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

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

Contrast enhanced ultrasound in the evaluation and percutaneous treatment of hepatic and renal tumors

none10siImage-guided percutaneous ablation techniques are increasingly being used for the treatment of malignant tumors of the liver and kidney. Contrast enhanced ultrasound (CEUS) is a real-time dynamic imaging technique that plays an important role in the pre-, intra-, and post-procedural management of these patients. This review will focus on the role of CEUS in the evaluation of patients undergoing treatment with percutaneous ablation for hepatic or renal tumors.Meloni, Maria Franca; Smolock, Amanda; Cantisani, Vito; Bezzi, Mario; D'Ambrosio, Ferdinando; Proiti, Maria; Lee, Fred; Aiani, Luca; Calliada, Fabrizio; Ferraioli, GiovannaMeloni, Maria Franca; Smolock, Amanda; Cantisani, Vito; Bezzi, Mario; D'Ambrosio, Ferdinando; Proiti, Maria; Lee, Fred; Aiani, Luca; Calliada, Fabrizio; Ferraioli, Giovann

Clinical translation of abdominal histotripsy: a review of preclinical studies in large animal models

AbstractHistotripsy is an emerging noninvasive, non-thermal, and non-ionizing focused ultrasound (US) therapy that can be used to destroy targeted tissue. Histotripsy has evolved from early laboratory prototypes to clinical systems which have been comprehensively evaluated in the preclinical environment to ensure safe translation to human use. This review summarizes the observations and results from preclinical histotripsy studies in the liver, kidney, and pancreas. Key findings from these studies include the ability to make a clinically relevant treatment zone in each organ with maintained collagenous architecture, potentially allowing treatments in areas not currently amenable to thermal ablation. Treatments across organ capsules have proven safe, including in anticoagulated models which may expand patients eligible for treatment or eliminate the risk associated with taking patients off anti-coagulation. Treatment zones are well-defined with imaging and rapidly resorb, which may allow improved evaluation of treatment zones for residual or recurrent tumor. Understanding the effects of histotripsy in animal models will help inform physicians adopting histotripsy for human clinical use