Cabozantinib in the treatment of metastatic renal cell carcinoma - final data analysis from four oncology centers in the Czech Republic.

BACKGROUND: Current standard treatments for patients with metastatic renal cell carcinoma (mRCC) involve tyrosine kinase inhibitors (TKI) that inhibit angiogenesis. Cabozantinib is a multi TKI used for the treatment of mRCC in the first- and second-line setting. PURPOSE: The aim of this study was the final analysis of treatment outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with cabozantinib after previous targeted therapy. PATIENTS AND METHODS: A total of 54 patients with mRCC from four oncology centers in the Czech Republic were evaluated retrospectively; the median follow-up was 18.5 months. Cabozantinib was administered in a dose of 60mg/day, a subset of patients received an initial dose of 40mg/day. The treatment was administered until the progression. The Kaplan-Meier analysis was used to calculate progression free survival (PFS) and overall survival (OS). We performed a multivariate analysis of risk factors for treatment outcomes (PFS, OS) by regression analysis. All statistics were evaluated at the significance level α = 0.05. RESULTS: The median PFS in all patients was 9.3 months (95% CI 7.2 - 11.4). The median OS in all patients was 21.9 months (95% CI 15.5 - 28.4). The median PFS in patients with bone metastases was not statistically significantly different compared with patients without bone metastases (9.3 vs 8.7 months, P = 0.53). The median OS in patients with bone metastases was statistically significantly shorter compared with patients without bone metastases (17.7 vs 26.8 months, P = 0.021). A treatment response was observed in 40.7 % of cases, including one complete remission. The regression analysis demonstrated a significant effect on OS in patients with the presence of subsequent treatment (P = 0.001), patients with treatment duration of first line therapy 6 months (P = 0.019) and 12 months (P = 0.003) and in patients without bone metastases (P = 0.021). CONCLUSION: Our final analysis of patients with mRCC treated with cabozantinib after previous targeted therapy confirmed its effectiveness.

Changes in expression of lysosomal membrane proteins in leucocytes of cancer patients treated with tyrosine kinase inhibitors.

Lysosomal sequestration of weak base drugs has been identified as one of the stress-related mechanisms that trigger in vitro lysosomal biogenesis controlled by transcription factor EB (TFEB). Whether such mechanism can induce lysosomal biogenesis in vivo is unknown. In this study, we addressed the question whether prolonged treatment with sunitinib (SUN) in patients with advanced renal cell carcinoma (n = 22) and with imatinib (IM) in those with gastrointestinal stromal tumor (n = 6) could induce lysosomal biogenesis in leukocytes. Lysosomal biogenesis was monitored using immunoblotting of three lysosomal membrane proteins: lysosome-associated membrane proteins 1 and 2 (LAMP1 and LAMP2) and vacuolar H+-ATPase, B2 subunit (ATP6V1B2). Present results indicate that prolonged treatment with SUN affects LAMP1 and LAMP2 expression only marginally in most patients. In contrast, changes in ATP6V1B2 expression were marked and resembled irregular oscillations. Very similar changes in the expression of lysosomal membrane proteins were also found in IM-treated patients. Conclusion: prolonged treatment of cancer patients with SUN and IM did not induce leucocyte lysosomal biogenesis but dramatically affected expression of ATP6V1B2.

Effect of a low salt diet on blood pressure and vasoactive hormones in the hereditary hypertriglyceridemic rat.

In hereditary HTG rats, basal systolic blood pressure using tail-cuff sphygmomanometry was significantly higher (122.1 +/- 2.1 mm Hg; n = 16) than that in NTG animals (107.1 +/- 1.52; n = 16). A low salt diet did not influence blood pressure in NTG rats during the consecutive 4 weekly periods. However, in the second week blood pressure in HTG rats rose significantly in both the control rats on a normal salt diet and those on a low salt diet (132.5 +/- 1.89, n = 8, and 132.6 +/- 1.93, n = 8). No further changes were registered in the third and fourth week in control HTG rats. On the other hand, blood pressure fell significantly in HTG rats on a low salt diet in the third week in comparison with the second week (119.5 +/- 3.2, n = 8), and it increased again in the fourth week (123.0 +/- 2.35, n = 8). Hormones in plasma were determined at the end of the experiment. Plasma levels of norepinephrine were not influenced by differences in salt intake and were significantly higher by about 45% in HTG than in NTG animals. The lowest concentration of corticosterone in plasma was found in control HTG rats (1.2 +/- 0.2 vs 4.6 +/- 0.8 micrograms/100 ml in control NTG rats). Nevertheless, corticosterone concentration increased in HTG rats on a low salt diet at comparable values found in NTG rats on a low salt diet (3.1 +/- 0.8 vs 4.3 +/- 1.5). Plasma renin activity and plasma aldosterone concentrations were not different in the NTG and HTG groups and were uninfluenced by the diets (Table 1). We conclude that the elevated blood pressure in HTG rats and its variations during the experiment may reflect more pronounced sympathetic activity in HTG rats rather than blood pressure dependency on different salt intake.

On the role of digoxin-like substances, ANP, and AVP in natriuresis induced by hypertonic saline infusion in dogs.

The increase of sodium concentration in cerebrospinal fluid or in plasma triggers the osmoregulatory mechanism, namely, the enhancement of renal free-water reabsorption and natriuresis. The increase of free-water reabsorption has been recognized for many years as a consequence of the osmotically released vasopressin (AVP). However, the control of renal sodium excretion in the mechanism of osmoregulation has not been clarified It has been suggested to be, at least in part, of hormonal nature, implying the decreased release of aldosterone and the increased release of atrial natriuretic peptide (ANP), digoxin-like substances (DLIS), and AVP. Neither of these factors, however, has been unequivocally linked to the mechanism of immediate natriuresis caused by an acute increase in cerebrospinal fluid or plasma sodium concentration. It was reconfirmed in our present experiments in anesthetized dogs that aldosterone, ANP, and DLIS could hardly play a role in the immediate natriuresis after the i.v. infusion of hypertonic saline (20% NaCl solution infused in 20 min in an amount that was 0.13% of body weight). However, the role of AVP in this type of natriuresis seems more promising as a V1/V2 receptor antagonist applied i.v. before the hypertonic saline loading completely prevented the increase of renal sodium excretion. Natriuresis after the isotonic saline load was not impaired by the same antagonist of vasopressin receptors.