Ethical issues in non-intervention trials for thyroid cancer.

In recent years, the increasing numbers of small, apparently indolent thyroid cancers diagnosed in the world have encouraged investigators to consider non-intervention as an alternative to surgical management. In the following pages, the prospect of a non-intervention trial for thyroid cancer is considered with attention to the ethical issues that such a trial might raise. Such a non-intervention trial is analyzed relative to 7 ethical considerations: the social or scientific value of the research, the scientific validity of the trial, the necessity of fair selection of participants, a favorable risk-benefit ratio for trial participants, independent review of the trial, informed consent, and allowing the study participants to withdraw from the trial. A non-intervention trial for thyroid cancer is also considered relative to the central concept of equipoise.

The impact of family history on non-medullary thyroid cancer.

INTRODUCTION: Around 10% of patients with non-medullary thyroid cancer (NMTC) will have a positive family history for the disease. Although many will be sporadic, families where 3 first-degree relatives are affected can be considered to represent true familial non-medullary thyroid cancer (FNMTC). The genetic basis, impact on clinical and pathological features, and overall effect on prognosis are poorly understood. METHODS: A literature review identified articles which report on genetic, clinical, therapeutic and screening aspects of FNMTC. The results are presented to allow an understanding of the genetic basis and the impact on clinical-pathological features and prognosis in order to inform clinical decision making. RESULTS: The genetic basis of FNMTC is unknown. Despite this, significant progress has been made in identifying potential susceptibility genes. The lack of a test for FNMTC has led to a clinical definition requiring a minimum of 3 first-degree relatives to be diagnosed with NMTC. Although some have shown an association with multi-centric disease, younger age and increased rates of extra-thyroidal extension and nodal metastases, these findings are not supported by all. The impact of FNMTC is unclear with all groups reporting good outcome, and some finding an association with more aggressive disease. The role of screening remains controversial. CONCLUSION: FNMTC is rare but can be diagnosed clinically. Its impact on prognostic factors and the subsequent role in influencing management is debated. For those patients who present with otherwise low-risk differentiated thyroid cancer, FNMTC should be included in risk assessment when discussing therapeutic options.

Treatment de-escalation in HPV-positive oropharyngeal carcinoma: ongoing trials, critical issues and perspectives.

Due to the generally poor prognosis of head and neck squamous cell carcinoma (HNSCC), treatment has been intensified, these last decades, leading to an increase of serious side effects. High-risk human papillomavirus (HR-HPV) infection has been recently etiologically linked to a subset of oropharyngeal squamous cell carcinoma (OPSCC), which is on the increase. These tumors are different, at the clinical and molecular level, when compared to tumors caused by traditional risk factors. Additionally, their prognosis is much more favorable which has led the medical community to consider new treatment strategies. Indeed, it is possible that less intensive treatment regimens could achieve similar efficacy with less toxicity and improved quality of life. Several clinical trials, investigating different ways to de-escalate treatment, are currently ongoing. In this article, we review these main approaches, discuss the rationale behind them and the issues raised by treatment de-escalation in HPV-positive OPSCC.

Oropharyngeal cancers: relationship between epidermal growth factor receptor alterations and human papillomavirus status.

High-risk human papillomavirus (HR-HPV), particularly type 16, is now recognised as a causative agent in a subset of oropharyngeal squamous cell carcinomas (OPSCCs). These tumours are on the increase and generally have a better prognosis than their HPV negative counterparts. This raises the question of de escalation therapy to reduce long term consequences in a younger cohort of patients with a long life expectancy. Several clinical trials with anti-epidermal growth factor receptor (EGFR) therapies, particularly cetuximab, are ongoing. Few data exist on the relationship between EGFR and HPV induced oropharyngeal cancers. We summarise the main studies in relation to EGFR alterations (gene copy number, protein expression and mutations) and the impact on prognosis of HPV positive tumours that express high levels of EGFR. We also discuss the opportunity of targeting this pathway in light of recent studies.

Paraneoplastic dermatomyositis accompanying nasopharyngeal carcinoma: diagnosis, treatment and prognosis.

