Giant cell tumors of the skull base: case series and current concepts.

OBJECTIVE: To study the clinical features, tumor characteristics and outcomes of giant cell tumors (GCTs) in the skull base based on long-term follow-up. We also report the largest series of GCTs in the temporal bone and the lateral skull base. MATERIALS AND METHODS: A retrospective study was conducted of all GCTs managed at the Gruppo Otologico, a quaternary referral skull base institute, in Italy from 1993 to 2013. The clinical features, investigations, surgical management and follow-up were recorded. The surgical approaches used were infratemporal fossa approach (ITFA) type B and D and middle cranial fossa (MCF) approaches. RESULTS AND OBSERVATIONS: A total of 7 patients with GCTs of the skull base were treated at our institution. The principal complaints were hearing loss reported in 6 (85.71%) patients, tinnitus in 5 (71.43%) and swelling in 3 (42.9%). Pure-tone audiometry showed conductive hearing loss in 5 (71.43%) patients. High-resolution CT scan and MRI with gadolinium enhancement were done in all patients. Radiology showed involvement of the ITF and middle ear in 6 (85.71%) patients each, temporomandibular joint in 4 (57.14%) patients, invasions of the squamous part of the temporal bone, mastoid, MCF and greater wing of sphenoid in 3 (42.9%) patients each and the petrous bone in 2 (28.6%) patients. ITFA type B was applied as an approach for tumor removal in 5 (71.43%) patients, including a case where an additional MCF approach was employed, and ITFA type D and the transmastoid approach were applied in 1 (14.3%) patient each. Total tumor removal and successful cure was achieved in 6 (85.71%) patients. Subtotal removal leading to recurrence and eventual mortality was the result in 1 (14.3%) patient. CONCLUSIONS: A thorough knowledge of the anatomy of the skull base and the various skull base approaches is necessary to tackle GCTs. ITFA type B and D combined with MCF approaches provide good exposure of the tumor with minimal postoperative sequelae and good locoregional control. Recurrence due to either subtotal removal or suboptimal treatment may have disastrous consequences for the patient.

DNA methylation variations in familial female and male breast cancer.

In total, ~25% of familial breast cancer (BC) is attributed to germline mutations of the BRCA1 and BRCA2 genes, while the rest of the cases are included in the BRCAX group. BC is also known to affect men, with a worldwide incidence of 1%. Epigenetic alterations, including DNA methylation, have been rarely studied in male breast cancer (MBC) on a genome-wide level. The aim of the present study was to examine the global DNA methylation profiles of patients with BC to identify differences between familial female breast cancer (FBC) and MBC, and according to BRCA1, BRCA2 or BRCAX mutation status. The genomic DNA of formalin-fixed paraffin-embedded tissues from 17 women and 7 men with BC was subjected to methylated DNA immunoprecipitation and hybridized on human promoter microarrays. The comparison between FBC and MBC revealed 2,846 significant differentially methylated regions corresponding to 2,486 annotated genes. Gene Ontology enrichment analysis revealed molecular function terms, such as the GTPase superfamily genes (particularly the GTPase Rho GAP/GEF and GTPase RAB), and cellular component terms associated with cytoskeletal architecture, such as 'cytoskeletal part', 'keratin filament' and 'intermediate filament'. When only FBC was considered, several cancer-associated pathways were among the most enriched KEGG pathways of differentially methylated genes when the BRCA2 group was compared with the BRCAX or BRCA1+BRCAX groups. The comparison between the BRCA1 and BRCA2+BRCAX groups comprised the molecular function term 'cytoskeletal protein binding'. Finally, the functional annotation of differentially methylated genes between the BRCAX and BRCA1+BRCA2 groups indicated that the most enriched molecular function terms were associated with GTPase activity. In conclusion, to the best of our knowledge, the present study was the first to compare the global DNA methylation profile of familial FBC and MBC. The results may provide useful insights into the epigenomic subtyping of BC and shed light on a possible novel molecular mechanism underlying BC carcinogenesis.

Molecular and functional characterization of allogantigen-specific anergic T cells suitable for cell therapy.

BACKGROUND: CD4(+) regulatory T cells are a specialized subset of T cells that actively control immune responses. Several experimental protocols have been used to expand natural regulatory T cells and to generate adaptive type 1 regulatory T cells for regulatory T-cell-based therapies. DESIGN AND METHODS: The ability of exogenous recombinant human interleukin-10 to induce alloantigen-specific anergy in T cells was investigated and compared to that of interleukin-10 derived from tolerogenic dendritic cells, in mixed lymphocyte cultures. A detailed characterization of the effector functions of the resulting anergized T cells is reported. RESULTS: Interleukin-10, whether exogenous or derived from tolerogenic dendritic cells, induces a population of alloantigen-specific T cells (interleukin-10-anergized T cells) containing type 1 regulatory T cells, which are anergic and actively suppress alloantigen-specific effector T cells present within the mixed population. Interleukin-10-induced anergy is transforming growth factor-ß independent, and is associated with a decreased frequency of alloantigen-specific cytotoxic T lymphocyte precursors, but interleukin-10-anergized T cells are still responsive to third-party, bacterial, and viral antigens. Tolerogenic dendritic cells are more powerful than exogenous interleukin-10 in generating type 1 regulatory T-cell precursors, and are also effective in the context of HLA-matched donors. CONCLUSIONS: Based on these studies, we have developed an efficient and reproducible in vitro method to generate antigen-specific type 1 regulatory T-cell precursors starting from total peripheral blood cells with minimal cell manipulation and suitable for generating type 1 regulatory T cells for regulatory T-cell-based therapies.

