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BACKGROUND: Sunitinib and sorafenib are tyrosine kinase inhibitors that have important antitumor activity in metastatic renal cell carcinoma (mRCC). Hypothyroidism constitutes a commonly reported side effect of both drugs, and particularly of sunitinib. The objective of this analysis was to investigate whether the occurrence of hypothyroidism during treatment with sunitinib and sorafenib affects the outcome of patients with mRCC. METHODS: Eighty-seven consecutive patients with mRCC who were to receive treatment with sunitinib or sorafenib were included in a prospective analysis. Thyroid function was assessed in each patient every 4 weeks during the first 2 months of treatment and every 2 to 4 months thereafter. Assessment included serum levels of thyroid-stimulating hormone (TSH), tri-iodthyronine (T3), and thyroxine (T4). Subclinical hypothyroidism was defined as an increase in TSH above the upper limit of normal (>3.77 lM/mL) with normal T3 and T4 levels. RESULTS: Subclinical hypothyroidism was evident in 5 patients at baseline and occurred in 30 patients (36.1%) within the first 2 months after treatment initiation. There was a statistically significant correlation between the occurrence of subclinical hypothyroidism during treatment and the rate of objective remission (hypothyroid patients vs euthyroid patients: 28.3% vs 3.3%, respectively; P < .001) and the median duration of survival (not reached vs 13.9 months, respectively; hazard ratio, 0.35; 95% confidence interval, 0.14-0.85; P ¼ .016). In multivariate analysis, the development of subclinical hypothyroidism was identified as an independent predictor of survival (hazard ratio, 0.31; P ¼ .014). CONCLUSIONS: The current results indicated that hypothyroidism may serve as a predictive marker of treatment outcome in patients with mRCC. Thus, the interpretation of hypothyroidism during treatment with sunitinib and sorafenib as an unwanted side effect should be reconsidered.

Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19ARF as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF–Mdm2–p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14ARF expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.

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Chronic inflammation may induce an increased growth pattern of fibromuscular tissue in BPH similar to that of wound healing.