Dermatomyositis (DM) is a multisystem inflammatory disorder primarily affecting the skin and muscles. Its pathophysiology is still very poorly understood, but humoral and cellular immune dysregulation is apparent. Diagnosis of DM is based on five criteria: proximal limb muscle weakness, serum muscle enzyme elevation, histopathologic muscle abnormalities on muscle biopsy, electromyographic abnormalities, and clinical inflammatory dermatological manifestations (heliotrope rash, poikiloderma, and inflammatory lesions on the hands and facing joints). DM is frequently associated with certain cancers, and may appear before, concurrent with, or after diagnosis of cancer. DM has been reported to be associated with approximately one per 1000 cases of nasopharyngeal carcinoma. Treatment is based on long-course nonselective immunosuppression, particularly corticosteroids, by general route, even when malignancy is present, but new-targeted therapies may modify the treatment strategy in the near future. Despite iatrogenic immunosuppression, the prognosis of nasopharyngeal cancer is not worse in patients with paraneoplastic DM. We report one case as an illustration of this paraneoplastic course (evolving in parallel with the cancer), and to make an update on the state of knowledge on paraneoplastic DM in such cancers.

[Alpha-1-blockers (alfuzosin) for obstructive salivary gland diseases]. / Les Alpha-1-Bloquants (alfuzosine) en pathologie salivaire obstructive.

INTRODUCTION: Alpha-blockers are used in urology to treat stenosis and lithiasis. The pathophysiology is similar in salivary glands. We had for aim to assess the safety and effectiveness of an alpha-blocker (Alfuzosin) in patients with ductal stenosis, allergic pseudo-parotitis or sialolithiasis after lithotripsy. PATIENTS AND METHODS: Three hundred and fifty-two patients were included, 194 of whom presented with sialolithiasis fragmented by extracorporeal lithotripsy (112 parotidic and 82 submandibular). Sixty-nine presented with ductal stenosis, and 89 with allergic pseudo-parotitis. This retrospective study lasted 3 years (January 2005 to January 2008) with a mean follow-up of 33 months (18 months to 4 years). Male patients were given 2.5mg tid of the alpha-blocker Alfuzosin and female patients 2.5mg bid for 3 to 24 months. After 6 months and up to 2 years of treatment, patients were assessed every 3 months by US and with a questionnaire on symptoms. RESULTS: Results were similar in male and female patients. Eighty percent of patients with colic-like pain due to stenosis reported a significant improvement after treatment. 78.6% of patients with allergic pseudo-parotitis felt they had improved and noted a sharp decrease of pruritus. Sixty-seven of the patients with residual parotid lithiasis after extracorporeal lithotripsy presented with less ductal lithiasis and fragments were evacuated more rapidly in the two months following lithotripsy. Forty-two percent of the patients treated for residual submandibular lithiasis reported a significant functional improvement and faster evacuation of fragments. Twelve patients out of 352 (3.4%) reported adverse effects. The incidence of orthostatic hypotension was 2.2%. DISCUSSION: A significant improvement of symptoms was observed in patients treated with Alfuzosin for obstructive salivary gland diseases. The drug was well tolerated. These preliminary results are good in terms of effectiveness and inocuity. They should be confirmed with a prospective controlled study.

Quality of life after free-flap tongue reconstruction.

