Prevalence of HPV Infection in Racial-Ethnic Subgroups of Head and Neck Cancer Patients.

The landscape of HPV infection in racial/ethnic subgroups of head and neck cancer (HNC) patients has not been evaluated carefully. In this study, a meta-analysis examined the prevalence of HPV in HNC patients of African ancestry. Additionally, a pooled analysis of subject-level data was also performed to investigate HPV prevalence and patterns of p16 (CDNK2A) expression amongst different racial groups. Eighteen publications (N = 798 Black HNC patients) were examined in the meta-analysis, and the pooled analysis included 29 datasets comprised of 3,129 HNC patients of diverse racial/ethnic background. The meta-analysis revealed that the prevalence of HPV16 was higher among Blacks with oropharyngeal cancer than Blacks with non-oropharyngeal cancer. However, there was great heterogeneity observed among studies (Q test P<0.0001). In the pooled analysis, after adjusting for each study, year of diagnosis, age, gender and smoking status, the prevalence of HPV16/18 in oropharyngeal cancer patients was highest in Whites (61.1%), followed by 58.0% in Blacks and 25.2% in Asians (P<0.0001). There was no statistically significant difference in HPV16/18 prevalence in non-oropharyngeal cancer by race (P=0.682). With regard to the pattern of HPV16/18 status and p16 expression, White patients had the highest proportion of HPV16/18+/p16+ oropharyngeal cancer (52.3%), while Asians and Blacks had significantly lower proportions (23.0% and 22.6%, respectively) [P <0.0001]. Our findings suggest that the pattern of HPV16/18 status and p16 expression in oropharyngeal cancer appears to differ by race and this may contribute to survival disparities.

Human papillomavirus-related cell cycle markers can predict survival outcomes following a transoral lateral oropharyngectomy for tonsillar squamous cell carcinoma.

OBJECTIVES: To identify the prognostic implications of human papillomavirus (HPV)-related cell cycle marker profiles in patients who have received a transoral lateral oropharyngectomy (TLO) as a primary treatment for tonsillar squamous cell carcinoma (TSCC). PATIENTS AND METHODS: Immunohistochemical profiles of HPV-related cell cycle markers, including p16, pRb, cyclin D1, p53, and the HPV DNA status of 42 consecutive TSCC patients who underwent TLO-based treatments were analyzed. The prognostic value of each marker was evaluated. RESULTS: Univariate analysis indicated that high p16, low pRb, and low p53 expression levels are significantly associated with a good disease-free and overall survival outcome. Clinicopathological parameters and the HPV DNA status did not show prognostic significance. When adjusted for age, overall stage and treatment strategy, a high p16 and low pRb level remained an effective prognostic marker for good survival outcomes. A high p16/low pRb combination showed superior survival prediction ability over high p16 or low pRb alone. CONCLUSION: HPV-related cell cycle markers may also be good indicators for predicting survival after TLO for TSCC. The de-escalation TLO surgery approach would be more effective if performed under the stringent guidance of these markers.

Surgical targeting of recurrent thyroid cancer using a novel mixture of 99m-technetium macroaggregated albumin and indocyanine green.

BACKGROUND: Precise targeting has played a pivotal role in the success of surgery for recurrent differentiated thyroid cancers (DTCs). To improve on current targeting methods, we developed a novel technique using (99m)Tc-macroaggregated human serum albumin and indocyanine green (TIGMA), with which surgeons effectively target lesions in real time by radiofluorescence dual guidance. METHODS: Seven patients with 10 recurrent DTC lesions were retrospectively enrolled in the study. Prior to the operation, we injected TIGMA into the target lesion under the guidance of ultrasonography. Resection was concurrently monitored using a gamma probe and a specially designed near infrared fluorescence camera. Outcomes were evaluated using imaging, surgical, and pathological records. RESULTS: In all enrolled cases, both injection of TIGMA and radiofluorescence dual guidance were well tolerated and easy to implement. The technical success rates were 100%, confirmed by final pathological examination, postoperative ultrasonography, and I-131 scan clearance. Complications such as temporary postoperative neck pain (n = 2) were minimal. CONCLUSIONS: TIGMA using radiofluorescence dual guidance facilitated the precise targeting of recurrent lesions. The entire procedure was feasible, safe, and successful. This method would help enhance surgical outcomes for recurrent DTCs.

Metachronous Second Primary Malignancies after Head and Neck Cancer in a Korean Cohort (1993-2010).

