SHARP1 suppresses breast cancer metastasis by promoting degradation of hypoxia-inducible factors.

The molecular determinants of malignant cell behaviours in breast cancer remain only partially understood. Here we show that SHARP1 (also known as BHLHE41 or DEC2) is a crucial regulator of the invasive and metastatic phenotype in triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer. SHARP1 is regulated by the p63 metastasis suppressor and inhibits TNBC aggressiveness through inhibition of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α (HIFs). SHARP1 opposes HIF-dependent TNBC cell migration in vitro, and invasive or metastatic behaviours in vivo. SHARP1 is required, and sufficient, to limit expression of HIF-target genes. In primary TNBC, endogenous SHARP1 levels are inversely correlated with those of HIF targets. Mechanistically, SHARP1 binds to HIFs and promotes HIF proteasomal degradation by serving as the HIF-presenting factor to the proteasome. This process is independent of pVHL (von Hippel-Lindau tumour suppressor), hypoxia and the ubiquitination machinery. SHARP1 therefore determines the intrinsic instability of HIF proteins to act in parallel to, and cooperate with, oxygen levels. This work sheds light on the mechanisms and pathways by which TNBC acquires invasiveness and metastatic propensity.

Renal angiomyolipoma with renal vein invasion.

Renal angiomyolipoma is a uncommon benign tumor, considered an hamartoma. The lesion, usually benign, can be single or multiple and well-circumscribed. In letterature only few cases of infiltrating angiomyolipomas have been described. The aim of the paper is to describe a paradigmatic case of a giant kidney angiomyolipoma, not associ- ated with tuberous sclerosis, invading the pelvis and the renal vein. The lesion have been discovered incidentally during abdominal ultrasound for other pathology. Owing to the extent of the lesion and the appreciable risk of bleeding, we opted for surgical treatment.

Expression of survivin, p53, and caspase 3 in Barrett's esophagus carcinogenesis.

The regulation of apoptosis, as a distinctive form of programmed cell death, in multistep Barrett's esophagus (BE) carcinogenesis is poorly understood. The aim of this study was to investigate, in the intestinal metaplasia-dysplasia-carcinoma sequence, the role of survivin, an inhibitor of apoptosis; the p53 protein, a tumor suppressor gene involved in cell cycle control; and caspase 3, a protease-inducing apoptosis and inhibited by survivin. Immunohistochemical expression was tested in 40 cases of BE, including 11 low-grade and 19 high-grade dysplasias (HGD), and samples were obtained from 40 surgical specimens of esophagectomy performed for HGD or Barrett's adenocarcinoma. To define the deregulation time of the proteins, overexpression was evaluated in relation to the proliferative and/or maturative compartment. In BE, cytoplasmic expression of survivin and caspase 3 (100% of cases) was significantly higher than expression of p53 (25%). The latter increased with increasing grade of dysplasia. In BE, the expression of survivin, p53, and caspase 3 mainly involved the proliferative compartment, whereas in LGD and HGD, the 3 proteins were coexpressed in both proliferative and maturative compartments. These results indicate that survivin overexpression is an early event in the proliferative compartment of BE, preceding both p53 accumulation and dysplastic changes. Cytoplasmic survivin location may indicate an initial antiapoptotic, more than proliferative, role in the early phases of Barrett carcinogenesis. Expression of caspase 3 in BE and dysplasia may be ascribed to accumulation of the nonactivated form, as the antibody used detects both cleaved and uncleaved caspase 3.

Neoadjuvant sunitinib effectiveness in T4 renal clear cell carcinoma: a case report.

INTRODUCTION: Sunitinib therapy showed an improvement in survival of patients with metastatic renal cell carcinoma. MATERIALS AND METHODS: A 51-year-old man, with Eastern Cooperative Oncology Group Score (ECOG) of 0, presented at our Institute in March 2012 for macrohematuria and urinary retention. A computed tomography (CT) scan of the abdomen showed a right renal lesion. The lesion had a diameter of 15 cm and was developing towards the liver, in the absence of cleavage planes between the liver and kidney. A 12 mm finding, suspected as secondary lesion, was detected at the level of the VII hepatic segment. Neoadjuvant chemotherapy with Sunitinib was proposed. RESULTS: The patient underwent a ultrasound-guided biopsy, which confirmed the presence of Clear Cell Carcinoma. The patient began chemotherapy treatment in May 2012 according to the scheme SUNITINIB 50 mg daily for 4 weeks every 6 weeks. After four courses of treatment, according to RECIST criteria for solid tumors, 40% (9 cm vs 15 cm) regression of the primary tumor and 33% (8 mm vs 12 mm) regression of the secondary lesion were observed at a CT scan of the abdomen. In February 2013, Laparoscopic Adrenal-Sparing Radical Nephrectomy was performed. At a follow-up of 3 months, performed with a thorax and abdomen CT scans, there was a complete remission of hepatic secondary lesion and no areas of secondary localization of disease. CONCLUSION: This case report showed the effectiveness of neoadjuvant chemotherapy with Sunitinib. The use of this chemotherapy agent can change the approach to the management of cRCC.

Complete remission of Sweet's syndrome after azacytidine treatment for concomitant myelodysplastic syndrome.

Sweet's syndrome is a rare condition with potentially disabling implications, characterized by painful skin lesions due to neutrophilic dermal infiltration and systemic inflammatory symptoms. A significant proportion of cases is malignancy associated. Hematologic neoplasms, particularly acute myeloid leukemia and myelodysplastic syndromes, are the most commonly associated malignant conditions. Here, we describe the first case of clinical remission of refractory Sweet's syndrome following hypomethylating therapy with azacytidine in a patient with myelodysplastic syndrome who concurrently obtained a complete hematologic response.