OBJECTIVE: To analyse correlations between quality of life measures, aspiration and extent of surgical resection in patients who have undergone free-flap tongue reconstruction. PATIENTS AND METHODS: Nine consecutive patients (seven men and two women; average age 51 years) who had been diagnosed with T4a carcinoma of the mobile tongue and/or tongue base and treated by glossectomy, free-flap reconstruction, and either radiation therapy or chemoradiation responded to the European Organization for Research and Treatment of Cancer Head and Neck-35 questionnaire, the performance status scale questionnaire and the hospital anxiety-depression scale questionnaire, an average of 43 months after treatment (range 18-83 months). Aspiration was evaluated by fibre-optic laryngoscopy. Correlations between quality of life domain scores, extent of surgery and the presence of aspiration were evaluated using non-parametric statistical analysis. RESULTS: Scores for the swallowing and aspiration domains of the European Organization for Research and Treatment of Cancer Head and Neck-35 questionnaire were significantly correlated with the extent of tongue base resection (Spearman's correlation, p = 0.037 and 0.042, respectively). Despite a strong correlation between the European Organization for Research and Treatment of Cancer Head and Neck-35 questionnaire results and the performance status scale global scores (correlation coefficient = 0.89, p = 0.048), the performance status scale domain scores were not correlated with the extent of tongue resection. Clinically apparent aspiration was not correlated with the extent of tongue resection, nor were the anxiety or depression scores. However, clinically apparent aspiration was significantly related to the swallowing and aspiration domain scores of the European Organization for Research and Treatment of Cancer Head and Neck-35 questionnaire (p = 0.017 in both cases). CONCLUSIONS: Our results imply that the volume of tongue base resection is a major factor in swallowing- and aspiration-related quality of life following tongue resection and free-flap reconstruction. Free-flap reconstruction does not seem to palliate the effect of the loss of functional tongue base volume, as regards swallowing-related quality of life.

Prediction and diagnosis of bone metastases in well-differentiated gastro-entero-pancreatic endocrine cancer: a prospective comparison of whole body magnetic resonance imaging and somatostatin receptor scintigraphy.

PURPOSE: Our purpose was to compare the sensitivity of whole body (WB) magnetic resonance imaging (MRI) and somatostatin receptor scintigraphy (SRS) for the diagnosis of bone metastases (BMs) in patients with well-differentiated gastro-entero-pancreatic endocrine cancer (WD-GEP-EC) and to determine predictive factors of BM. PATIENTS AND METHODS: WB-MRI and SRS were prospectively performed in 79 patients with bronchial (11), thymic (five), gastric (two), duodeno-pancreatic (24), ileal (26), colic (one), or unknown primary (10) WD-GEP-EC. RESULTS: A total of 36 patients (46%) had 333 BMs involving 119 skeletal segments. WB-MRI and SRS were equally sensitive for detecting patients with BM (86 vs. 81%; P = 0.56), with 33% of the patients diagnosed with only one procedure. WB-MRI detected more BMs than SRS (80 vs. 57%; P = 0.017). Compared with SRS, WB-MRI detected more spine BMs (96 vs. 45%; P < 0.001) and tended to detect more pelvic and lower limb BMs (P = 0.054 and P = 0.06, respectively). Compared with WB-MRI, SRS detected more skull BMs (100 vs. 0%; P < 0.001) and tended to detect more rib BMs (P = 0.08). Sternal and upper-limb BMs were equally detected with WB-MRI and SRS (P = 0.32 and P = 0.46, respectively). Bone staging with SRS and spine MRI rather than WB-MRI would have detected 92% of the patients with BMs and 83% of all BMs. The extent of liver involvement and bronchial-thymic primary tumors were independent predictive factors for BM. CONCLUSIONS: We recommend bone staging with SRS and spine MRI in all patients with bronchial-thymic or unknown primary WD-GEP-EC. In case of duodeno-pancreatic or ileal primary, bone imaging may be restricted to patients with liver metastases.

Botulinum toxin A for quality of life improvement in post-parotidectomy gustatory sweating (Frey's syndrome).

OBJECTIVE: To measure patient-reported quality of life before and after botulinum toxin A treatment of post-parotidectomy Frey's syndrome (gustatory sweating). PATIENTS AND METHODS: A questionnaire concerning functional, social and emotional aspects of Frey's syndrome (14 questions, with responses on a zero to three point scale) was administered to 17 patients (13 women and four men) before and one month after intradermal injection of botulinum toxin A. Parotidectomy had been performed one to 19 years previously, for benign (n = 10) or malignant (n = 7) tumours, with gustatory sweating occurring a median of 15 months after surgery (range: one month to 14 years). Pre- and post-treatment quality of life scores were compared using Wilcoxon's test (p < 0.05). RESULTS: Patients' reported functional quality of life improved significantly (p = 0.0004). Their social and emotional scores were not significantly modified (p = 0.155 and 0.142, respectively). Seven patients (41 per cent) found the injections painful, but all patients said that the effects were beneficial, that they would undergo new injections if necessary and that they would recommend this treatment to other patients. The benefit lasted over 1.5 years for 60 per cent of patients. No correlation was found between duration of the effect and the extent of parotidectomy (p = 0.067). CONCLUSIONS: Botulinum toxin A significantly improved patients' functional quality of life, without significant improvement in their social or emotional quality of life, according to our questionnaire results. The duration of the effect was longer than the reported physiological effect of botulinum toxin A on acetylcholine receptors.