Second primary malignancy (SPM) is the major long-term cause of patient mortality with head and neck squamous cell carcinoma (HNSCC). As the incidence of high-risk human papillomavirus (HPV)-related HNSCC is increasing globally, we analyzed the patterns of SPM occurrence, the effect of the index tumor site along with attributes to HPV, and the effect of SPM on survival in South Korean patients with head and neck cancer (HNC). Data were retrieved from the Korea Central Cancer Registry, a nationwide population-based cancer registry, from 1993 to 2010. Standardized incidence ratios were analyzed and compared between index tumor sites, particularly oropharyngeal vs. non-oropharyngeal sites. After adjustment for competing risks, 3- and 5-year SPM rates were calculated using the cumulative incidence function. The effects of SPM occurrence on overall survival (OS) were then analyzed. SPM rates were significantly lower for HPV-attributable oropharyngeal sites than for non-oropharyngeal sites, such as the larynx and hypopharynx (p<0.001). SPM rates were also lower for oral cavity first primary sites than for non-oropharyngeal first primary sites (p<0.001). SPMs typically occurred in the esophagus, lungs and the head and neck. Uterine cervical cancers occurred significantly more frequently after index oropharyngeal cancer in women. The 5-year and 10-year OS rates were 57.8 and 45.7% in all HNC patients, respectively. The OS after SPM occurrence was poor (5-year, 31.8%; 10-year, 20.8%) compared to after index HNC occurrence (5-year, 68.4%; 10-year, 41.2%). SPM occurrence in the esophagus and lung/bronchus showed a worse OS than SPM localized to the head and neck. South Korean HNC patient, the first primary cancer site affected SPM risk and distribution. The 5- and 10-year OS rates deteriorated after SPM occurrence, particularly in the esophagus and lungs. Further optimization of follow-up strategies for effective surveillance of SPM, particularly in the esophagus and lungs, is warranted.

Low-dose cisplatin converts the tumor microenvironment into a permissive state for HSVtk-induced antitumor immunity in HPV16-related tonsillar carcinoma.

An adenovirus harboring the HSV thymidine kinase (HSVtk) gene under the regulation of a trans-splicing ribozyme that targets telomerase is cytotoxic to cancer cells because it inhibits DNA replication (Ad5mTR). Furthermore, it induces anti-tumor immunity by activating cytotoxic T cells. Because multiple chemotherapeutic agents also activate cytotoxic T-cell immunity during the direct killing process of tumor cells, we herein explored whether low-dose cisplatin could synergize with cytotoxic Ad5mTR to potentiate its therapeutic effect by boosting anti-tumor immunity in a murine HPV16-associated tonsillar carcinoma model. Tumor regression was enhanced when low-dose (1 mg/kg) cisplatin was added to suicide gene therapy using Ad5mTR. Meanwhile, 1 mg/kg cisplatin alone had no tumor-suppressive effects and did not result in any systemic toxicity. Thus, cisplatin along with Ad5mTR improved tumor clearance by increasing the number of E7-specific CD8+ T cells. Specifically, analysis of the tumors and lymph nodes supported improved immune clearance by increasing the number of E7-specific CD8+ T cells inside tumors (40%, P < 0.05) as a result of the combination of suicide gene and cisplatin therapy. These results suggest that a low dose of cisplatin potentiates CD8+ T-cell-mediated anti-tumor immunity, and its addition to the HSVtk-based adenovirus results in additional therapeutic benefits for HPV16-positive head and neck cancer patients.

Voice Changes in Elderly Adults: Prevalence and the Effect of Social, Behavioral, and Health Status on Voice Quality.

OBJECTIVES: To estimate the prevalence of dysphonia and the effect of several risk factors on vocal quality in a representative population of older adults. DESIGN: Cross-sectional. SETTING: Korea. PARTICIPANTS: Individuals aged 65 and older who underwent laryngoscopy from 2008 to 2010 (N = 3,759). MEASUREMENTS: The prevalence of dysphonia and the effect of potential risk factors on voice quality in elderly adults were measured. RESULTS: The mean age of participants was 72.4. The prevalence of dysphonia was 8.5% (95% confidence interval (CI) = 7.4-9.8). There was no significant difference in prevalence according to age. Multivariable analysis after adjusting for age, sex, vocal fold disease, and all variables that were identified in the univariate analysis revealed that urban residence (odds ratio (OR) = 1.83, 95% CI = 1.11-3.04), underweight (OR = 2.79, 95% CI = 1.45-5.38) or normal weight (OR = 1.63, 95% CI = 1.03-2.59), poor (OR = 2.00, 95% CI = 1.19-3.34) or intermediate (OR = 2.08, 95% CI = 1.15-3.78) subjective health status, asthma (OR = 2.08, 95% CI = 1.12-3.86), chronic obstructive pulmonary disease (OR = 2.49, 95% CI = 1.10-5.62), thyroid disease (OR = 3.08, 95% CI = 1.50-6.34), and vocal fold disease (OR = 3.72, 95% CI = 2.16-6.42) were independently associated with dysphonia in elderly adults. CONCLUSION: This study provides valuable information regarding the prevalence of dysphonia and the risk factors that contribute to vocal quality in older adults. These factors are mostly associated with social, behavioral, and underlying health status variables. Multidisciplinary treatment should be considered to improve voice conditions in elderly adults.

