An Electrode Array for Limiting Blood Loss During Liver Resection: Optimization via Mathematical Modeling.

Liver resection is the current standard treatment for patients with both primary and metastatic liver cancer. The principal causes of morbidity and mortality after liver resection are related to blood loss (typically between 0.5 and 1 L), especially in cases where transfusion is required. Blood transfusions have been correlated with decreased long-term survival, increased risk of perioperative mortality and complications. The goal of this study was to evaluate different designs of a radiofrequency (RF) electrode array for use during liver resection. The purpose of this electrode array is to coagulate a slice of tissue including large vessels before resecting along that plane, thereby significantly reducing blood loss. Finite Element Method models were created to evaluate monopolar and bipolar power application, needle and blade shaped electrodes, as well as different electrode distances. Electric current density, temperature distribution, and coagulation zone sizes were measured. The best performance was achieved with a design of blade shaped electrodes (5 x 0.1 mm cross section) spaced 1.5 cm apart. The electrodes have power applied in bipolar mode to two adjacent electrodes, then switched sequentially in short intervals between electrode pairs to rapidly heat the tissue slice. This device produces a ~1.5 cm wide coagulation zone, with temperatures over 97 masculineC throughout the tissue slice within 3 min, and may facilitate coagulation of large vessels.

An electrode array that minimizes blood loss for radiofrequency-assisted hepatic resection.

Hepatic resection is currently the standard treatment for liver cancer. During hepatic resection part of the liver containing the tumor is surgically removed. This type of surgery is accompanied by high blood loss of approximately 0.6-1.35 L. Blood loss is associated with increased complication rates, prolonged hospital stay, and reduced patient survival, especially when transfusion is required. Other researchers have suggested using radiofrequency (rf) or microwave ablation to coagulate a tissue slice before resection to reduce blood loss, but conventional devices typically take several hours. We developed a device consisting of a linear array of blade-shaped, 1 cm wide radiofrequency (rf) electrodes 1.5 cm apart. Bipolar rf power is applied between pairs of adjacent electrodes, leading to high tissue temperatures between the electrodes that promote coagulation of large vessels (>3 mm) in the resection plane. Rapid switching of applied power between pairs of adjacent electrodes allows simultaneous heating and coagulation of the entire resection plane within 3-6 min. In seven in vivo trials in a porcine model, resection along a plane pre-coagulated with the device resulted in little (<20 mL) to no blood loss, while coagulating all vessels (up to 4.5 mm diameter in this study). Average treatment time (from placement of the device to transection) was 6.8+/-0.5 min when four electrodes were used, and 11.3+/-1.2 min when 5-7 electrodes were used. This device may reduce blood loss related morbidity during resection and reduce treatment time by coagulating all vessels in the resection plane.

Frozen section analysis for intraoperative margin assessment during breast-conserving surgery results in low rates of re-excision and local recurrence.

BACKGROUND: Negative surgical margins minimize the risk of local recurrence after breast-conserving surgery. Intraoperative frozen section analysis (FSA) is one method for margin evaluation. We retrospectively analyzed records of patients who received breast-conserving therapy with intraoperative FSA of the lumpectomy cavity to assess re-excision rates and local control. METHODS: Records were retrospectively reviewed for individuals who underwent breast-conserving surgery for ductal carcinoma in situ (DCIS) or invasive carcinoma between 1993 and 2003. Inclusion criteria were a minimum of 2 years follow-up and intact tumor at the time of operation. The major outcome measure was local recurrence. The Kaplan-Meier test was used to evaluate local recurrence rates between groups. RESULTS: 290 subjects with an average age of 57.2 years (range 27-89) underwent 292 lumpectomies with FSA. 11.3% had DCIS, 73.3% had infiltrating ductal, 5.8% had infiltrating lobular, and 9.6% exhibited other forms of invasive carcinoma. 70 subjects underwent additional resection at the time of breast surgery, 16 underwent subsequent re-excision, and 17 underwent subsequent mastectomy. At a median follow-up of 53.4 months (range 5.8-137.8), there were six local recurrences (2.74%) in patients who had breast-conserving procedures and two local recurrences in patients who underwent mastectomy. There were no statistically significant associations among local recurrence rate, tumor size, nodal status, or overall stage. Local recurrences were higher in patients with DCIS compared with invasive carcinoma, and tumors >2cm. CONCLUSIONS: Intraoperative FSA allows resection of suspicious or positive margins at the time of lumpectomy and results in low rates of local recurrence and re-excision. The low local recurrence rate reported here is comparable to those reported with other margin assessment techniques.

