Inhibitors of cyclooxygenase 2 (COX 2) and the mammalian target of rapamycin (mTOR) show direct and indirect antitumor effects in a variety of cancers. This study was designed to investigate the effects of the mTOR antagonist rapamycin and the COX 2 inhibitor celecoxib on cell growth and apoptosis in malignant melanoma. Cell proliferation was analysed by the cell proliferation ELISA BrdU and alamarBlue assay and apoptosis was measured by caspase 3 and 7 activity in two out of six melanoma cell lines (A375 and Mel Ho) that were selected for the heterogeneous levels of the COX 2 mRNA expression. The quantitative real-time reverse transcription polymerase chain reaction showed a 337-fold higher COX 2 mRNA level in the A375 than in the Mel Ho melanoma cells. However, both celecoxib and rapamycin caused significant growth inhibition in the two cell lines. By combining both agents, additive growth inhibitory effects were observed in the A375 cells. Treatment with celecoxib, but not rapamycin, increased apoptosis in the two cell lines. Our data indicate that rapamycin and celecoxib inhibit melanoma cell growth as single agents and a combination of both drugs have additive antitumor effects. Notably, the antiproliferative and proapoptotic effects of celecoxib seem to be independent of the COX 2 expression. Both rapamycin and celecoxib represent promising drugs for the palliative therapy of metastasised malignant melanoma and should be considered for future trials.

Tumor cells depend on and are able to modulate the tumor stroma establishing a permissive and supportive environment of their own. Targeting the tumor stroma has evolved as a novel concept that has attracted attention of cancer researchers aiming at the treatment of metastatic cancer. The novel paradigm is that modulating the stroma will possibly not cure the cancer, but will make it a manageable disease for long periods of time by prohibiting the cancer from growing beyond a certain mass. Accordingly, in the last years, a multitude of stroma-targeting agents were developed comprising either classic small molecule drugs (e.g. sorafenib, an inhibitor of multiple tyrosine kinases) or recombinant antibodies (e.g. anti-VEGF) for targeting of tumor angiogenesis. Apart from these specifically targeted drugs, some well established drugs, primarily designed for non-oncologic diseases, have revealed antitumor activity on the basis of nuclear receptor modulation unfolding pleiotropic biological effects including stroma modulation. Peroxisome Proliferator Activated Receptor (PPAR) agonists, particularly thiazolidinedione derivatives such as pioglitazone and ciglitazone, are promising examples as they exert both a direct antitumoral and a broad spectrum of anti-stromal, antiangiogenic and immuno-modulating activities. This review will focus on the stroma-mediated anticancer activities of PPAR agonists.

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Postoperative delirium (POD) is an acute and serious complication following extended surgery. The aim of this study was to identify possible risk factors and scores associated with POD in patients undergoing reconstructive head and neck surgery. A collective of 225 patients was retrospectively evaluated after receiving reconstructive surgery in the head and neck region, between 2013 to 2018. The incidence of POD was examined with regards to distinct patient-specific clinical as well as perioperative parameters. Uni- and multivariate statistics were performed for data analysis. POD occurred in 49 patients (21.8%) and was strongly associated with an increased age-adjusted Charlson Comorbidity Index (ACCI) and a prolonged stay in the ICU (p = 0.009 and p = 0.000, respectively). Analogous, binary logistic regression analysis revealed time in the ICU (p < 0.001), an increased ACCI (p = 0.022) and a Nutritional Risk Screening (NRS) score ≠ 0 (p = 0.005) as significant predictors for a diagnosis of POD. In contrast, the extent of reconstructive surgery in terms of parameters such as type of transplant or duration of surgery did not correlate with the occurrence of POD. The extension of reconstructive interventions in the head and neck region is not decisive for the development of postoperative delirium, whereas patient-specific parameters such as age and comorbidities, as well as nutritional parameters, represent predictors of POD occurrence.

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