BRAF mutation and RASSF1A expression in thyroid carcinoma of southern Italy.

Aim of this work is to provide a detailed comparison of clinical-pathologic features between well-differentiated and poorly differentiated tumors according to their BRAF and RASSF1A status. We analyzed RASSF1A methylation by MSP and BRAF mutation by LCRT-PCR with LightMix® kit BRAF V600E in neoplastic thyroid tissues. Immunohistochemical evaluation of RASSF1A expression was also performed by standard automated LSAB-HRP technique. An overall higher degree of RASSF1A over-expression than normal thyroid parenchyma surrounding tumors (P < 0.05) has been found in all malignant well-differentiated lesions. Moreover, statistically significant higher levels of RASSF1A expression were observed in differentiated cancers associated to an inflammatory autoimmune background (P = 0.01). Amplifiable DNA for LC PCR with LightMix® kit BRAF V600E was obtained in nine PTCs, four FVPTCs, five ATCs, and one control. The V600E mutation was found in 13 of 18 (72%) tumors. BRAF was mutated in 6 of 9 (66%) classical PTC, in 2 of 4 (50%) follicular variant PTC and in all ACs (100%). The overall frequency of RASSF1A promoter methylation observed was 20.5% (9 cases out 44). Hypermethylation of RASSF1A in primary tumors was variable according to histotypes ranging from100% (5/5) in ACs to only 12.5% (4/32) in PTCs. We show a correlation between RASSF1A methylation status and RASSF1A protein expression. Finally, we conclude that BRAF V600E mutation and RASSF1A methylation were pathogenetic event restricted to a subgroup of PTC/FVPTCs in early stage and to clinically aggressive ATCs.

Endometrial Cancer Immune Escape Mechanisms: Let Us Learn From the Fetal-Maternal Interface.

The immune escape mechanisms at the base of tumor progression in endometrial cancer mimic immune tolerance mechanisms occurring at the maternal-fetal interface. The biological and immunological processes behind the maternal-fetal interface are finely tuned in time and space during embryo implantation and subsequent pregnancy stages; conversely, those behind cancer progression are often aberrant. The environment composition at the maternal-fetal interface parallels the pro-tumor microenvironment identified in many cancers, pointing to the possibility for the use of the maternal-fetal interface as a model to depict immune therapeutic targets in cancer. The framework of cancer environment signatures involved in immune adaptations, precisely timed in cancer progression, could reveal a specific "immune clock" in endometrial cancer, which might guide clinicians in patient risk class assessment, diagnostic workup, management, surgical and therapeutic approach, and surveillance strategies. Here, we review studies approaching this hypothesis, focusing on what is known so far about oncofetal similarities in immunity with the idea to individualize personalized immunotherapy targets, through the downregulation of the immune escape stage or the reactivation of the pro-inflammatory processes suppressed by the tumor.

Spine Surgery in Patients with Metastatic Breast Cancer: A Retrospective Analysis.

BACKGROUND: Pathologic or iatrogenic symptomatic spinal lesions are common in metastatic breast cancer. Given the longer duration of overall survival provided by modern oncologic therapies, a prompt and effective treatment of such lesions may have a significant impact on patient's quality of life, improving pain and preventing deterioration of neurologic functions. METHODS: A retrospective review was conducted on patients with breast cancer operated to the spine between 2005 and 2013. The series includes 41 patients and 57 vertebral levels treated (4 cervical, 35 dorsal, and 18 lumbar). There were 28 patients who received palliative surgery and 13 who received excisional surgery, according to their clinical conditions, Spinal Instability Neoplastic Score, and Tokuhashi scores. RESULTS: Of the 41 patients, 38 presented with a median survival of 50 months (95% confidence interval [CI], 39-61), still preserving a Karnofsky Performance Status Scale score ≥60 and a retained ability to ambulate independently. The median overall survival after the first spine surgery was also 50 months (95% CI, 35-65), suggesting that in this cohort of patients, a reasonable quality of life was preserved almost to the end of their clinical history. In patients treated with palliative surgery, the median survival was 37 months (95% CI, 26-48). In those treated with complex surgery, it was 57 months (95% CI, 41-73; P = 0.03). CONCLUSIONS: Major excisional surgery, albeit associated with an increased length of hospital stay, allowed in our series a prolonged survival compared with less aggressive types of surgery. However, percutaneous or open balloon kyphoplasty techniques have expanded indications for palliative surgery and even patients with lower Tokuhashi scores may benefit from rapid and sustained pain relief, preservation of neurologic function, and early mobilization.

