The effect of salivary bypass tube use on the prevention of pharyngo-cutaneous fistulas after total laryngectomy.

INTRODUCTION: The aim of this retrospective study was to assess the efficacy of Salivary Bypass Tube (SBT) for preventing pharyngo-cutaneous fistula (PCF) in a recent cohort of patients who underwent primary and salvage total laryngectomy (TL). METHODS: A consecutive series of 133 patients who underwent total laryngectomy between 1997 and 2019 was reviewed. The incidence of PCF was compared between patients who did not receive SBT (nSBT group; n = 55) and those preventively receiving SBT (SBT group; n = 78) in both primary and salvage TL. Risk factors for PCF were evaluated in a univariate and multivariate analyses. RESULTS: The overall PCF rate was 30%. Preoperative characteristics were similar between the nSBT and SBT groups, except for older age (p = 0.016), lower preoperative hemoglobin (p = 0.043), and lesser neoadjuvant chemotherapy (p = 0.015) in the SBT group. The rate of PCF the nSBT group, was 41.5%, compared to 21.8% in the SBT group (p = 0.020). In multivariate analysis, only the use of SBT was associated with lower risk of PCF (OR = 0.41 (95% CI 0.19-0.89), p = 0.026). This effect was verified only in the subgroup of patient operated for salvage TL (OR = 0.225; 95% CI 0.09-0.7; p = 0.008). CONCLUSION: The use of SBT in our series in salvage TL, appears to be associated with a decreased risk of PCF.

Quality assurance in head and neck surgery: special considerations to catch up.

PURPOSE: Quality assurance is much more difficult to achieve in surgical oncology than in medical oncology and radiotherapy where doses are standardized and toxicities are well-classified. To better define what is required in surgery, we analyzed recent articles addressing the point in head and neck surgery. RESULTS: The surgical report should match with the pathological description of the resected specimen with accurate delineation of the margins, number and level(s) of lymph nodes (capsular rupture if any). Complications (minor and major) should be standardized and meticulously recorded; as well as comorbidities and patient status. The acuity of the procedure should be defined by metrics collected in check-lists. Age > 60 years, male gender, tumor site and T4 stage, neck dissection(s), flap reconstruction, alcohol and tobacco consumption, are acknowledged risk factors for more complications and longer hospital stay (or readmission). NEEDS: Randomized controlled trials should be designed adopting the consolidated standards of reporting trials (CONSORT). Training young head and neck surgeons should encompass formation in designing, conducting and interpreting clinical trials.

Benign tumors of the parotid gland: a retrospective study of 339 patients.

AIM: Among 339 patients operated for benign tumor of the parotid gland: the recurrences and the postoperative complications rates were compared WITH those published in literature. MATERIALS AND METHODS: About 339 patients operated: 274 primarily and 65 for recurrence or residual tumor. VARIABLES: sex, age, surgical techniques, pre- or postoperative radiotherapy, histology, size and localization of the tumors, disease free intervals, recurrences and postoperative complications. RESULTS: 177 men and 162 women. Median age: 55 years and mean follow-up: 10.4 years. About 39 patients had adjuvant radiotherapy (11.5%). After primary surgery, four patients experienced recurrences (1.5%). After salvage surgery, eight patients recurred (12.3%). The recurrence rate was the highest among pleomorphic adenomas. Facial paralysis was more frequent after salvage surgery. DISCUSSION: Recurrence rate 10 years later was lower after primary than after salvage surgery (p = 0.01). There was no relation between adjuvant radiotherapy and recurrence rate probably because the low rate of recurrences. CONCLUSION: Recurrence rate after primary surgery is lower after superficial or total parotidectomy than after other surgical techniques. Pleomorphic adenomas have the highest rate of recurrences. Age and sex have no significant influence over the rate of recurrences. The most frequent postoperative complications are facial paralysis and Frey's syndrome.

New global analysis of the microRNA transcriptome of primary tumors and lymph node metastases of papillary thyroid cancer.

