Aradhana M. Venkatesan

Clinical Utility of Real-Time Fusion Guidance for Biopsy and Ablation

PURPOSE To show utility, accuracy, and clinical outcomes of electromagnetic tracking and multimodality image fusion for guidance of biopsy and radiofrequency (RF) ablation procedures. MATERIALS AND METHODS A combination of conventional image guidance (ultrasound[US]/computed tomography [CT]) and a research navigation system was used in 40 patients undergoing biopsy or RF ablation to assist in target localization and needle and electrode placement. The navigation system displays electromagnetically tracked needles and US images relative to a preprocedural CT scan. Additional images (prior positron emission tomography [PET] or magnetic resonance [MR] imaging) can be fused with CT as needed. Needle aiming with and without tracking were compared, the utility of navigation for each procedure was assessed, the systems off-target tracking error for two different registration methods was evaluated, and setup time was recorded. RESULTS The tracking error could be evaluated in 35 of 40 patients. A basic tracking error of 3.8 mm ± 2.3 was shown using skin fiducial markers for registration. The error improved to 2.7 mm ± 1.6 when using prior internal needle positions as additional fiducial markers. Real-time fusion of US with CT and registration with prior PET and MR imaging were successful and provided clinically relevant guidance information, enabling 19 of the 40 procedures. CONCLUSIONS The spatial accuracy of the navigation system is sufficient to display clinically relevant image guidance information during biopsy and RF ablation. Breath holding and respiratory gating are effective in minimizing the error associated with tissue motion. In 48% of cases, the navigation system provided information crucial for successful execution of the procedure. Fusion of real-time US with CT or prior diagnostic images may enable procedures that are not feasible with standard, single-modality image guidance.

Multimodality image fusion-guided procedures: technique, accuracy, and applications.

Personalized therapies play an increasingly critical role in cancer care: Image guidance with multimodality image fusion facilitates the targeting of specific tissue for tissue characterization and plays a role in drug discovery and optimization of tailored therapies. Positron-emission tomography (PET), magnetic resonance imaging (MRI), and contrast-enhanced computed tomography (CT) may offer additional information not otherwise available to the operator during minimally invasive image-guided procedures, such as biopsy and ablation. With use of multimodality image fusion for image-guided interventions, navigation with advanced modalities does not require the physical presence of the PET, MRI, or CT imaging system. Several commercially available methods of image-fusion and device navigation are reviewed along with an explanation of common tracking hardware and software. An overview of current clinical applications for multimodality navigation is provided.

Real-time FDG PET Guidance during Biopsies and Radiofrequency Ablation Using Multimodality Fusion with Electromagnetic Navigation

PURPOSE To assess the feasibility of combined electromagnetic device tracking and computed tomography (CT)/ultrasonography (US)/fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) fusion for real-time feedback during percutaneous and intraoperative biopsies and hepatic radiofrequency (RF) ablation. MATERIALS AND METHODS In this HIPAA-compliant, institutional review board-approved prospective study with written informed consent, 25 patients (17 men, eight women) underwent 33 percutaneous and three intraoperative biopsies of 36 FDG-avid targets between November 2007 and August 2010. One patient underwent biopsy and RF ablation of an FDG-avid hepatic focus. Targets demonstrated heterogeneous FDG uptake or were not well seen or were totally inapparent at conventional imaging. Preprocedural FDG PET scans were rigidly registered through a semiautomatic method to intraprocedural CT scans. Coaxial biopsy needle introducer tips and RF ablation electrode guider needle tips containing electromagnetic sensor coils were spatially tracked through an electromagnetic field generator. Real-time US scans were registered through a fiducial-based method, allowing US scans to be fused with intraprocedural CT and preacquired FDG PET scans. A visual display of US/CT image fusion with overlaid coregistered FDG PET targets was used for guidance; navigation software enabled real-time biopsy needle and needle electrode navigation and feedback. RESULTS Successful fusion of real-time US to coregistered CT and FDG PET scans was achieved in all patients. Thirty-one of 36 biopsies were diagnostic (malignancy in 18 cases, benign processes in 13 cases). RF ablation resulted in resolution of targeted FDG avidity, with no local treatment failure during short follow-up (56 days). CONCLUSION Combined electromagnetic device tracking and image fusion with real-time feedback may facilitate biopsies and ablations of focal FDG PET abnormalities that would be challenging with conventional image guidance.

