Pilot Study on the Use of Untargeted Metabolomic Fingerprinting of Liquid-Cytology Fluids as a Diagnostic Tool of Malignancy for Thyroid Nodules.

Although it is the gold standard for assessing the malignancy of thyroid nodules (TNs) preoperatively, the cytological analysis of fine-needle aspiration cytology (FNAC) samples results in 20-30% of cases in indeterminate lesions (ITNs). As two-thirds of these lesions will appear benign after diagnostic surgery, improved preoperative diagnostic methods need to be developed. In this pilot study, we evaluate if the metabolomic profiles of liquid-based (CytoRich®) FNAC samples of benign and malignant nodules can allow the molecular diagnosis of TNs. We performed untargeted metabolomic analyses with CytoRich® FNAC in a monocentric retrospective study. The cohort was composed of cytologically benign TNs, histologically benign or papillary thyroid carcinomas (PTCs) cytologically ITNs, and suspicious/malignant TNs histologically confirmed as PTCs. The diagnostic performance of the identified metabolomic signature was assessed using several supervised classification methods. Seventy-eight patients were enrolled in the study. We identified 7690 peaks, of which 2697 ions were included for further analysis. We selected a metabolomic signature composed of the top 15 metabolites. Among all the supervised classification methods, the supervised autoencoder deep neural network exhibited the best performance, with an accuracy of 0.957 (0.842-1), an AUC of 0.945 (0.833-1), and an F1 score of 0.947 (0.842-1). Here, we report a promising new ancillary molecular technique to differentiate PTCs from benign TNs (including among ITNs) based on the metabolomic signature of FNAC sample fluids. Further studies with larger cohorts are now needed to identify a larger number of biomarkers and obtain more robust signatures.

SENODAY: A New Perspective of Handling Breast Cancer.

BACKGROUND: To evaluate the feasibility of a same day breast cancer diagnosis and management protocol, consequently decreasing time to treatment and immediately reassuring patients with benign diagnosis. MATERIALS AND METHODS: A total of 60 women underwent breast exam during SENODAY in our cancer center between January 2020 and December 2022. Patients are first seen by a breast surgeon who mentions whether the patient's history and physical exam are suspicious of malignancy. Patients are then sent to the radiologist who performs a complete radiologic assessment, classifies the lesions, and performs a biopsy when necessary. The specimen is sent to the pathologist who uses the imprint cytology technique to obtain a preliminary diagnosis. Effective counseling is established in case of breast cancer diagnosis. RESULTS: Among 60 women, 25 patients were reassured by breast imaging and 35 underwent histopathological analysis (17 patients with a 1-day protocol and 18 with the standard definitive technique). Clinical examination was found to have a sensitivity of 100% and a specificity of 89.47%. The positive predictive value was 80 % and the negative predictive value was 100%. However, we did not find a strong correlation between imaging and definitive pathology. Moreover, on imprint cytology, sensitivity, specificity, PPV, and NPV were 100%. Finally, the mean time-to-treat was 28.6 days. CONCLUSIONS: SENODAY reassured 68.3% of patients. It also offered effective counseling and a treatment plan to newly diagnosed breast cancer patients within 1 day. Same day histological diagnosis by imprint cytology is effective and feasible with an excellent accuracy.

Validation of RUBY for Breast Cancer Knowledge Extraction From a Large French Electronic Medical Record System.

PURPOSE: RUBY is a tool for extracting clinical data on breast cancer from French medical records on the basis of named entity recognition models combined with keyword extraction and postprocessing rules. Although initial results showed a high precision of the system in extracting clinical information from surgery, pathology, and biopsy reports (≥92.7%) and good precision in extracting data from consultation reports (81.8%), its validation is needed before its use in routine practice. METHODS: In this work, we analyzed RUBY's performance compared with the manual entry and we evaluated the generalizability of the approach on different sets of reports collected on a span of 40 years. RESULTS: RUBY performed similarly or better than the manual entry for 15 of 27 variables. It showed similar performances when structuring newer reports but failed to extract entities for which changes in terminology appeared. Finally, our tool could automatically structure 15,990 reports in 77 minutes. CONCLUSION: RUBY can automate the data entry process of a set of variables and reduce its burden, but a continuous evaluation of the format and structure of the reports and a subsequent update of the system is necessary to ensure its robustness.

