Therapeutic potential of CDK4/6 inhibitors in renal cell carcinoma.

The treatment of advanced and metastatic kidney cancer has entered a golden era with the addition of more therapeutic options, improved survival and new targeted therapies. Tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors and immune checkpoint blockade have all been shown to be promising strategies in the treatment of renal cell carcinoma (RCC). However, little is known about the best therapeutic approach for individual patients with RCC and how to combat therapeutic resistance. Cancers, including RCC, rely on sustained replicative potential. The cyclin-dependent kinases CDK4 and CDK6 are involved in cell-cycle regulation with additional roles in metabolism, immunogenicity and antitumour immune response. Inhibitors of CDK4 and CDK6 are now commonly used as approved and investigative treatments in breast cancer, as well as several other tumours. Furthermore, CDK4/6 inhibitors have been shown to work synergistically with other kinase inhibitors, including mTOR inhibitors, as well as with immune checkpoint inhibitors in preclinical cancer models. The effect of CDK4/6 inhibitors in kidney cancer is relatively understudied compared with other cancers, but the preclinical studies available are promising. Collectively, growing evidence suggests that targeting CDK4 and CDK6 in kidney cancer, alone and in combination with current therapeutics including mTOR and immune checkpoint inhibitors, might have therapeutic benefit and should be further explored.

Detailed imaging of abducens nerve anatomy using contrast-enhanced 3D-TOF MR angiography.

PURPOSE: Cranial nerves (CNs), particularly CN IV and VI are difficult to visualize with conventional MRI techniques, particularly within the cavernous sinus region. The aim of this study was to evaluate the capacity of high-resolution contrast enhanced 3D time-of-flight (TOF) MR angiography using new generation 3 T imaging technology to provide detailed visualization of CN VI anatomy, particularly within the cavernous sinus and petroclival regions. METHODS: Two neuroradiologists conducted bilateral evaluation of CN VI visibility in 23 patients for nerve segments located in the petroclival segment (dural cave and Dorello's canal), and three divisions of the cavernous sinus. All images were collected using contrast enhanced TOF MR angiography using a new generation 3 T machine. RESULTS: Of the CN VI segments assessed, average visibility of CN VI was best achieved in Dorello's canal. Overall visibility of CN VI within the regions inspected was best achieved in the axial view, with the exception of the dural cave, which was best assessed using the coronal view. We also identified strong agreement in assessment of nerve visibility between the two reviewers. We also identified a putative CN6 duplication and a small schwannoma, highlighting the fidelity of our approach. CONCLUSION: Contrast enhanced 3D TOF MR angiography can visualize CN VI anatomy, particularly within the petrocavernosal region and cavernous sinus with simultaneous visualization of arterial and venous structures. This cannot be easily achieved using traditional MRI techniques. This imaging technique might be used with new generation machines to evaluate CN VI anatomy and pathologies within the petrocavernosal region and cavernous sinus, especially relating to vascular pathologies.

"Robotic fatigue?" - The impact of case order on positive surgical margins in robotic-assisted laparoscopic prostatectomy.

PURPOSE: Multiple robotic-assisted surgeries are often performed within a single operating day; however, the impact of this practice on patient outcomes has not been examined. We aim to determine whether outcomes for robotic-assisted laparoscopic prostatectomy (RALP) differed when performed sequentially. MATERIALS AND METHODS: A multi-institutional, retrospective cohort study was conducted involving a total of 8 academic centers between years 2015 and 2018. Participants were adult males undergoing RALP for localized prostate cancer on operative days in which 2 RALP cases were performed sequentially by the same resident-attending team. The primary outcome of the study was presence of positive surgical margin (PSM). Secondary outcomes were lymph node yield, operative time, and estimated blood loss. The primary analysis was a random effects meta-analysis model for PSM. RESULTS: Overall, 898 RALP cases (449 sequential pairs) were included in the study. There was no significant difference in PSM rate (27.2% vs. 30.3%, P= 0.338) between first and second case groups, respectively. Utilizing random effects meta-analysis, the second case cohort had no increased risk of PSM (OR 0.761.231.97, P= 0.40). Higher blood loss was noted in the second case cohort (186.7 ml vs. 221.7 ml, P = 0.002). Additionally, factors associated with PSM were increasing prostate specific antigen, higher percent tumor involvement, extraprostatic extension, and seminal vesicle invasion. CONCLUSION: Case sequence was not associated with PSM, lymph node yield, or operative time for RALP. Disease specific factors and institutional experience are associated with increased risk for positive surgical margin which can aid providers in scheduling of patients.

