Peter R. Mueller

Tissue ablation with radiofrequency: Effect of probe size, gauge, duration, and temperature on lesion volume

RATIONALE AND OBJECTIVES We evaluated the parameters affecting the size and distribution of thermal tissue damage produced by radiofrequency electrodes. METHODS Thermal lesions were produced by electrodes connected to a radiofrequency generator in specimens of liver (n = 143) and muscle (n = 20). Various combinations of probe tip exposure (0.5-8 cm), gauge (12-24 gauge), duration of treatment (0.5-12 min), and temperature (80-90 degrees C) were studied. The resulting volumes of tissue coagulation were measured and compared. RESULTS Lesions equal to or less than 1.6 cm in diameter were symmetrically distributed around the electrode. Lesion diameter (but not length) increased with probe gauge and duration of treatment to a maximum of 6 min. However, lesions with mean diameters larger than 1.6 cm could not be produced using a single probe with any technique. Lesion length correlated with probe tip exposure from 1 to 8 cm (r2 = .996). Over the limited range investigated, increased temperature had minimal effects, except for tip exposures greater than 5 cm, in which larger and more uniform lesions resulted. Lesions varied equal to or less than 3 mm in diameter and equal to or less than 5 mm in length for each combination of variables. CONCLUSION Radiofrequency ablation can accurately and reproducibly cause coagulative tissue necrosis. Necrosed tissue volume increases with length of exposed probe tip, larger probes, and sessions lasting at least 6 min.

Dicer, Drosha, and outcomes in patients with ovarian cancer.

BACKGROUND We studied Dicer and Drosha, components of the RNA-interference machinery, in ovarian cancer. METHODS We measured messenger RNA (mRNA) levels of Dicer and Drosha in specimens of invasive epithelial ovarian cancer from 111 patients, using a quantitative reverse-transcriptase-polymerase-chain-reaction assay, and compared the results with clinical outcomes. Validation was performed with the use of published microarray data from cohorts of patients with ovarian, breast, and lung cancer. Mutational analyses of genomic DNA from the Dicer and Drosha genes were performed in a subgroup of ovarian-cancer specimens. Dicer-dependent functional assays were performed by means of in vitro transfection with small interfering RNA (siRNA) and short hairpin RNA (shRNA). RESULTS Levels of Dicer and Drosha mRNA correlated with the levels of expression of the corresponding protein and were decreased in 60% and 51% of ovarian-cancer specimens, respectively. Low Dicer expression was significantly associated with advanced tumor stage (P=0.007), and low Drosha expression with suboptimal surgical cytoreduction (P=0.02). Cancer specimens with both high Dicer expression and high Drosha expression were associated with increased median survival (>11 years, vs. 2.66 years for other subgroups; P<0.001). We found three independent predictors of reduced disease-specific survival in multivariate analyses: low Dicer expression (hazard ratio, 2.10; P=0.02), high-grade histologic features (hazard ratio, 2.46; P=0.03), and poor response to chemotherapy (hazard ratio, 3.95; P<0.001). Poor clinical outcomes among patients with low Dicer expression were validated in additional cohorts of patients. Rare missense mutations were found in the Dicer and Drosha genes, but their presence or absence did not correlate with the level of expression. Functional assays indicated that gene silencing with shRNA, but not siRNA, may be impaired in cells with low Dicer expression. CONCLUSIONS Our findings indicate that levels of Dicer and Drosha mRNA in ovarian-cancer cells have associations with outcomes in patients with ovarian cancer.

PERCUTANEOUS RADIOFREQUENCY TISSUE ABLATION : DOES PERFUSION-MEDIATED TISSUE COOLING LIMIT COAGULATION NECROSIS ?