RUBY: Natural Language Processing of French Electronic Medical Records for Breast Cancer Research.

PURPOSE: Electronic medical records are a valuable source of information about patients' clinical status but are often free-text documents that require laborious manual review to be exploited. Techniques from computer science have been investigated, but the literature has marginally focused on non-English language texts. We developed RUBY, a tool designed in collaboration with IBM-France to automatically structure clinical information from French medical records of patients with breast cancer. MATERIALS AND METHODS: RUBY, which exploits state-of-the-art Named Entity Recognition models combined with keyword extraction and postprocessing rules, was applied on clinical texts. We investigated the precision of RUBY in extracting the target information. RESULTS: RUBY has an average precision of 92.8% for the Surgery report, 92.7% for the Pathology report, 98.1% for the Biopsy report, and 81.8% for the Consultation report. CONCLUSION: These results show that the automatic approach has the potential to effectively extract clinical knowledge from an extensive set of electronic medical records, reducing the manual effort required and saving a significant amount of time. A deeper semantic analysis and further understanding of the context in the text, as well as training on a larger and more recent set of reports, including those containing highly variable entities and the use of ontologies, could further improve the results.

[2021 update of the GEFPICS' recommendations for HER2 status assessment in invasive breast cancer in France]. / Mise à jour 2021 des recommandations du GEFPICS pour l'évaluation du statut HER2 dans les cancers infiltrants du sein en France.

The last international guidelines on HER2 determination in breast cancer have been updated in 2018 by the American Society of Clinical Oncology and College of American Pathologists, on the basis of a twenty-year practice and results of numerous clinical trials. Moreover, the emerging HER2-low concept for 1+ and 2+ non amplified breast cancers lead to refine French practices for HER2 status assessment. The GEFPICS group, composed of expert pathologists, herein presents the latest French recommendations for HER2 status evaluation in breast cancer, taking into account the ASCO/CAP guidelines and introducing the HER2-low concept. In the era of personalized medicine, HER2 status assessment remains one of the most important biomarkers in breast cancer and its quality guaranties the optimal patients' care. French pathologists' commitment in theranostic biomarker quality is more than ever required to provide the most efficient cares in oncology.

[Is preoperative axillary radio-cytology justified after ACOSOG Z001?] / La radio-cytologie axillaire préopératoire est-elle justifiée après l'ACOSOG Z001 ?

INTRODUCTION: Invasive breast cancer without clinical adenopathy (cN0) is currently explored by the sentinel node (GS) technique, except in the case of positive preoperative radio-cytological screening, where axillary curage (CA) remains systematic from the outset. Since the publication of the ACOSOG-Z0011 trial, abstention from CA is possible in patients presenting less than three metastatic GS. As a result, the value of axillary radio-cytological screening is being questioned as it could potentially lead to axillary surgical over-treatment. The objective of this study was to study clinically N0 patients with positive axillary cytology and to compare it to a group of patients with positive GS. METHOD: One hundred and forty-seven patients with cN0 pN+ breast cancer treated between 2014 and 2016 were selected retrospectively. Two groups were constituted according to the initial radio-cytological evaluation. A CA was systematically performed. RESULTS: Thirty-one patients with positive axillary cytology (n=31 vs. n=116) had more metastatic lymph nodes (P=0.01) in the AC, larger (P<0.001), less differentiated (P<0.001) tumours, and shorter recurrence-free survival (P=0.0114). It also appeared that 38.7 % of patients with a positive cytology had at most two metastatic nodes and could, according to the results of ACOSOG, benefit from therapeutic de-escalation. CONCLUSION: X-ray cytological screening remains essential in order to select a subgroup of patients with a high lymph node tumour load. Additional studies are necessary in order to be able to offer therapeutic de-escalation to 1/3 of these patients without the risk of under-treatment for the remaining 2/3.

