Palbociclib has antitumour effects on Pten‐deficient endometrial neoplasias

PTEN is one of the most frequently mutated genes in human cancers. The frequency of PTEN alterations is particularly high in endometrial carcinomas. Loss of PTEN leads to dysregulation of cell division, and promotes the accumulation of cell cycle complexes such as cyclin D1–CDK4/6, which is an important feature of the tumour phenotype. Cell cycle proteins have been presented as key targets in the treatment of the pathogenesis of cancer, and several CDK inhibitors have been developed as a strategy to generate new anticancer drugs. Palbociclib (PD‐332991) specifically inhibits CDK4/6, and it has been approved for use in metastatic breast cancer in combination with letrazole. Here, we used a tamoxifen‐inducible Pten knockout mouse model to assess the antitumour effects of cyclin D1 knockout and CDK4/6 inhibition by palbociclib on endometrial tumours. Interestingly, both cyclin D1 deficiency and palbociclib treatment triggered shrinkage of endometrial neoplasias. In addition, palbociclib treatment significantly increased the survival of Pten‐deficient mice, and, as expected, had a general effect in reducing tumour cell proliferation. To further analyse the effects of palbociclib on endometrial carcinoma, we established subcutaneous tumours with human endometrial cancer cell lines and primary endometrial cancer xenografts, which allowed us to provide more translational and predictive data. To date, this is the first preclinical study evaluating the response to CDK4/6 inhibition in endometrial malignancies driven by PTEN deficiency, and it reveals an important role of cyclin D–CDK4/6 activity in their development. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Emerging drugs for non-small-cell lung cancer

Non-small-cell lung cancer (NSCLC) accounts for 80% of all lung cancer cases and is the leading cause of cancer mortality. Despite the optimization of chemotherapy regimens, treatment outcomes for advanced disease are still disappointing. The EGFR tyrosine kinase inhibitor, erlotinib, and the recombinant monoclonal antibody against the VEGF, bevacizumab, have proven active in NSCLC. In the BR.21 trial, a 2-month benefit in overall survival was observed for previously treated NSCLC patients who received erlotinib versus placebo. The combination of chemotherapy plus bevacizumab yielded superior overall survival or progression-free survival in one randomized trial in advanced non-squamous NSCLC patients. However, despite the introduction of more effective agents, new treatment strategies are clearly needed in lung cancer management. The review focuses on a number of new targeted agents/chemotherapy drugs now in clinical trials directed at improving NSCLC management. Mature results regarding their activity and usefulness can be expected in the near future.     

Treatment With Cinacalcet of Secondary Hyperparathyroidism After Renal Transplantation

Background

The treatment of posttransplant secondary hyperparathyroidism (SHP) with vitamin D analogues is determined by their effectiveness to reverse hypercalcemia. Calcimimetics inhibit parathyroid hormone (PTH) secretion by modulating the calcium-sensing receptor in the parathyroid gland. Cinacalcet, a calcimimetic drug, has proven its effectiveness for the treatment of SHP among patients in phase V of chronic renal disease.

Patients and Methods

This retrospective analysis included 48 patients with SHP who were treated with cinacalcet. The initial dose of 30 mg/d could be increased to 180 mg, administering calcitriol also, depending on the serum calcium and PTH levels. The objectives were a PTH level between 75 and 125 pg/mL or a decrease >40%, and a serum calcium level below 10.5 mg/dL.

Results

The average PTH at baseline was 244 pg/mL, decreasing to 131 pg/mL at 1 year (P < .01). The average calcium at baseline was 10.1 mg/dL descending to 9.2 mg/dL at 1 year (P < .01). Among patients with hypercalcemia, the calcium decreased from 11 to 9.6 mg/dL at 1 year (P < .01). Seventy percent of patients without hypercalcemia reached the desired value of PTH, and 100% of those with hypercalcemia. Among patients with hypercalcemia, the desired calcium level was reached in 91% of cases. Ten patients developed hypocalcemia. In 3 cases we stopped the treatment with cinacalcet due to digestive intolerance.