Myasthenia gravis mimicking unilateral vocal fold paralysis at presentation.

OBJECTIVES: To demonstrate the importance of detailed clinical analysis in the differential diagnosis of unilateral vocal fold paralysis, and to provide an update on current knowledge and treatment of myasthenia gravis. CASE REPORT: A female patient presented with left unilateral vocal fold immobility. Diagnostic investigation revealed a 10 mm thyroid adenoma, but no other abnormality likely to cause unilateral vocal fold paralysis. Follow-up flexible endoscopy at three months showed laryngeal remobilisation with persistent left vocal fold bowing and vertical asymmetry of the vocal folds on phonation. Over the following months, voice quality varied between normal and breathy, with the breathy periods lasting from three days to one month. Laryngeal electromyography (EMG) showed a slight bilateral paradoxical activation of both posterior crico-arytenoid muscles on phonation. Magnetic resonance imaging of the brain and brainstem was normal. A diagnostic test for myasthenia gravis with intravenous edrophonium bromide (Tensilon) lead to an immediate improvement in voice quality. The patient was subsequently treated with pyridostigmine bromide, with complete resolution of dysphonia. CONCLUSIONS: Myasthenia gravis affecting the larynx may mimic unilateral vocal fold paresis or paralysis. A personal or family history of auto-immune disease, fluctuating symptoms, motor deficits in cranial nerve territories, and normal or subnormal laryngeal EMG results should lead the physician to reconsider a diagnosis of idiopathic unilateral vocal fold paralysis and to perform specific testing.

Free flap reconstruction in the treatment of tumors involving the hard palate.

AIM: To report our experience in free flap reconstruction of the hard palate after malignant tumor resection, in terms of reconstruction method, immediate post-operative course and subjective functional results. PATIENTS AND METHODS: Files from 1988 to 1999 were reviewed for patients having undergone microvascular reconstruction of the hard palate. The immediate post-operative course (during the first month) was reviewed to determine the occurrence of complications. The surgeon's evaluation 1 year post-operatively was used to determine the intelligibility of speech, type of diet and the quality of nasal permeability. RESULTS: Thirty eight patients (28 men and 10 women) with malignant tumors involving the hard palate had undergone surgical reconstruction using microvascular free flap techniques: free radial forearm flap (13 cases), scapular flap (24 cases) or fibular flap (five cases). Two different flaps were employed in two cases (scapula plus fibula). A second flap was used with success in two cases of failure of the first flap, for a total of 42 free flaps for 38 patients. Complications occurred in seven cases, with two cases of flap necrosis. At 1 year, 33 patients achieved a normal diet and 35 normal or easily intelligible speech. CONCLUSIONS: Microsurgical reconstruction using free tissue transfer allows reconstruction of large defects of the hard palate, with low morbidity and an excellent functional outcome. We propose criteria for free flap reconstruction and choice of flap.

[Dysphonia: current methods of evaluation]. / Méthodes actuelles d'évaluation des dysphonies.

OBJECTIVES: The aim of this review article was to provide an update on current techniques for evaluation of dysphonia in routine clinical practice. MATERIALS AND METHODS: Recent medical and other scientific literature was reviewed and pertinent current theories concerning the physiology of laryngeal function described. RESULTS: Perceptual voice quality evaluation by a professional jury of listeners is still considered to be the most reliable and complete means of evaluating pathologic voice, even though it is difficult to perform in routine and the results lack reproducibility. The objective evaluation of the vocal fundamental frequency and its variations and the spectral characteristics of voice has the advantage of being simple to perform, reproducible and quantifiable. However, automatic measurements need to be analyzed with precaution for severe dysphonia, the computer algorithms being designed for voices retaining a certain periodicity. Aerodynamic measurements are quantifiable and reproducible and provide information as to the quality of laryngeal function as a transducer of aerodynamic energy into acoustic energy. Videostroboscopy and electroglottography provide information as to the quality of the laryngeal vibrations, the source of sound production. CONCLUSIONS: All of these types of analysis are complementary, informing as to different aspects of vocal quality and laryngeal function. No one measurement alone can diagnose or characterize dysphonia.

