Mid-term evaluation of the surgical management of patulous Eustachian tube dysfunction: a STROBE observational study.

INTRODUCTION: Patulous Eustachian tube (PET) is a condition affecting approximately 0.3% to 6.6% of the population, with autophony being the predominant complain. The management of PET lacks a well-defined standard in the literature as no effective medical treatments have been documented but various surgical options are available. This study aims to report mid-term outcomes following surgical management of PET. MATERIALS AND METHODS: All patients who underwent surgical intervention for PET between September 2017 and June 2022 were enrolled. Data encompassing general demographics, quality of life (GBI), and procedure-specific data were collected. RESULTS: A total of 30 PET cases (in 19 patients) underwent surgical intervention including 9 injections of hyaluronic acid, 13 fat injections, 6 endoscopic shim insertions, 1 cartilage graft, and 1 injection of hydroxy apatite. After an average follow-up of 22 ± 14 months, 16 cases (53%) achieved complete symptom relief, while 8 cases (26.6%) reported partial relief. Additionally, 11(36%) cases required multiple surgeries. No specific surgical technique demonstrated superiority. Quality of life improved in 77% of cases based on 10 out of 13 GBI collected. Recurrence of PET symptoms occurred on average 10.6 ± 9.7 months after initial surgery, with an estimated global risk of 75% at 3 years. Transient serous otitis media was observed in only 4 cases (13.3%). CONCLUSION: Surgical intervention for PET was found to be effective, achieving complete symptom relief in 53% of cases and significantly improving quality of life 2 years post-surgery. However, a substantial portion of cases necessitated one or more re-interventions. The durability of effectiveness appears to diminish over time.

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.

Application of machine learning methods to guide patient management by predicting the risk of malignancy of Bethesda III-V thyroid nodules.

OBJECTIVE: Indeterminate thyroid nodules (ITN) are common and often lead to (sometimes unnecessary) diagnostic surgery. We aimed to evaluate the performance of two machine learning methods (ML), based on routinely available features to predict the risk of malignancy (RM) of ITN. DESIGN: Multi-centric diagnostic retrospective cohort study conducted between 2010 and 2020. METHODS: Adult patients who underwent surgery for at least one Bethesda III-V thyroid nodule (TN) with fully available medical records were included. Of the 7917 records reviewed, eligibility criteria were met in 1288 patients with 1335 TN. Patients were divided into training (940 TN) and validation cohort (395 TN). The diagnostic performance of a multivariate logistic regression model (LR) and its nomogram, and a random forest model (RF) in predicting the nature and RM of a TN were evaluated. All available clinical, biological, ultrasound, and cytological data of the patients were collected and used to construct the two algorithms. RESULTS: There were 253 (19%), 693 (52%), and 389 (29%) TN classified as Bethesda III, IV, and V, respectively, with an overall RM of 35%. Both cohorts were well-balanced for baseline characteristics. Both models were validated on the validation cohort, with performances in terms of specificity, sensitivity, positive predictive value, negative predictive value, and area under the receiver operating characteristic curve of 90%, 57.3%, 73.4%, 81.4%, 84% (CI95%: 78.5%-89.5%) for the LR model, and 87.6%, 54.7%, 68.1%, 80%, 82.6% (CI95%: 77.4%-87.9%) for the RF model, respectively. CONCLUSIONS: Our ML models performed well in predicting the nature of Bethesda III-V TN. In addition, our freely available online nomogram helped to refine the RM, identifying low-risk TN that may benefit from surveillance in up to a third of ITN, and thus may reduce the number of unnecessary surgeries.

What about using sniffin' sticks 12 items test to screen post-COVID-19 olfactory disorders?

BACKGROUND: Post-COVID-19 Olfactory impairment has a negative impact on quality of life. The Sniffin Sticks test 12 items (SST-12) can be used in quick olfactory disorders screening. Its evaluation in a post-covid-19 situation was the main objective of this work. METHODS: All patient impaired with a post-COVID olfactory loss were included while consulting to the ENT department. The clinical examination included an olfaction recovery self-assessment (VAS), a nasofibroscopy, a quality of life (QoL) assessment, the complete Sniffin' Sticks Test (SST), and the SST-12. RESULTS: Among the 54 patients included, 92% (n = 50) were correctly screened as olfactory impaired by SST-12. We report excellent correlations between SST-12 and SST (rho (52) = 0.98, p < 0.001), QoL(rho(52) = 0.33 p = 0.016), or VAS (rho(52) = 0.49, p < 0.001) assessments. CONCLUSIONS: SST-12 is a quick and reliable tool to screen large-scale population of post-COVID-19 olfactory impaired patients and could be used in a general daily clinical practice.

