The need for standards in the management of patients with endocrine tumors of the digestive system prompted the European Neuroendocrine Tumor Society (ENETS) to organize a first Consensus Conference, which was held in Frascati (Rome) and was based on the recently published ENETS guidelines on the diagnosis and treatment of digestive neuroendocrine tumors (NET). Here, we report the tumor-node-metastasis proposal for foregut NETs of the stomach, duodenum, and pancreas that was designed, discussed, and consensually approved at this conference. In addition, we report the proposal for a working formulation for the grading of digestive NETs based on mitotic count and Ki-67 index. This proposal, which needs to be validated, is meant to help clinicians in the stratification, treatment, and follow-up of patients.

Reactivation of telomerase has been implicated in human tumorigenesis, but the underlying mechanisms remain poorly understood. Here we report the presence of recurrent somatic mutations in the TERT promoter in cancers of the central nervous system (43%), bladder (59%), thyroid (follicular cell-derived, 10%) and skin (melanoma, 29%). In thyroid cancers, the presence of TERT promoter mutations (when occurring together with BRAF mutations) is significantly associated with higher TERT mRNA expression, and in glioblastoma we find a trend for increased telomerase expression in cases harbouring TERT promoter mutations. Both in thyroid cancers and glioblastoma, TERT promoter mutations are significantly associated with older age of the patients. Our results show that TERT promoter mutations are relatively frequent in specific types of human cancers, where they lead to enhanced expression of telomerase.

Criteria for the staging and grading of neuroendocrine tumors (NETs) of midgut and hindgut origin were established at the second Consensus Conference in Frascati (Rome) organized by the European Neuroendocrine Tumor Society (ENETS). The proposed tumor-node-metastasis (TNM) classifications are based on the recently published ENETS Guidelines for the Diagnosis and Treatment of gastroenteropancreatic NETs and follow our previous proposal for foregut tumors. The new TNM classifications for NETs of the ileum, appendix, colon, and rectum, and the grading system were designed, discussed, and consensually approved by all conference participants. These proposals need to be validated and are meant to help clinicians in the stratification, treatment and follow-up of patients.

The conserved serine/threonine kinase mTOR (the mammalian target of rapamycin), a downstream effector of the PI3K/AKT pathway, forms two distinct multiprotein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to rapamycin, activates S6K1 and 4EBP1, which are involved in mRNA translation. It is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals, and essential signalling pathways, such as PI3K, MAPK and AMPK, in order to control cell growth, proliferation and survival. mTORC2 is considered resistant to rapamycin and is generally insensitive to nutrients and energy signals. It activates PKC-α and AKT and regulates the actin cytoskeleton. Deregulation of multiple elements of the mTOR pathway (PI3K amplification/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1 and eIF4E overexpression) has been reported in many types of cancers, particularly in melanoma, where alterations in major components of the mTOR pathway were reported to have significant effects on tumour progression. Therefore, mTOR is an appealing therapeutic target and mTOR inhibitors, including the rapamycin analogues deforolimus, everolimus and temsirolimus, are submitted to clinical trials for treating multiple cancers, alone or in combination with inhibitors of other pathways. Importantly, temsirolimus and everolimus were recently approved by the FDA for the treatment of renal cell carcinoma, PNET and giant cell astrocytoma. Small molecules that inhibit mTOR kinase activity and dual PI3K-mTOR inhibitors are also being developed. In this review, we aim to survey relevant research, the molecular mechanisms of signalling, including upstream activation and downstream effectors, and the role of mTOR in cancer, mainly in melanoma.

No abstract

Melanoma represents the most aggressive and the deadliest form of skin cancer. Current therapeutic approaches include surgical resection, chemotherapy, photodynamic therapy, immunotherapy, biochemotherapy, and targeted therapy. The therapeutic strategy can include single agents or combined therapies, depending on the patient’s health, stage, and location of the tumor. The efficiency of these treatments can be decreased due to the development of diverse resistance mechanisms. New therapeutic targets have emerged from studies of the genetic profile of melanocytes and from the identification of molecular factors involved in the pathogenesis of the malignant transformation. In this review, we aim to survey therapies approved and under evaluation for melanoma treatment and relevant research on the molecular mechanisms underlying melanomagenesis.

No abstract

There are distinct genetic pathways leading to the glioblastoma, the most malignant astrocytic brain tumor. Primary (de novo) glioblastomas develop in older patients and are characterized by epidermal growth factor (EGF) receptor amplification/overexpression, p16 deletion, and PTEN mutations, whereas secondary glioblastomas that progressed from low-grade or anaplastic astrocytoma develop in younger patients and frequently contain p53 mutations. In this study, we assessed the genetic profile of gliosarcoma, a rare glioblastoma variant characterized by a biphasic tissue pattern with alternating areas displaying glial and mesenchymal differentiation. Single-strand conformation polymorphism followed by direct DNA sequencing revealed p53 mutations in five of 19 gliosarcomas (26%) and PTEN mutations in seven cases (37%). Homozygous p16 deletion was detected by differential polymerase chain reaction in seven (37%) gliosarcomas. The overall incidence of alterations in the Rb pathway (p16 deletion, CDK4 amplification, or loss of pRb immunoreactivity) was 53%, and these changes were mutually exclusive. Coamplification of CDK4 and MDM2 was detected in one gliosarcoma. None of the gliosarcomas showed amplification or overexpression of the EGF receptor. Thus gliosarcomas exhibit a genetic profile similar to that of primary (de novo) glioblastomas, except for the absence of EGFR amplification/overexpression. Identical PTEN mutations in the gliomatous and sarcomatous tumor components were found in two cases. Other biopsies contained p16 deletions, an identical p53 mutation, or coamplification of MDM2 and CDK4 in both tumor areas. This strongly supports the concept of a monoclonal origin of gliosarcomas and an evolution of the sarcomatous component due to aberrant mesenchymal differentiation in a highly