BACKGROUND: Papillary Thyroid Cancer (PTC) is the most prevalent type of endocrine cancer. Its incidence has rapidly increased in recent decades but little is known regarding its complete microRNA transcriptome (miRNome). In addition, there is a need for molecular biomarkers allowing improved PTC diagnosis. METHODS: We performed small RNA deep-sequencing of 3 PTC, their matching normal tissues and lymph node metastases (LNM). We designed a new bioinformatics framework to handle each aspect of the miRNome: whole expression profiles, isomiRs distribution, non-templated additions distributions, RNA-editing or mutation. Results were validated experimentally by qRT-PCR on normal samples, tumors and LNM from 14 independent patients and in silico using the dataset from The Cancer Genome Atlas (small RNA deepsequencing of 59 normal samples, 495 PTC, and 8 LNM). RESULTS: We performed small RNA deep-sequencing of 3 PTC, their matching normal tissues and lymph node metastases (LNM). We designed a new bioinformatics framework to handle each aspect of the miRNome: whole expression profiles, isomiRs distribution, non-templated additions distributions, RNA-editing or mutation. Results were validated experimentally by qRT-PCR on normal samples, tumors and LNM from 14 independent patients and in silico using the dataset from The Cancer Genome Atlas (small RNA deep-sequencing of 59 normal samples, 495 PTC, and 8 LNM). We confirmed already described up-regulations of microRNAs in PTC, such as miR-146b-5p or miR-222-3p, but we also identified down-regulated microRNAs, such as miR-7-5p or miR-30c-2-3p. We showed that these down-regulations are linked to the tumorigenesis process of thyrocytes. We selected the 14 most down-regulated microRNAs in PTC and we showed that they are potential biomarkers of PTC samples. Nevertheless, they can distinguish histological classical variants and follicular variants of PTC in the TCGA dataset. In addition, 12 of the 14 down-regulated microRNAs are significantly less expressed in aggressive PTC compared to non-aggressive PTC. We showed that the associated aggressive expression profile is mainly due to the presence of the BRAF V600E mutation. In general, primary tumors and LNM presented similar microRNA expression profiles but specific variations like the down-regulation of miR-7-2-3p and miR-30c-2-3p in LNM were observed. Investigations of the 5p-to-3p arm expression ratios, non-templated additions or isomiRs distributions revealed no major implication in PTC tumorigenesis process or LNM appearance. CONCLUSIONS: Our results showed that down-regulated microRNAs can be used as new potential common biomarkers of PTC and to distinguish main subtypes of PTC. MicroRNA expressions can be linked to the development of LNM of PTC. The bioinformatics framework that we have developed can be used as a starting point for the global analysis of any microRNA deep-sequencing data in an unbiased way.

The impact of electronic versus paper-based data capture on data collection logistics and on missing scores in thyroid cancer patients.

PURPOSE: The purpose of this study was to investigate the impact of the type of data capture on the time and help needed for collecting patient-reported outcomes as well as on the proportion of missing scores. METHODS: In a multinational prospective study, thyroid cancer patients from 17 countries completed a validated questionnaire measuring quality of life. Electronic data capture was compared to the paper-based approach using multivariate logistic regression. RESULTS: A total of 437 patients were included, of whom 13% used electronic data capture. The relation between data capture and time needed was modified by the emotional functioning of the patients. Those with clinical impairments in that respect needed more time to complete the questionnaire when they used electronic data capture compared to paper and pencil (ORadj 24.0; p = 0.006). This was not the case when patients had sub-threshold emotional problems (ORadj 1.9; p = 0.48). The odds of having the researcher reading the questions out (instead of the patient doing this themselves) (ORadj 0.1; p = 0.01) and of needing any help (ORadj 0.1; p = 0.01) were lower when electronic data capture was used. The proportion of missing scores was equivalent in both groups (ORadj 0.4, p = 0.42). CONCLUSIONS: The advantages of electronic data capture, such as real-time assessment and fewer data entry errors, may come at the price of more time required for data collection when the patients have mental health problems. As this is not uncommon in thyroid cancer, researchers need to choose the type of data capture wisely for their particular research question.

