 and 28%, respectively. ThyroSeq v2 achieves the highest theoretical negative and positive predictive values (NPV and PPV) in Bethesda III (98 and 75%) and Bethesda IV categories (96 and 83%). At our institution, miRInform detected a mutation in 16% of 109 indeterminate nodules tested, all in Bethesda IV specimens. Histology was available in 56 (51%) nodules. The observed sensitivity and specificity in Bethesda IV specimens were 63 and 86%, yielding an NPV and a PPV of 75 and 77%, respectively. CONCLUSIONS: For our current Bethesda III and IV PoM, the actual performance of miRInform was worse than expected. Theoretically ThyroSeq v2 should have the best performance, but it could be affected in the same way as miRInform, given the similarities between the tests. Assessing the institutional performance of each test is necessary along with PoM individualization.

Determining optimal follow-up in the management of human papillomavirus-positive oropharyngeal cancer.

BACKGROUND: Determining the optimal follow-up for patients can help maximize the use of health care resources. This is particularly true in a growing epidemic such as human papillomavirus-positive oropharyngeal squamous cell carcinoma (HPV+OPSCC). The objective of the current study was to evaluate time to disease recurrence or late toxicity in this cohort of patients to optimize patient management. METHODS: An institutional database identified 232 patients with biopsy-proven, nonmetastatic HPV+OPSCC who were treated with radiotherapy. A retrospective review was conducted in patients who were followed every 3 months for the first year, every 4 months in year 2, and every 6 months in years 3 to 5. Late toxicity (grade ≥ 3; toxicity was scored based on National Cancer Institute Common Terminology Criteria for Adverse Events [version 4]), locoregional control, distant control, and overall survival were assessed. RESULTS: The median follow-up was 33 months. Based on Radiation Therapy Oncology Group (RTOG) 0129 study risk groupings, patients were either considered to be at low (162 patients; 70%) or intermediate (70 patients; 30%) risk. Concurrent systemic therapy was used in 85% of patients (196 patients). The 3-year locoregional control, distant control, and overall survival rates were 94%, 91%, and 91%, respectively. Late toxicity occurred in 9% of patients (21 patients). Overall, 64% of toxicity and failure events occurred within the first 6 months of follow-up, with a < 2% event incidence noted at each subsequent follow-up. Only 4 patients experienced their first event after 2 years. CONCLUSIONS: HPV+OPSCC has a low risk of disease recurrence and late toxicity after treatment; approximately two-thirds of events occur within the first 6 months of follow-up. These data suggest that it may be reasonable to reduce follow-up in patients with HPV+OPSCC to every 3 months for the first 6 months, every 6 months for the first 2 years, and annually thereafter.

Outcomes of mucosal melanoma of the head and neck.

INTRODUCTION: Mucosal melanoma of the head and neck is a rare disease with limited data available on outcomes; therefore, we reviewed our institutional experience. METHODS: An institutional database was queried and 38 patients with head and neck mucosal melanoma were identified. Charts were abstracted and local control (LC), progression-free survival (PFS) and overall survival (OS) were calculated. RESULTS: Most patients had T4 disease (86%), although nodes were positive in 11%. En bloc or endoscopic resection was performed on 93%. Adjuvant or definitive radiotherapy to a median dose of 60 Gy was utilized in 90%. Chemotherapy was given in 21%, and 16% received interferon. Three-year LC, PFS and OS were 90%, 48% and 59%, respectively. Median OS was 4.6 years. Site of first failure was distant in 52% of cases. CONCLUSION: With aggressive therapy median OS was 4.6 years in this cohort. Distant recurrence remains the primary mode of failure. It may be reasonable to include mucosal melanoma patients in trials of systemic agents along with high-risk cutaneous melanomas.

Comparison of every 3 week cisplatin or weekly cetuximab with concurrent radiotherapy for locally advanced head and neck cancer.

BACKGROUND: Cisplatin dosed every 3 weeks (CIS) or weekly cetuximab (CTX) concurrent with radiotherapy are standards of care for locally advanced head and neck squamous cell carcinoma (LAHNC). Retrospective comparisons of CIS and CTX have offered mixed conclusions. We compared outcomes between CIS and CTX in this patient population. METHODS: Between January 2006 and December 2011, we identified 279 patients who underwent definitive radiotherapy and concurrent systemic therapy for LAHNC. The median age difference between the CIS and CTX groups was relatively small (58 vs. 62 years, respectively) and CIS patients had a slightly higher rate of N2 disease than CTX patients (74% vs. 61%, respectively). RESULTS: Median follow-up was 27 months. Systemic therapy consisted of CIS in 241 (86.4%) and CTX in 38 (13.6%). Actuarial locoregional control of the CIS and CTX groups at 2 years were 91% and 90% (p=0.74), respectively. Actuarial 2 year distant metastasis rates between the groups were 8% and 12%, respectively (p=0.55), and actuarial 2 year overall survival between the groups were 87% and 89%, respectively (p=0.47). CONCLUSIONS: We found no difference in locoregional control, distant metastasis rate, or overall survival between patients treated with concurrent CIS or CTX.

