Renal Mass Ablation in the Octogenarian and Nonagenarian Population

Introduction: The gold standard for the management of T1a and T1b renal tumors is partial nephrectomy. This study aims to analyze the outcomes of renal mass thermal ablations as an alternative therapy in the octogenarian and nonagenarian patient population, specifically. Methods: Departmental database of all percutaneous renal ablations performed between February 2008 and August 2019 was reviewed. 34 tumors were ablated in 19 males and 15 females with a mean age of 84.1 ± 3.1 years (range 80-92 years). Patient demographics, procedural and postprocedural data were evaluated. Results: Ten microwave and 24 cryoablations were performed, all ablations were performed under CT guidance for 27 T1a and 7 T1b renal tumors (1.4-5.9cm). The mean Charlson comorbidity index was 6.7. Thirty-one ablations were performed as the primary management, 3 were performed for tumor recurrence following partial nephrectomy (2) or prior ablation (1). The average number of probes used in cryoablation was 3.3 compared to 2.7 probes used in microwave ablation. Overall complication rate in cases in the 31 cases in which there was sufficient follow up was 23% and major complication rate was 13%, including two episodes of bleeding requiring red blood cell transfusion. Additionally there was one incidentally detected pseudoaneurysm in the ablation cavity of an asymptomatic patient which was subsequently embolized more than one year following the ablation. The mean pre procedure creatinine was 1.20 and mean creatinine at least 3 months post procedure was 1.23. Of the 25 patients with at least 3 months of CT or MR follow up, there was no local recurrence and median follow-up was 23.7 months (range 1.1-94.9 months). Concurrent biopsies were performed in 31 of the 34 cases. The pathology showed a majority of clear cell renal cell carcinoma (15), followed by oncocytic neoplasm (7), nondiagnostic specimen (4) and papillary renal cell carcinoma (3). Discussion: Thermal ablation of renal masses in the elderly population is an effective treatment option with a low recurrence rate. Complications are higher than previously reported in the literature which may be related the advanced age and comorbidities of these patients

Hepatocellular Carcinoma Treated with Microwave Ablation Prior to Liver Transplantation

Introduction: Ablation is a minimally invasive procedure that limits local liver tumor progression and prolongs patients’ transplantation eligibility. Microwave ablation (MWA) utilizes higher temperatures than the standard of care, radiofrequency ablation (RFA), which increases efficiency. Meta-analyses compared MWA with RFA for the treatment of HCC and showed similar efficacy and safety between these modalities. However, limited pathologic data exists determining whether explanted tumors remained viable after MWA. Methods: Our database was reviewed retrospectively for patients with HCC who underwent MWA prior to liver transplantation between 2013 and 2019. Patient demographics, etiology of disease, tumor size, procedure details, bilirubin, MELD, and Child-Pugh score were reviewed. Tumors were classified as viable or nonviable based on pathology. Imaging and clinical follow-up were available for surveillance and post-transplant. Results: 29 patients (23 males, 6 females) with 40 tumors underwent MWA. The average patient age was 60 years. The mean tumor size was 2.2 cm (range 1-3.7). Twenty-six patients were alive at follow-up. Pathological analysis showed 38 of the 40 tumors ablated to be non-viable at explant. Imaging prior to transplant reported one case with recurrent tumor at the ablation site and another case as equivocal. No cases of metastatic HCC were identified by imaging post-transplant. Discussion: Previous studies have not included this pathologic data. Determining tumor viability provides valuable information regarding whether tumors are likely to recur locally, even after transplantation. These results suggest that MWA is an effective treatment of small HCC prior to transplant with a low incidence of local tumor recurrence

Phorbol 12,13-Dibutyrate-Induced, Protein Kinase C-Mediated Contraction of Rabbit Bladder Smooth Muscle

Contraction of bladder smooth muscle is predominantly initiated by M3 muscarinic receptor-mediated activation of the Gq/11-phospholipase C β-protein kinase C (PKC) and the G12/13-RhoGEF-Rho kinase (ROCK) pathways. However, these pathways and their downstream effectors are not well understood in bladder smooth muscle. We used phorbol 12,13-dibutyrate (PDBu), and 1,2-dioctanoyl-sn-glycerol (DOG), activators of PKC, in this investigation. We were interested in dissecting the role(s) of PKC and to clarify the signaling pathways in bladder smooth muscle contraction, especially the potential cross-talk with ROCK and their downstream effectors in regulating myosin light chain phosphatase activity and force. To achieve this goal, the study was performed in the presence or absence of the PKC inhibitor bisindolylmaleimide-1 (Bis) or the ROCK inhibitor H-1152. Phosphorylation levels of Thr38-CPI-17 and Thr696/Thr850 myosin phosphatase target subunit (MYPT1) were measured during PDBu or DOG stimulation using site specific antibodies. PDBu-induced contraction in bladder smooth muscle involved both activation of PKC and PKC-dependent activation of ROCK. CPI-17 as a major downstream effector, is phosphorylated by PKC and ROCK during PDBu and DOG stimulation. Our results suggest that Thr696 and Thr850-MYPT1 phosphorylation are not involved in the regulation of a PDBu-induced contraction. The results also demonstrate that bladder smooth muscle contains a constitutively active isoform of ROCK that may play an important role in the regulation of bladder smooth muscle basal tone. Together with the results from our previous study, we developed a working model to describe the complex signaling pathways that regulate contraction of bladder smooth muscle