Role of Epac and protein kinase A in thyrotropin-induced gene expression in primary thyrocytes.

cAMP pathway activation by thyrotropin (TSH) induces differentiation and gene expression in thyrocytes. We investigated which partners of the cAMP cascade regulate gene expression modulations: protein kinase A and/or the exchange proteins directly activated by cAMP (Epac). Human primary cultured thyrocytes were analysed by microarrays after treatment with the adenylate cyclase activator forskolin, the protein kinase A (PKA) activator 6-MB-cAMP and the Epac-selective cAMP analog 8-pCPT-2'-O-Me-cAMP (007) alone or combined with 6-MB-cAMP. Profiles were compared to those of TSH. Cultures treated with the adenylate cyclase- or the PKA activator alone or the latter combined with 007 had profiles similar to those induced by TSH. mRNA profiles of 007-treated cultures were highly distinct from TSH-treated cells, suggesting that TSH-modulated gene expressions are mainly modulated by cAMP and PKA and not through Epac in cultured human thyroid cells. To investigate whether the Epac-Rap-RapGAP pathway could play a potential role in thyroid tumorigenesis, the mRNA expressions of its constituent proteins were investigated in two malignant thyroid tumor types. Modulations of this pathway suggest an increased Rap pathway activity in these cancers independent from cAMP activation.

Follow-up strategies in head and neck cancer other than upper aerodigestive tract squamous cell carcinoma.

Post-therapy follow-up for patients with head and neck cancer other than upper aerodigestive tract squamous cell carcinoma should meet several objectives: to detect both local, regional or distant recurrences, to evaluate acute and long-term treatment-related side effects, to guide the rehabilitation process, and to provide psychosocial support when needed. To our knowledge, there are no published reports in the literature dedicated to the follow-up of patients with these tumours. A comprehensive literature search for post-treatment follow-up strategies spanning from 1980 to 2012 was performed on several databases. This review focuses on malignant salivary gland tumors, soft tissue sarcomas, cutaneous squamous cell carcinomas, and sinonasal adenocarcinomas. Given the varying biological behavior and treatment-related factors and based on the literature, different recommendations are made on the follow-up of patients with the above-mentioned tumors.

Post-therapeutic surveillance strategies in head and neck squamous cell carcinoma.

The management of head and neck squamous cell carcinomas does not end with the completion of ablative therapy. The oncologic objectives of post-treatment follow-up are to detect recurrences and second primary tumors; beyond that, follow-up should evaluate acute and chronic treatment-related side effects, guide the rehabilitation process, alleviate functional loss, manage pain, restore nutritional status and assess psychosocial factors. In this structured review, we address the questions of timing and the tools required to achieve a complete and coherent routine surveillance. Several guidelines and consensus statements recommend clinical examination as the cornerstone of follow-up which should be performed for at least 5 years, although there are no data in favor of any one particular follow-up program, and only low-level evidence suggests an improvement in oncologic outcomes by close follow-up. Baseline imaging (computed tomography and magnetic resonance imaging) should be obtained within 2-6 months after definitive therapy if used for treatment response evaluation. Metabolic response, if indicated, should be assessed preferably after 3 months in patients who undergo curative-intent therapy with (chemo)-radiotherapy. Chest computed tomography is more sensitive than plain radiography, if used in follow-up, but the benefit and cost-effectiveness of routine chest computed tomography has not been demonstrated. There are no current data supporting modifications specific to the surveillance plan of patients with human papillomavirus-associated disease.

CDK4 phosphorylation status and rational use for combining CDK4/6 and BRAF/MEK inhibition in advanced thyroid carcinomas.