Administration of Radioactive Iodine Therapy Within 1 Year After Total Thyroidectomy Does Not Affect Vocal Function.

UNLABELLED: The purpose of this study was to evaluate the impact of radioactive iodine therapy (RIT) on vocal function during the early follow-up period after total thyroidectomy (TT) using perceptive and objective measurements, questionnaires regarding subjective symptoms, and data on vocal function in a prospectively enrolled and serially followed thyroid cancer cohort. METHODS: Of 212 patients who underwent TT and were screened between January and December 2010 at our hospital, 160 were included in the final analysis. Patients with the following histories were excluded: lateral neck dissection, organic vocal fold disease, external radiotherapy, and voice evaluation during thyroxine withdrawal. Patients were stratified into 3 groups: TT, TT with low-dose RIT (1.1-2.2 GBq), and TT with high-dose RIT (≥3.7 GBq). Voice evaluations were performed before surgery and at 1, 6, and 12 mo after TT. RESULTS: Vocal characteristics were altered after TT, including changes on the grade, roughness, and strain scale; increased amplitude perturbation; decreased fundamental frequency; narrowed pitch range; and global disturbances in subjective functional parameters on the voice handicap index. However, the degree of vocal changes among the 3 groups did not significantly differ within the 1-y postoperative follow-up period. According to the results of subgroup analyses of patients who demonstrated good voice outcomes after TT, there were no significant functional differences among the 3 groups. CONCLUSION: RIT at any dose does not affect vocal function within 1 y of TT.

Postoperative simultaneous integrated boost-intensity modulated radiation therapy for patients with locoregionally advanced papillary thyroid carcinoma: preliminary results of a phase II trial and propensity score analysis.

CONTEXT: With recent technical advances in radiotherapy (RT) planning, simultaneous integrated boost intensity modulated radiotherapy (SIB-IMRT) has made possible the delivery of high radiation dose to the tumor, minimizing surrounding normal tissues. OBJECTIVE: This study aimed to evaluate the clinical effectiveness and safety of postoperative SIB-IMRT in patients with locoregionally advanced papillary thyroid cancer (PTC). DESIGN AND SETTING: This was a propensity score-matched case control study conducted at a tertiary referring center. PATIENTS OR OTHER PARTICIPANTS: This study included locoregionally advanced patients with PTC (pT4 or N1b) who underwent thyroid cancer surgery and radioactive iodine ablation (RIA) followed by postoperative SIB-IMRT (RT group) under a phase II trial or no postoperative RT (Non-RT group) Intervention: Postoperative SIB-IMRT was the intervention. MAIN OUTCOME MEASURES: locoregional relapse-free survival (LRFS) was compared between RT group and Non-RT group. RESULTS: Multivariate analysis showed that several factors, including sex, American Thyroid Association risk category, and use of postoperative RT were significantly associated with LRFS in all 201 patients (P < .05 each). In the 118 propensity score-matched patients, there were no significant differences in baseline characteristics between the RT and Non-RT groups, but the LRFS rate was significantly higher in the RT than in the Non-RT group (4 y: 100% vs 84.6%, P = .002). Overall, SIB-IMRT was well tolerated, with no grade ≥3 toxicity, and was completed as planned in all patients. CONCLUSIONS: Postoperative SIB-IMRT is feasible and effective in improving locoregional control in patients with locally advanced PTC. Large-scale randomized studies are warranted.

Identification of occult tumors by whole-specimen mapping in solitary papillary thyroid carcinoma.