PURPOSE To determine, by decreasing hepatic perfusion during radiofrequency (RF) ablation, whether perfusion-mediated tissue cooling can explain the reduced coagulation observed in in vivo studies compared to that seen with RF application in ex vivo tissue. MATERIALS AND METHODS RF was applied in vivo with use of cooled-tip electrodes to normal porcine liver without (n = 8) and with balloon occlusion of the portal vein (n = 8), celiac artery (n = 3), or hepatic artery (n = 2), and to ex vivo calf liver (n = 10). In vivo trials of vasopressin (0.3-0.6 U/min) infusion during RF application with (n = 10) and without (n = 2) arterial balloon occlusion were also performed. Intraoperative RF was subsequently performed in seven patients with hepatic colorectal metastases with and without portal inflow occlusion. Remote thermometry was performed in four patients. RESULTS RF application (12 minutes) during portal venous occlusion produced larger areas of coagulation necrosis than RF with unaltered blood flow (2.9 cm +/- 0.1 vs 2.4 cm +/- 0.2 diameter; P < .01). With celiac and hepatic artery occlusion, coagulation diameter measured 2.7 cm +/- 0.2 and 2.5 cm +/- 0.1, respectively. Infusion of vasopressin without vascular occlusion reduced coagulation diameter to 1.1 cm. However, different methods of hepatic or celiac arterial balloon occlusion with simultaneous vasopressin infusion produced a mean 3.4 cm +/- 0.2 of necrosis. Coagulation in ex vivo liver was 2.9 cm +/- 0.1 in diameter. Clinical studies demonstrated greater coagulation diameter for metastases treated during portal inflow occlusion (4.0 cm +/- 1.3) than for tumors treated with normal blood flow (2.5 cm +/- 0.8; P < .05). Thermometry documented a 10 degrees C increase compared to baseline at 10 mm and 20 mm from the electrode after 5 minutes of portal inflow occlusion during constant RF application. CONCLUSIONS Perfusion-mediated tissue cooling reduces coagulation necrosis achievable with RF ablation. Reduction of blood flow during RF application increases coagulation in both an animal model and human liver metastases.

Cystic Tumors of the Pancreas

Cystic neoplasms of the pancreas are rare but in the last years more frequently detected. Within a 10-year-period we treated 30 patients, including 8 serous cystadenomas, 6 mucinous cystadenomas, 12 mucinous cystadenocarcinomas, 2 cystic neuro-endocrine tumors and 1 papillary cystic tumor respectively acinar cell cyst-adenocarcinoma. 80% of the patients had symptoms, experienced abdominal pain, weight loss, weakness or abdominal mass. In eight patients the tumors had been misdiagnosed as a pancreatic pseudocyst. The correct type of cystic tumor was diagnosed by preoperative investigations only a few cases. All patients with serous or mucinous cystadenomas are well and without evident recurrence after resection of the tumor. However the survival time of malignant cystic tumors varied strongly. The curative resection of these tumors give patients the chance of long-term survival.

Radiofrequency tissue ablation: Increased lesion diameter with a perfusion electrode

RATIONALE AND OBJECTIVES We sought to induce large zones of coagulation necrosis using radiofrequency (RF) with perfusion electrodes and to define optimal parameters for this system. METHODS We developed RF electrodes with internal cannulas to enable tip perfusion. Lesions were created with monopolar RF in ex vivo and in vivo liver and muscle tissue with and without perfusion of the electrode tip using 0 degree C saline. In separate experiments, wattage, current, procedure duration, tip exposure, and perfused tip temperatures were studied. RESULTS In ex vivo liver tissue, a maximum lesion diameter of 3.1 cm without charring occurred with perfusion at 12 min and 50 W. In in vivo liver tissue with perfusion (tip temperature = 25-35 degrees C) and a 3-cm tip exposure, 80 W were deposited in muscle tissue and 65 W in liver tissue for 12 min without inducing charring. Lesion diameters were 4.5 cm and 2.4 cm, respectively. By comparison, without perfusion a maximum of 20 W could be deposited into either tissue type, resulting in 1.8-cm muscle lesions and 1.2-cm liver lesions. Tip temperatures between 45 degrees C and 55 degrees C resulted in charring. Smaller but predictable lesion diameters were created with a lower power, a shorter tip exposure, or both. Of all the parameters, diameter correlated best with the current applied. CONCLUSION Perfusion of RF electrodes with chilled saline allows for increased power deposition without tissue charring, increasing the volume of coagulation necrosis created with a single electrode insertion. Perfusion electrodes therefore might decrease the number of probe insertions required for percutaneous tumor ablation therapy or allow for the treatment of larger lesions.

Radiofrequency tissue ablation: importance of local temperature along the electrode tip exposure in determining lesion shape and size.