Induction docetaxel, Cisplatin, and 5-Fluorouracil precludes definitive chemoradiotherapy in a substantial proportion of patients with head and neck cancer in a low socioeconomic status population.

OBJECTIVES: In this retrospective study we evaluate the tolerability and outcomes after induction chemotherapy for patients with predominately low socioeconomic status (SES) with locally advanced head and neck cancer (LAHNC). METHODS: One hundred eighteen patients with LAHNC of the hypopharynx, larynx, oral cavity, or oropharynx began curative intent therapy with induction cisplatin (75 or 100 mg/m), docetaxel (75 mg/m), and 5-fluorouracil (750 mg/m×5 d or 1000 mg/m×4 d; continuous infusion) every 3 weeks (DPF) for a planned 2 to 3 cycles. All patients were to receive curative radiotherapy with concurrent systemic therapy. Associations were tested using χ test, and survival estimates were calculated using the Kaplan-Meier method. RESULTS: Most patients (75.4%) were of low SES. Induction DPF was delivered for a median of 2 cycles (range, 1 to 3) and 14% of the patients (n=17) died during induction DPF. After DPF, 38.2% of patients were unable to complete or receive planned definitive therapy. Overall 15.3% of patients died during therapy, and mortality was associated with a Karnofsky performance status <80 (P=0.04). At 2 years the locoregional control was 52.7%, whereas the distant metastases free rate was 72.6%, and the overall survival rate was 34.1%. Low SES patients were less likely to achieve locoregional control (P=0.05) or survive (P=0.08). CONCLUSIONS: In this population of LAHNC patients of low SES with a high tumor burden and poor performance status, use of induction DPF was associated with 15.3% mortality during therapy and precluded 38.2% of patients from initiating or completing planned definitive therapy.

Diminishing diagnosis of follicular thyroid carcinoma.

BACKGROUND: Follicular carcinomas have been reported as 10% to 15% of thyroid malignancies. Refinements in the histologic criteria applied in the classification of follicular lesions have occurred. We aim to document the true incidence of follicular cancers in a cohort from a high-volume endocrine practice. METHODS: Patient charts were reviewed and cancers were classified into major subtypes; papillary cancers were further classified by common variants. Proportions were compared to historic Surveillance, Epidemiology, and End Results (SEER) database proportions. RESULTS: Only 2.7% of patients had follicular carcinoma. The proportion of patients with follicular cancer was less than the reported rates of 10% to 15%, and less than the 6.7% extrapolated from SEER. CONCLUSION: The proportion of follicular cancers is less than traditionally reported. This change is due to an increased incidence of papillary cancers, and modifications of the histologic criteria used for classification of encapsulated follicular lesions. There are potential prognostic consequences, as follicular cancers have been perceived as more aggressive.

Operative findings in the frontal recess at time of revision surgery.

OBJECTIVE: Endoscopic sinus surgery is the gold standard for the treatment of medically refractory chronic rhinosinusitis. There is, however, a population of patients for whom persistent disease is a problem. Of all the sinuses, the frontal sinus is the most likely to have recurrent obstruction. We evaluated the findings causing frontal recess obstruction at the time of revision surgery. STUDY DESIGN AND SETTING: A retrospective review was performed in a tertiary care academic otolaryngology department. RESULTS: Findings obstructing the frontal recess at the time of revision sinus surgery were reviewed. Two hundred eighty-nine frontal sinuses were included. Seven findings were identified: mucosal disease (67%), retained ethmoid cells (53%), lateralized middle turbinates (30%), retained agger nasi cells (13%), scar (12%), retained frontal cells (8%), and neoosteogenesis (7%). Most frontal recesses had multiple etiologies for failure listed above, with an average of 1.6. CONCLUSIONS: Multiple findings can be identified that contribute to frontal recess obstruction requiring revision sinus surgery. A comprehensive approach to address all factors is necessary to prevent surgical failure among patients presenting for endoscopic frontal sinus surgery.

E6 and E7 oncogene expression by human papilloma virus (HPV) and the aggressive behavior of recurrent laryngeal papillomatosis (RLP).

