Background: The health-related quality of life (HRQoL) of patients with differentiated thyroid carcinoma (DTC), especially their mental health, can be compromised by various factors beyond disease prognosis and treatment stage. However, predictors of poor emotional functioning (EF) in DTC patients have not been thoroughly studied. To inform targeted interventions that could improve or preserve HRQoL in patients with DTC, this study aimed to identify predictors of impaired EF, and particularly modifiable factors. Methods: Data analyzed were from the phase IV international validation study of the European Organization for Research and Treatment of Cancer thyroid cancer-specific HRQoL questionnaire (QLQ-THY34). Patients (n = 196) were assessed at three timepoints before treatment (t1), 6 weeks after the start of treatment (t2), and 6 months after t2 (t3). Multilevel, multivariable logistic regression models were used to assess the likelihood of impaired EF at t3 according to predefined potential predictors at t1 and t2. Results: Impaired EF at t1 or t2 predicted impaired EF at t3. Exhaustion, head and neck discomfort and body image issues were significantly associated with poor EF at t3. More specifically, temporal changes of these three variables from t1 to t2 were independent predictors of poor EF at t3 with an odds ratio of 1.04 (p < 0.001), 1.01 (p = 0.04), and 1.01 (p = 0.001) per score point, respectively. There was no evidence that worry about important others, lacking social support, sex, stage, or Karnofsky performance score are associated with EF at t3. Conclusions: Exhaustion, head and neck discomfort, and body image concerns emerged as modifiable factors that predict future impaired EF in patients with DTC undergoing treatment. These factors could be targeted in prehabilitation, rehabilitation or other interventional programs to potentially improve or preserve patients' EF.

Hypoparathyroidism (HypoPT) is one of the most common complications of surgical treatment for thyroid cancer and afflicated patients often report symptoms or impairments in quality of life (QoL). We aimed to investigate differences in various QoL domains between thyroid cancer survivors with and without permanent hypoparathyroidism. Thyroid cancer survivors with a minimum of 1.5 years post-diagnosis completed the EORTC core questionnaire (EORTC QLQ-C30) and the EORTC thyroid module (QLQ-THY34). Sociodemographic and clinical information were obtained from the patients themselves and their medical charts. Analysis of covariance was used to compare QoL between survivors with and without hypoparathyroidism (adjusting for age, gender, time since diagnosis, and comorbidity). Of the 126 participants, 21 (17

Background: The diagnosis of malignant thyroid nodules is mainly based on the fine-needle aspiration biopsy (FNAB). To improve the detection of malignant nodules, different molecular tests have been developed. We present a new molecular signature based on altered miRNA expressions and specific mutations. Methods: This is a prospective non-interventional study, including all Bethesda categories, carried out on an FNAB sampled in suspicious nodule(s) during thyroidectomy. miRNA quantification and mutations detection were performed. The reference diagnosis was the pathological assessment of the surgical specimen. Different classification algorithms were trained with molecular data to correctly classify the samples. Results: A total of 294 samples were recorded and randomly divided in two equal groups. The random forest algorithm showed the highest accuracy and used mostly miRNAs to classify the nodules. The sensitivity and the specificity of our signature were, respectively, 76% and 96%, and the positive and negative predictive values were both 90% (disease prevalence of 30%). Conclusions: We have identified a molecular classifier that combines miRNA expressions with mutations detection. This signature could potentially help clinicians, as complementary to the Bethesda classification, to discriminate indeterminate FNABs.

Supplementary Figure 2 from Human Thyroid Tumor Cell Lines Derived from Different Tumor Types Present a Common Dedifferentiated Phenotype

Supplementary Table 2 from Human Thyroid Tumor Cell Lines Derived from Different Tumor Types Present a Common Dedifferentiated Phenotype

Supplementary Materials and Methods from Human Thyroid Tumor Cell Lines Derived from Different Tumor Types Present a Common Dedifferentiated Phenotype

BackgroundCDK4/6 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.MethodsWe 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.ResultsCDK4 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.ConclusionOur 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.