Intratumoral injection of IL-12 plasmid DNA--results of a phase I/IB clinical trial.

Effective eradication of established tumor and generation of a lasting systemic immune response are the goals of cancer immunotherapy. The objective of this phase IB study was to assess the safety and toxicity of treatment to metastatic tumor underlying the skin with the DNA encoding interleukin-12 (IL-12). This treatment strategy allowed the patient's own tumor to serve as a source of autologous antigen in the tumor microenvironment. We proposed that IL-12 protein produced by the transfected cells would result in the generation of both a local and systemic antitumor response. The tumor was treated with either three or six intratumoral injections of plasmid containing IL-12 DNA. This treatment strategy resulted in no significant local or systemic toxicity. The treatment did not result in an increase in serum IL-12 protein. The size of the treated lesion decreased significantly (greater than 30%) in five of the 12 patients. However, nontreated subcutaneous lesions or other disease did not decrease in size.

A device for radiofrequency assisted hepatic resection.

Hepatic resection is the current standard treatment for hepatic malignancies. During hepatic resection part of the liver containing the tumor is surgically removed. This type of surgery is associated with high blood loss of approximately 1 L. Blood loss is associated with increased complication rates, prolonged hospital stay and reduced patient survival, especially when transfusion is required. We present a device that allows coagulation of a plane of tissue 1 to 2 cm wide, including coagulation of large vessels. This enables reduction of blood loss to a minimum by performing surgery along the coagulated tissue plane. The device consists of a linear array of radiofrequency (RF) electrodes 1.5 cm apart. By application of RF current in bipolar mode between two adjacent electrodes, temperatures close to 100 degrees C are obtained in-between electrodes enabling coagulation of large vessels. Rapid switching of applied current between all adjacent electrode pairs enables rapid heating of a tissue slice. We present a prototype device including results from ex vivo and in vivo experiments.

Hepatic bipolar radiofrequency ablation creates coagulation zones close to blood vessels: a finite element study.

Radiofrequency (RF) ablation has become an important means of treatment of non-resectable primary and metastatic liver tumours. Recurrence of treated tumours is associated with cancer cell survival next to blood vessels. The paper examines the performance of classical monopolar, and two configurations of bipolar, RF ablation using a LeVeen ten-prong catheter. Finite element method models of monopolar and bipolar configurations were created at 5 mm distance from a vessel of the size of a typical portal vein (10 mm diameter). In one bipolar configuration, the probes were oriented in the same axial direction (asymmetric configuration); in the second bipolar configuration, the two probes were facing each other (symmetric configuration). The distribution of temperature and current density was analysed for three different flow conditions: normal flow, reduced flow due to portal hypertension and high flow. For normal flow, the distance between the formed coagulation zone and the blood vessel was 1.8 mm for monopolar, 1 mm for asymmetric bipolar, and 0.2 mm for symmetric bipolar, configurations. Symmetric bipolar RF ablation creates coagulation zones significantly closer to blood vessels compared with monopolar RF ablation. This may reduce tumour cell survival next to blood vessels and reduce recurrence rates.

In vivo electrical conductivity of hepatic tumours.

Knowledge of electrical tissue conductivity is necessary to determine deposition of electromagnetic energy and can further be used to diagnostically differentiate between normal and neoplastic tissue. We measured 17 rats with a total of 24 tumours of the K12/TRb rat colon cancer cell line. In each animal we measured in vivo hepatic tumour and normal tissue conductivity at seven frequencies from 10 Hz to 1 MHz, at different tumour stages between 6 and 12 weeks after induction. Conductivity of normal liver tissue was 1.26 +/- 0.15 mS cm(-1) at 10 Hz, and 4.61 +/- 0.42 mS cm(-1) at 1 MHz. Conductivity of tumour was 2.69 +/- 0.91 mS cm(-1) at 10 Hz, and 5.23 +/- 0.82 mS cm(-1) at 1 MHz. Conductivity was significantly different between normal and tumour tissue (p < 0.05). We determined the percentage of necrosis and fibrosis at the measurement site. We fitted the conductivity data to the Cole-Cole model. For the tumour data we determined Spearman's correlation coefficients between the Cole-Cole parameters and age, necrosis, fibrosis and tumour volume and found significant correlation between necrosis and the Cole-Cole parameters (p < 0.05). We conclude that necrosis within the tumour and the associated membrane breakdown is likely responsible for the observed change in conductivity.

