Faculty Bibliography

Introduction: Recently, radiofrequency ablation (RFA) has been increasingly used for the treatment of thyroid nodules. However, immediate morphological changes associated with bipolar devices are poorly shown. Aims: To present the results of analysis of gross and microscopic alterations in human thyroid tissue induced by RFA delivered through the application of the original patented device. Materials and methods: In total, there were 37 surgically removed thyroid glands in females aged 32-67 at presentation: 16 nodules were follicular adenoma (labelled as 'parenchymal' solid benign nodules) and adenomatous colloid goitre was represented by 21 cases. The thyroid gland was routinely processed and the nodules were sliced into two parts - one was a subject for histological routine processing according to the principles that universally apply in surgical pathology, the other one was used for the RFA procedure. Results: No significant difference in size reduction between parenchymal and colloid nodules was revealed (p>0.1, t-test) straight after the treatment. In addition, RFA equally effectively induced necrosis in follicular adenoma and adenomatous colloid goitre (p>0.1, analysis of variance test). As expected, tumour size correlated with size reduction (the smaller the size of the nodule, the greater percentage of the nodule volume that was ablated): r=-0.48 (p<0.0001). Conclusion: The results make it possible to move from ex vivo experiments to clinical practice.

BACKGROUND:We previously reported the safety of concurrent cetuximab, an antibody against epidermal growth factor receptor (EGFR), pemetrexed, and radiation therapy (RT) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In this non-comparative phase II randomized trial, we evaluated this non-platinum combination with or without bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF). PATIENTS AND METHODS:Patients with previously untreated stage III-IVB SCCHN were randomized to receive: conventionally fractionated radiation (70 Gy), concurrent cetuximab, and concurrent pemetrexed (arm A); or the identical regimen plus concurrent bevacizumab followed by bevacizumab maintenance for 24 weeks (arm B). The primary end point was 2-year progression-free survival (PFS), with each arm compared with historical control. Exploratory analyses included the relationship of established prognostic factors to PFS and quality of life (QoL). RESULTS:Seventy-eight patients were randomized: 66 oropharynx (42 HPV-positive, 15 HPV-negative, 9 unknown) and 12 larynx; 38 (49%) had heavy tobacco exposure. Two-year PFS was 79% [90% confidence interval (CI) 0.69-0.92; P < 0.0001] for arm A and 75% (90% CI 0.64-0.88; P < 0.0001) for arm B, both higher than historical control. No differences in PFS were observed for stage, tobacco history, HPV status, or type of center (community versus academic). A significantly increased rate of hemorrhage occurred in arm B. SCCHN-specific QoL declined acutely, with marked improvement but residual symptom burden 1 year post-treatment. CONCLUSIONS:RT with a concurrent non-platinum regimen of cetuximab and pemetrexed is feasible in academic and community settings, demonstrating expected toxicities and promising efficacy. Adding bevacizumab increased toxicity without apparent improvement in efficacy, countering the hypothesis that dual EGFR-VEGF targeting would overcome radiation resistance, and enhance clinical benefit. Further development of cetuximab, pemetrexed, and RT will require additional prospective study in defined, high-risk populations where treatment intensification is justified.

This review covers potential complications of frontal sinus surgical management and strategies for prevention of these complications. Accordingly, recent advances in frontal sinus surgical techniques are described, and the management of complications stemming both from these and traditional techniques are detailed.