Despite overall good prognosis associated to thyroid cancer (TC), poorly differentiated carcinomas (PDTC) and anaplastic carcinomas (ATC, one of the most lethal human malignancies) represent major clinical challenges. We have shown that the presence of active T172-phosphorylated CDK4 predicts sensitivity to CDK4/6 inhibitory drugs (CDK4/6i) including palbociclib. Here, CDK4 phosphorylation was detected in all well-differentiated TC (n=29), 19/20 PDTC, 16/23 ATC, and 18/21 TC cell lines including 11 ATC-derived ones. The cell lines lacking CDK4 phosphorylation were insensitive to CDK4/6i. RNA-sequencing and immunohistochemistry revealed that tumors and cell lines without phosphorylated CDK4 presented very high p16 CDKN2A levels that were associated with proliferative activity. No RB1 mutations were found in 5 of these 7 tumors. p16/KI67 immunohistochemistry and a previously developed 11-gene signature identified the likely insensitive tumors lacking CDK4 phosphorylation. In cell lines, palbociclib synergized with dabrafenib/trametinib, completely and irreversibly arresting proliferation. The combined drugs prevented resistance mechanisms induced by palbociclib, most notably Cyclin E1-CDK2 activation and a paradoxical stabilization of phosphorylated CDK4 complexes. Our study supports the evaluation of CDK4/6i for ATC/PDTC treatment, including in combination with MEK/BRAF inhibitors.

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 (OR adj 24.0; p = 0.006). This was not the case when patients had sub-threshold emotional problems (OR adj 1.9; p = 0.48). The odds of having the researcher reading the questions out (instead of the patient doing this themselves) (OR adj 0.1; p = 0.01) and of needing any help (OR adj 0.1; p = 0.01) were lower when electronic data capture was used. The proportion of missing scores was equivalent in both groups (OR adj 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.

Supplementary Table 3 from Human Thyroid Tumor Cell Lines Derived from Different Tumor Types Present a Common Dedifferentiated Phenotype

Supplementary Figure 4 from Human Thyroid Tumor Cell Lines Derived from Different Tumor Types Present a Common Dedifferentiated Phenotype

Supplementary Figure 1 from Human Thyroid Tumor Cell Lines Derived from Different Tumor Types Present a Common Dedifferentiated Phenotype

Supplementary Figure 3 from Human Thyroid Tumor Cell Lines Derived from Different Tumor Types Present a Common Dedifferentiated Phenotype

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 & GE;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 & GE;|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.

Purpose The lymph node (LN) status is one of the most important prognostic factors of melanoma. The first treatment of LN metastasis is the lymph node dissection (LND). To date the surgical technic for neck metastasis is discussed. The lymph node ratio (LNR) is defined as the number of invaded LNs dividing by the total number of removed LNs. The aim of our study was to evaluate the impact of the LNR and the extent of neck LND on the prognosis. Methods We recorded LNDs for neck LN metastasis during 16 years. Selective LND (SLND) was limited to the level with LN metastasis. Extensive LND (ELND) was extended to the adjacent LN level. The LNRs were categorized using cutoff points. Among the 62 included patients, 48 LNRs were available for the survival analysis. Time to event endpoint were defined as the time between the event and the date of the previous recurrence. The cut-off p-value for significant statistic was 0.05. Results Breslow thickness < 2mm presented a longer OS (p=0.035) and extracapsular spread presented a shorter overall survival (OS) (p=0.035). Clark levels III and IV presented a longer systemic disease free survival. The OS and the regional control were longer when the LNRs were respectively < 5% and < 10%. ELND improved the regional control, compared to SLND (p=0.02). Conclusion The ELND could improve the regional control compared to SLND. The LNR of neck LNDs could be a prognostic factor and should be low as possible to improve the outcomes.

Background: 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).

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.