Proteomics Reveals mRNA Regulation and the Action of Annexins in Thyroid Cancer.

Differentiated thyroid cancer is the most common malignancy of the endocrine system. Although most thyroid nodules are benign, given the high incidence of thyroid nodules in the population, it is important to understand the differences between benign and malignant thyroid cancer and the molecular alterations associated with malignancy to improve detection and signal potential diagnostic, prognostic, and therapeutic targets. Proteomics analysis of benign and malignant human thyroid tissue largely revealed changes indicating modifications in RNA regulation, a common cancer characteristic. In addition, changes in the immune system and cell membrane/endocytic processes were also suggested to be involved. Annexin A1 was considered a potential malignancy biomarker and, similarly to other annexins, it was found to increase in the malignant group. Furthermore, a bioinformatics approach points to the transcription factor Sp1 as being potentially involved in most of the alterations seen in the malignant thyroid nodules.

Peptidomics Unveils Distinct Acetylation Patterns of Histone and Annexin A1 in Differentiated Thyroid Cancer.

Thyroid cancer is a common malignancy of the endocrine system. Nodules are routinely evaluated for malignancy risk by fine needle aspiration biopsy (FNAB), and in cases such as follicular lesions, differential diagnosis between benign and malignant nodules is highly uncertain. Therefore, the discovery of new biomarkers for this disease could be helpful in improving diagnostic accuracy. Thyroid nodule biopsies were subjected to a precipitation step with both the insoluble and supernatant fractions subjected to proteome and peptidome profiling. Proteomic analysis identified annexin A1 as a potential biomarker of thyroid cancer malignancy, with its levels increased in malignant samples. Also upregulated were the acetylated peptides of annexin A1, revealed by the peptidome analysis of the supernatant fraction. In addition, supernatant peptidomic analysis revealed a number of acetylated histone peptides that were significantly elevated in the malignant group, suggesting higher gene transcription activity in malignant tissue. Two of these peptides were found to be robust malignancy predictors, with an area under the receiver operating a characteristic curve (ROC AUC) above 0.95. Thus, this combination of proteomics and peptidomics analyses improved the detection of malignant lesions and also provided new evidence linking thyroid cancer development to heightened transcription activity. This study demonstrates the importance of peptidomic profiling in complementing traditional proteomics approaches.

TERT Promoter Mutational Status in the Management of Cutaneous Melanoma: Comparison with Sentinel Lymph Node Biopsy.

BACKGROUND: While BRAF mutations seem important for early melanomagenesis, mutations in the TERT promoter (TERTp) are related to metastasis. Yet, in conventional melanoma management, risk stratification does not depend on molecular biomarkers that can indicate the stage of progression, but rather on clinical, pathological, sentinel lymph node (SLN), and radiologic evaluation. The aim of this work was to evaluate the frequency and prognostic impact of TERTp mutations, comparing their predictive value to those of conventional procedures in melanoma management. METHODS: Mutational analysis of a series of 91 cases was performed. The correlations between TERTp and BRAF mutational status and clinicopathological features were assessed. RESULTS: The mutation rate was 33% for TERTp and 30% for BRAF. There was 68% concordance between primary and metastatic samples for TERTp mutations and 92% for BRAF mutations. TERTp mutations are significantly associated with the presence of BRAF mutations, features of worse prognosis, and a reduced disease-free survival. Also, TERTp mutational status was similar to SLN biopsy as a predictive factor of cutaneous melanoma recurrence and metastasis. CONCLUSIONS: The predictive value of TERTp mutations may be similar to that of SLN biopsy and its integration in the management algorithm of melanoma patients should be considered.

TERTp mutations and p53 expression in head and neck cutaneous basal cell carcinomas with different aggressive features.

Cutaneous basal cell carcinoma (cBCC) is an economic burden to health services, due to its great morbidity and increasing incidence in old people. Infiltrative cBCCs and cBCCs with micronodular pattern are considered as more aggressive. The role of p53 expression and TERTp mutation on cBCC behavior remains to be clarified. We aimed to assess TERTp mutations and p53 expression in relation to the cBCC histological subtype in a cohort of patients referred to an ENT Department of a tertiary Hospital of Northern Portugal. We performed a retrospective clinicopathological and histological review of the head and neck cBCCs followed-up at the otorhinolaryngology department of Trás-os-Montes e Alto Douro hospital (January 2007-June 2018). We assessed TERTp mutations in 142 cBCCs and p53 protein expression, through immunohistochemistry, in 157 cBCCs. We detected TERTp mutations in 43.7% of cBCCs and p53 overexpression in 60.5% of cBCCs. We spotted association of p53 overexpression and TERTp mutation with necrosis. In the infitrative-growth pattern cBCCs, there was no significant association with the clinical and histological features evaluated, except for necrosis. In the indolent-growth cBCCs, we identified a significant association of TERTp mutation status with female sex, necrosis, multiple cBCCs, and p53 positive expression. Our results suggest that TERTp mutation may be useful to identify more aggressive features in the indolent-growth pattern cBCCs (nodular and superficial subtypes). Further studies with larger cohorts are warranted to clarify the relevance of TERTp mutation in cBCCs.