Immunization by particle-mediated transfer of the granulocyte-macrophage colony-stimulating factor gene into autologous tumor cells in melanoma or sarcoma patients: report of a phase I/IB study.

The primary objective of this phase I study was to determine the safety of an autologous tumor vaccine given by intradermal injection of lethally irradiated granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transfected autologous melanoma and sarcoma cells. Secondary objectives included validation of the gene delivery technology (particle-mediated gene transfer), determining the host immune response to the tumor after vaccination, and monitoring patients for evidence of antitumor response. Sixteen patients were treated with either of two different doses of GM-CSF-treated tumor cells. One patient received treatment with both doses of tumor cells. No treatment-related local or systemic toxicity was noted in any patient. Patients administered 100% treated cells (i.e., with a preparation of tumor cells that had all been exposed to GM-CSF DNA transfection) had a more extensive lymphocytic infiltrate at the vaccine site than did patients given 10% treated cells (a preparation of tumor cells in which 10% had been exposed to GM-CSF transfection) or nontreated tumor. The generation of a systemic immune response to autologous tumor by a delayed-type hypersensitivity response to the intradermal placement of nontransfected tumor cells was noted in one patient. One patient had a transient partial response of metastatic tumor sites. The entire procedure, from tumor removal to vaccine placement, was accomplished in less than 6 hr in all patients. Four of 17 patient tumor preparations produced greater than 3.0 ng of GM-CSF per 10(6) cells per 24 hr in vitro. The one patient with greater than 30 ng of GM-CSF per 10(6) cells per 24 hr in vitro had positive DTH, a significant histologic inflammatory response, and clinically stable disease. This technique of gene transfer was safe and feasible, but resulted in clinically relevant levels of gene expression in only a minority of patients.

Hepatic bipolar radio-frequency ablation between separated multiprong electrodes.

Radio-frequency (RF) ablation has become an important means of treatment of nonresectable primary and metastatic liver tumors. Major limitations are small lesion size, which make multiple applications necessary, and incomplete killing of tumor cells, resulting in high recurrence rates. We examined a new bipolar RF ablation method incorporating two probes with hooked electrodes (RITA model 30). We performed monopolar and bipolar in vivo experiments on three pigs. The electrodes were 2.5 cm apart and rotated 45 degrees relative to each other. We used temperature-controlled mode at 95 degrees C. Lesion volumes were 3.9+/-1.8 cm3 (n=7) for the monopolar case and 12.2 +/- 3 cm3 (n=10) for the bipolar case. We generated finite-element models (FEMs) of monopolar and bipolar configurations. We analyzed the distribution of temperature and electric field of the finite element model. The lesion volumes for the FEM are 7.95 cm3 for the monopolar and 18.79 cm3 for the bipolar case. The new bipolar method creates larger lesions and is less dependent on local inhomogenities in liver tissue-such as blood perfusion-compared with monopolar RF ablation. A limitation of the new method is that the power dissipation of the two probes cannot be controlled independently in response to different conditions in the vicinity of each probe. This may result in nonuniform lesions and decreased lesion size.

Impact of surgery and chemotherapy on the quality of life of younger women with breast carcinoma: a prospective study.