Relationship of breast volume, obesity and central obesity with different prognostic factors of breast cancer.

The objective of this study was to investigate whether the BC tumor biology in women with larger breast volume, in obese women and especially in women with central adiposity at the moment of diagnosis of BC is more aggressive than in those women without these characteristics. 347 pre- and postmenopausal women with a recent diagnosis of BC were analyzed. In all patients, anthropometric measurements at the time of diagnosis was collected. In 103 of them, the breast volume was measured by the Archimedes method. The Breast volume, BMI, WHR and the menopausal status were related to different well-known pathological prognostic factors for BC. At the time of diagnosis, 35.4% were obese (BMI > 30 kg/m2), 60.2% had a WHR ≥ 0.85, 68.8% were postmenopausal and 44.7% had a breast volume considered "large" (> 600 cc). Between patients with a large breast volume, only a higher prevalence of ER (+) tumors was found (95.3% vs. 77.2%; p = 0.04) compared to those with small breast volumes. The obese BC patients showed significantly higher rates of large tumors (45.5% vs. 40.6%; p = 0.04), axillary invasion (53.6% vs. 38.8%; p = 0.04), undifferentiated tumors (38.2% vs. 23.2%) and unfavorable NPI (p = 0.04) than non-obese women. Those with WHR ≥ 0.85 presented higher postsurgical tumor stages (61.7% vs. 57.8%; p = 0.03), higher axillary invasion (39.9% vs. 36.0%; p = 0.004), more undifferentiated tumors (30.0% vs. 22.3%; p = 0.009), higher lymphovascular infiltration (6.5% vs. 1.6%; p = 0.02), and a higher NPI (3.6 ± 1.8 vs. 3.2 ± 1.8; p = 0.04). No statistically significant differences were found according to menopausal status. We conclude that obesity, but especially central obesity can be associated with a more aggressive tumour phenotype. No relation between breast volume and tumoral prognostic factors was found, except for a higher proportion of ER (+) tumor in women with higher breast volume.

From biomarkers to therapeutic targets: the promise of PD-L1 in thyroid autoimmunity and cancer.

The programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) immune checkpoint proteins hold promise as diagnostic, prognostic, and therapeutic targets for precision oncology. By restoring antitumor T cell surveillance, the high degree of effectiveness of the immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment. However, the majority of patients (65-80 %) treated with ICIs experience significant side effects, called immune-related adverse events (irAEs), resulting in autoimmune damage to various organs. Therefore, broadening the clinical applicability of these treatments to all cancer types requires an improved understanding of the mechanisms linking cancer immune evasion and autoimmunity. The thyroid is the endocrine gland the most frequently involved in autoimmunity and cancer, the growing incidence of which is raising serious public health issues worldwide. In addition, the risk of developing thyroid cancer is increased in patients with autoimmune thyroid disease and thyroid dysfunction is one of the most common irAEs, especially with PD­1/PD-L1 blockade. Therefore, we chose the thyroid as a model for the study of the link between autoimmunity, irAEs, and cancer. We provide an update into the current knowledge of the PD­1/PD-L1 axis and discuss the growing interest of this axis in the diagnosis, prognosis, and management of thyroid diseases within the context of autoimmunity and cancer, while embracing personalized medicine.

Prospective Multicentric Follow-up Study of Cochlear Implantation in Adults With Single-Sided Deafness: Tinnitus and Audiological Outcomes.

OBJECTIVE: This study investigated the audiological and tinnitus outcomes of cochlear implantation (CI) in adults with single-sided deafness (SSD) and tinnitus. STUDY DESIGN: Multicentered prospective, non-randomized intervention study. SETTING: Six French CI centers. PATIENTS: Twenty-six patients with SSD and incapacitating tinnitus (Tinnitus Handicap Inventory [THI] >58) underwent cochlear implantation. INTERVENTIONS: First, CIs delivered only masking white noise stimulation for 1 month and then standard CI stimulation. MAIN OUTCOME MEASURES: Before and after CI surgery, patients completed the THI, Tinnitus Reaction Questionnaire (TRQ), Subjective Tinnitus Severity Scale (STSS), and two visual analogue scales quantifying tinnitus loudness and annoyance. Speech perception in spatialized noise was tested at 13 months. RESULTS: The first month of white noise stimulation triggered a significant improvement in THI scores (72 ±â€Š9 to 55 ±â€Š20, p < 0.05). No change was observed for the other measures. After 1 year of standard CI stimulation, 23 patients (92%) reported a significant improvement in tinnitus. This improvement started 1 to 2 months after CI and exceeded 40% improvement for 14 patients (54%). Average speech-in-noise perception after 1 year significantly improved for the 23 patients who completed these measures. CONCLUSIONS: CI is efficacious to reduce the handicap of patient with SSD and incapacitating tinnitus, leading to a decrease in reported tinnitus and partial restoration of binaural hearing abilities.