BACKGROUND: Oral leukoplakia is a relatively common oral lesion that, in a small proportion of people, precedes the development of oral cancer. Most leukoplakias are asymptomatic; therefore, the primary objective of treatment should be to prevent onset of cancer. This review updates our previous review, published in 2006. OBJECTIVES: To assess the effectiveness, safety and acceptability of treatments for leukoplakia in preventing oral cancer. SEARCH METHODS: We searched the following electronic databases: Cochrane Oral Health's Trials Register (to 16 May 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2016, Issue 4), MEDLINE Ovid (1946 to 16 May 2016), Embase Ovid (1980 to 16 May 2016) and CancerLit via PubMed (1950 to 16 May 2016). We searched the metaRegister of Controlled Trials (to 10 February 2015), ClinicalTrials.gov (to 16 May 2016) and the World Health Organization (WHO) International Clinical Trials Registry Platform for ongoing trials (to 16 May 2016). We placed no restrictions on the language or date of publication when searching electronic databases. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that enrolled people with a diagnosis of oral leukoplakia and compared any treatment versus placebo or no treatment. DATA COLLECTION AND ANALYSIS: We collected data using a data extraction form. Oral cancer development, demonstrated by histopathological examination, was our primary outcome. Secondary outcomes were clinical resolution of the lesion, improvement of histological features and adverse events. We contacted trial authors for further details when information was unclear. When valid and relevant data were available, we conducted a meta-analysis of the data using a fixed-effect model when we identified fewer than four studies with no heterogeneity. For dichotomous outcomes, we calculated risk ratios (RRs) and 95% confidence intervals (CIs). We assessed risk of bias in studies by using the Cochrane tool. We assessed the overall quality of the evidence by using standardised criteria (Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE)). MAIN RESULTS: We included 14 studies (909 participants) in this review. Surgical interventions, including laser therapy and cryotherapy, have never been studied by means of an RCT that included a no treatment or placebo arm. The included trials tested a range of medical and complementary treatments, in particular, vitamin A and retinoids (four studies); beta carotene or carotenoids (three studies); non-steroidal anti-inflammatory drugs (NSAIDs), specifically ketorolac and celecoxib (two studies); herbal extracts (four studies), including tea components, a Chinese herbal mixture and freeze-dried black raspberry gel; bleomycin (one study); and Bowman-Birk inhibitor (one study).We judged one study to be at low risk of bias, seven at unclear risk and six at high risk. In general, we judged the overall quality of the evidence to be low or very low, so findings are uncertain and further research is needed.Five studies recorded cancer incidence, only three of which provided useable data. None of the studies provided evidence that active treatment reduced the risk of oral cancer more than placebo: systemic vitamin A (RR 0.11, 95% CI 0.01 to 2.05; 85 participants, one study); systemic beta carotene (RR 0.71, 95% CI 0.24 to 2.09; 132 participants, two studies); and topical bleomycin (RR 3.00, 95% CI 0.32 to 27.83; 20 participants, one study). Follow-up ranged between two and seven years.Some individual studies suggested effectiveness of some proposed treatments, namely, systemic vitamin A, beta carotene and lycopene, for achieving clinical resolution of lesions more often than placebo. Similarly, single studies found that systemic retinoic acid and lycopene may provide some benefit in terms of improvement in histological features. Some studies also reported a high rate of relapse.Side effects of varying severity were often described; however, it seems likely that interventions were well accepted by participants because drop-out rates were similar between treatment and control groups. AUTHORS' CONCLUSIONS: Surgical treatment for oral leukoplakia has not been assessed in an RCT that included a no treatment or placebo comparison. Nor has cessation of risk factors such as smoking been assessed. The available evidence on medical and complementary interventions for treating people with leukoplakia is very limited. We do not currently have evidence of a treatment that is effective for preventing the development of oral cancer. Treatments such as vitamin A and beta carotene may be effective in healing oral lesions, but relapses and adverse effects are common. Larger trials of longer duration are required to properly evaluate the effects of leukoplakia treatments on the risk of developing oral cancer. High-quality research is particularly needed to assess surgical treatment and to assess the effects of risk factor cessation in people with leukoplakia.

PURPOSE: Posterior fossa ependymoma comprises two distinct molecular variants termed EPN_PFA and EPN_PFB that have a distinct biology and natural history. The therapeutic value of cytoreductive surgery and radiation therapy for posterior fossa ependymoma after accounting for molecular subgroup is not known. METHODS: Four independent nonoverlapping retrospective cohorts of posterior fossa ependymomas (n = 820) were profiled using genome-wide methylation arrays. Risk stratification models were designed based on known clinical and newly described molecular biomarkers identified by multivariable Cox proportional hazards analyses. RESULTS: Molecular subgroup is a powerful independent predictor of outcome even when accounting for age or treatment regimen. Incompletely resected EPN_PFA ependymomas have a dismal prognosis, with a 5-year progression-free survival ranging from 26.1% to 56.8% across all four cohorts. Although first-line (adjuvant) radiation is clearly beneficial for completely resected EPN_PFA, a substantial proportion of patients with EPN_PFB can be cured with surgery alone, and patients with relapsed EPN_PFB can often be treated successfully with delayed external-beam irradiation. CONCLUSION: The most impactful biomarker for posterior fossa ependymoma is molecular subgroup affiliation, independent of other demographic or treatment variables. However, both EPN_PFA and EPN_PFB still benefit from increased extent of resection, with the survival rates being particularly poor for subtotally resected EPN_PFA, even with adjuvant radiation therapy. Patients with EPN_PFB who undergo gross total resection are at lower risk for relapse and should be considered for inclusion in a randomized clinical trial of observation alone with radiation reserved for those who experience recurrence.