Phenotypic discordance between primary and metastatic breast cancer in the large-scale real-life multicenter French ESME cohort.

Expression of hormone receptor (HR) for estrogens (ER) and progesterone (PR) and HER2 remains the cornerstone to define the therapeutic strategy for breast cancer patients. We aimed to compare phenotypic profiles between matched primary and metastatic breast cancer (MBC) in the ESME database, a National real-life multicenter cohort of MBC patients. Patients with results available on both primary tumour and metastatic disease within 6 months of MBC diagnosis and before any tumour progression were eligible for the main analysis. Among the 16,703 patients included in the database, 1677 (10.0%) had available biopsy results at MBC diagnosis and on matched primary tumour. The change rate of either HR or HER2 was 27.0%. Global HR status changed (from positive = either ER or PR positive, to negative = both negative; and reverse) in 14.2% of the cases (expression loss in 72.5% and gain in 27.5%). HER2 status changed in 7.8% (amplification loss in 45.2%). The discordance rate appeared similar across different biopsy sites. Metastasis to bone, HER2+ and RH+/HER2- subtypes and previous adjuvant endocrine therapy, but not relapse interval were associated with an HR discordance in multivariable analysis. Loss of HR status was significantly associated with a risk of death (HR adjusted = 1.51, p = 0.002) while gain of HR and HER2 discordance was not. In conclusion, discordance of HR and HER2 expression between primary and metastatic breast cancer cannot be neglected. In addition, HR loss is associated with worse survival. Sampling metastatic sites is essential for treatment adjustment.

[Preoperative breast imaging review: Interests and limits of specialized validation in oncology]. / Relecture préopératoire en sénologie : intérêts et limites d'une validation spécialisée en oncologie.

OBJECTIVES: To evaluate the impact of systematic radiological review by breast specialist radiologist of malignant breast lesion imaging on the therapeutic management of patients. MATERIALS AND METHODS: Data collection was performed for patients with histopathologically proved breast cancer or suspicious breast lesion on imaging realized out of our institution. Patients underwent systematic mammary and axillary ultrasound, imaging review and if necessary complementary mammographic images. We analyzed the number of additional breast biopsies and axillary lymph node fine needle aspiration (FNA) with their histopathological results. We assessed their impact by comparing the final surgical treatment to the one planned before review. RESULTS: Two hundred and seventeen patients were included, with a total of 230 BIRADS 0, 4, 5 or 6 breast lesions. Seventy-six additional breast core biopsies were realized, leading to diagnose 43 additional BIRADS 6 lesions (24 infiltrative carcinomas, 9 DCIS and 10 atypical lesions) in 30 patients (13.82%). Thirty-five additional lymph node FNA were realized with 12 metastatic nodes and 3 false negative samples. Imaging review lead to change surgical treatment in 59 patients (27.19%, P<0.01) with modification in breast surgery in 37 patients, axillary surgery in 8 patients and both sites surgery in 12 patients. CONCLUSION: This study shows an impact of systematic radiological review by breast specialist radiologist in therapeutic management of patients treated for malignant breast lesion.

[GEFPICS' guidelines for management of breast cancer tissue samples in the neoadjuvant setting]. / Recommandations du GEFPICS pour la prise en charge des prélèvements dans le cadre du traitement néoadjuvant du cancer du sein.

Neoadjuvant therapy is an increasing treatment option in the management of breast cancer. The tumor response to neoadjuvant therapy, especially the pathological complete response, is a validated endpoint frequently used in clinical trials. However, there is still a lack of standardization for the surgical specimen management in the neoadjuvant setting. This leads to heterogeneity in the specimen handling and might lead to significant bias for the prognostic assessment of patients or in clinical trials. The GEFPICS group, composed of expert breast cancer pathologists, herein presents guidelines for the management of breast and axillary specimen before treatment (management of biopsy, items of the pathological report) and after neoadjuvant therapy (specimen handling, histological assessment of response, items of the pathological report and response grading systems).

Robotic Stereotactic Boost in Early Breast Cancer, a Phase 2 Trial.