Background: CDK4/6 inhibitors (CDK4/6i) have been established as standard treatment against advanced Estrogen Receptor-positive breast cancers. These drugs are being tested against several cancers, including in combinations with other therapies. We identified the T172-phosphorylation of CDK4 as the step determining its activity, retinoblastoma protein (RB) inactivation, cell cycle commitment and sensitivity to CDK4/6i. Poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinomas, the latter considered one of the most lethal human malignancies, represent major clinical challenges. Several molecular evidence suggest that CDK4/6i could be considered for treating these advanced thyroid cancers. Methods: We analyzed by two-dimensional gel electrophoresis the CDK4 modification profile and the presence of T172-phosphorylated CDK4 in a collection of 98 fresh-frozen tissues and in 21 cell lines. A sub-cohort of samples was characterized by RNA sequencing and immunohistochemistry. Sensitivity to CDK4/6i (palbociclib and abemaciclib) was assessed by BrdU incorporation/viability assays. Treatment of cell lines with CDK4/6i and combination with BRAF/MEK inhibitors (dabrafenib/trametinib) was comprehensively evaluated by western blot, characterization of immunoprecipitated CDK4 and CDK2 complexes and clonogenic assays. Results: CDK4 phosphorylation was detected in all well-differentiated thyroid carcinomas (n=29), 19/20 PDTC, 16/23 ATC and 18/21 thyroid cancer cell lines, including 11 ATC-derived ones. Tumors and cell lines without phosphorylated CDK4 presented very high p16CDKN2A levels, which were associated with proliferative activity. Absence of CDK4 phosphorylation in cell lines was associated with CDK4/6i insensitivity. RB1 defects (the primary cause of intrinsic CDK4/6i resistance) were not found in 5/7 tumors without detectable phosphorylated CDK4. A previously developed 11-gene expression signature identified the likely unresponsive tumors, lacking CDK4 phosphorylation. In cell lines, palbociclib synergized with dabrafenib/trametinib by completely and permanently arresting proliferation. These combinations prevented resistance mechanisms induced by palbociclib, most notably Cyclin E1-CDK2 activation and a paradoxical stabilization of phosphorylated CDK4 complexes. Conclusion: Our study supports further clinical evaluation of CDK4/6i and their combination with anti-BRAF/MEK therapies as a novel effective treatment against advanced thyroid tumors. Moreover, the complementary use of our 11 genes predictor with p16/KI67 evaluation could represent a prompt tool for recognizing the intrinsically CDK4/6i insensitive patients, who are potentially better candidates to immediate chemotherapy.

International Phase IV Field Study for the Reliability and Validity of the European Organisation for Research and Treatment of Cancer Thyroid Cancer Module EORTC QLQ-THY34.

Purpose: The aim of this study was to validate the new European Organisation for Research and Treatment of Cancer Quality of Life Thyroid Cancer Module (EORTC QLQ-THY34). Methods: We enrolled 437 thyroid cancer patients from 17 countries. One group (n = 303), undergoing treatment or best supportive care, completed the questionnaires at three time points (before therapy [t1], 6 weeks later [t2], and 6 months after t2 [t3]). A second group (survivors ≥2 years after diagnosis, n = 134) completed it at a random baseline time point and a second time 1 week later. We determined internal consistency (using Cronbach's alpha), the scale structure (with confirmatory factor analysis), and discriminant validity (using known-group comparisons). Group 1 data were used to assess responsiveness and group 2 data to determine test-retest reliability using intra-class correlations (ICC). Results: All 34 items fulfilled the criteria to be kept in the questionnaire. Cronbach's alpha was >0.70 in 8 of the 9 multi-item scales. All standardized factor loadings exceeded 0.40, confirming the proposed scale structure. The ICC was >0.70 in all scales expressing good test-retest reliability. Differences in scale scores between patients with different histology were >5 points in all scales. In all but one of the pre-specified scales (Dry Mouth), changes over time were ≥|4| points between at least two time points. Conclusion: The EORTC QLQ-THY34 with its 9 multi-item and 8 single-item scales is a reliable and valid tool to measure quality of life in thyroid cancer patients and can be used in future trials and studies.

MiR-7-5p inhibits thyroid cell proliferation by targeting the EGFR/MAPK and IRS2/PI3K signaling pathways.

The aberrant expression of miRNAs is often correlated to tumor development. MiR-7-5p is a recently discovered downregulated miRNA in thyroid papillary carcinoma (PTC). The goal of this project was to characterize its functional role in thyroid tumorigenesis and to identify the targeted modulated pathways. MiR-7-5p overexpression following transfection in TPC1 and HT-ori3 cells decreased proliferation of the two thyroid cell lines. Analysis of global transcriptome modifications showed that miR-7-5p inhibits thyroid cell proliferation by modulating the MAPK and PI3K signaling pathways which are both necessary for normal thyroid proliferation and play central roles in PTC tumorigenesis. Several effectors of these pathways are indeed targets of miR-7-5p, among which EGFR and IRS2, two upstream activators. We confirmed the upregulation of IRS2 and EGFR in human PTC and showed the existence of a negative correlation between the decreased expression of miR-7-5p and the increased expression of IRS2 or EGFR. Our results thus support a tumor-suppressor activity of miR-7-5p. The decreased expression of miR-7-5p during PTC tumorigenesis might give the cells a proliferative advantage and delivery of miR-7-5p may represent an innovative approach for therapy.

Near total thyroidectomy is an optimal treatment for graves' disease.