BACKGROUND: Studies that prospectively and simultaneously evaluate, within the first year of diagnosis, the impact of surgery and chemotherapy on quality of life (QOL) of younger women (60 years or younger) with early stage breast carcinoma are limited. METHODS: Quality of life of 103 women who had surgery (lumpectomy, 49; mastectomy, 54) approximately 1 month before the start of the study was evaluated at baseline and again after 5 months. Thirty-two women received chemotherapy during the study. RESULTS: Over time, subjects reported improvement in body image and physical, emotional, and functional well-being (P < 0.001). They were less bothered by swollen/tender arms and worried less about risk of cancer to family members (P < 0.001). However, satisfaction with sex life, social support, and social/family well-being declined (P < 0.001). In the period closer to surgery, women with mastectomy reported poorer body image (P = 0.001) and worse functional (P = 0.08) and physical well-being (P = 0.10). Women with lumpectomy worried more about the effects of stress on their illness (P < 0.01) and had lower emotional well-being (P = 0.06). By 6 months after surgery, the two groups reported similar QOL scores. Chemotherapy had a negative impact on women's sexual functioning (P = 0.01) and their physical well-being (P = 0.09). Women who received chemotherapy also reported more shortness of breath (P = 0.07). Post hoc analysis showed that women with breast reconstruction had higher emotional well-being at baseline than those with lumpectomy (P = 0.001) and mastectomy alone (P < 0.01). CONCLUSIONS: Younger women with breast carcinoma could experience a range of adjustment problems at various points in the treatment cycle. Interventions that would help reduce the negative impact of treatment on QOL need to be designed and integrated into routine clinical practice.

Rationale for the combination of cryoablation with surgical resection of hepatic tumors.

Only 5% to 10% of metastatic and primary liver tumors are amenable to surgical resection. Hepatic cryoablation has increased the number of patients who are suitable for curative treatment. The aim of this study was to evaluate survival and intrahepatic recurrence in patients treated with cryoablation and resection. From June 1994 to July 1999, thirty-eight surgically unresectable patients underwent a total of 42 cryoablative procedures for 65 malignant hepatic lesions. Twenty patients underwent cryoablation alone, and 18 patients were treated with a combination of resection and cryoablation, with a minimum of 18 months' follow-up. The 38 patients had the following malignancies: primary hepatocellular carcinoma (n = 8) and metastases from colorectal cancer (n = 21), neuroendocrine tumors (n = 3), ovarian cancer (n = 3), leiomyosarcoma (n = 1), testicular cancer (n = 1), and endometrial cancer (n = 1). Patients were evaluated preoperatively with spiral CT scans and intraoperatively with ultrasound examinations for lesion location and cryoprobe guidance. Local recurrence was detected by CT. Major complications included bleeding in three patients and acute renal failure, transient liver insufficiency, and postoperative pneumonia in one patient each. Two patients (5%) died during the early postoperative interval; mean hospital stay was 7.1 days. Median follow-up was 28 months (range 18 to 51 months). Overall survival according to Kaplan-Meier analysis was 82%, 65%, and 54% at 12, 24, and 48 months, respectively. Forty-eight-month survival was not significantly different between those patients undergoing cryoablation alone (64%) and those treated with a combination of resection and cryoablation (42%). Disease-free survival at 45 months was 36% for patients undergoing cryoablation plus resection compared to 25% for those undergoing cryoablation alone. Local recurrences were detected at five cryosurgical sites, for a rate of 12% overall (5 of 42), 11% (2 of 18) for patients in the cryoablation plus resection group, and 12% (3 of 24) for those in the cryoablation alone group. For patients with colorectal metastases, survival was 70% at 30 months compared to 33% for hepatocellular cancer and 66% for other types of tumors. Patients with tumors larger than 5 cm or numbering more than three did not have significantly decreased survival. Cryoablation of hepatic tumors is a safe and effective treatment for some patients not amenable to resection. The combination of cryoablation and resection results in survival comparable to that achieved with cryoablation alone.

Visceral artery aneurysm rupture.

PURPOSE: Aneurysms of the visceral arteries are infrequently encountered. Many are found incidentally and are thought to have a benign outcome. To better characterize these lesions and their clinical course, we reviewed our experience with visceral artery aneurysms (VAAs) at a single institution. METHODS: A retrospective analysis of all VAAs diagnosed at our institution over the past 10 years was performed. The presentation, management, and outcome of therapy was examined for each patient. RESULTS: Thirty-four VAAs in 26 patients were diagnosed over the past 10 years. Four patients had multiple VAAs: splenic (17), hepatic (7), celiac (3), superior mesenteric (2), gastroduodenal (2), pancreaticoduodenal (1), right gastric (1), ileal (1) artery aneurysms. Associated aneurysms were found in 31% of patients and involved the thoracic aorta (3 patients), abdominal aorta (4 patients), renal arteries (2 patients), iliac artery (3 patients), lower extremity (1 patient), and intracranium (1 patient). In 15 patients (58%), VAAs were detected before rupture by chance or because abdominal symptoms resulted in diagnostic evaluation. Eight of these underwent elective surgery, and there were no deaths. Of those 15 patients with known VAAs, one patient died of rupture and hemorrhage from an untreated splenic artery aneurysm. Eleven patients (42%) presented unexpectedly with rupture, and two died despite prompt surgical treatment. The mortality rate in patients who had ruptured VAAs was 25%, including those who presented with ruptured aneurysms and those observed whose aneurysms eventually ruptured. CONCLUSIONS: Aneurysms of the visceral arteries are rare but important vascular lesions. Associated aneurysms are common. Because of the risk of rupture, often with a fatal outcome, an aggressive approach to the treatment of VAA is essential.