PURPOSE: To evaluate the feasibility and toxicity of a single-fraction 8-Gy stereotactic boost after whole-breast irradiation in early breast cancer. The primary aim of this phase 2 study was to evaluate cutaneous breast toxicity using National Cancer Institute Common Terminology Criteria for Adverse Events (version 4) 3 months after the boost. Secondary objectives were local control, survival, and patient-reported quality of life using the European Organisation for Research and Treatment of Cancer QLQ-C30 and breast-specific European Organisation for Research and Treatment of Cancer QLQ-BR 23 questionnaires. METHODS AND MATERIALS: Patients with invasive ductal or lobular pT1-2 breast cancer treated with lumpectomy with clear margins and pN0 were included. Patients requiring chemotherapy were excluded. RESULTS: Twenty-eight eligible patients received the planned boost, and 26 had hormonal therapy. The procedure was technically successful without procedural complications. A median of 3 fiducials were tracked, and 115 beams were used. There were 22 acute grade 1 breast skin toxicities, including fibrosis, pain, erythema, or pigmentation. There were 2 acute grade 2 erythemas. Median skin boost dose was inversely correlated with acute skin toxicity (P = .028). QLQ-C30 scores revealed acute dyspnea and arm symptoms without correlation to the boost dose. Breast symptom QLQ-BR23 scores did not deteriorate, although upset with hair loss and systemic side effects of hormonal therapy were observed. After a median follow-up of 38 months, 1 patient had in-boost-field relapse, and there were 5 late grade 1 and 1 grade 2 skin toxicities. CONCLUSIONS: Single-fraction stereotactic boost after conventional whole-breast irradiation in early breast cancer is feasible with minor toxicities. Quality of life and specific breast items showed excellent patient acceptance.

Primary radical ablative surgery and fibula free-flap reconstruction for T4 oral cavity squamous cell carcinoma with mandibular invasion: oncologic and functional results and their predictive factors.

The aims of this study were to evaluate clinical outcomes and to determine their predictive factors in patients with oral cavity squamous cell carcinoma (OCSCC) invading the mandibular bone (T4) who underwent primary radical surgery and fibula free-flap reconstruction. Between 2001 and 2013, all patients who underwent primary surgery and mandibular fibula free-flap reconstruction for OCSCC were enrolled in this retrospective study. Predictive factors of oncologic and functional outcomes were assessed in univariate and multivariate analysis. 77 patients (55 men and 22 women, mean age 62 ± 10.6 years) were enrolled in this study. Free-flap failure and local and general complication rates were 9, 31, and 22 %, respectively. In multivariate analysis, ASA score (p = 0.002), pathologic N-stage (p = 0.01), and close surgical margins (p = 0.03) were independent predictors of overall survival. Six months after therapy, oral diet, speech intelligibility, and mouth opening functions were normal or slightly impaired in, respectively, 79, 88, and 83 % of patients. 6.5 % of patients remaining dependent on enteral nutrition 6 months after therapy. With acceptable postoperative outcomes and satisfactory oncologic and functional results, segmental mandibulectomy with fibula free-flap reconstruction should be considered the gold standard primary treatment for patients with OCSCC invading mandible bone. Oncologic outcomes are dependent on three main factors: ASA score, pathologic N-stage, and surgical margin status.

Nutritional status and feeding-tube placement in patients with locally advanced hypopharyngeal cancer included in an induction chemotherapy-based larynx preservation program.