Surgical management of Graves' disease is still debated. We report our current experience with thyroidectomy for Graves' disease at a tertiary center. A retrospective database of 132 patients who underwent surgery for Graves' disease from January 1985 to December 2008 was collected. During that period, 16 patients underwent subtotal thyroidectomy and 116 patients underwent near total thyroidectomy. Eighty-seven patients (66%) underwent surgery for recurrent disease after medical therapy. Forty-five patients (34%) had surgery as a primary treatment, the indications were large goiter size in 22 (17%), patient preference in 19 (14%), and associated cold nodule in 3 (2%). The incidence of cancer was 4.4%. Permanent hypoparathyroidism was observed in one patient who underwent a second surgery for recurrence. Unilateral transitory vocal cord palsy was observed in nine patients (7%), bilateral transitory vocal cord palsy was observed in one patient, and no definitive vocal cord palsy was observed. Two patients (1.5%) experienced post-operative hemorrhagia requiring surgical revision. Near total thyroidectomy for Graves' disease provides an immediate and definitive treatment with a low complication rate. Near total thyroidectomy offers an appropriate treatment for coexisting malignancy. This procedure can be safely recommended as a primary treatment, in experienced hands.

Quality of Life in Patients With Hypoparathyroidism After Treatment for Thyroid Cancer.

PURPOSE: Surgical complications such as hypoparathyroidism (HPT) or vocal cord palsy are seldom assessed when the quality of life (QOL) in thyroid cancer patients is investigated. The aim of this study was to measure the QOL difference in thyroid cancer survivors with and without HPT. METHODS: Participants for this analysis were enrolled in 13 countries from a study that pilot-tested a thyroid cancer-specific QOL instrument. They were included if they had been diagnosed with thyroid cancer at least 9 months previously. QOL was measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core (EORTC QLQ-C30) and some items on HPT symptoms (eg, tingling in fingers or toes). HPT status and other clinical data were extracted from the patients' medical charts. Comparisons of QOL domains between patients with and without HPT were performed using Mann-Whitney U test. The occurrence of HPT-related symptoms was compared using chi-square tests. Multiple ordinal regression analysis was performed to evaluate factors that might affect QOL. RESULTS: Eighty-nine patients participated in this study, 17 of whom were considered to have HPT. Patients in the HPT group reported significantly reduced QOL in 9 of the 15 scales of the EORTC QLQ-C30 compared to patients without HPT. Regression analysis showed that HPT was independently negatively associated with various scales of the QLQ-C30. Both groups showed a high prevalence of typical HPT symptoms. CONCLUSION: Thyroid cancer patients with HPT report significantly impaired QOL compared to thyroid cancer survivors without HPT. The assessment of HPT should be considered when measuring QOL in thyroid cancer patients.

Human thyroid tumor cell lines derived from different tumor types present a common dedifferentiated phenotype.

Cell lines are crucial to elucidate mechanisms of tumorigenesis and serve as tools for cancer treatment screenings. Therefore, careful validation of whether these models have conserved properties of in vivo tumors is highly important. Thyrocyte-derived tumors are very interesting for cancer biology studies because from one cell type, at least five histologically characterized different benign and malignant tumor types can arise. To investigate whether thyroid tumor-derived cell lines are representative in vitro models, characteristics of eight of those cell lines were investigated with microarrays, differentiation markers, and karyotyping. Our results indicate that these cell lines derived from differentiated and undifferentiated tumor types have evolved in vitro into similar phenotypes with gene expression profiles the closest to in vivo undifferentiated tumors. Accordingly, the absence of expression of most thyrocyte-specific genes, the nonresponsiveness to thyrotropin, as well as their large number of chromosomal abnormalities, suggest that these cell lines have acquired characteristics of fully dedifferentiated cells. They represent the outcome of an adaptation and evolution in vitro, which questions the reliability of these cell lines as models for differentiated tumors. However, they may represent useful models for undifferentiated cancers, and by their comparison with differentiated cells, can help to define the genes involved in the differentiation/dedifferentiation process. The use of any cell line as a model for a cancer therefore requires prior careful and thorough validation for the investigated property.

Reprogramming of Energy Metabolism: Increased Expression and Roles of Pyruvate Carboxylase in Papillary Thyroid Cancer.