Impact of metabolic syndrome on the outcomes of superficial femoral artery interventions

BackgroundMetabolic syndrome (MetSyn) is an epidemic in the United States and is associated with early onset of atherosclerosis, increased thrombotic events, and increased complications after cardiovascular intervention. MetSyn is found in ∼50% of patients with peripheral vascular disease. However, its impact on peripheral interventions is unknown. The aim of this study is to determine the outcomes of superficial femoral artery (SFA) interventions in patients with and without MetSyn.MethodsA database of patients undergoing endovascular treatment of SFA disease between 1999 and 2009 was retrospectively queried. MetSyn was defined as the presence of ≥3 of the following criteria: blood pressure ≥130 mm Hg/≥85 mm Hg; triglycerides ≥150 mg/dL; high-density lipoprotein ≤50 mg/dL for women and ≤40 mg/dL for men; fasting blood glucose ≥110 mg/dL; or body mass index ≥30 kg/m2. Kaplan-Meier survival analyses were performed to assess time-dependent outcomes. Factor analyses were performed using a Cox proportional hazard model for time-dependent variables.ResultsA total of 1018 limbs in 738 patients (64% male, average age 67 years) underwent endovascular treatment for symptomatic SFA disease with 45% of patients meeting the criteria for MetSyn. MetSyn patients were more likely to be female (P = .001), to present with critical ischemia (rest pain/tissue loss: 55% MetSyn vs 45% non-MetSyn; P = .001), have poorer ambulatory status (P = .001), and have more advanced SFA lesions (TransAtlantic Inter-Society Consensus II C/D: 51% vs 11%; P = .001) and worse tibial runoff (P = .001). MetSyn patients required more complex interventions (P = .0001). There was no difference in mortality and major adverse cardiac events, but systemic complications (4% vs 1%; P = .001) and major adverse limb events (12% vs 7%; P = .0009) were significantly higher in the MetSyn group. Immediate postprocedural hemodynamic improvement, resolved or improved symptoms, and restoration of impaired ambulation were equivalent in both groups. Early failure (<6 months) was more common in those with MetSyn. At 5 years, primary, assisted primary, and secondary patencies were not affected by the presence of MetSyn. The presence of MetSyn was associated with a decrease in clinical efficacy, decreased freedom from recurrent symptoms, and decreased freedom from major amputation at 5 years.ConclusionsMetSyn is present in nearly half of the patients presenting with SFA disease. These patients present with more advanced disease and have poorer symptomatic and functional outcomes compared with those patients without MetSyn

US-triggered Microbubble Destruction for Augmenting Hepatocellular Carcinoma Response to Transarterial Radioembolization: A Randomized Pilot Clinical Trial.

Combined US-triggered microbubble destruction and hepatocellular carcinoma radioembolization showed improved treatment response compared with radioembolization alone and no changes in vital signs or liver function. Background US contrast agents are gas-filled microbubbles (MBs) that can be locally destroyed by using external US. Among other bioeffects, US-triggered MB destruction, also known as UTMD, has been shown to sensitize solid tumors to radiation in preclinical models through localized insult to the vascular endothelial cells. Purpose: To evaluate the safety and preliminary efficacy of combining US-triggered MB destruction and transarterial radioembolization (TARE) in participants with hepatocellular carcinoma (HCC). Materials and Methods: In this pilot clinical trial, participants with HCC scheduled for sublobar TARE were randomized to undergo either TARE or TARE with US-triggered MB destruction 1–4 hours and approximately 1 and 2 weeks after TARE. Enrollment took place between July 2017 and February 2020. Safety of US-triggered MB destruction was evaluated by physiologic monitoring, changes in liver function tests, adverse events, and radiopharmaceutical distribution. Treatment efficacy was evaluated by using modified Response Evaluation Criteria in Solid Tumors (mRECIST) on cross-sectional images, time to required next treatment, transplant rates, and overall survival. Differences across mRECIST reads were compared by using a Mann-Whitney U test, and the difference in prevalence of tumor response was evaluated by Fisher exact test, whereas differences in time to required next treatment and overall survival curves were compared by using a log-rank (Mantel-Cox) test. Results: Safety results from 28 participants (mean age, 70 years ± 10 [standard deviation]; 17 men) demonstrated no significant changes in temperature (P = .31), heart rate (P = .92), diastolic pressure (P = .31), or systolic pressure (P = .06) before and after US-triggered MB destruction. No changes in liver function tests between treatment arms were observed 1 month after TARE (P \u3e .15). Preliminary efficacy results showed a greater prevalence of tumor response (14 of 15 [93%; 95% CI: 68, 100] vs five of 10 [50%; 95% CI: 19, 81]; P = .02) in participants who underwent both US-triggered MB destruction and TARE (P = .02). Conclusion: The combination of US-triggered microbubble destruction and transarterial radioembolization is feasible with an excellent safety profile in this patient population and appears to result in improved hepatocellular carcinoma treatment response