A Rare Cause of Stapedotomy Failure: When the Depth Marker Becomes a Locking Device: A Report on 2 Cases.

We report 2 cases of stapes surgery failure due to the depth marker groove of the piston of a Big Easy titanium prosthesis getting caught at the edge of the stapedotomy hole. In the first case, the stapedotomy failure, detected peroperatively, was corrected by modifying the angulation of the shaft of the prosthesis. In the second case, the failure occurred after a delay during which scar tissue developed around the depth marker groove, hampering the movement of the prosthesis. The usual postoperative imaging did not detect this complication. The diagnosis was made during revision surgery and the condition was treated by enlarging the hole in the footplate. Alternatively, the use of a piston without a depth marker groove would have resolved the problem. Although a rare event, the possibility of stapes surgery failure due to the depth marker groove should not be overlooked.

An original procedure for orbitonasal cutaneous infiltrative tumor repair, using combined forehead and melolabial propeller flaps.

INTRODUCTION: Resections of cutaneous tumors in the medial orbitonasal region can be transfixing. Repairs using a single local flap run the risk of failure and that of secondary sinonasal fistula, especially in cases of surgery on a radiated field. We propose an original and reliable repair procedure using two pedicled regional flaps vascularized by two distinct arterial systems clinched together to reconstruct the mucosal and cutaneous planes. MATERIALS AND METHODS: A first melolabial propeller flap (MPF) with a superior perforating pedicle was elevated and the cutaneous side was sutured to the deep plane of the loss of substance (mucosal lining). A second homolateral or contralateral paramedian forehead flap (PFF) was then lifted and sutured over the first flap (superficial plane). The forehead pedicle flap was divided at 1 month. RESULTS: No trophic complication or failure was recorded on two patients. The 7-year carcinologic, aesthetic, and functional results were satisfying. CONCLUSION: This technique involving the superimposition of two local flaps, vascularized by two different arterial systems, appears to offer a simple and reliable repair technique for transfixing cutaneous losses of substance in the medial orbitonasal region. It could be used in the first-line treatment, particularly if an additional radiotherapy is to be performed.

Association of the Duration of Antibiotic Therapy With Major Surgical Site Infection in Cochlear Implantation.

Importance: Infection after cochlear implantation is a rare but serious event that can lead to meningitis. There is no consensus on prevention of infection in these patients, and each center applies its own strategy. Objective: To describe the rates of major surgical site infection for patients undergoing cochlear implantation who receive prolonged antibiotic treatment compared with those who receive a single perioperative dose of antibiotic prophylaxis. Design, Setting, and Participants: Retrospective cohort study of patients who underwent cochlear implantation between January 1, 2011, and July 8, 2015, with a postoperative follow-up of 1 to 3 years. In this multicenter study at 8 French university centers, 1180 patients (509 children and 671 adults) who underwent cochlear implantation during this period were included. Interventions: Prolonged antibiotic treatment vs single-dose antibiotic prophylaxis. Main Outcomes and Measures: Major infection and explantation. Results: Among 1180 patients (509 children [51.7% female] with a mean [SD] age of 4.6 [3.8] years and 671 adults [54.9% female] with a mean [SD] age of 54.8 [17.0] years), 12 patients (1.0%) developed a major infection, with 4 infections occurring in the prolonged antibiotic treatment group and 8 infections occurring in the antibiotic prophylaxis group (odds ratio, 2.45; 95% CI, 0.73-8.17). Children (9 of 509 [1.8%]) were more likely to develop infection than adults (3 of 671 [0.4%]). Among children, 4 infections occurred in the prolonged antibiotic group (n = 344), and 5 infections occurred in the antibiotic prophylaxis group (n = 158) (odds ratio, 2.78; 95% CI, 0.74-10.49). Among adults, 3 infections occurred in the antibiotic prophylaxis group (n = 365), whereas no infections occurred in the prolonged antibiotic treatment group (n = 290). Conclusions and Relevance: After cochlear implantation, infection was rare, was less common among those who received prolonged antibiotic treatment, and was less likely to occur in adults than in children.