We undertook this study to estimate an accurate incidence and spread patterns of occult papillary thyroid carcinoma (PTC) in patients with a preoperative diagnosis of solitary PTC by using whole-specimen mapping of all specimens after a total thyroidectomy. Enrolled prospectively in this whole-thyroid mapping study are 82 consecutive patients who underwent a total thyroidectomy under a preoperative diagnosis of solitary PTC. All thyroidectomy specimens were serially sectioned in 2 mm thickness and whole-thyroid mapping was carried out for additional foci of occult PTC. The frequencies of occult lesions detected in the whole and contralateral lobe were determined, and clinicopathologic factors associated with multifocality were assessed. Whole-thyroid mapping revealed 66 occult PTC lesions missed by preoperative ultrasound in 37 (45.1%) of the 82 patients. The great majority (92.5%) of the occult PTC was smaller than 3 mm in size and 25 patients (30.5%) had contralateral lesions. We found that the male sex was an independent predictor of multifocality (odds ratio (OR), 3.00; 95% CI, 1.11-8.14), adjusting for preoperative findings. Analysis with pathologic parameters showed that the male sex (OR, 5.03; 95% CI, 1.68-15.08) and extrathyroidal extensions (OR, 3.03; 95% CI, 1.03-8.95) were associated with multifocal PTC. However, none of the clinicopathologic factors evaluated predicted contralateral PTC. Our study demonstrates the diagnostic limitations of ultrasound for the detection of multifocal PTC and the need to consider the possibility of occult lesions in the management of solitary PTC, especially in male patients.

Trends of human papillomavirus-related head and neck cancers in Korea: national cancer registry data.

OBJECTIVES/HYPOTHESIS: The incidence of human papillomavirus (HPV)-positive head and neck cancers (HNCs) is increasing sharply worldwide, while their HPV-negative counterparts are showing a decreased frequency. However, epidemiologic data related to these changes are sparse in Korea, which is rapidly adopting more westernized lifestyles. STUDY DESIGN: Data from the Korea Central Cancer Registry, a nationwide population-based cancer registry, from 1999 to 2009 were retrieved. METHODS: Age-standardized rates (ASRs), their annual percent changes (APC) and male-to-female incidence rate ratios (IRRs) were analyzed and compared between HPV-related and HPV-unrelated primary sites. RESULTS: HPV-related sites (oropharynx) had increased significantly over the period 1999 to 2009 (APC = 2.35%, P = 0.017), particularly in young men (30-59 years, APC = 2.65%, P = 0.031), whereas HPV-unrelated sites such as larynx and hypopharynx decreased markedly in both sexes. Interestingly, tongue cancer was found to have increased gradually (APC = 2.35%, P = 0.003) in both sexes. The male-to-female IRRs and the median age of occurrence remained stable. CONCLUSIONS: Although the cultural and ethnic background differs from the United States, cancers of HPV-related sites are increasing in Korea, whereas cancers of HPV-unrelated sites are decreasing, which is similar to the trends observed in the United States. Greater public awareness in Korea of HPV-related HNCs is therefore warranted.

Extent of thyroidectomy affects vocal and throat functions: a prospective observational study of lobectomy versus total thyroidectomy.

BACKGROUND: Voice and throat dysfunction may occur in patients after thyroidectomy, even in the absence of apparent laryngeal nerve injury. We evaluated the impact of thyroid surgery on voice and throat function using perceptive, objective, and subjective measurements in a prospectively enrolled and serially followed cohort of thyroid cancer patients. We assessed the impact of surgical extent and intensity of postoperative treatment, including addition radioactive iodine treatment (RIT), on these functions. METHODS: Consenting patients undergoing thyroid lobectomy (TL; n = 33), total thyroidectomy (TT; n = 41), or TT plus RIT (n = 81), none of whom had laryngeal nerve dysfunction perioperatively, were enrolled prospectively. All underwent comprehensive functional evaluations, including perceptive voice quality using the grade, roughness, breathiness, asthenia, strain (GRBAS) scale and acoustic voice analysis with multiple parameters, and filled out subjective questionnaires, including the Voice Handicap Index (VHI) and the Glasgow Edinburgh Throat Scale, before thyroidectomy and at 1, 6, and 12 months postoperatively. RESULTS: In this study, 14-83% of the patients developed some element of voice and throat dysfunction, shown consistently in different evaluations. Typical patterns were alterations of perceptive voice, deranged acoustic parameters, and subjective worsening on the VHI and GETS. Moreover, these changes were correlated with the extent of treatment, especially within 3 months after operation, and often persisted 12 months postoperatively. RIT had no effects on voice outcomes throughout the follow-up. CONCLUSION: Voice and throat dysfunction are evident after thyroidectomy, more severely after TT than TL. These potential disabilities should be considered carefully to further enhance patients' quality of life.