Conclusions

Treatment with cinacalcet controlled hyperparathyroidism and hypercalcemia among patients with posttransplant SHP. It was a safe drug, with a low incidence of side effects.     

Levels and Profiles of Polychlorinated Dibenzo-p-Dioxins, Polychlorinated Dibenzofurans, and Polychlorinated Biphenyls in Feedstuffs and Milk From Farms in the Vicinity of Incineration Plants in Tuscany, Italy

Levels of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorobiphenyls (PCBs) were determined in samples of bovine and ovine milk collected in farms located in the province of Grosseto, Tuscany, in the vicinity of two incineration plants as well as in farms located in areas with presumable background levels of contamination. Samples of feedstuffs of local origin used in the investigated farms were also collected and analysed. The cumulative levels of PCDDs, PCDFs, and dioxin-like PCBs (DL-PCBs) in feedstuffs ranged from 0.25 to 0.61 pg WHO-TE/g fresh weight (fw) in the farms under impact from incinerator emissions and from 0.21 to 0.34 pg WHO-TE/g fw in the control area farms. The sums of the six non–dioxin-like indicator PCB (NDL-PCB) congeners were 0.13 to 9.3 ng/g fw and 1.2 to 1.9 ng/g fw, respectively. In milk samples, the levels detected were 0.71 to 2.9 pg WHO-TE/g fat and 0.52 to 0.59 pg WHO-TE/g fat in farms under impact from the incinerators and in the control area farms, respectively. The corresponding sums of the six indicator PCB congeners were 1.4 to 8.2 ng/g fat and 0.90 to 1.6 ng/g fat. In all samples, contamination levels were below the limits set by the European Community (EC; Commission Directive 2006/13/EC and Commission Regulation 1881/2006/EC.) No relevant differences were found between samples collected in potentially exposed areas and control areas for total toxic equivalents and cumulative analytic levels of PCDDs, PCDFs, DL-PCBs, and NDL-PCBs (p > 0.05, Mann-Whitney U test). Observed levels were in agreement with those found in other countries in areas with background levels of exposure. Congener levels and profiles of PCDDs, PCDFs, and PCBs in feedstuffs and milk samples that were compared describe congener-specific transfer behavior.     

Population-based incidence and survival of gastrointestinal stromal tumours (GIST) in Girona, Spain

BackgroundGastrointestinal stromal tumours (GIST) are rare malignancies characterised by their association with KIT oncogene mutations. Until now, population-based reports of the incidence or survival of kit-confirmed GIST have been rare, and none have originated in Southern Europe.Materials and methodsWe used the Girona Cancer Registry to identify malignant mesenchymal tumours of the digestive tract between 1994 and 2001, and performed c-kit testing in the tumour samples. Age-adjusted incidence rates and survival rates were calculated, and they were also analysed by sex and NIH risk categories.ResultsForty-six cases were categorised as GIST. Fifty percent were localised in the stomach, 43.5% in small intestine, 4.3% in the omentum, and 2.2% in colon. Thirty-seven percent were classified as high risk of an aggressive behaviour, 30.4% as intermediate risk and 32.6% as low or very low risk. Only one patient received treatment with imatinib mesilate. The annual incidence by 100,000 inhabitants in crude rate, European age-standardised rate and world age-standardised rate was, respectively, 1.09, 0.90 and 0.65 cases. The relative 5-year survival rate was 74.7% for the entire cohort, and it was markedly lower in the high-risk cases (20.3%).ConclusionsWe report the first population-based study of GIST incidence and survival in Southern Europe. The incidence rate is low and comparable with that of cancer registries from Northern Europe. Survival was favourable in our pre-imatinib population although it was low in high risk cases. Prognostic discrimination of the cases with intermediate, low, or very low risk is inadequate, and these categories should be considered jointly in the future. Our results will help researchers in establishing baseline values against which they can compare, in the future, the impact of imatinib and other Kit tyrosine inhibitors on survival.