The objective of the study is to evaluate the nutritional status and determine its impact on clinical outcomes in patients with locally advanced hypopharyngeal cancer included in an induction chemotherapy (ICT)-based larynx preservation program without prophylactic feeding-tube placement. All patients with locally advanced (T3/4, N0-3, M0) hypopharyngeal squamous cell carcinoma, technically suitable for total pharyngolaryngectomy, treated by docetaxel, cisplatin and 5-fluorouracil (TPF)-ICT for larynx preservation at our institution between 2004 and 2013, were included in this retrospective study. Patients' nutritional status was closely monitored. Enteral nutrition was used if and when a patient was unable to sustain per-oral nutrition and hydration. The impact of nutritional status on clinical outcomes was investigated in univariate and multivariate analysis. A total of 53 patients (42 men and 11 women, mean age = 58.6 ± 8.2 years) were included in this study. Six (11.3 %) patients had lost more than 10 % of their usual body weight before therapy. Compared with patients' usual weight, the mean maximum patient weight loss during therapeutic management was 8.7 ± 4.5 kg. Enteral nutrition was required in 17 patients (32 %). We found no influence of the tested nutritional status-related factors on response to ICT, toxicity of ICT, overall, cause-specific and recurrence-free survival, and on post-therapeutic swallowing outcome. Maximum weight loss was significantly associated with a higher risk of enteral tube feeding during therapy (p = 0.03) and of complications (grade ≥3, p = 0.006) during RT. Without prophylactic feeding-tube placement, approximately one-third of the patients required enteral nutrition. There was no significant impact of nutritional status on oncologic or functional outcomes.

Salvage surgery for recurrent oropharyngeal cancer: post-operative oncologic and functional outcomes.

CONCLUSION: Post-operative outcomes of salvage surgery for recurrent oropharyngeal squamous-cell carcinoma (OPSCC) were acceptable. Pathologic overall, T- or N-stage and patient comorbidities were the main predictors of patient clinical outcomes. OBJECTIVES: To evaluate post-operative outcomes of salvage surgery in patients with recurrent OPSCC and to determine their predictive factors. MATERIALS AND METHODS: This study retrospectively reviewed the electronic medical records of all patients who underwent salvage surgery for recurrent OPSCC, between 2000-2013, in our institution. Overall survival (OS) and cause-specific survival (SS) were determined by Kaplan-Meier analysis. Predictive factors of post-operative outcomes were investigated by using univariate and multivariate analyses. RESULTS: A total of 34 patients were included in this study. Local and general post-operative complication rates were 26% and 27%, respectively. A high level of comorbidity (Kaplan Feinstein Index: KFI ≥ 2) was the only factor associated with a higher risk of local (p = 0.03) and general (p = 0.04) complications. OS and SS rates at 3 years were 48% and 61%, respectively. In multivariate analysis, pathologic overall stage ≥ III was a significant predictor of OS (p = 0.02) and pathologic T-stage ≥ 3 was a significant predictor of SS (p = 0.01). Mean pre-operative and post-operative DOSS (dysphagia outcome and severity scale) scores were 4.4 and 3.9, respectively.

Contemporary therapeutic management of locally advanced hypopharyngeal cancer: oncologic and functional outcomes - a report on 100 cases.

CONCLUSION: A significant proportion of patients with locally advanced hypopharyngeal cancer could not be managed by larynx-sparing therapy. T4 stage is one of the main predictive factors of oncologic and functional outcomes. OBJECTIVES: To analyze the therapeutic management of patients with locally advanced hypopharyngeal cancer in clinical practice and to report oncologic and functional outcomes. METHODS: This was a retrospective study of all patients treated for a locally advanced hypopharyngeal squamous cell carcinoma between 2001 and 2012 at our institution. RESULTS: A total of 100 patients were included in this study. Induction chemotherapy (CT) followed by radiotherapy (RT) ± CT, primary RT + CT, and primary total pharyngolaryngectomy (TPL) comprised the initial therapeutic management for 54, 24, and 20 patients, respectively. Two patients received only supportive care. Overall survival (OS) and cause-specific survival (SS) were 50% and 60% at 3 years, respectively. In the group of patients referred for induction CT, the 3-year OS and SS were 58% and 70%, respectively. In multivariate analysis, T stage (p = 0.05) and ASA score (p = 0.02) were significant predictive factors of OS. T4 tumor stage had a pejorative impact on swallowing function after therapy (p = 0.006). The rate of patients alive, disease-free, and with a functional larynx at 2 years was 23%.