B7.1 expression eliminates tumor resistance to IL-12 gene therapy.

IL-12 gene therapy results in tumor regression in some, but not all, murine models. We hypothesized that expression of B7.1 on the tumor cell surface was necessary for IL-12-mediated tumor regression. In addition, we hypothesized that all cells must express B7.1 for this to be effective. To evaluate this hypothesis, tumor nodules were established in mice with either wild-type B16 melanoma or with B16 melanoma modified to express B7.1. IL-12 cDNA was transferred to the tumor by particle-mediated gene transfer. All tumors modified to express B7.1 regressed completely after IL-12 cDNA treatment. When the percent of B7.1-transfected B16 cells was decreased to 50%, no animals survived after treatment. Animals rendered tumor-free were then challenged with wild-type B16. Fifty percent of mice was protected from this tumor challenge. Expression of CD28 (the stimulatory B7.1 ligand) was significantly increased in both CD8(+) T cells and natural killer cell populations of mice rejecting tumor challenge compared to mice with tumor growth. These results suggest that the costimulatory molecule B7.1 is required for initial tumor sensitivity to IL-12 gene therapy and that protection from subsequent challenge with B7.1 (-) tumor is mediated by CD28(+) immune effector cells.

Interleukin 12 gene transfer into skin distant from the tumor site elicits antimetastatic effects equivalent to local gene transfer.

We have reported that particle-mediated interleukin 12 (IL-12) gene transfer into the skin overlying the local tumor inhibits systemic metastases. To further characterize this effect, we compared the antitumor and antimetastatic effects of IL-12 cDNA delivered at the local tumor site versus at a site distant from the primary tumor, in a spontaneous metastasis model of LLC-F5 tumor. Local IL-12 gene delivery into the skin overlying the intradermal tumor (local IL-12 treatment) on days 7, 9, and 11 after tumor implantation resulted in the most suppression of the growth of the primary LLC-F5 tumor, whereas IL-12 gene transfer into the skin distant from the tumor (distant IL-12 treatment) was less effective. In contrast, both local IL-12 and distant IL-12 treatment, followed by tumor excision, inhibited lung metastases to a similar extent, resulting in significantly extended survival of test mice. The results of in vivo studies using depleting anti-asialo GM1 antibody and anti-CD4/anti-CD8 monoclonal antibodies, or neutralizing anti-interferon gamma (IFN-gamma) monoclonal antibody demonstrated that natural killer (NK) cells, CD8(+) T cells, and IFN-gamma contributed to the antimetastatic effects in both treatment groups. Furthermore, the levels of mRNA expression of vascular endothelial growth factor and matrix methalloproteinase 9 at the tumor microenvironment were suppressed after both local and distant IL-12 treatment. These results suggest that the current particle-mediated IL-12 gene delivery in the spontaneous LLC-F5 metastasis model can confer antimetastatic activities, irrespective of the gene transfection site, via a combination of several mechanisms involving CD8(+) T cells, NK cells, IFN-gamma, and antiangiogenesis.

Screening for occult nodal metastasis in squamous cell carcinoma of the vulva.

Metastases to inguinofemoral lymph nodes in patients with carcinoma of the vulva alter the prognosis and treatment of this disease. Our goal was to determine if immunohistochemical staining could reveal occult metastatic nodal disease not detected with routine hematoxylin and eosin staining. We retrospectively examined a total of 110 lymph nodes from 10 patients who had undergone lymph node dissection and found to have all negative nodes. Paraffin embedded lymph nodes were immunostained with a monoclonal antibody directed against multiple low- and high-molecular weight cytokeratins. Micrometastases were not detected in any lymph nodes examined with immunohistochemistry. All positive and negative controls yielded satisfactory results. It is concluded that immunohistochemistry with cytokeratin antibodies does not provide greater sensitivity than routine hematoxylin and eosin staining for the detection of nodal metastases in vulvar carcinoma.