A Developmental Perspective on Paragangliar Tumorigenesis.

In this review, we propose that paraganglioma is a fundamentally organized, albeit aberrant, tissue composed of neoplastic vascular and neural cell types that share a common origin from a multipotent mesenchymal-like stem/progenitor cell. This view is consistent with the pseudohypoxic footprint implicated in the molecular pathogenesis of the disease, is in harmony with the neural crest origin of the paraganglia, and is strongly supported by the physiological model of carotid body hyperplasia. Our immunomorphological and molecular studies of head and neck paragangliomas demonstrate in all cases relationships between the vascular and the neural tumor compartments, that share mesenchymal and immature vasculo-neural markers, conserved in derived cell cultures. This immature, multipotent phenotype is supported by constitutive amplification of NOTCH signaling genes and by loss of the microRNA-200s and -34s, which control NOTCH1, ZEB1, and PDGFRA in head and neck paraganglioma cells. Importantly, the neuroepithelial component is distinguished by extreme mitochondrial alterations, associated with collapse of the ΔΨm. Finally, our xenograft models of head and neck paraganglioma demonstrate that mesenchymal-like cells first give rise to a vasculo-angiogenic network, and then self-organize into neuroepithelial-like clusters, a process inhibited by treatment with imatinib.

Novel BRAF mutation in melanoma: A case report.

In melanoma, a number of specific genetic and genomic aberrations have been identified to be important in tumorigenesis. In particular, the mutant B-Raf proto-oncogene, Serine/Threonine kinase (BRAF) gene is the target of tailored therapy with kinase inhibitor molecules. Identification of the array of mutations in patients with melanoma will be useful in determining a genetic profile of the tumor with potential implications for treatment decisions. A rare aminoacidic insertion in codon 599 of the BRAF gene (c.1797_1798insACA, T599insT) was detected by using both direct (Sanger) sequencing and pyrosequencing techniques in a metastatic melanoma of a female elderly patient. As suggested in other clinical contexts including pilocytic astrocytoma, papillary thyroid carcinomas and anaplastic thyroid carcinomas, this unusual mutation may be associated with a modified spatial structure of activated P-loop, resulting in a constitutional activation of the BRAF protein. The patient died shortly following the test, thus no biological therapy was performed. Comparable data regarding treatment of melanoma patients with rare BRAF mutations is lacking, and the response to BRAF inhibitors requires further investigation.

Gefitinib in pretreated non-small-cell lung cancer (NSCLC): analysis of efficacy and correlation with HER2 and epidermal growth factor receptor expression in locally advanced or metastatic NSCLC.

PURPOSE: To evaluate the correlation between HER2 expression and gefitinib (ZD 1839, Iressa; AstraZeneca, London, United Kingdom) efficacy in terms of response rate, time to progression (TTP), and overall survival (OS) time. PATIENTS AND METHODS: Patients with pretreated advanced non-small-cell lung cancer (NSCLC) received gefitinib at a daily dose of 250 mg until disease progression. Tumor tissue specimens obtained at the time of primary diagnosis were collected to determine HER2/epidermal growth factor receptor (EGFR) status by immunohistochemistry. RESULTS: From February 2001 to June 2002, 63 consecutive patients were enrolled onto the study. The overall disease control rate was 58.7% (partial response [PR], 15.9%; stable disease [SD], 42.8%), median TTP was 3.3 months, and median OS was 4.1 months. Among the 43 patients in whom EGFR/HER2 status was determined, we observed six PRs (14%) and 18 SDs (42%). Disease control, including PR and SD, was 40% in the 15 patients overexpressing HER2 and 64.3% in the 28 patients not overexpressing HER2 (P =.126). No difference was found between the two groups in terms of TTP (3.5 v 3.7 months, respectively) and OS (5.7 v 6.8 months, respectively). In addition, we did not find any difference in TTP, OS, toxicity, and symptom outcome in the group of patients overexpressing both HER2 and EGFR compared with patients who had no overexpression of HER2 CONCLUSION: According to these data, efficacy, toxicity, and symptom outcome in patients with NSCLC treated with gefitinib do not seem to be related to HER2 expression.

Salivary gland choristoma of the middle ear.