Background: Energy metabolism is described to be deregulated in cancer, and the Warburg effect is considered to be a major hallmark. Recently, cellular heterogeneity in tumors and the tumor microenvironment has been recognized to play an important role in several metabolic pathways in cancer. However, its contribution to papillary thyroid cancer (PTC) development and metabolism is still poorly understood. Methods: A proteomic analysis of five PTC was performed, and the cellular distribution of several upregulated metabolic proteins was investigated in the cancerous and stromal cells of these tumors. Results: Tandem mass spectrometry analysis revealed the upregulation of many metabolism-related proteins, among them pyruvate carboxylase (PC). PC knockdown in thyroid cell lines alters their proliferative and motility capacities, and measurements of oxygen consumption rates show that this enzyme is involved in the replenishment of the tricarboxylic acid cycle. Immunostainings of several upregulated metabolic proteins show that thyroid cancer cells have an increased mitochondrial oxidative metabolism compared to stromal cells. Conclusions: PTC has a very active tricarboxylic acid cycle, continuously replenished by a PC-mediated anaplerosis. This is specifically observed in the tumor cells.

Distinctive Desmoplastic 3D Morphology Associated With BRAFV600E in Papillary Thyroid Cancers.

Context: Although 60% of papillary thyroid carcinomas are BRAFV600E mutant (PTCV600E), the increased aggressiveness of these cancers is still debated. Objective: For PTCV600E we aimed to further characterize the extent of the stroma and its activation, the three-dimensional (3D) tumor-stroma interface, and the proliferation rates of tumor and stromal fibroblasts. Design: We analyzed exomes, transcriptomes, and images of 364 papillary thyroid carcinoma (PTCs) from The Cancer Genome Atlas (TCGA), including 211 PTCV600E; stained 22 independent PTCs for BRAFV600E and Ki67; sequenced the exomes and stained BRAFV600E in 5 primary tumor blocks and 4 nodal metastases from one patient with PTCV600E; and reconstructed the 3D volumes of one tumor and one metastatic block at histological resolution. Results: In TCGA, BRAFV600E was associated with higher expression of proliferation markers and lower expression of thyroid differentiation markers, independently of tumor purity. Moreover, PTCV600E, in line with their overall lower purity, also had higher expression of fibroblast- and T cell-associated genes and presented more fibrosis. Tumor cells that appeared disconnected on two-dimensional histological slices were revealed to be part of a unique tumor component in the 3D reconstructed microvolumes, and they formed a surprisingly complex connected space, infiltrating a proliferative stroma. Finally, in our PTC set, both stromal fibroblasts and tumor cells presented higher proliferation rates in PTCV600E. Conclusions: Our results support the increased aggressiveness associated with BRAFV600E in PTC and shed light on the important role of the stroma in tumor expansion. The greater and more active fibrotic component predicts better efficiency of combined targeted treatments, as previously proposed for melanomaV600E.

Surgical quality assurance in head and neck cancer trials: an EORTC Head and Neck Cancer Group position paper based on the EORTC 1420 'Best of' and 24954 'larynx preservation' study.

Quality improvement of care for patients with head and neck cancer remains a constant objective for the multidisciplinary team of physicians managing these patients. The purpose of quality assurance (QA) for head and neck surgical oncology and surgical trials however differs. While QA for the general head and neck patient aims to improve global outcome through structural changes of health-care systems, QA for surgical trials pursues the goal to help providing meaningful results from a clinical trial through the definition of structure, process and outcome measures within the trial. Establishing a QA program for surgical trials is challenging largely due to the variation in the execution of surgical techniques. Within this article, we describe the surgical QA program, which was developed for the phase III European Organisation for Research and Treatment of Cancer (EORTC) 1420 study, a trial assessing swallowing function after transoral surgery compared with radiation therapy. We propose based on our experience to further develop surgical QA for surgical clinical trials by introducing two separate components, one adaptable and one non-adaptable. The adaptable is tailored to the scientific question and specific procedure; the non-adaptable consists of minimal structural requirements of the clinical unit to participate in surgical trials at EORTC as well as guidelines and incentives for protocol adherence based on our experience in EORTC 24954. Finally, we strongly believe that surgical QA designed for clinical trials may serve as a basis for the development of QA surgical guidelines in clinical practice.

Thyroid follicular adenomas and carcinomas: molecular profiling provides evidence for a continuous evolution.