Automated analysis of human cochlea shape variability from segmented µCT images.

The aim of this study is to define an automated and reproducible framework for cochlear anatomical analysis from high-resolution segmented images and to provide a comprehensive and objective shape variability study suitable for cochlear implant design and surgery planning. For the scala tympani (ST), the scala vestibuli (SV) and the whole cochlea, the variability of the arc lengths and the radial and longitudinal components of the lateral, central and modiolar paths are studied. The robustness of the automated cochlear coordinate system estimation is validated with synthetic and real data. Cochlear cross-sections are statistically analyzed using area, height and width measurements. The cross-section tilt angle is objectively measured and this data documents a significant feature for occurrence of surgical trauma.

MicroRNA-375/SEC23A as biomarkers of the in vitro efficacy of vandetanib.

In this study, we performed microRNA (miRNA) expression profiling on a large series of sporadic and hereditary forms of medullary thyroid carcinomas (MTC). More than 60 miRNAs were significantly deregulated in tumor vs adjacent non-tumor tissues, partially overlapping with results of previous studies. We focused our attention on the strongest up-regulated miRNA in MTC samples, miR-375, the deregulation of which has been previously observed in a variety of human malignancies including MTC. We identified miR-375 targets by combining gene expression signatures from human MTC (TT) and normal follicular (Nthy-ori 3-1) cell lines transfected with an antagomiR-375 inhibitor or a miR-375 mimic, respectively, and from an in silico analysis of thyroid cell lines of Cancer Cell Line Encyclopedia datasets. This approach identified SEC23A as a bona fide miR-375 target, which we validated by immunoblotting and immunohistochemistry of non-tumor and pathological thyroid tissue. Furthermore, we observed that miR-375 overexpression was associated with decreased cell proliferation and synergistically increased sensitivity to vandetanib, the clinically relevant treatment of metastatic MTC. We found that miR-375 increased PARP cleavage and decreased AKT phosphorylation, affecting both cell proliferation and viability. We confirmed these results through SEC23A direct silencing in combination with vandetanib, highlighting the importance of SEC23A in the miR-375-associated increased sensitivity to vandetanib.Since the combination of increased expression of miR-375 and decreased expression of SEC23A point to sensitivity to vandetanib, we question if the expression levels of miR-375 and SEC23A should be evaluated as an indicator of eligibility for treatment of MTC patients with vandetanib.

Clinical evaluation of the xDP output compression strategy for cochlear implants.

Technological advances in the domain of digital signal processing adapted to cochlear implants (CI) are partially responsible for the ever-improving outcomes observed with this neural prosthesis. The goal of the present study was to evaluate audiometric outcomes with a new signal processing strategy implemented in Oticon Medical-Neurelec cochlear implant systems, the xDP strategy. The core of this approach is a preset-based back-end output compression system, modulating a multi-channel transfer function depending on the intensity and information content of input sounds. Twenty adult CI patients, matched for age and CI experience, were included in this study. Pure-tone thresholds and vocal audiometry scores were measured with their former signal processing strategy and with xDP. Speech perception was assessed using dissyllabic words presented in quiet, at different intensity levels: 40, 55, 70, and 85 dB SPL, and in a cocktail party noise at a signal-to-noise ratio of +10 dB. Results with the xDP strategy showed, as awaited, no major modification of pure-tone thresholds. A global increase of speech perception scores was observed after a 1-month habituation period, with significant improvements for speech perception in quiet for moderate (55 dB SPL), loud speech sounds (85 dB SPL), and speech-in-noise comprehension. Subjective signal quality assessment showed a preference for Crystalis(xDP) over the former strategy. These results allow the quantification of improvements provided by the xDP signal processing strategy.

Impact of the surgical experience on cochleostomy location: a comparative temporal bone study between endaural and posterior tympanotomy approaches for cochlear implantation.

