Unusual Cushing's Syndrome and Hypercalcitoninaemia due to a Small Cell Prostate Carcinoma.

A 75-year-old man was hospitalized because of severe hypokalaemia due to ACTH dependent Cushing's syndrome. Total body computed tomography (TBCT) and 68 Gallium DOTATATE PET/CT localized a voluminous prostate tumour. A subsequent transurethral prostate biopsy documented a small cell carcinoma positive for ACTH and calcitonin and negative for prostatic specific antigen (PSA) at immunocytochemical study; serum prostatic specific antigen (PSA) was normal. Despite medical treatments, Cushing's syndrome was not controlled and the patient's clinical condition progressively worsened. Surgical resection was excluded; the patient underwent a cycle of chemotherapy followed by febrile neutropenia and fatal intestinal perforation. This case report describes a rare case of Cushing's syndrome and hypercalcitoninaemia due to a small cell carcinoma of the prostate, a rare tumour with very few therapeutic options and negative prognosis.

Prognostic relevance of histological grade and its components in node-negative breast cancer patients.

Available results highlight the lack of good level of evidence studies on the pure prognostic value of histological grade. In the present study, the prognostic relevance of histological grade and of its three components, tubule formation, nuclear pleomorphism and mitotic count, was analyzed in a series of 372 patients with node-negative breast cancer treated with locoregional therapy alone until early relapse. Histological grade was determined blindly by two observers and discordance between evaluations was resolved after joint review using a multihead microscope. No relation was observed between histological grade and any of its three components and disease-free survival. Conversely, a significant relation was observed between histological grade and distant metastasis-free survival (at 6 years, 94, 86 and 76% for grades 1, 2 and 3, respectively, P=0.013) as well as overall survival (98, 90 and 86%, P=0.001). A breakdown analysis as a function of the three components showed that neither tubule formation nor nuclear pleomorphism was associated with prognosis, and only mitotic count strongly influenced both distant metastasis-free survival (91, 82 and 74%, P=0.014) and overall survival (97, 87 and 85%, P=0.011). Histological grade suffers from a much higher subjectivity than any other microscopic evaluation of biomarkers as it is the sum of three different morphological features. Within the Italian Network for Quality Assessment of Tumor Biomarkers program we observed that histological grade is an independent prognostic variable, but also that this role is ascribable only to the number of mitotic figures. In conclusion, due to the ever smaller size of diagnosed breast cancers, resulting in less cancer tissue for biofunctional and molecular analysis, mitotic count evaluated under strict quality control conditions seems to be an accurate and feasible prognostic variable.

Karyotype instability and anchorage-independent growth in telomerase-immortalized fibroblasts from two centenarian individuals.

Several reports have shown that the ectopic expression of the human telomerase catalytic subunit gene (hTERT) leads to an indefinite extension of the life span of human fibroblasts cultured in vitro without the appearance of cancer-associated changes. We infected two fibroblast strains derived from centenarian individuals with an hTERT containing retrovirus and isolated transduced massive populations (cen2tel and cen3tel). In both populations, hTERT expression reconstituted telomerase activity and extended the life span. In cen2tel, a net telomere lengthening was observed while, in cen3tel, telomeres stabilized at a length lower than that detected in senescent parental cells. Interestingly, both cen2tel and cen3tel cells developed chromosome anomalies, numerical first and structural thereafter. Moreover, cen3tel cells acquired the ability to grow in the absence of solid support, a typical feature of transformed cells. The results we present here highlight an unexpected possible outcome of cellular immortalization driven by telomerase reactivation, and indicate that, in some cases, an artificial extension of cellular replicative capacity can increase the probability of occurrence of genomic alterations, which can lead to cellular transformation.

Gamma-ray and hydrogen peroxide induction of gene amplification in hamster cells deficient in DNA double strand break repair.

To investigate the role of DNA double strand breaks (DSBs) and of their repair in gene amplification, we analyzed this process in the V3 Chinese hamster cell line and in the parental line AA8, after exposure to gamma-rays and to hydrogen peroxide (H2O2). V3 is defective in DSB repair because of a mutation in the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) gene, a gene involved in the non-homologous end-joining pathway. As a measure of gene amplification we used the frequency of colonies resistant to N-(phosphonacetyl)-L-aspartate (PALA), since in rodent cells PALA resistance is mainly achieved through the amplification of the CAD (carbamyl-P-synthetase, aspartate transcarbamylase, dihydro-orotase) gene. After treatment with different doses of gamma-rays and of H2O2, we found a dose related increase in the frequency of gene amplification and of chromosome aberrations. When the same doses of damaging agents were used, these increments were higher in V3 than in AA8. These results indicate that DSBs that are not efficiently repaired can be responsible for the induction of gene amplification. H2O2 stimulates gene amplification as well as gamma-rays, however, at similar levels of amplification induction, chromosome damage was about 50% lower. This suggests that gene amplification can be induced by H2O2 through pathways alternative to a direct DNA damage. Stimulation of gene amplification by H2O2, which is one of the products of the aerobic metabolism, supports the hypothesis that cellular metabolic products themselves can be a source of genome instability.