Choristoma of the middle ear is a rare condition characterized by the presence of normal salivary gland tissue in the middle ear space. Salivary gland choristomas are benign lesions that are frequently associated with ossicular chain and facial nerve anomalies. Total surgical excision is indicated when there is no risk of damaging the facial nerve. We describe a new case of salivary gland choristoma of the middle ear, and we discuss the etiology, histologic features, and management of such lesions. Our patient was a 22-year-old woman in whom we surgically removed a whitish retrotympanic mass. Intraoperatively, we also detected an ossicular chain malformation. Histologic examination of the choristoma revealed the presence of salivary gland tissue. Furthermore, the lesion contained an extensive and previously undescribed component: a well-defined pseudostratified respiratory-type epithelium, similar to that of a normal eustachian tube. Ten months after removal of the choristoma, we surgically repaired the ossicular chain anomalies. No recurrence was noted on follow-up.

Primary squamous cell carcinoma of the breast after cured bilateral breast cancer.

BACKGROUND: Primary squamous cell carcinoma (SCC) of the breast is a rare and aggressive neoplasm that constitutes approximately 0.1% of all breast carcinomas. Before the tumor can be classified as a true SCC of the breast, certain criteria need to be fulfilled. These are: i) more than 90% of the malignant cells must be of squamous cells origin; ii) tumor is independent from the overlying skin and nipple; iii) other sites of primary SCC have been excluded. CASE REPORT: We describe a case of pure SCC of the breast that arose 15 years after local radiation for a primary adenocarcinoma of the breast in a 54-year-old woman with history of bilateral breast cancer. The tumor was triple-negative with a high Ki-67 index. The patient underwent adjuvant chemotherapy with docetaxel and oral fluorouracil. CONCLUSION: There are no specific guidelines for the treatment of primary SCC of the breast. Larger series are necessary to determine if different strategies of treatment and follow-up are necessary and if prognosis is really comparable to other histotypes of cancers of the breast.

Unusual myogenic and melanocytic differentiation of soft tissue pPNETs: an immunohistochemical and molecular study of 3 cases.

All of the members of the peripheral primitive neuroectodermal tumor family (Ewing sarcomas, neuroectodermal tumors of bone, peripheral neuroepitheliomas, and Askin tumors) have similar morphologic and immunophenotypical features (ie, the proliferation of small and medium-sized round cells in a fibrous background showing strong and diffuse immunohistochemical positivity for CD99), and the common cytogenetic abnormality of a nonrandom translocation involving the EWS gene and one of several members of the erythroblastosis virus transforming sequence family of transcription factors. The combination of clinical information and morphologic/immunophenotypical characteristics is usually sufficient for a correct diagnosis, but there are rare cases in which an unusual predominant or multidirectional immunophenotypical differentiation makes diagnosis a challenge and requires the use of molecular cytogenetic or molecular techniques. We describe 3 such cases in which we employed fluorescence in-situ hybridization analysis to detect translocation involving the EWS gene and reverse transcription polymerase chain reaction followed by sequencing to detect the fusion transcript EWS-FLI1.

Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer.

BACKGROUND: Gefitinib, a specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, has activity against approximately 10% of unselected non-small-cell lung cancer (NSCLC) patients. Phosphatidylinositol 3'-kinase (PI3K)/Akt and Ras/Raf/mitogen-activated protein kinase (MAPK), the two main EGFR-signaling pathways, mediate EGFR effects on proliferation and survival. Because activation of these pathways is dependent on the phosphorylation status of the components, we evaluated the association between phosphorylation status of Akt (P-Akt) and MAPK (P-MAPK) and gefitinib activity in patients with advanced NSCLC. METHODS: Consecutive patients (n = 106) with NSCLC who had progressed or relapsed on standard therapy received gefitinib (250 mg/day) until disease progression, unacceptable toxicity, or patient refusal. P-Akt and P-MAPK positivity was determined with immunohistochemistry using tumor tissues obtained before any anticancer treatment. Association of P-Akt and time to progression was determined by univariable and multivariable analyses. All statistical tests were two-sided. RESULTS: Of the 103 evaluable patients, 51 (49.5%) had tumors that were positive for P-Akt, and 23 (22.3%) had tumors that were positive for P-MAPK. P-Akt-positivity status was statistically significantly associated with being female (P<.001), with never-smoking history (P =.004), and with bronchioloalveolar carcinoma histology (P =.034). Compared with patients whose tumors were negative for P-Akt, patients whose tumors were positive for P-Akt had a better response rate (26.1% versus 3.9%; P =.003), disease control rate (60.9% versus 23.5%; P<.001), and time to progression (5.5 versus 2.8 months; P =.004). Response rate, disease control rate, and time to progression did not differ according to P-MAPK status. The multivariable analysis showed that P-Akt positivity was associated with a reduced risk of disease progression (hazard ratio = 0.58, 95% confidence interval = 0.35 to 0.94). CONCLUSIONS: Patients with P-Akt-positive tumors who received gefitinib had a better response rate, disease control rate, and time to progression than patients with P-Akt-negative tumors, suggesting that gefitinib may be most effective in patients with basal Akt activation.