Predictors of Postoperative Urinary Incontinence After Holmium Laser Enucleation of the Prostate: 12 Months Follow-Up.

OBJECTIVE: To identify pre- and perioperative factors associated with incontinence after holmium laser enucleation of the prostate for benign prostatic hyperplasia. METHODS: Retrospective review of our single-surgeon database identified 88 patients with 12 months' follow-up who underwent surgery between December 2014 and November 2016. Postoperative urinary incontinence was defined as 1 or more pads per day. Patients were evaluated at 6 weeks, 6 months, and 12 months postoperatively. RESULTS: Preoperative variables associated with incontinence at all follow-ups included pre-existing incontinence and higher detrusor voiding pressure. Higher maximum urinary flow and lower postvoid residual were predictors of transient urinary incontinence. On multivariate analysis, pre-existing incontinence remained significant as a 12-month predictor, whereas a higher detrusor voiding pressure was only significant as a 6-week predictor. De novo incontinence at 12 months was identified in only 1/44 patients (2%). Among patients with pre-existing incontinence, 30/40 (75%) reported resolution of their incontinence at 12 months. Numerous demographic, urinary, urodynamic, and operative factors were not significant for predicting incontinence. The mean decrease in pads per day between 6 weeks and 6 months was -1.6 and between 6 months and 12 months was -0.75. Medical management did not significantly impact rates of postoperative incontinence when compared to observation alone. CONCLUSION: Pre-existing urinary incontinence and/or higher detrusor voiding pressure may predict urinary incontinence 12 months after holmium laser enucleation of the prostate.

Upfront boost Gamma Knife "leading-edge" radiosurgery to FLAIR MRI-defined tumor migration pathways in 174 patients with glioblastoma multiforme: a 15-year assessment of a novel therapy.

OBJECTIVE Glioblastoma multiforme (GBM) is composed of cells that migrate through the brain along predictable white matter pathways. Targeting white matter pathways adjacent to, and leading away from, the original contrast-enhancing tumor site (termed leading-edge radiosurgery [LERS]) with single-fraction stereotactic radiosurgery as a boost to standard therapy could limit the spread of glioma cells and improve clinical outcomes. METHODS Between December 2000 and May 2016, after an initial diagnosis of GBM and prior to or during standard radiation therapy and carmustine or temozolomide chemotherapy, 174 patients treated with radiosurgery to the leading edge (LE) of tumor cell migration were reviewed. The LE was defined as a region outside the contrast-enhancing tumor nidus, defined by FLAIR MRI. The median age of patients was 59 years (range 22-87 years). Patients underwent LERS a median of 18 days from original diagnosis. The median target volume of 48.5 cm3 (range 2.5-220.0 cm3) of LE tissue was targeted using a median dose of 8 Gy (range 6-14 Gy) at the 50% isodose line. RESULTS The median overall survival was 23 months (mean 43 months) from diagnosis. The 2-, 3-, 5-, 7-, and 10-year actual overall survival rates after LERS were 39%, 26%, 16%, 10%, and 4%, respectively. Nine percent of patients developed treatment-related imaging-documented changes due to LERS. Nineteen percent of patients were hospitalized for management of edema, 22% for resection of a tumor cyst or new tumor bulk, and 2% for shunting to treat hydrocephalus throughout the course of their disease. Of the patients still alive, Karnofsky Performance Scale scores remained stable in 90% of patients and decreased by 1-3 grades in 10% due to symptomatic treatment-related imaging changes. CONCLUSIONS LERS is a safe and effective upfront adjunctive therapy for patients with newly diagnosed GBM. Limitations of this study include a single-center experience and single-institution determination of the LE tumor target. Use of a leading-edge calculation algorithm will be described to achieve a consistent approach to defining the LE target for general use. A multicenter trial will further elucidate its value in the treatment of GBM.

Evaluation of acetylcholine, seizure activity and neuropathology following high-dose nerve agent exposure and delayed neuroprotective treatment drugs in freely moving rats.

