Comprehensive germline mutation analysis and clinical profile in a large cohort of Brazilian xeroderma pigmentosum patients.

BACKGROUND: Xeroderma pigmentosum (XP) patients present a high risk of developing skin cancer and other complications at an early age. This disease is characterized by mutations in the genes related to the DNA repair system. OBJECTIVES: To describe the clinical and molecular findings in a cohort of 32 Brazilian individuals who received a clinical diagnosis of XP. METHODS: Twenty-seven families were screened for germline variants in eight XP-related genes. RESULTS: All patients (N = 32) were diagnosed with bi-allelic germline pathogenic or potentially pathogenic variants, including nine variants previously undescribed. The c.2251-1G>C XPC pathogenic variant, reported as the founder mutation in Comorian and Pakistani patients, was observed in 15 cases in homozygous or compound heterozygous. Seven homozygous patients for POLH/XPV variants developed their symptoms by an average age of 7.7 years. ERCC2/XPD, DDB2/XPE and ERCC5/XPG variants were found in a few patients. Aside from melanoma and non-melanoma skin tumours, a set of patients developed skin sebaceous carcinoma, leiomyosarcoma, angiosarcoma, mucoepidermoid carcinoma, gastric adenocarcinoma and serous ovarian carcinoma. CONCLUSIONS: We reported a high frequency of XPC variants in 32 XP Brazilian patients. Nine new variants in XP-related genes, unexpected non-skin cancer lesions and an anticipation of the clinical manifestation in POLH/XPV cases were also described.

Immunohistochemical evaluation of Sonic Hedgehog signaling pathway proteins (Shh, Ptch1, Ptch2, Smo, Gli1, Gli2, and Gli3) in sporadic and syndromic odontogenic keratocysts.

AIMS: The aim of this study was to compare the clinical and demographic features of 62 patients presenting sporadic odontogenic keratocysts (OKCs) or OKCs associated with nevoid basal cell carcinoma syndrome (NBCCS). In conjunction with this, we also evaluated the immunohistochemical expression of Shh, Ptch1, Ptch2, Smo, Gli1, Gli2 and Gli3 proteins in 86 OKCs. By doing this, we add to the understanding of the biology of this type of lesion, providing tools that will help facilitate the early diagnosis of NBCCS in those patients where the first manifestation is that of OKCs. METHODS: This is a retrospective study; patients were classified into two groups: group 1 which consisted of those who were not affected by NBCCS (49 patients and 57 OKCs) and group 2 which consisted of those who were diagnosed with NBCCS (13 patients and 29 OKCs). The clinical and demographic features were studied and the immunohistochemical expression of Sonic Hedgehog proteins (Shh, Ptch1, Ptch2, Smo, Gli1, Gli2, and Gli3) was analyzed in all samples. RESULTS: There was an increase in the expression of three proteins in the syndromic OKC, when compared to that of sporadic cysts. Shh and Gli1 showed higher cytoplasmic expression, while Smo revealed stronger nuclear and cytoplasmic expressions. CONCLUSION AND CLINICAL RELEVANCE: Our findings suggest that the expression patterns of important Shh pathway proteins can represent valuable markers for early diagnosis of NBCCS-associated OKCs, as the major criterion for the diagnosis of NBCCS is currently based on the late appearance of basal cellular carcinomas. Thus, standardizing a new diagnostic tool for diagnosis of NBCCS could be of great importance in the identification of therapeutic targets. We therefore suggest, as based on our findings, that OKCs showing high expression of Shh, Smo, and Gli1 are potentially associated with NBCCS.

Oncogenic drivers in 11q13 associated with prognosis and response to therapy in advanced oropharyngeal carcinomas.