[Pre-analytical stage for biomarker assessment in breast cancer: 2014 update of the GEFPICS' guidelines in France]. / Recommandations du GEFPICS concernant la phase pré-analytique pour l'évaluation de HER2 et des récepteurs hormonaux dans le cancer du sein : mise à jour 2014.

Biomarker assessment of breast cancer tumor samples is part of the routine workflow of pathology laboratories. International guidelines have recently been updated, with special regards to the pre-analytical steps that are critical for the quality of immunohistochemical and in situ hybridization procedures, whatever the biomarker analyzed. Fixation and specimen handling protocols must be standardized, validated and carefully tracked. Cooperation and training of the personnel involved in the specimen workflow (e.g. radiologists, surgeons, nurses, technicians and pathologists) are of paramount importance. The GEFPICS' update of the recommendations herein details and comments the different steps of the pre-analytical process. Application of these guidelines and participation to quality insurance programs are mandatory to ensure the correct evaluation of oncotheranostic biomarkers.

[2014 update of the GEFPICS' recommendations for HER2 status determination in breast cancers in France]. / Mise à jour 2014 des recommandations du GEFPICS pour l'évaluation du statut HER2 dans les cancers du sein en France.

International guidelines on HER2 determination in breast cancer have just been updated by the American Society of Clinical Oncology (ASCO) and College of American Pathologists (CAP), on the basis of more than ten-year practice, results of clinical trials and concordance studies. The GEFPICS group, composed of expert pathologists in breast cancer, herein presents these recommendations, adapted to the French routine practice. These guidelines highlight the possible diagnosis difficulties with regards to HER2 status determination, such as intra-tumor heterogeneity, special histological subtypes and biomarker re-evaluation during metastatic relapse. Pre-analytical issues and updated scoring criteria (especially for equivocal cases) are detailed, in order to decrease the occurrence of false negative cases. In the era of personalized medicine, pathologists are more than ever involved in the quality of oncotheranostic biomarker evaluation.

Long-term functional outcomes and quality of life after oncologic surgery and microvascular reconstruction in patients with oral or oropharyngeal cancer.

CONCLUSIONS: Surgery for oral or oropharyngeal cancer with free-flap reconstruction is associated with moderate but persistent functional and quality of life (QoL) problems. Patient age, tumor stage, tumor site, and radiotherapy were the main predictors of functional outcome. OBJECTIVES: To evaluate long-term functional outcomes and QoL, and to determine their predictive factors in patients with oral or oropharyngeal cancer after oncologic surgery and free-flap reconstruction. METHODS: Patients who underwent surgery with free-flap reconstruction for oral or oropharyngeal cancer between 2000 and 2009 who were alive at least 1 year after therapy were included in this study. Patients completed the Voice Handicap Index (VHI-10) questionnaire and the European Organization for Research and Treatment of Cancer (EORTC) QoL questionnaires QLQ-C30 and H&N35. Swallowing was evaluated using the Dysphagia Outcome and Severity Scale (DOSS) and by flexible fiberoptic laryngoscopy. RESULTS: Sixty-four patients were included in the study. VHI-10 mean score was 11.2 ± 9 and its predictive factors were T stage (p = 0.005) and tumor involvement of the tongue base (p = 0.01). The mean DOSS score was 4 ± 0.8. Age (p = 0.008), gender (p = 0.04), and radiotherapy (p = 0.001) were the main predictive factors of the DOSS score.

Diagnostic value of immunohistochemistry for the detection of the BRAF(V600E) mutation in papillary thyroid carcinoma: comparative analysis with three DNA-based assays.