Laparoscopic lumbar spinal fusion: the role of the general surgeon.

The refinement of minimally invasive surgical techniques has impacted all areas of surgical practice. Laparoscopic approaches to lumbar spine fusion via the transperitoneal and retroperitoneal routes have similarly evolved with the development of new techniques and instruments unique to this procedure. The benefits of laparoscopic fusion techniques include shorter hospital stay, improved postoperative relief of pain, and preservation of critical spinal musculature. A general surgical laparoscopist is a critical member of the operative team. Although the technical details of the procedure are becoming standardized, patient selection is critical to maximize benefit and minimize risk.

Synergistic inhibition of tumor growth in a murine mammary adenocarcinoma model by combinational gene therapy using IL-12, pro-IL-18, and IL-1beta converting enzyme cDNA.

We report here that a cancer gene therapy protocol using a combination of IL-12, pro-IL-18, and IL-1beta converting enzyme (ICE) cDNA expression vectors simultaneously delivered via gene gun can significantly augment antitumor effects, evidently by generating increased levels of bioactive IL-18 and consequently IFN-gamma. First, we compared the levels of IFN-gamma secreted by mouse splenocytes stimulated with tumor cells transfected with various test genes, including IL-12 alone; pro-IL-18 alone; pro-IL-18 and ICE; IL-12 and pro-IL-18; and IL-12, pro-IL-18, and ICE. Among these treatments, the combination of IL-12, pro-IL-18, and ICE cDNA resulted in the highest level of IFN-gamma production from splenocytes in vitro, and similar results were obtained when these same treatments were delivered to the skin of a mouse by gene gun and IFN-gamma levels were measured at the skin transfection site in vivo. Furthermore, the triple gene combinatorial gene therapy protocol was the most effective among all tested groups at suppressing the growth of TS/A (murine mammary adenocarcinoma) tumors previously implanted intradermally at the skin site receiving DNA transfer by gene gun on days 6, 8, 10, and 12 after tumor implantation. Fifty percent of mice treated with the combined three-gene protocol underwent complete tumor regression. In vivo depletion experiments showed that this antitumor effect was CD8(+) T cell-mediated and partially IFN-gamma-dependent. These results suggest that a combinatorial gene therapy protocol using a mixture of IL-12, pro-IL-18, and ICE cDNAs can confer potent antitumor activities against established TS/A tumors via cytotoxic CD8(+) T cells and IFN-gamma-dependent pathways.

CT-monitored percutaneous cryoablation in a pig liver model: pilot study.

PURPOSE: To determine the safety and feasibility of percutaneous cryoablation with computed tomographic (CT) guidance in a pig liver model. MATERIALS AND METHODS: Nine angiographic balloons (mean diameter, 9 mm) were placed in the livers of seven domestic pigs (mean weight, 30.0 kg +/- 14.0 [SD]) as tumor-mimicking lesions. By using ultrasonographic and CT guidance, two 2.4- or 3.0-mm cryoprobes were placed flanking the balloon, and a 15-20-minute freezing process was performed. Hemostasis was achieved by placing absorbable cellulose fabric down the probe tract. After 24-96 hours, animals were sacrificed, and their livers were removed and were sectioned axially at 5-mm intervals for comparison with CT images. RESULTS: All animals survived the procedure without complication. No serious hemorrhage was found in any case. Ice balls were readily visualized at CT because they appeared as areas of decreased attenuation (1.0 HU +/- 20.7) when compared with areas of normal liver (48.2 HU +/- 6.3, P < .05). The mean ablative margin was 1.7 cm, and only one of nine cases, the one with probe failure, had a positive margin. Beam-hardening artifact from the metal probes was present but did not interfere with the procedure. Ice-ball size and shape corresponded closely to the area of necrosis determined at histopathologic analysis. CONCLUSION: CT-monitored percutaneous cryoablation is feasible and safe in this pig liver model.