OBJECTIVES: To identify potential molecular drivers associated with prognosis and response to treatment in advanced oropharyngeal squamous cell carcinomas (OPSCC). MATERIALS AND METHODS: Thirty-three OPSCC biopsies from untreated Brazilian patients were evaluated for human papilloma virus genotyping, genome wide copy number alterations and gene expression profiling. Data were integrated using CONEXIC algorithm. Validation with TCGA dataset and confirmation by RT-qPCR of candidate genes were performed. RESULTS: High-risk HPV positive cases, detected in 55% of advanced OPSCC, were associated with better outcome. Losses of 8p11.23-p11.22, 14q11.1-q11.2 and 15q11.2, and gains of 11q13.2 and 11q13.2-q13.3 were detected as recurrent alterations. Gains of 3q26.31 and 11q13.2 and losses of 9p21.3 were exclusively detected in HPV-negative tumors. Two clusters of expression profiles were observed, being one composed mostly by HPV positive cases (83%). HPV-positive enriched cluster showed predominantly immune response-related pathways. Integrative analysis identified 10 modulators mapped in 11q13, which were frequently cancer-related. These 10 genes showed copy number gains, overexpression and an association with worse survival, further validated by TCGA database analyses. Overexpression of four genes (ORAOV1, CPT1A, SHANK2 and PPFIA1) evaluated by RT-qPCR confirmed their association with poor survival. Multivariate analysis showed that PPFIA1 overexpression and HPV status are independent prognostic markers. Moreover, SHANK2 overexpression was significantly associated with incomplete response to treatment. CONCLUSION: The integrative genomic and transcriptomic data revealed potential driver genes mapped in 11q13 associated with worse prognosis and response to treatment, giving fundamentals for the identification of novel therapeutic targets in OPSCC.

Head and neck mucosal melanoma: clinicopathological analysis of 51 cases treated in a single cancer centre and review of the literature.

Head and neck mucosal melanoma (HNMM) is a rare and aggressive malignancy. The objective of this study was to describe the outcomes of patients with HNMM. Clinical and pathological data from 51 patients with primary HNMM were reviewed. All patients were treated at a single cancer centre between 1954 and 2012. Most tumours involved the nasal cavity (35.3%) and upper gingiva (29.4%). The majority of lesions were ulcerated (54.9%) and pigmented (84.3%). Forty-three patients underwent surgical treatment and 21 (41.2%) underwent adjuvant chemotherapy and/or radiotherapy. Eight patients (15.7%) received palliative treatment. The median follow-up period was 21 months. During this period, 30 (58.8%) patients had tumour recurrences. At the last clinical evaluation, only seven (13.7%) patients were alive with no evidence of disease and three (5.9%) were alive with HNMM. There were significant differences in overall survival probability according to the presence of ulceration (P=0.004), metastatic lymph nodes (P=0.003), and treatment including a radical surgical procedure (P<0.001). On multivariate analysis, ulceration was the only variable associated with an increased risk of death. Despite the poor prognosis, there was significant improvement in overall survival in the most recent years in this sample, mainly due to advances in diagnosis and reconstruction techniques.

Effects of chronic passive smoking on the regeneration of rat femoral defects filled with hydroxyapatite and stimulated by laser therapy.

Defects associated with bone mass loss are frequently treated by autogenous bone grafting. However, synthetic biomaterials such as calcium phosphate ceramics can substitute autologous grafts as long as they are biocompatible with bone tissue. In addition, low-level laser therapy (LLLT) is used to enhance bone regeneration by stimulating the local microcirculation and increasing the synthesis of collagen by bone cells. However, bone health is fundamental for osseointegration of the graft and bone repair. In this respect, excessive tobacco consumption can compromise expected outcomes because of its deleterious effects on bone metabolism that predispose to the development of osteoporosis. The objective of this study was to evaluate the regeneration of bone defects implanted with biomaterial and stimulated by LLLT in rats submitted to passive cigarette smoking. Porous hydroxyapatite granules were implanted into critical-size defects induced experimentally in the distal epiphysis of the right femur of 20 female Wistar rats submitted to passive smoking for 8 months in a smoking box. The defect site was irradiated with a gallium-arsenide laser at an intensity of 5.0 J/cm2. The animals were divided into four groups: control (non-smoking) rates submitted (G2) or not (G1) to laser irradiation, and smoking rats submitted (G4) or not (G3) to laser irradiation. The animals were sacrificed 8 weeks after biomaterial implantation. The right femurs were removed for photodocumentation, radiographed, and processed for routine histology. The results showed good radiopacity of the implant site and of the hydroxyapatite granules. Histologically, formation of new trabecular bone was observed adjacent to the hydroxyapatite granules in G1 and G2. In G3 and G4, the granules were surrounded mainly by connective tissue. In conclusion, passive smoking compromised bone neoformation in the defects and the LLLT protocol was not adequate to stimulate local osteogenesis.

Fatty acid synthase expression in squamous cell carcinoma of the tongue: clinicopathological findings.