Recurrent laryngeal papillomatosis (RLP), a chronic disease associated with human papilloma virus (HPV), requires serial surgical procedures for debulking, resulting in debilitating long-term dysphonia, laryngeal scarring, and rarely malignant degeneration. Human papilloma virus 11 tumors have been widely accepted as more aggressive than HPV 6 tumors; however, the clinical course has been difficult to predict at disease onset, and the biologic mediators of proliferation have not been well characterized. A retrospective case review of 43 patients (4 months to 10 years at diagnosis) was performed on children treated for recurrent laryngeal papillomatosis. Patient charts were reviewed for demographic information, age at RLP diagnosis, approximate frequency of surgical intervention, and absolute number of surgical procedures performed. Human papilloma virus subtyping was performed. Expression analysis of the HPV-encoded E6 and E7 oncogenes was performed by reverse-transcriptase polymerase chain reaction. Fourteen patients had subtype 11 (33%) and 29 patients had subtype 6 (67%). As expected, HPV 11 patients showed a more aggressive clinical course than HPV 6 patients. However, 38% of patients with subtype 6 (11 patients) followed a clinical course that mirrored the more severe subtype 11 patients. These patients expressed the disease at a younger age (P < 0.0002) and showed higher levels of E6 and E7 oncogenes compared to the patients with the more indolent course. Although HPV subtype and early onset of RLP are well characterized prognostic factors, our study documents the significance of E6 and E7 oncogene expression as potential biologic mediators of proliferation and thereby clinical behavior.

Sigmoid sinus diverticulum: a new surgical approach to the correction of pulsatile tinnitus.

OBJECTIVE: Tinnitus represents a bothersome symptom not infrequently encountered in an otology practice. Tinnitus can be the harbinger of identifiable middle or inner ear abnormality; but more frequently, tinnitus stands alone as a subjective symptom with no easy treatment. When a patient complains of tinnitus that is pulsatile in nature, a thorough workup is indicated to rule out vascular abnormality. We report of a new diagnostic finding and method of surgical correction for select patients with pulsatile tinnitus. STUDY DESIGN: Retrospective case series. SETTING: Tertiary care, academic referral center. PATIENTS: Among patients seen for complaints of unilateral or bilateral pulsatile tinnitus, five were identified with diverticula of the sigmoid sinus. All patients had normal in-office otoscopic, tympanometric, and audiometric evaluations. Patients with paragangliomas or benign intracranial hypertension were excluded. Auscultation of the pinna or mastoid revealed an audible bruit in most patients. All patients underwent computed tomographic angiography of the temporal bone. In all cases, this finding was on the side coincident with the tinnitus. INTERVENTION: Three of five patients underwent transmastoid reconstruction of the sigmoid sinus. MAIN OUTCOME MEASURE: Patients were evaluated clinically for presence or absence of pulsatile tinnitus after reconstructive surgery. RESULTS: All patients electing surgical reconstruction had immediate and lasting resolution of the tinnitus. CONCLUSION: Surgical reconstruction can provide lasting symptom relief for patients with pulsatile tinnitus and computed tomographic evidence of a sigmoid sinus diverticulum.

Invasive fungal rhinosinusitis: what is the appropriate follow-up?

BACKGROUND: Early detection and aggressive surgical and medical management have been associated with higher overall survival rates among patients with invasive fungal rhinosinusitis (IFS). With improved survival comes the question of how to appropriately manage these patients once disease stability has been achieved. Previous reports suggest follow-up only as long as the patients remain immunocompromised. This study attempts to answer the question of long-term clinical follow-up and suggests a regimen suitable for ensuring minimal posttreatment complications. METHODS: A retrospective review included all patients diagnosed with IFS between 1988 and 2004. The study group included patients who survived the initial treatment course, with at least 30 days of posttreatment follow-up of their IFS. Patient records were reviewed for significant complications, evidence of chronic sinus disease, the clinical status of their underlying medical comorbidities, and frequency and mode of follow-up. RESULTS: Thirteen patients were included. The average follow-up time was 633 days. Significant complications included one patient with acute bacterial sinusitis with resultant visual loss and one patient with chronic osteomyelitis of the orbit and skull base. Six of 13 patients had persistent chronic bacterial rhinosinusitis with crusting and bone sequestration. All complications were noted to occur after initial IFS eradication was thought to have taken place. CONCLUSION: Significant complications of IFS can occur after medical remission and recovery of immune competence. Patients with IFS should be followed long term until remucosalization of the sinuses, resolution of crusting, and cessation of bony sequestration has occurred.