Prognostic Significance of RAS Mutations and P53 Expression in Cutaneous Squamous Cell Carcinomas.

TP53 is considered the most commonly-altered gene in cutaneous squamous cell carcinoma (cSCC). Conversely, RAS mutations have been reported in a low percentage of cSCC. The objective of our study was to evaluate the frequency of p53 expression and RAS mutations in cSCC and correlate them with clinicopathological features and patient outcome. We performed immunohistochemistry for p53 and genetic profiling for RAS mutations in a retrospective series of cSCC. The predictive value of p53 expression, RAS mutations, and clinicopathological parameters was assessed using logistic regression models. The overall frequency of RAS mutations was 9.3% (15/162), and 82.1% of the cases (133/162) had p53 overexpression. RAS mutations rate was 3.2% (1/31) of in situ cSCCs and 10.7% (14/131) of invasive cSCCs. RAS mutations were more frequently associated with an infiltrative than an expansive pattern of invasion (p = 0.046). p53 overexpression was a predictor of recurrence in the univariate analysis. Our results indicate that RAS mutations associate with features of local aggressiveness. Larger studies with more recurrent and metastatic cSCCs are necessary to further address the prognostic significance of p53 overexpression in patients' risk stratification.

Surgical outcomes of sinonasal inverted papilloma: a 17 year review / Resultados cirúrgicos do papiloma invertido nasossinusal: uma revisão de 17 anos

Abstract Introduction: Inverted papillomas represent one of the most common benign neoplasic lesions located in the sinonasal tract. Owing to the local erosive behavior, tendency to recur and the potential for malignant transformation, surgical management of inverted papillomas is often challenging. Objective: This study aimed to analyze the surgical outcomes of patients with inverted papillomas, according to the Krouse staging and the different surgical approaches. Methods: Retrospective study of patients diagnosed with sinonasal inverted papillomas who underwent surgical treatment between 2000 and 2016 at a tertiary referral hospital. Cases with follow-up less than 12 months were excluded. The rate and the time of recurrence were the main outcomes. Values of p < 0.05 were considered statistically significant. Results: Thirty-six cases with mean age of 60 years, predominantly male (72%), were included. The follow-up period ranged from 1 to 16 years, with an average of 4.5 years. Krouse T1 Stage corresponded to 11.1%; T2 occurred in 50% of cases; while T3 and T4 Stages accounted for 30.6% and 8.3% of patients, respectively. Most cases were approached by an endoscopic technique alone (83.3%), with a recurrence rate of 13.3%. Patients treated via a combined or open approach revealed a recurrence of 16.7%. No differences in the recurrence rate were reported when comparing endoscopic surgery with the open or combined techniques. Krouse Stage T3 had a significant association with inverted papillomas recurrence (p = 0.023). All inverted papilloma relapses occurred up to 2 years post-operatively. One case of malignant transformation was recorded (2.7%). Conclusion: Endoscopic surgery did not increase the recurrence rates and can be a safe and efficient alternative to open or combined techniques. The recurrence of inverted papillomas seem to be related to the persistence of the disease and tend to occur early after primary surgery. Krouse T3 Stages may be associated with a higher recurrence of inverted papillomas.