Percutaneous Ablation in the Kidney

Percutaneous ablation in the kidney is now performed as a standard therapeutic nephron-sparing option in patients who are poor candidates for resection. Its increasing use has been largely prompted by the rising incidental detection of renal cell carcinomas with cross-sectional imaging and the need to preserve renal function in patients with comorbid conditions, multiple renal cell carcinomas, and/or heritable renal cancer syndromes. Clinical studies to date indicate that radiofrequency ablation and cryoablation are effective therapies with acceptable short- to intermediate-term outcomes and with a low risk in the appropriate setting, with attention to pre-, peri-, and postprocedural detail. The results following percutaneous radiofrequency ablation and cryoablation in the treatment of renal cell carcinoma are reviewed in this article, including those of several larger scale studies of ablation of T1a tumors. Clinical and technical considerations unique to ablation in the kidney are presented, and potential complications are discussed.

Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma

BACKGROUND & AIMS Tremelimumab is a fully human monoclonal antibody that binds to cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of activated T lymphocytes. Ablative therapies induce a peripheral immune response which may enhance the effect of anti-CTLA4 treatment in patients with advanced hepatocellular carcinoma (HCC). This study aimed to demonstrate whether tremelimumab could be combined safely and feasibly with ablation. METHODS Thirty-two patients with HCC were enrolled: male:female: 28:4; median age: 62 (range 36-76). Patients were given tremelimumab at two dose levels (3.5 and 10mg/kg i.v.) every 4weeks for 6 doses, followed by 3-monthly infusions until off-treatment criteria were met. On day 36, patients underwent subtotal radiofrequency ablation or chemoablation. Staging was performed by contrast-enhanced CT or MRI scan every 8weeks. RESULTS No dose-limiting toxicities were encountered. The most common toxicity was pruritus. Of the 19 evaluable patients, five (26.3%; 95% CI: 9.1-51.2%) achieved a confirmed partial response. Twelve of 14 patients with quantifiable HCV experienced a marked reduction in viral load. Six-week tumor biopsies showed a clear increase in CD8+ T cells in patients showing a clinical benefit only. Six and 12-month probabilities of tumor progression free survival for this refractory HCC population were 57.1% and 33.1% respectively, with median time to tumor progression of 7.4months (95% CI 4.7 to 19.4months). Median overall survival was 12.3months (95% CI 9.3 to 15.4months). CONCLUSIONS Tremelimumab in combination with tumor ablation is a potential new treatment for patients with advanced HCC, and leads to the accumulation of intratumoral CD8+ T cells. Positive clinical activity was seen, with a possible surrogate reduction in HCV viral load. LAY SUMMARY Studies have shown that the killing of tumors by direct methods (known as ablation) can result in the immune system being activated or switched on. The immune system could potentially also recognize and kill the cancer that is left behind. There are new drugs available known as immune checkpoint inhibitors which could enhance this effect. Here, we test one of these drugs (tremelimumab) together with ablation. CLINICAL TRIAL NUMBER ClinicalTrials.gov: NCT01853618.

Navigation Systems for Ablation

Navigation systems, devices, and intraprocedural software are changing the way interventional oncology is practiced. Before the development of precision navigation tools integrated with imaging systems, thermal ablation of hard-to-image lesions was highly dependent on operator experience, spatial skills, and estimation of positron emission tomography-avid or arterial-phase targets. Numerous navigation systems for ablation bring the opportunity for standardization and accuracy that extends the operators ability to use imaging feedback during procedures. In this report, existing systems and techniques are reviewed and specific clinical applications for ablation are discussed to better define how these novel technologies address specific clinical needs and fit into clinical practice.

Use of Patient-specific MRI-based Prostate Mold for Validation of Multiparametric MRI in Localization of Prostate Cancer

OBJECTIVE To demonstrate the use of a patient-specific magnetic resonance imaging (MRI)-based prostate mold to generate histologic sections that directly correlate to axial MRI slices in a patient with anteriorly located prostate cancer. Anteriorly located prostate cancer has traditionally been difficult to detect on digital rectal examination and transrectal ultrasound-guided biopsy. Multiparametric MRI has potential as a valuable tool for the diagnosis and focal treatment of prostate cancer. A significant difficulty to date has been accurate correlation between the magnetic resonance images and histopathologic specimens. METHODS A patient-specific mold from a preoperative T2-weighted MRI scan was created to hold and shape the prostate specimen. Slots for slicing were positioned at 6-mm increments coplanar to the axial MRI slices. After surgical excision, the specimen was inked to maintain the orientation and fixed in formalin. The seminal vesicles were excised, and the prostate was oriented in the mold such that the color-coding matched the anatomic labels on the mold. The specimen was sliced with a single blade and the resultant 6-mm tissue blocks were used for histologic analysis. RESULTS Preoperative multiparametric MRI revealed a lesion in the right anterior transition zone that was positive on T2-weighed MRI, apparent diffusion coefficient maps of diffusion-weighted MRI, magnetic resonance spectroscopy, and dynamic contrast-enhanced MRI. The histologic sections obtained using the mold demonstrated a similar Gleason score 6 (3+3) lesion in the right anterior transition zone, correlating with the MRI findings. CONCLUSION The use of patient-specific prostate molds to register the MRI findings with the histopathologic specimen in prostate cancer could offer several benefits compared with current specimen processing techniques. This technique might further validate MRI as an accurate tool for prostate cancer localization and staging.