Epigenetic silencing of miR-145-5p contributes to brain metastasis.

Brain metastasis is a major cause of morbidity and mortality of lung cancer patients. We assessed whether aberrant expression of specific microRNAs could contribute to brain metastasis. Comparison of primary lung tumors and their matched metastatic brain disseminations identified shared patterns of several microRNAs, including common down-regulation of miR-145-5p. Down-regulation was attributed to methylation of miR-145's promoter and affiliated elevation of several protein targets, such as EGFR, OCT-4, MUC-1, c-MYC and, interestingly, tumor protein D52 (TPD52). In line with these observations, restored expression of miR-145-5p and selective depletion of individual targets markedly reduced in vitro and in vivo cancer cell migration. In aggregate, our results attribute to miR-145-5p and its direct targets pivotal roles in malignancy progression and in metastasis.

Malignant peripheral nerve sheath tumors of the lateral skull base.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive spindle cell tumors that develop from peripheral nerve sheath cells and account for 5% of all soft tissue sarcomas. MPNSTs involving the lateral skull base are an extremely rare subgroup of these lesions. The article deals with the case of a 51-year-old man with a huge primary MPNST: the disease involved the left frontozygomatic and retroauricolar regions of the scalp with erosion of the outer table of the calvaria and diffuse infiltration of the temporal, infratemporal, and pterygoid fossae. Radical surgery via left transfacial- transparotid approach and reconstruction with microvascular flap were performed. Intraoperative radiotherapy and postoperative radiotherapy were also delivered. Twenty-two months postoperatively, the patient is alive despite recurrence of the tumor in the neck and lung metastases. The article reviews the few series of patients and the small number of case reports of MPNSTs involving the lateral skull base that are available in the English literature describing current concept of pathophysiology, diagnosis, and management of the disease. Although MPNSTs of the lateral skull base have an adverse prognosis, an acceptable survival time and a good quality of life are possible; however, they require an early and correct diagnosis as well as an adequate and aggressive combination therapy.

Fixed dose-rate gemcitabine as radiosensitizer for newly diagnosed glioblastoma: a dose-finding study.

In patients with newly diagnosed glioblastoma multiforme (GBM), concurrent chemo-radiotherapy with temozolomide is the new standard of care. In the present phase I study we investigated the association of gemcitabine, a cell-cycle antimetabolite with radiosensitizing properties, with radiotherapy (RT) in the first line treatment. Gemcitabine was delivered at a fixed dose-rate of 10 mg/m(2)/min weekly for 6 weeks starting 24-72 h prior to, and then concomitantly with RT (2.0 Gy per fraction, total dose 60 Gys). The primary end-point was the identification of dose-limiting toxicity (DLT), and maximum tolerated dose (MTD). Planned dose levels of gemcitabine started from 200 mg/m(2)/weekly (level 1), with sequential dose escalations of 25 mg/m(2). Ten patients were enrolled, all with evaluable disease after surgery. Six patients were male, median age was 55 years (44-75), and median baseline Karnofsky performance status was 85 (70-100). Four patients entered level 1, one patient being excluded from the study because of early disease progression. At this level, two of three patients developed progressive neurological deterioration, potentially related to the experimental treatment. On this basis gemcitabine dose was prudentially reduced to 175 mg/m(2)/weekly in the subsequent step (level -1). No DLT was encountered in the six patients enrolled at this level. Interestingly, at this dose only two grade three toxicities (one neutropenia and one raise in serum transaminases) were reported. Thus, fixed dose-rate gemcitabine at 175 mg/m(2)/weekly is the recommended regimen for further evaluation in a phase II study that is presently in progress.