Sridhar Shankar

Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients

A large number of cancer-associated gene products evoke immune recognition, but host reactions rarely impede disease progression. The weak immunogenicity of nascent tumors contributes to this failure in host defense. Therapeutic vaccines that enhance dendritic cell presentation of cancer antigens increase specific cellular and humoral responses, thereby effectuating tumor destruction in some cases. The attenuation of T cell activation by cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) further limits the potency of tumor immunity. In murine systems, the administration of antibodies that block CTLA-4 function inhibits the growth of moderately immunogenic tumors and, in combination with cancer vaccines, increases the rejection of poorly immunogenic tumors, albeit with a loss of tolerance to normal differentiation antigens. To gain a preliminary assessment of the biologic activity of antagonizing CTLA-4 function in humans, we infused a CTLA-4 blocking antibody (MDX-CTLA4) into nine previously immunized advanced cancer patients. MDX-CTLA4 stimulated extensive tumor necrosis with lymphocyte and granulocyte infiltrates in three of three metastatic melanoma patients and the reduction or stabilization of CA-125 levels in two of two metastatic ovarian carcinoma patients previously vaccinated with irradiated, autologous granulocyte–macrophage colony-stimulating factor-secreting tumor cells. MDX-CTLA4 did not elicit tumor necrosis in four of four metastatic melanoma patients previously immunized with defined melanosomal antigens. No serious toxicities directly attributable to the antibody were observed, although five of seven melanoma patients developed T cell reactivity to normal melanocytes. These findings suggest that CTLA-4 antibody blockade increases tumor immunity in some previously vaccinated cancer patients.

Neoadjuvant Docetaxel before Radical Prostatectomy in Patients with High-Risk Localized Prostate Cancer

Purpose: To determine the clinical, pathologic, and molecular effects of neoadjuvant docetaxel chemotherapy in high-risk localized prostate cancer. Experimental Design: Patients with biopsy Gleason scores of 8 to 10, serum prostate-specific antigen levels >20 ng/mL, and/or clinical stage T3 disease received weekly docetaxel (36 mg/m2) for 6 months, followed by radical prostatectomy, and were monitored with weekly visits, serum prostate-specific antigen measurements, and endorectal magnetic resonance imaging (MRI). Frozen tumor specimens were collected for microarray analysis. Results: The 19 patients enrolled received 82% of the planned chemotherapy. Toxicity was mild to moderate; fatigue and taste disturbance were common. Prostate-specific antigen declines of >50% were seen in 11 of 19 patients (58%; 95% confidence interval, 33-80%) and endorectal MRI showed maximum tumor volume reduction of at least 25% in 13 of 19 patients (68%; 95% confidence interval, 47-85%) and at least 50% in 4 patients (21%; 95% confidence interval, 6-46%). Sixteen patients completed chemotherapy and had radical prostatectomy; none achieved pathologic complete response. Microarray analysis identified coordinate up-regulation of genes involved in androgen metabolism associated with docetaxel therapy. Specifically, RNA expression for genes that decrease cellular levels of bioactive androgens was coordinately increased in response to chemotherapy. Conclusions: Neoadjuvant docetaxel administered for 6 months before radical prostatectomy is feasible, well tolerated, and often results in prostate-specific antigen declines of >50% and decreased tumor volume on endorectal MRI. No pathologic complete responses were observed. Altered androgen metabolism may partially account for the noted declines in prostate-specific antigen and be a mechanism for chemotherapy resistance.

Clonal Evolution of Resistance to Imatinib in Patients with Metastatic Gastrointestinal Stromal Tumors

Purpose: Resistance to imatinib mesylate is emerging as a clinical challenge in patients with metastatic gastrointestinal stromal tumors (GIST). Novel patterns of progression have been noted in a number of these patients. The objective of this study was to correlate molecular and radiologic patterns of imitinib-refractory disease with existing conventional criteria for disease progression. Experimental Design: Patients with metastatic GIST treated with imatinib were followed with serial computed tomography/magnetic resonance imaging and [18F]fluoro-2-deoxy-d-glucose positron emission tomography. Where feasible, biopsies were done to document disease progression. Results: A total of 89 patients were followed for a median of 43 months. Forty-eight patients developed progressive disease. A unique “resistant clonal nodule” pattern (defined as a new enhancing nodular focus enclosed within a preexisting tumor mass) was seen in 23 of 48 patients and was thought to represent emergence of clones resistant to imatinib. Nodules were demonstrable a median of 5 months (range, 0-13 months) before objective progression defined by tumor size criteria and were the first sign of progression in 18 of 23 patients. Median survival among patients whose first progression was nodular was 35.1 months, compared with 44.6 months for patients whose first progression met Southwest Oncology Group criteria (P = 0.31). Comparative tumor biopsies were done in 10 patients at baseline and from progressing nodules. Genotypic analyses of KIT and PDGFRA kinases were done, revealing new activating kinase mutations in 80% (8 of 10) of these patients. Conclusion: The resistant clonal nodule is a unique pattern of disease progression seen in patients with GISTs after an initial response to imatinib and reflects the emergence of imatinib-resistant clones. Conventional tumor measurements (Southwest Oncology Group/Response Evaluation Criteria in Solid Tumors) do not detect this subtle finding. A new enhancing nodule growing within a preexisting tumor mass should be classified as a new lesion and be regarded, at least, as partial progression of GIST.