Organophosphorus nerve agents such as soman (GD) inhibit acetylcholinesterase, producing an excess of acetylcholine (ACh), which results in respiratory distress, convulsions and status epilepticus that leads to neuropathology. Several drugs (topiramate, clobazam, pregnanolone, allopregnanolone, UBP 302, cyclopentyladenosine [CPA], ketamine, midazolam and scopolamine) have been identified as potential neuroprotectants that may terminate seizures and reduce brain damage. To systematically evaluate their efficacy, this study employed in vivo striatal microdialysis and liquid chromatography to respectively collect and analyze extracellular ACh in freely moving rats treated with these drugs 20 min after seizure onset induced by a high dose of GD. Along with microdialysis, EEG activity was recorded and neuropathology assessed at 24 h. GD induced a marked increase of ACh, which peaked at 30 min post-exposure to 800% of control levels and then steadily decreased toward baseline levels. Approximately 40 min after treatment, only midazolam (10 mg/kg) and CPA (60 mg/kg) caused a significant reduction of ACh levels, with CPA reducing ACh levels more rapidly than midazolam. Both drugs facilitated a return to baseline levels at least 55 min after treatment. At 24 h, only animals treated with CPA (67%), midazolam (18%) and scopolamine (27%) exhibited seizure termination. While all treatments except for topiramate reduced neuropathology, CPA, midazolam and scopolamine showed the greatest reduction in pathology. Our results suggest that delayed treatment with CPA, midazolam, or scopolamine is effective at reducing GD-induced seizure activity and neuropathology, with CPA and midazolam capable of facilitating a reduction in GD-induced ACh elevation.

Both serum 25-hydroxyvitamin D and calcium levels may increase the risk of incident prostate cancer in Caribbean men of African ancestry.

Circulating 25-hydroxyvitamin D [25(OH)D] concentrations have been associated with both higher and lower risk of prostate cancer (PCa), whereas elevated levels of circulating calcium has been related to higher risks. However, there are few studies that account for effects of both calcium and 25(OH)D concentrations on incident PCa in a black population. We examined these relationships in a case-control study of men 40-80 years old with newly diagnosed, histologically confirmed PCa in Jamaica, a tropical country. Mean serum calcium concentrations was higher among cases (2.32 ± 0.19 mmol/L) than controls, (2.27 ± 0.30 mmol/L) (P = 0.023) however, there were no differences in 25(OH)D by cancer status (cases, 33.67 ± 12.71 ng/mL; controls (32.25 ± 12.59 ng/mL). Serum calcium was not correlated with 25(OH)D (partial correlation: r, 0.06; P = 0.287). Multivariable-adjusted models showed a positive linear relationship between PCa and serum calcium (OR, 1.12; CI, 1.00-1.25 per 0.1 nmol/L). Serum 25(OH)D concentration also showed a positive association with PCa (OR, 1.23; CI, 1.01-1.49 per 10 ng/mL). The odds of PCa in men with serum 25(OH)D tertile 2 was OR, 2.18; CI, 1.04-4.43 and OR, 2.47 CI, 1.20-4.90 for tertile 3 (P(trend) = 0.013). Dietary intakes of calcium showed no relationship with PCa. Despite the strong relationship between serum calcium and vitamin D the mechanism by which each affects prostate cancer risk in men of African ancestry needs additional investigation.

Soft tissue response to titanium dioxide nanotube modified implants.

Titanium is widely used clinically, yet little is known regarding the effects of modifying its three-dimensional surface geometry at the nanoscale level. In this project we have explored the in vivo response in terms of nitric oxide scavenging and fibrotic capsule formation to nano-modified titanium implant surfaces. We compared titanium dioxide (TiO(2)) nanotubes with 100 nm diameters fabricated by electrochemical anodization with TiO(2) control surfaces. Significantly lower nitric oxide was observed for the nanostructured surface in solution, suggesting that nanotubes break down nitric oxide. To evaluate the soft tissue response in vivo TiO(2) nanotube and TiO(2) control implants were placed in the rat abdominal wall for 1 and 6 weeks. A reduced fibrotic capsule thickness was observed for the nanotube surfaces for both time points. Significantly lower nitric oxide activity, measured as the presence of nitrotyrosine (P<0.05), was observed on the nanotube surface after 1 week, indicating that the reactive nitrogen species interaction is of importance. The differences observed between the titanium surfaces may be due to the catalytic properties of TiO(2), which are increased by the nanotube structure. These findings may be significant for the interaction between titanium implants in soft tissue as well as bone tissue and provide a mechanism by which to improve future clinical implants.