[Carbon dioxide laser transoral microsurgery for glottic carcinoma in situ]. / Microchirurgie par voie endoscopique au laser CO2 des carcinomes in situ glottiques.

OBJECTIVE: To evaluate the oncologic results of glottic carcinoma in situ (CIS) treated with transoral carbon dioxide laser microsurgery. METHODS: A retrospective review of 12 patients with glottic CIS previously untreated, treated with carbon dioxide laser transoral microsurgery between January 1990 and December 1999 was conducted. RESULTS: Initial and ultimate local control rates were 75%, and 100%, respectively. Three local failures occurred: two glottic CIS were treated by carbon dioxide laser transoral microsurgery, one squamous cell glottic carcinoma was treated by supracricoid partial laryngectomy with cricohyoidoepiglottopexy. The ultimate rate of laryngeal preservation rate was 100%. CONCLUSIONS: Based on the material of this study, recommended treatment for glottic CIS should be carbon dioxide laser transoral microsurgery. Difficulties in endoscopic exposure of the larynx is a contraindication. Further studies are necessary to confirm these preliminary results.

Objective voice quality analysis before and after onset of unilateral vocal fold paralysis.

This study was designed to investigate objective voice quality measurements in unilateral vocal fold paralysis (UVFP) by eliminating intersubject variability. To our knowledge this is the first report objectively analyzing paralytic dysphonia as compared to the same voice before onset of UVFP. The voices of two male subjects were prospectively recorded before and after the onset of iatrogenic UVFP (thoracic surgery). The following acoustic measurements of the vowel /a/ were performed using the CSL and MDVP (Kay Elemetrics): jitter, shimmer, harmonics-to-noise ratio, cepstral peak prominence, the relative energy levels of the first harmonic, the first formant and the third formant, the spectral slope in the low-frequency zone (0-1 kHz and 0-2 kHz), and the relative level of energy above 6 kHz. Distribution of spectral energy was analyzed from a long-term average spectrum of 40 seconds of text. Laryngeal aerodynamic measurements were obtained for one patient before and after onset of paralysis using the Aerophone II (Kay Elemetrics). Pitch and amplitude perturbation increased secondary to UVFP, while the harmonics-to-noise ratio and the cepstral peak prominence decreased. A relative increase in the mid-frequency and high-frequency ranges and a decrease in the low-frequency spectral slope were observed. Mean airflow rate and intraoral pressure increased, and glottal resistance and vocal efficiency decreased secondary to UVFP. The findings of this self-paired study confirm some but not all the results of previous studies. Measures involving the fundamental and the formants did not corroborate previous findings. Further investigation with vocal tract modeling is warranted.

Objective voice analysis after autologous fat injection for unilateral vocal fold paralysis.

This study was designed to objectively compare a patient's voice after onset of unilateral vocal fold paralysis (UVFP) to his or her own normal voice, and to compare the results after treatment by intrafold injection of autologous fat. Acoustic recordings were obtained for 2 male patients before thoracic surgery and after the onset of iatrogenic left UVFP. Vocal fold augmentation was performed 10 days after UVFP. The acoustic recordings were repeated within 3 days and at 1 month. The phonation quotient, pitch perturbation quotient, amplitude perturbation quotient, harmonics-to-noise ratio, cepstral peak prominence, and long-term average spectrum were analyzed. All parameters improved after treatment, with a return to preparalytic values for most. During the first month, some deterioration was noted. This is the first study comparing a subject's own normal voice to his or her voice after vocal fold augmentation. We recommend overinjection of fat if vocal fold atrophy is expected.