Corticosteroid Therapy for Liver Abscess in Chronic Granulomatous Disease

Liver abscesses in chronic granulomatous disease (CGD) are typically difficult to treat and often require surgery. We describe 9 X-linked CGD patients with staphylococcal liver abscesses refractory to conventional therapy successfully treated with corticosteroids and antibiotics. Corticosteroids may have a role in treatment of Staphylococcus aureus liver abscesses in CGD.

The GYMSSA trial: a prospective randomized trial comparing gastrectomy, metastasectomy plus systemic therapy versus systemic therapy alone

BackgroundThe standard of care for metastatic gastric cancer (MGC) is systemic chemotherapy which leads to a median survival of 6-15 months. Survival beyond 3 years is rare. For selected groups of patients with limited MGC, retrospective studies have shown improved overall survival following gastrectomy and metastasectomies including peritoneal stripping with continuous hyperthermic peritoneal perfusion (CHPP), liver resection, and pulmonary resection. Median survival after liver resection for MGC is up to 34 months, with a five year survival rate of 24.5%. Similarly, reported median survival after pulmonary resection of MGC is 21 months with long term survival of greater than 5 years a possibility. Several case reports and small studies have documented evidence of long-term survival in select individuals who undergo CHPP for MGC.DesignThe GYMSSA trial is a prospective randomized trial for patients with MGC. It is designed to compare two therapeutic approaches: gastrectomy with metastasectomy plus systemic chemotherapy (GYMS) versus systemic chemotherapy alone (SA). Systemic therapy will be composed of the FOLFOXIRI regimen. The aim of the study is to evaluate overall survival and potential selection criteria to determine those patients who may benefit from surgery plus systemic therapy. The study will be conducted by the Surgery Branch at the National Cancer Institute (NCI), National Institutes of Health (NIH) in Bethesda, Maryland. Surgeries and followup will be done at the NCI, and chemotherapy will be given by either the local oncologist or the medical oncology branch at NCI.Trial RegistrationClinicalTrials.gov ID. NCT00941655

A Hereditary Form of Small Intestinal Carcinoid Associated With a Germline Mutation in Inositol Polyphosphate Multikinase

BACKGROUND & AIMS Small intestinal carcinoids are rare and difficult to diagnose and patients often present with advanced incurable disease. Although the disease occurs sporadically, there have been reports of family clusters. Hereditary small intestinal carcinoid has not been recognized and genetic factors have not been identified. We performed a genetic analysis of families with small intestinal carcinoids to establish a hereditary basis and find genes that might cause this cancer. METHODS We performed a prospective study of 33 families with at least 2 cases of small intestinal carcinoids. Affected members were characterized clinically and asymptomatic relatives were screened and underwent exploratory laparotomy for suspected tumors. Disease-associated mutations were sought using linkage analysis, whole-exome sequencing, and copy number analyses of germline and tumor DNA collected from members of a single large family. We assessed expression of mutant protein, protein activity, and regulation of apoptosis and senescence in lymphoblasts derived from the cases. RESULTS Familial and sporadic carcinoids are clinically indistinguishable except for the multiple synchronous primary tumors observed in most familial cases. Nearly 34% of asymptomatic relatives older than age 50 were found to have occult tumors; the tumors were cleared surgically from 87% of these individuals (20 of 23). Linkage analysis and whole-exome sequencing identified a germline 4-bp deletion in the gene inositol polyphosphate multikinase (IPMK), which truncates the protein. This mutation was detected in all 11 individuals with small intestinal carcinoids and in 17 of 35 family members whose carcinoid status was unknown. Mutant IPMK had reduced kinase activity and nuclear localization, compared with the full-length protein. This reduced activation of p53 and increased cell survival. CONCLUSIONS We found that small intestinal carcinoids can occur as an inherited autosomal-dominant disease. The familial form is characterized by multiple synchronous primary tumors, which might account for 22%-35% of cases previously considered sporadic. Relatives of patients with familial carcinoids should be screened to detect curable early stage disease. IPMK haploinsufficiency promotes carcinoid tumorigenesis.