IMPORTANCE/OBJECTIVE:The paramedian forehead flap (PMFF) donor site scar is hard to disguise and may be a source of patient dissatisfaction. OBJECTIVE:To evaluate the aesthetic outcome of W-plasty vs traditional straight-line (SL) closure techniques of the PMFF donor site. DESIGN, SETTING, AND PARTICIPANTS/METHODS:A retrospective cohort study was conducted at the University of California, San Francisco Medical Center. Clinical history and operative reports were reviewed for 31 patients who underwent a PMFF procedure performed between November 1, 2011, and May 29, 2014. Blinded photographic analysis of postoperative photographs was performed. INTERVENTIONS/METHODS:The pedicled component of the PMFF was raised primarily with either a W-plasty or traditional SL design. MAIN OUTCOMES AND MEASURES/METHODS:Standard photographs of the donor site, obtained at least 90 days after surgery, were reviewed and scored in a blinded fashion by 4 dermatologic surgeons using a 100-point visual analog scale (from 0 [worst possible outcome] to 100 [best possible outcome]) and a 5-point Likert scale (from very poor to excellent). Interrater reliability was assessed via Cronbach α testing. RESULTS:All 31 forehead flaps survived during this study period; 16 PMFFs were raised with the W-plasty technique and 15 were raised with the SL technique. The W-plasty and SL groups were similar in terms of age, sex, and race/ethnicity (mean [SD] age, 68.4 [12.4] vs 61.8 [11.6] years; 13 [84%] vs 9 [60%] men; and 15 [94%] vs 13 [87%] white). Patients undergoing W-plasty closure had significantly higher mean visual analog scale scores compared with those undergoing SL closure (72.8 [18.3] vs 65.6 [18.1]; P = .03). Mean Likert scale scores for W-plasty were higher than those for SL closure, but the difference was not significant (3.77 [1.02] vs 3.43 [0.98]; P = .08). Overall interrater reliability for the visual analog scale and Likert scale scores were 0.67 and 0.58, respectively. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:Patients undergoing PMFF donor site closure using a primary W-plasty technique demonstrated better mean scar appearance of the forehead donor site compared with SL closure. The primary W-plasty technique did not result in any PMFF losses and should be considered for appropriate patients. LEVEL OF EVIDENCE/METHODS:3.

The human vocal folds are complex structures made up of distinct layers that vary in cellular and extracellular composition. The mechanical properties of vocal fold tissue are fundamental to the study of both the acoustics and biomechanics of voice production. To date, quantitative methods have been applied to characterize the vocal fold tissue in both normal and pathologic conditions. This review describes, summarizes, and discusses the most commonly employed methods for vocal fold biomechanical testing. Force-elongation, torsional parallel plate rheometry, simple-shear parallel plate rheometry, linear skin rheometry, and indentation are the most frequently employed biomechanical tests for vocal fold tissues and each provide material properties data that can be used to compare native tissue to diseased or treated tissue. Force-elongation testing is clinically useful, as it allows for functional unit testing, while rheometry provides physiologically relevant shear data, and nanoindentation permits micrometer scale testing across different areas of the vocal fold as well as whole organ testing. Thoughtful selection of the testing technique during experimental design to evaluate a hypothesis is critical to optimize biomechanical testing of vocal fold tissues.

PURPOSE:To report a 10-year update of our institutional experience with stereotactic body radiation therapy (SBRT) for reirradiation of locally recurrent head and neck cancer, focusing on predictors of toxicity. METHODS AND MATERIALS:A retrospective review was performed on 291 patients treated with SBRT for recurrent, previously irradiated head and neck cancer between April 2002 and March 2013. Logistic regression analysis was performed to identify predictors of severe acute and late toxicity. Patients with <3 months of follow-up (n=43) or who died within 3 months of treatment (n=21) were excluded from late toxicity analysis. RESULTS:Median time to death or last clinical follow-up was 9.8 months among the entire cohort and 53.1 months among surviving patients. Overall, 33 patients (11.3%) experienced grade ≥3 acute toxicity and 43 (18.9%) experienced grade ≥3 late toxicity. Compared with larynx/hypopharynx, treatment of nodal recurrence was associated with a lower risk of severe acute toxicity (P=.03), with no significant differences in severe acute toxicity among other sites. Patients treated for a recurrence in the larynx/hypopharynx experienced significantly more severe late toxicity compared with those with oropharyngeal, oral cavity, base of skull/paranasal sinus, salivary gland, or nodal site of recurrence (P<.05 for all). Sixteen patients (50%) with laryngeal/hypopharyngeal recurrence experienced severe late toxicity, compared with 6-20% for other sites. CONCLUSIONS:Salvage SBRT is a safe and effective option for most patients with previously irradiated head and neck cancer. However, patients treated to the larynx or hypopharynx experience significantly more late toxicity compared with others and should be carefully selected for treatment, with consideration given to patient performance status, pre-existing organ dysfunction, and goals of care. Treatment toxicity in these patients may be mitigated with more conformal plans to allow for increased sparing of adjacent normal tissues.