Regulated expression of matrix metalloproteinases, inflammatory mediators, and endometrial matrix remodeling by 17beta-estradiol in the immature rat uterus

<p>Abstract</p> <p>Background</p> <p>Administration of a single physiological dose of 17beta-estradiol (E2:40 microg/kg) to the ovariectomized immature rat rapidly induces uterine growth and remodeling. The response is characterized by changes in endometrial stromal architecture during an inflammatory-like response that likely involves activated matrix-metalloproteinases (MMPs). While estrogen is known as an inducer of endometrial growth, its role in specific expression of MMP family members in vivo is poorly characterized. E2-induced changes in MMP-2, -3, -7, and -9 mRNA and protein expression were analyzed to survey regulation along an extended time course 0-72 hours post-treatment. Because E2 effects inflammatory-like changes that may alter MMP expression, we assessed changes in tissue levels of TNF-alpha and MCP-1, and we utilized dexamethasone (600 microg/kg) to better understand the role of inflammation on matrix remodeling.</p> <p>Methods</p> <p>Ovariectomized 21 day-old female Sprague-Dawley rats were administered E2 and uterine tissues were extracted and prepared for transmission electron microscopy (TEM), mRNA extraction and real-time RT-PCR, protein extraction and Western blot, or gelatin zymography. In inhibitor studies, pretreatment compounds were administered prior to E2 and tissues were harvested at 4 hours post-hormone challenge.</p> <p>Results</p> <p>Using a novel TEM method to quantitatively assess changes in stromal collagen density, we show that E2-induced matrix remodeling is rapid in onset (< 1 hour) and leads to a 70% reduction in collagen density by 4 hours. Matrix remodeling is MMP-dependent, as pretreatment with batimastat ablates the hormone effect. MMP-3, -7, and -9 and inflammatory markers (TNF-alpha and MCP-1) are transiently upregulated with peak expression at 4 hours post-E2 treatment. MMP-2 expression is increased by E2 but highest expression and activity occur later in the response (48 hours). Dexamethasone inhibits E2-modulated changes in collagen density and expression of MMPs although these effects are variable. Dexamethasone upregulates MMP-3 mRNA but not protein levels, inhibiting E2-induced upregulation of MMP-7, and -9, and MCP-1 mRNA and protein but not inhibiting the hormone-induced increase in TNF-alpha mRNA.</p> <p>Conclusion</p> <p>The data demonstrate that E2-regulated endometrial remodeling is rapid in onset (<1 hour) and peak expression of MMPs and inflammatory mediators correlates temporally with the period of lowest stromal collagen density during uterine tissue hypertrophy.</p

The roles of calpain and protein kinase C in type 1 diabetic vascular dysfunction

Endothelial dysfunction is an early change associated with cardiovascular disease in diabetes. The calcium-dependent protease calpain is activated in the endothelium by acute hyperglycemia and type 2 diabetes. The endothelial dysfunction associated with diabetic calpain activity is astonishingly similar to that caused by diabetic PKC activity. Biochemical studies indicate bidirectional crosstalk between calpain and PKC in vitro. Therefore, we hypothesized that type 1 diabetes activates vascular calpain in the signaling cascade of vascular PKC to induce endothelial dysfunction in type 1 diabetes. Measurements of the proteolysis of a fluorogenic calpain substrate indicated increased calpain activity in the mesenteric microvasculature of type 1 diabetic rats. Using intravital microscopy, the calpain signal was localized to the endothelium of mesenteric post-capillary venules in vivo. In vitro studies demonstrated that endothelial calpain is activated acutely by hyperglycemia, which is the hallmark of type 1 diabetes. Radioactive measurements indicated that PKC is activated independently of calpain in the type 1 diabetic vasculature. Conversely, type 1 diabetes activates endothelial calpain downstream of PKC, as demonstrated by intravital microscopy of mesenteric post-capillary venules. Local hyperglycemia of the mesenteric microvasculature also increases endothelial calpain in a PKC-dependent manner, thus identifying hyperglycemia as a key activator of PKC-calpain signaling in type 1 diabetes. In vitro experiments implicated the PKC β isoform in the activation of endothelial calpain, and western blot analysis revealed that type 1 diabetes preferentially activates the vascular ì-calpain isoform