RATIONALE AND OBJECTIVES We determined whether heat distribution along a radiofrequency (RF) electrode would be uniform when longer tip exposures are used and whether local temperature effects would influence the shape of induced tissue coagulation. METHODS Thermistors were embedded within 18-gauge RF electrodes at both ends and in the middle of the exposed tip. The length of tip exposure varied from 1 to 7 cm. RF was applied in vitro to pig liver for 6 min using a constant tip temperature, which was varied in 10 degrees C increments from 60 degrees C to 110 degrees C. Experiments were performed in triplicate. The 3- and 5-cm probes were used at a 90 degrees C tip temperature to create lesions in live pig liver and muscle using similar parameters. Temperature was measured throughout the procedure. Observable coagulation necrosis was measured at the end of the treatment. Regression analysis was used to evaluate the local temperature-lesion diameter relationship. RESULTS Temperatures were not uniform along the tip exposure for any given trial. Temperature variation increased with higher tip temperatures and longer tip exposures. The diameter of local coagulation necrosis was a function of the local mean temperature. For in vitro trials, no coagulation was seen when the local temperature was less than 50 degrees C. Temperatures above this threshold resulted in progressively greater lesion diameter, with a minimum of 1 cm of necrosis occurring at 71 degrees C. Additional increases in lesion diameter (1.4-1.6 cm) were observed at approximately 90 degrees C. Mathematical modeling demonstrated a best-fit curve: lesion diameter (in cm) = ¿1.4 + 0.03 (tip exposure)¿ ¿1 - e [-0.067(local temp - 49.5 degrees C)]¿, r2 = .986, SD = 0.14 cm for each curve. In living tissue, less uniformity in the shape of coagulation necrosis was seen around the electrodes. Local temperature-lesion diameter data fit the same logarithmic relation, but the threshold for coagulation necrosis was 8.5 degrees C higher than for in vitro specimens. CONCLUSION Using a single-probe technique for RF-induced tissue necrosis, the diameter of tissue coagulation may be predicted by the local temperature along the exposed electrode. The uniformity of temperature decreases with increased tip exposures. This effect may be partially corrected by creating lesions at higher tip temperatures, where necrosis diameter is increased. Because effects are more pronounced in vivo, uniform volumes of tissue necrosis are limited to tip exposures of 3 cm or less.

Discovery and development of telaprevir: an NS3-4A protease inhibitor for treating genotype 1 chronic hepatitis C virus

Infection with hepatitis C virus (HCV) is a major medical problem with over 170 million people infected worldwide. Substantial morbidity and mortality are associated with hepatic manifestations (cirrhosis and hepatocellular carcinoma), which develop with increasing frequency in people infected with HCV for more than 20 years. Less well known is the burden of HCV disease associated with extrahepatic manifestations (diabetes, B-cell proliferative disorders, depression, cognitive disorders, arthritis and Sjögrens syndrome). For patients infected with genotype 1 HCV, treatment with polyethylene glycol decorated interferon (peginterferon) α and ribavirin (PR) is associated with a low (40–50%) success rate, substantial treatment-limiting side effects and a long (48-week) duration of treatment. In the past 15 years, major scientific advances have enabled the development of new classes of HCV therapy, the direct-acting antiviral agents, also known as specifically targeted antiviral therapy for hepatitis C (STAT-C). In combination with PR, the HCV NS3-4A protease inhibitor telaprevir has recently been approved for treatment of genotype 1 chronic HCV in the United States, Canada, European Union and Japan. Compared with PR, telaprevir combination therapy offers significantly improved viral cure rates and the possibility of shortened treatment duration for diverse patient populations. Developers of innovative drugs have to blaze a new path with few validated sign posts to guide the way. Indeed, telaprevirs development was once put on hold because of its performance in a standard IC50 assay. Data from new hypotheses and novel experiments were required to justify further investment and reduce risk that the drug might fail in the clinic. In addition, the poor drug-like properties of telaprevir were a formidable hurdle, which the manufacturing and formulation teams had to overcome to make the drug. Finally, novel clinical trial designs were developed to improve efficacy and shorten treatment in parallel instead of sequentially. Lessons learned from the development of telaprevir suggest that makers of innovative medicines cannot rely solely on traditional drug discovery metrics, but must develop innovative, scientifically guided pathways for success.

Imaging guided biopsy of renal masses: indications, accuracy and impact on clinical management.

PURPOSE We evaluated the indications, accuracy and impact of image guided biopsy of focal renal masses. MATERIALS AND METHODS We retrospectively reviewed 79 image guided renal biopsies in 73 patients. Indications, imaging, and histological and clinical features were analyzed. We assumed that nephrectomy, partial nephrectomy or surgical biopsy of suspicious masses would be done when no percutaneous biopsy had been performed. A change in management was defined as surgical to nonsurgical. RESULTS Clinical management was altered due to results in 32 of the 79 biopsies (41%) in cases managed nonoperatively, including positive and negative biopsies in those followed clinically and with imaging. Of 79 biopsies 49 (62%) were diagnosed positive for malignancy, including 15 (31%) that were not and 34 (69%) that were renal cell carcinoma. The histological diagnosis was negative on 25 biopsies (32%) and positive or negative on 74 (94%). All 5 of the 79 false-negative biopsies (6%) were due to insufficient tissue and involved highly suspicious imaging findings that required further evaluation, such as repeat biopsy or surgery. Renal cell carcinoma was identified in 4 of the 5 cases. In 12 of the 24 patients (50%) with a pre-biopsy history of nonrenal cancer biopsies were diagnostic of nonrenal cancer. No patient had major complications and in 4 small hematomas were treated with observation only. CONCLUSIONS Image guided renal mass biopsy is safe, reliable and accurate, and it changes clinical management in many cases by avoiding nephrectomy or other surgical options. Radiologists should promote imaging guided biopsy as a potentially useful option for managing suspicious or indeterminate renal masses.