Resumo Introdução: Os papilomas invertidos são uma das lesões neoplásicas benignas mais comuns no trato nasossinusal. Devido ao seu comportamento localmente agressivo, tendência para recidivar e potencial de malignização, o tratamento cirúrgico dos papilomas invertidos constitui frequentemente um desafio. Objetivo: Analisar os resultados cirúrgicos dos papilomas invertidos segundo o estadiamento de Krouse, bem como avaliar as diferentes abordagens cirúrgicas. Método: Estudo retrospectivo de pacientes com diagnóstico de papiloma invertido nasossinusal submetidos a tratamento cirúrgico entre 2000 e 2016 em hospital terciário. Casos com acompanhamento inferior a 12 meses foram excluídos. A taxa e o tempo de recidiva foram os principais resultados analisados desfechos avaliados. Valores p < 0,05 foram considerados estatisticamente significativos. Resultados: Foram incluídos 36 casos, com média de idade de 60 anos, predominantemente do sexo masculino (72%). O período de acompanhamento variou de 1 a 16 anos, em uma média de 4,5 anos. Relativamente ao estadiamento, 11,1% dos pacientes foram classificados como estadio Krouse T1, 50% como T2, 30,6% como T3 e 8,3% como T4. A maioria dos casos foi tratada exclusivamente por cirurgia endoscópica (83,3%), com taxa de recidiva de 13,3%. Pacientes tratados com uma técnica combinada ou aberta apresentaram recidiva de 16,7%. Não foram observadas diferenças quanto à taxa de recidiva entre os casos abordados por via endoscópica e os casos tratados com técnica aberta ou combinada. Verificou-se uma associação significativa entre o estadio T3 de Krouse e recidiva de papilomas invertidos (p = 0,023). Todas as recidivas de papilomas invertidos foram observadas até dois anos após a cirurgia. Um caso de transformação maligna foi registrado (2,7%). Conclusão: A cirurgia endoscópica não aumentou as taxas de recidiva e pode ser uma alternativa segura e eficiente às técnicas abertas ou combinadas. Os casos de recidiva do papiloma invertido parecem estar relacionados com a persistência da doença e tendem a ocorrer precocemente após a cirurgia primária. Os estadios T3 de Krouse podem estar associados a uma maior recidiva.

Surgical outcomes of sinonasal inverted papilloma: a 17 year review.

INTRODUCTION: Inverted papillomas represent one of the most common benign neoplasic lesions located in the sinonasal tract. Owing to the local erosive behavior, tendency to recur and the potential for malignant transformation, surgical management of inverted papillomas is often challenging. OBJECTIVE: This study aimed to analyze the surgical outcomes of patients with inverted papillomas, according to the Krouse staging and the different surgical approaches. METHODS: Retrospective study of patients diagnosed with sinonasal inverted papillomas who underwent surgical treatment between 2000 and 2016 at a tertiary referral hospital. Cases with follow-up less than 12 months were excluded. The rate and the time of recurrence were the main outcomes. Values of p<0.05 were considered statistically significant. RESULTS: Thirty-six cases with mean age of 60 years, predominantly male (72%), were included. The follow-up period ranged from 1 to 16 years, with an average of 4.5 years. Krouse T1 Stage corresponded to 11.1%; T2 occurred in 50% of cases; while T3 and T4 Stages accounted for 30.6% and 8.3% of patients, respectively. Most cases were approached by an endoscopic technique alone (83.3%), with a recurrence rate of 13.3%. Patients treated via a combined or open approach revealed a recurrence of 16.7%. No differences in the recurrence rate were reported when comparing endoscopic surgery with the open or combined techniques. Krouse Stage T3 had a significant association with inverted papillomas recurrence (p=0.023). All inverted papilloma relapses occurred up to 2 years post-operatively. One case of malignant transformation was recorded (2.7%). CONCLUSION: Endoscopic surgery did not increase the recurrence rates and can be a safe and efficient alternative to open or combined techniques. The recurrence of inverted papillomas seem to be related to the persistence of the disease and tend to occur early after primary surgery. Krouse T3 Stages may be associated with a higher recurrence of inverted papillomas.

Is the femoral lateral condyle's bone morphology the trochlea of the ACL?

PURPOSE: The purpose of this study was to investigate the association of different osteoarticular femoral and tibial morphology and morphometric parameters with the risk of anterior cruciate ligament (ACL) rupture. METHODS: Thirty-six patients (29 male and 7 female) with an ACL rupture (<6 months) and 36 age and sex-matched controls were included. The anatomomorphological parameters and morphometrics of the distal epiphysis of the femur and proximal epiphysis of the tibia were measured through conventional lateral radiography of the knee. RESULTS: It was found statistically significant smaller heights of femur's lateral condyle, AP distances of the tibial plateaus and smaller XY and WX distances, as well as, higher XY/AB and B/AB ratios (p < 0.05). In turn, women had smaller AP distances of the femur's lateral condyle, AP distances of the femur's diaphysis, AP distances of the tibial plateaus and heights of femur's lateral condyle, as well as, higher values of XY/AB (Porto ratio) and B/AB ratios (p < 0.05). CONCLUSIONS: Several femoral and tibial bone morphological parameters were identified as potential risk factors for sustaining an ACL injury. These parameters are clinically relevant to identify individuals with higher risk of ACL injury, decide between conservative or surgical treatment and identify individuals who may benefit from preventive neuromuscular programs. LEVEL OF EVIDENCE: Case-control study, Level III.