Organ-specific off-target effects of Pim/ZIP kinase inhibitors suggest lack of contractile Pim kinase activity in prostate, bladder, and vascular smooth muscle.

Smooth muscle contraction by Pim kinases and ZIPK has been suggested, but evidence for lower urinary tract organs or using Pim-selective inhibitor concentrations is not yet available. Here, we assessed effects of the Pim inhibitors AZD1208 and TCS PIM-1 and the dual ZIPK/Pim inhibitor HS38 on contractions of human prostate and bladder tissues and of porcine interlobar arteries. Human tissues were obtained from radical prostatectomy and radical cystectomy and renal interlobar arteries from pigs. Contractions were studied in an organ bath. Noradrenaline-, phenylephrine- and methoxamine-induced contractions were reduced (up to > 50%) with 500-nM AZD1208 in prostate tissues and to lesser degree and not consistently with all agonists in interlobar arteries. A total of 100-nM AZD1208 or 500-nM TCS PIM-1 did not affect agonist-induced contractions in prostate tissues. Decreases in agonist-induced contractions with 3-µM HS38 in prostate tissues and interlobar arteries were of small extent and did not occur with each agonist. Carbachol-induced contractions in detrusor tissues were unchanged with AZD1208 (500 nM) or HS38. Electric field stimulation-induced contractions were not affected with AZD1208 or HS38 in any tissue, but slightly reduced with 500-nM TCS PIM-1 in prostate tissues. Concentration-dependent effects of Pim inhibitors suggest lacking Pim-driven smooth muscle contraction in the prostate, bladder, and interlobar arteries but point to organ-specific functions of off-targets. Procontractile functions of ZIPK in the prostate and interlobar arteries may be limited and are lacking in the detrusor.

Long-Term Follow-Up in Patients Undergoing Renal Mass Biopsy: Seeding is not Anecdotal.

INTRODUCTION: Renal biopsy is recommended if the outcome might alter therapeutic decisions for patients who present with renal masses of unclear etiology. However, little is known about long-term risks related to this procedure. PATIENTS AND METHODS: We performed a retrospective analysis of an institutional database maintained by a tertiary referral center that included patients who underwent renal biopsies between 2003 and 2005 with a follow-up of at least 15 years. Renal biopsies were taken percutaneously with a coaxial technique according to guideline recommendations and included off-line ultrasound guidance. RESULTS: We identified 106 patients who underwent biopsies for a renal mass of unclear etiology. The median age was 58.7 years (43.7-66.2). A median of 4.2 (3-6) biopsies were collected from each patient. Tumor seeding leading to local growth was identified in 6 patients (5,7%) after a median follow-up of 8.2 years. Four of these lesions that were resected exhibited the same histology as the original biopsy result; these patients experienced no further recurrence. In 45 patients (42%), the biopsy results led to a therapy other than surgery (n = 28 lymphoma, n = 6 metastasis from other malignancies, n = 11 oncocytoma). The remaining 61 patients (58%) were diagnosed with renal cell carcinoma treated either surgically or with ablation. None of the patients developed metastatic spread related to tumor seeding. CONCLUSION: Tumor seeding after renal mass biopsy is a rare, but relevant risk associated with this procedure. As indications for renal mass biopsy increase, longer-term follow-up and improved biopsy techniques should be considered to address this complication.

Image-Guided Robotic Radiosurgery for the Treatment of Lung Metastases of Renal Cell Carcinoma-A Retrospective, Single Center Analysis.

Pulmonary metastases are the most frequent site of metastases in renal cell carcinoma (RCC). Metastases directed treatment remains an important treatment option despite advances in systemic therapies. However, the safety and efficacy of robotic radiosurgery (RRS) for the treatment of lung metastases of RCC remains unclear. Patients with metastatic RCC and lung metastases treated by RRS were retrospectively analyzed for overall survival (OS), progression-free survival (PFS), local recurrence free survival (LRFS) and adverse events. The Kaplan-Meier method was used for survival analysis and the common terminology criteria for adverse events (CTCAE; Version 5.0) classification for assessment of adverse events. A total of 50 patients were included in this study. Median age was 64 (range 45-92) years at the time of RRS. Prior to RRS, 20 patients (40.0%) had received either tyrosine kinase inhibitors or immunotherapy and 27 patients (54.0%) were treatment naïve. In our patient cohort, the median PFS was 13 months (range: 2-93). LRFS was 96.7% after two years with only one patient revealing progressive disease of the treated metastases 13 months after RRS. Median OS was 35 months (range 2-94). Adverse events were documented in six patients (12%) and were limited to grade 2. Fatigue (n = 4) and pneumonitis (n = 2) were observed within 3 months after RRS. In conclusion, RRS is safe and effective for patients with metastatic RCC and pulmonary metastases. Radiation induced pneumonitis is specific in the treatment of pulmonary lesions, but not clinically relevant and survival rates seem favorable in this highly selected patient cohort. Future directions are the implementation of RRS in multimodal treatment approaches for oligometastatic or oligoprogressive disease.