The goal of this study was to evaluate, in the hands of an inexperienced surgeon, the cochleostomy location of an endaural approach (MINV) compared to the conventional posterior tympanotomy (MPT) approach. Since 2010, we use in the ENT department of Nice a new surgical endaural approach to perform cochlear implantation. In the hands of an inexperienced surgeon, the position of the cochleostomy has not yet been studied in detail for this technique. This is a prospective study of 24 human heads. Straight electrode arrays were implanted by an inexperienced surgeon: on one side using MPT and on the other side using MINV. The cochleostomies were all antero-inferior, but they were performed through an endaural approach with the MINV or a posterior tympanotomy approach with the MPT. The positioning of the cochleostomies into the scala tympani was evaluated by microdissection. Cochleostomies performed through the endaural approach were well placed into the scala tympani more frequently than those performed through the posterior tympanotomy approach (87.5 and 16.7 %, respectively, p ≤ 0.001). This study highlights the biggest challenge for an inexperienced surgeon to achieve a reliable cochleostomy through a posterior tympanotomy, which requires years of experience. In case of an uncomfortable view through a posterior tympanotomy, an inexperienced surgeon might be able to successfully perform a cochleostomy through an endaural (combined approach) or an extended round window approach in order to avoid opening the scala vestibuli.

Influence of Ionizing Radiation on Two Generations of Cochlear Implants.

The purpose of the present study was to test the behavior of two different generations of cochlear implant systems subjected to a clinical radiotherapy scheme and to determine the maximal acceptable cumulative radiation levels at which the devices show out-of-specification behaviors. Using stereotactic irradiation (Cyberknife, 6 MV photon beam), three Digisonic SP and three Neuro devices were submitted to 5 Gy doses that cumulated to 60 Gy (12 sessions) and 80 Gy (16 sessions), respectively. A follow-up series of irradiation was then applied, in which Digisonic SP devices received two additional fractions of 50 Gy each, cumulating to 160 Gy, and Neuro devices three additional fractions of 20, 40, and 150 Gy, cumulating to 290 Gy. Output current values were monitored during the treatment. At clinical doses, with 60 or 80 Gy cumulative radiation exposure, no single measurement showed more than 10% divergence from the reference measure. The cochlear implants tested in this study showed high resistance to clinically relevant cumulative radiation doses and showed no out-of-bounds behavior up to cumulative doses of 140 or 160 Gy. These observations suggest that cochlear implant users can undergo radiotherapy up to cumulative doses well above those currently used in clinical situations without risk of failure.

Effects and consequences of Digisonic SP cochlear implant on radiotherapy planning.

The aim of this study was to assess dose attenuation by a Digisonic SP cochlear implant (CI) and evaluate its impact on treatment planning. The Digisonic CI was irradiated with 6 MV photons. Overall dose attenuation was assessed with MOSFET dosimeters and Gafchromic films. In addition, we evaluated the attenuation of separate CI components. Dose attenuation was also calculated using different radiation treatment planning systems (TPS) softwares and dose calculation algorithms. The CI was placed on a head phantom. Single-beam and multiple-beam plans were evaluated for dose attenuation using two radiation techniques (Conformal and Stereotactic radiotherapy) and four different algorithms (Clarkson, Point Kernel-Superposition, Ray Tracing and Monte Carlo). MOSFET and Gafchromics film showed maximal 6-7.5% radiation dose attenuation, at the center of the CI. Computerized TPS-based dose attenuation by the implant was 4-8.1%, using a single ipsilateral field. No clinically meaningful dose attenuation was found in multiple field plans owing to the contribution of various beam paths with only a couple going through the implant using either conventional conformal or stereotactic treatment plans. Dose attenuation induced by a Digisonic SP CI is about 6%, for single 6 MV photon field. This dose reduction is unlikely to be clinically significant, as single-field radiotherapy plans to this anatomic region are uncommon.

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.

[Treatment of primary thyroid lymphomas]. / Traitement des lymphomes thyroïdiens primitifs de stade localisé

Primary lymphomas of the thyroid (LPT) are a rare entity. LPT represent between 5 and 15% of all thyroid neoplasms. Cytology has limited value; biopsy should be recommended. The differential diagnosis of thyroid carcinoma is differentiated forms indolent or aggressive forms for anaplastic and high grade that may occur by a mass rapidly progressive and compressive. LPT represent a histologically and clinically heterogeneous disease. The most common forms are high-grade LPT (DBLCL) of diffuse large cell type or mucosa-associated lymphoid tissue (MALT). DBLCL receive chemotherapy. The benefit of irradiation is highly debated in view of the data from randomized lymphoma studies (nodal with a minority of extranodal forms) versus those of retrospective studies specifically addressing the case of LPT. Localized MALT lymphomas can be treated with radiation alone. The treatment of other LPT is presented.

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.