Non-autonomous thyroid nodules are common in the general population with a proportion found to be cancerous. A current challenge in the field is to be able to distinguish benign adenoma (FA) from preoperatively malignant thyroid follicular carcinoma (FTC), which are very similar both histologically and genetically. One controversial issue, which is currently not understood, is whether both tumor types represent different molecular entities or rather a biological continuum. To gain a better insight into FA and FTC tumorigenesis, we defined their molecular profiles by mRNA and miRNA microarray. Expression data were analyzed, validated by qRT-PCR and compared with previously published data sets. The majority of deregulated mRNAs were common between FA and FTC and were downregulated, however FTC showed additional deregulated mRNA. Both types of tumors share deregulated pathways, molecular functions and biological processes. The additional deregulations in FTC include the lipid transport process that may be involved in tumor progression. The strongest candidate genes which may be able to discriminate follicular adenomas and carcinomas, CRABP1, FABP4 and HMGA2, were validated in independent samples by qRT-PCR and immunohistochemistry. However, they were not able to adequately classify FA or FTC, supporting the notion of continuous evolving tumors, whereby FA and FTC appear to show quantitative rather than qualitative changes. Conversely, miRNA expression profiles showed few dysregulations in FTC, and even fewer in FA, suggesting that miRNA play a minor, if any, role in tumor progression.

The EORTC module for quality of life in patients with thyroid cancer: phase III.

The purpose of the study was to pilot-test a questionnaire measuring health-related quality of life (QoL) in thyroid cancer patients to be used with the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire EORTC QLQ-C30. A provisional questionnaire with 47 items was administered to patients treated for thyroid cancer within the last 2 years. Patients were interviewed about time and help needed to complete the questionnaire, and whether they found the items understandable, confusing or annoying. Items were kept in the questionnaire if they fulfilled pre-defined criteria: relevant to the patients, easy to understand, not confusing, few missing values, neither floor nor ceiling effects, and high variance. A total of 182 thyroid cancer patients in 15 countries participated (n = 115 with papillary, n = 31 with follicular, n = 22 with medullary, n = 6 with anaplastic, and n = 8 with other types of thyroid cancer). Sixty-six percent of the patients needed 15 min or less to complete the questionnaire. Of the 47 items, 31 fulfilled the predefined criteria and were kept unchanged, 14 were removed, and 2 were changed. Shoulder dysfunction was mentioned by 5 patients as missing and an item covering this issue was added. To conclude, the EORTC quality of life module for thyroid cancer (EORTC QLQ-THY34) is ready for the final validation phase IV.

Gene expression in thyroid autonomous adenomas provides insight into their physiopathology.

The purpose of this study was to use the microarray technology to define expression profiles characteristic of thyroid autonomous adenomas and relate these findings to physiological mechanisms. Experiments were performed on a series of separated adenomas and their normal counterparts on Micromax cDNA microarrays covering 2400 genes (analysis I), and on a pool of adenomatous tissues and their corresponding normal counterparts using microarrays of 18,000 spots (analysis II). Results for genes present on the two arrays corroborated and several gene regulations previously determined by Northern blotting or microarrays in similar lesions were confirmed. Five overexpressed and 24 underexpressed genes were also confirmed by real-time RT-PCR in some of the samples used for microarray analysis, and in additional tumor specimens. Our results show: (1) a change in the cell populations of the tumor, with a marked decrease in lymphocytes and blood cells and an increase in endothelial cells. The latter increase would correspond to the establishment of a close relation between thyrocytes and endothelial cells and is related to increased N-cadherin expression. It explains the increased blood flow in the tumor; (2) a homogeneity of tumor samples correlating with their common physiopathological mechanism: the constitutive activation of the thyrotropin (TSH)/cAMP cascade; (3) a low proportion of regulated genes consistent with the concept of a minimal deviation tumor; (4) a higher expression of genes coding for specific functional proteins, consistent with the functional hyperactivity of the tumors; (5) an increase of phosphodiesterase gene expression which explains the relatively low cyclic AMP levels measured in these tumors; (6) an overexpression of antiapoptotic genes and underexpression of proapoptotic genes compatible with their low apoptosis rate; (7) an overexpression of N-cadherin and downregulation of caveolins, which casts doubt about the use of these expressions as markers for malignancy.