Early surgical débridement of symptomatic pancreatic necrosis is beneficial irrespective of infection

In order to assess the recent trend of nonoperative management of pancreatic necrosis, we reviewed 82 variables in 73 consecutive patients with symptomatic necrotizing pancreatitis. The mortality rate for the series was 25% (18 of 73). The only preintervention variables that correlated with mortality were APACHE II score greater than 15 (p = 0.01), preintervention blood transfusion (p less than 0.001), respiratory failure (p less than 0.001), and shock (p less than 0.01). Patients who developed recurrent sepsis following the initial intervention had a significantly higher mortality rate (17 of 34) than those who did not (1 of 39) (p less than 0.001). The rate of recurrent sepsis varied widely among individual surgeons and correlated with APACHE II score. The presence of infected versus noninfected necrosis did not correlate significantly with outcome. When percutaneous radiologically guided drainage was the initial therapeutic modality (n = 6), recurrent sepsis requiring surgical drainage inevitably occurred. Patients treated with percutaneous drainage (often in combination with surgical drainage) had a longer hospital stay (82 versus 42 days, p less than 0.001), spent more days in the intensive care unit (31 versus 6 days, p less than 0.001), and required more days of total parenteral nutrition (57 versus 27 days, p less than 0.001) than those treated solely by surgical means. We conclude that aggressive initial surgical débridement should be the first step in managing symptomatic pancreatic necrosis and that the presence of infection should not be the sole determinant of intervention.

Long-Term Oncologic Outcomes After Radiofrequency Ablation for T1 Renal Cell Carcinoma

BACKGROUND Radiofrequency ablation (RFA) of renal cell carcinoma (RCC) is used to obtain local control of small renal masses. However, available long-term oncologic outcomes for RFA of RCC are limited by small numbers, short follow-up, and lack of pathologic diagnoses. OBJECTIVE To assess the oncologic effectiveness of RFA for the treatment of biopsy-proven RCC. DESIGN, SETTING, AND PARTICIPANTS Exclusion criteria included prior RCC or metastatic RCC, familial syndromes, or T2 RCC. We retrospectively reviewed long-term oncologic outcomes for 185 patients with sporadic T1 RCC. Median follow-up was 6.43 yr (interquartile range [IQR]: 5.3-7.7). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The chi-square test and Wilcoxon rank-sum tests were used to compare proportions and medians, respectively. Disease-specific survival and overall survival (OS) were calculated using Kaplan-Meier analysis, then stratified by tumor stage, and comparisons were made using log-rank analysis. The 5-yr disease-free survival (DFS) and OS rates are reported. A p value <0.05 was considered statistically significant. RESULTS AND LIMITATIONS Median tumor size was 3 cm (IQR: 2.1-3.9 cm). Tumor stage was T1a: 143 (77.3%) or T1b: 42 (22.7%). Twenty-four patients (13%) were retreated for residual disease. There were 12 local recurrences (6.5%), 6 recurrences in T1a disease (4.2%) and 6 in T1b disease (14.3%) (p=0.0196). Median time to recurrence was 2.5 yr. Local salvage RFA was performed in six patients, of whom five remain disease free at 3.8-yr median follow-up. Tumor stage was the only significant predictor of DFS on multivariate analysis. At last follow-up, 164 patients (88.6%) were disease free (T1a: n=132 [92.3%]; T1b: n=32 [76.2%]; p=0.0038). OS was similar regardless of stage (p=0.06). Five patients developed metachronous renal tumors (2.7%). Four patients developed extrarenal metastases (2.2%), three of whom died of metastatic RCC (1.6%). CONCLUSIONS In poor surgical candidates, RFA results in durable local control and low risk of recurrence in T1a RCC. Higher stage correlates with a decreased disease-free survival. Long-term surveillance is necessary following RFA. Patient selection based on tumor characteristics, comorbid disease, and life expectancy is of paramount importance.