Prospective geriatric assessment for perioperative risk stratification in partial nephrectomy.

PURPOSE: Comorbidities and frailty are determinants of surgical outcome. The aim of the study was to examine various measures of frailty and comorbidities in predicting postoperative outcome of partial nephrectomy (PN). METHODS: We prospectively analyzed the frailty and comorbidity status of 150 patients undergoing PN between 2015 and 2018. Primary endpoint was the occurrence of major postoperative complications (MPC) and secondary endpoints were the failure of Trifecta achievement and the need for hospital readmissions. For the transfer into clinical practice the most significant frailty parameters were summarized in a multi-dimensional test. RESULTS: Median age was 67 (33-93) years, 64.7% of the patients were male. Univariable regression analysis showed, that patients with increased frailty indices (Hopkins frailty score ≥2 (OR = 3.74, p = 0.005), Groningen frailty index ≥4 (OR = 2.85, p = 0.036)) are at higher risk to develop MPC. Furthermore, poor physical performance, such as a low handgrip strength or a Full-Tandem-Stand (FTS) < 10 s were associated with MPC (OR = 4.76, p = 0.014; OR = 4.48, p = 0.018) and Trifecta failure (OR = 3.60, p = 0.037, OR = 5.50, p = 0.010). Six measures were combined to the geriatric assessment in partial nephrectomy score (GAPN). A GAPN-score ≥3 proved to be a significant predictor for MPC (OR = 4.30, p = 0.029) and for Trifecta failure (OR = 0.20, p = 0.011) in multivariable regression analysis. CONCLUSION: The frailty status and comorbidities are important determinants of the postoperative course after PN. These parameters should be assessed preoperatively and included in the treatment planning, especially in light of available alternative therapies. In this context, the GAPN-score may be a suitable tool.

Omacetaxine mepesuccinate prevents cytokine-dependent resistance to nilotinib in vitro: potential role of the common ß-subunit c of cytokine receptors.

Overcoming resistance against BCR-ABL-inhibitors in chronic myeloid leukemia (CML) is central to prevent progression to advanced phase disease. Kinase mutations of BCR-ABL and cytokine-mediated modulation of response to tyrosine kinase inhibitors (TKIs) are key mechanisms governing clinical response to imatinib and second generation TKIs. Omacetaxine mepesuccinate is effective in imatinib-resistant CML with reported stem cell activity. We specifically thought to explore omacetaxine in the context of the pan-resistant mutant T315I, and in its potential to modify cytokine-dependent resistance. Omacetaxine was investigated in cell lines and primary CD34+ enriched progenitor cells from patients with CML. Addition of cytokines, shown to revert the efficacy of TKIs in BCR-ABL-positive cells, does not affect omacetaxine mediated antiproliferative activity, neither in cell lines nor in primary CML CD34+ progenitor cells. Looking at potential mechanisms, we found marked downregulation of the common ß-subunit c of the cytokine-receptors (cCRßc) for IL3, IL5 and GM-CSF by omacetaxine in cell lines and primary progenitor cultures. The observed cytokine-independent in-vitro cytotoxicity of omacetaxine may be explained by downregulation of cCRßc. Whether this can be used clinically as a means to optimize the stem cell activity of TKIs merits further evaluation.