BACKGROUND: The aim of this study was to compare the detection of BRAF(V600E) by immunohistochemistry (IHC) using a mutation-specific antibody with molecular biology methods for evaluation of papillary thyroid carcinoma (PTC) patients. PATIENTS AND METHODS: This study concerned 198 consecutive conventional PTC patients, of which the majority were women (133/198; 67%), with a mean age of 56 years (range 19-79 years). BRAF mutation analysis was performed using DNA-based (direct sequencing, pyrosequencing, and SNaPshot) and IHC (VE1 antibody) methods. The sensitivity and specificity of IHC for BRAF(V600E) was compared with the molecular biology data. RESULTS: A BRAF mutational result was obtained in 194 cases. A BRAF(V600E) mutation was detected in 153/194 (79%) cases of PTC when using at least one molecular method, and in 151/194 (78%) cases with IHC. No false positive results were noted using IHC to detect the BRAF(V600E) mutation. Besides this mutation, other rare BRAF mutations (BRAF(V600K) and BRAF(K601E)), used as negative controls, were consistently negative with IHC. The sensitivity and specificity of IHC for the detection of this mutation were 98.7% and 100% respectively. The IHC test demonstrated excellent performance at a level equivalent to two DNA-based counterparts (pyrosequencing and SNaPshot). Failure to achieve a result was more frequent with the direct sequencing method than with the three other methods. CONCLUSION: IHC using the VE1 antibody is a specific and sensitive method for the detection of the BRAF(V600E) mutation in PTC. IHC may be an alternative to molecular biology approaches for the routine detection of this mutation in PTC patients.

In papillary thyroid carcinoma, TIMP-1 expression correlates with BRAF (V600E) mutation status and together with hypoxia-related proteins predicts aggressive behavior.

BRAF (V600E) causes upregulation of tissue inhibitor of metalloproteinase-1 (TIMP-1), which promotes cell invasion in papillary thyroid carcinoma (PTC). Hypoxia-inducible factor-1α (HIF- α) is regulated by hypoxia and also by the BRAF-mediated signaling pathway in PTC. We assessed the association of expression of TIMP-1, HIF-1α, and hypoxia-inducible carbonic anhydrase IX (CAIX) and XII (CAXII) with clinical parameters in PTC. TPC-1/BRAF (WT) wild-type and BcPAP/BRAF (V600E) -mutated PTC cell lines were selected to study the effects of the BRAF (V600E) mutation and hypoxia on expression in vitro of TIMP-1, CAIX, and CAXII proteins by immunoblotting. Higher expression of all proteins was detected in BcPAP cells exposed to hypoxia. Tissue microarray immunohistochemistry analysis was performed to study protein expression in 114 BRAF-genotyped PTC samples. Expression data on tumor tissue were compared with clinicopathological variables. TIMP-1 expression had a sensitivity of 87 % and a specificity of 83 % in identifying a BRAF mutation (P < 0.001) and was associated with pT stage (P = 0.001), pN stage (P = 0.02), and multifocality (P = 0.03). HIF-1α expression correlated with pT stage (P = 0.05). CAIX expression was associated with pN stage (P = 0.02), and both CAIX (P = 0.004) and CAXII (P = 0.05) were strongly associated with vascular invasion. We conclude that TIMP-1 protein expression is a reliable surrogate marker for BRAF-mutated status in PTC. TIMP-1 and hypoxia-regulated proteins are promising as predictors of aggressiveness in PTC and warrant further investigation as new therapeutic targets for the treatment of highly aggressive forms of PTC.

Conservative multimodal management of a primitive neuroectodermal tumor of the thyroid.

Primitive neuroectodermal tumors (PNET) represent 1% of sarcomas. Head and neck peripheral PNETs have an intermediate prognosis between abdominopelvic disease and extremities. We here report the case of a 40-year old male who presented with primitive neuroectodermal tumor of the thyroid and was treated by multimodal treatment, including surgery, chemotherapy and intermediate dose radiotherapy. The patient is alive and fit with a functional larynx at 27 months. Multimodal treatments yield five-year survival rates of about 60%. Major drug regimens use vincristine, doxorubicin, ifosfamide or cyclophosphamide, dactinomycin and/or etoposide. Complete surgical excision is undertaken whenever possible to improve long-term survival. However, the relative radiosensitivity of tumors of the Ewing family, suggest multimodal treatment including adjuvant conformal radiotherapy in case of positive margins or poor response to chemotherapy rather than resection with 2-3 cm margins, which would imply laryngeal sacrifice for thyroid tumors. The role of expert rare tumor networks is crucial for optimal decision-making and management of such rare tumors on a case by case basis.