BACKGROUND: Overexpression of fatty acid synthase (FAS), the cytosolic enzyme responsible for the conversion of dietary carbohydrates to fatty acids, has been reported in several human malignancies and pointed as a potential prognostic marker for some tumors. This study investigated whether FAS immunohistochemical expression is correlated with the clinicopathological characteristics of oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: The clinical features of 102 patients with OSCC of the tongue treated in a single institution were obtained from the medical records and all histopathological diagnoses were reviewed. The expression of FAS was determined by the standard immunoperoxidase technique in formalin-fixed and paraffin-embedded specimens and correlated with the clinicopathological characteristics of the tumors. RESULTS: Eighty-one cases (79.41%) were positive for FAS. Microscopic characteristics such as histological grade (P < 0.05), lymphatic permeation (P < 0.001), perineural infiltration (P < 0.05), and nodal metastasis (P < 0.02) were associated with FAS status. A significantly lower survival probability for patients with advanced clinical stage (log-rank test, P < 0.001), lymph nodes metastasis (log-rank test, P < 0.001), presence of vascular permeation (log-rank test, P = 0.05), and perineural invasion (log-rank test, P = 0.01) was observed in the studied samples. CONCLUSION: The expression of FAS in OSCC of the tongue is associated with the microscopic characteristics that determine disease progression and prognosis.

High frequency of immature dendritic cells and altered in situ production of interleukin-4 and tumor necrosis factor-alpha in lung cancer.

INTRODUCTION: Antigen-presenting cells, like dendritic cells (DCs) and macrophages, play a significant role in the induction of an immune response and an imbalance in the proportion of macrophages, immature and mature DCs within the tumor could affect significantly the immune response to cancer. DCs and macrophages can differentiate from monocytes, depending on the milieu, where cytokines, like interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF) induce DC differentiation and tumor necrosis factor (TNF)-alpha induce DC maturation. Thus, the aim of this work was to analyze by immunohistochemistry the presence of DCs (S100+ or CD1a+), macrophages (CD68+), IL-4 and TNF-alpha within the microenvironment of primary lung carcinomas. RESULTS: Higher frequencies of both immature DCs and macrophages were detected in the tumor-affected lung, when compared to the non-affected lung. Also, TNF-alpha-positive cells were more frequent, while IL-4-positive cells were less frequent in neoplastic tissues. This decreased frequency of mature DCs within the tumor was further confirmed by the lower frequency of CD14-CD80+ cells in cell suspensions obtained from the same lung tissues analyzed by flow cytometry. CONCLUSION: These data are discussed and interpreted as the result of an environment that does not oppose monocyte differentiation into DCs, but that could impair DC maturation, thus affecting the induction of effective immune responses against the tumor.

Expression of a dendritic cell maturation marker CD83 on tumor cells from lung cancer patients and several human tumor cell lines: is there a biological meaning behind it?

The present paper shows, for the first time, the membrane expression of the dendritic cell maturation marker CD83 on tumor cells from lung cancer patients. CD83 was also detected on freshly cultured fibroblast-like cells from these tissues and on several adherent human tumor cell lines (lung adenocarcinomas P9, A459 and A549, melanomas A375 and C81-61, breast adenocarcinomas SKBR-3 and MCF-7 and colon carcinoma AR42-J), but not in the non-adherent MOT leukemia cell line. CD83 may have immunosuppressive properties and its expression by cancer cells could have a role in facilitating tumor growth.

Long-term survival rates in young patients with thyroid carcinoma

Thyroid carcinoma in patients younger than 18 years is rare. It is associated with a greater risk of metastases. However, the prognosis for these patients is better when compared with that of adults.To present the experience of a single institution in the treatment of patients with thyroid carcinoma during childhood and adolescence.Thirty-eight patients, ranging in age from 4 to 18 years, were diagnosed as having thyroid carcinoma. Pathologic types of carcinoma included 29 papillary, 4 follicular, 1 Hürthle cell, and 4 medullary cases. Hypocalcemia was the main complication, being transitory in 9 patients (24%) and permanent in 6 patients (16%). Vocal cord palsy occurred in 2 patients (5%). Two patients (5%) had a surgical site infection. After a mean follow-up of 9.5 years (range, 1-40 years), 28 patients (74%) were alive and had no evidence of disease, 3 (8%) were alive and had recurrent disease, 4 (11%) died (2 of the disease and 2 of non-cancer-related causes), and 3 (8%) were lost to follow-up. The survival rates at 10 years for the patients with papillary, follicular, and medullary carcinoma were 93%, 100%, and 50%, respectively. Thyroid carcinoma in patients younger than 18 years has a good prognosis even in the presence of neck or distant metastasis. Total thyroidectomy, associated with adjuvant radioactive iodine therapy and thyroidal suppression or not, is effective in patients with a well-differentiated thyroid carcinoma.