MRI-guided percutaneous cryotherapy for soft-tissue and bone metastases: initial experience.

OBJECTIVE We sought to determine the safety and feasibility of percutaneous MRI-guided cryotherapy in the care of patients with refractory or painful metastatic lesions of soft tissue and bone adjacent to critical structures. MATERIALS AND METHODS Twenty-seven biopsy-proven metastatic lesions of soft tissue (n = 17) and bone (n = 10) in 22 patients (15 men, seven women; age range, 24-85 years) were managed with MRI-guided percutaneous cryotherapy. The mean lesion diameter was 5.2 cm. Each lesion was adjacent to or encasing one or more critical structures, including bowel, bladder, and major blood vessels. A 0.5-T open interventional MRI system was used for cryoprobe placement and ice-ball monitoring. Complications were assessed for all treatments. CT or MRI was used to determine local control of 21 tumors. Pain palliation was assessed clinically in 19 cases. The mean follow-up period was 19.5 weeks. RESULTS Twenty-two (81%) of 27 tumors were managed without injury to adjacent critical structures. Two patients had transient lower extremity numbness, and two had both urinary retention and transient lower extremity paresthesia. One patient had chronic serous vaginal discharge, and one sustained a femoral neck fracture at the ablation site 6 weeks after treatment. Thirteen (62%) of the 21 tumors for which follow-up information was available either remained the same size as before treatment or regressed. Eight tumors progressed (mean local progression-free interval, 5.6 months; range, 3-18 months). Pain was palliated in 17 of 19 patients; six of the 17 experienced complete relief, and 11 had partial relief. CONCLUSION MRI-guided percutaneous cryotherapy for metastatic lesions of soft tissue and bone adjacent to critical structures is safe and can provide local tumor control and pain relief in most patients.

Small-bowel obstruction after laparoscopic roux-en-Y gastric bypass surgery

Purpose: The purpose of this study was to review the etiology and computed tomography (CT) findings of small-bowel obstruction (SBO) in patients who have undergone bariatric laparoscopic Roux-en-Y gastric bypass (LGBP) surgery. Materials and Methods: Prospectively entered data from a surgical database of 835 consecutive patients who underwent antecolic-antegastric LGBP for morbid obesity from June 1999 to April 2005 in a single institution were retrospectively reviewed. A total of 42 cases of bowel obstruction were observed in 41 patients. Surgical proof was available in 38 cases, and 4 cases had characteristic imaging features and/or clinical follow-up. Seventeen CT scans were reviewed to determine cause and level of obstruction, and this was correlated with surgical findings and clinical follow-up. Results: Internal hernia was the most common (13 cases) and also the most frequently missed etiology of SBO on CT scans, with the diagnosis being made prospectively in only 2 of 6 cases, in which CT was done. Adhesions, ventral hernia, postoperative ileus, and jejunojejunal (JJ) anastomotic strictures, in that order, were the other commonly observed etiologies for SBO, with 11, 7, 5, and 4 cases, respectively. Some causes of SBO post-LGBP (JJ anastomotic stricture and postoperative ileus) developed relatively early, whereas others (internal hernia) tended to develop later or had a bimodal distribution (adhesions and ventral hernia). Fifteen (36%) of 42 cases had SBO at or near the level of jejunojejunostomy site; causes included internal hernia (5 cases), adhesions/kinking of small bowel (5 cases), JJ anastomotic stricture (4 cases), and JJ intussusception (1 case). Conclusion: The time interval between LGBP and development of SBO might provide a useful clinical clue to its etiology. The JJ level is an important location for SBO post-LGBP because of a variety of causes, and special attention must be paid to this site at imaging of post-LGBP patients.

Imaging and Percutaneous Management of Acute Complicated Pancreatitis

Acute pancreatitis varies from a mild, self-limited disease to one with significant morbidity and mortality in its most severe forms. While clinical criteria abound, imaging has become indispensable to diagnose the extent of the disease and its complications, as well as to guide and monitor therapy. Percutaneous interventional techniques offer options that can be life-saving, surgery-sparing or important adjuncts to operation. Close cooperation and communication between the surgeon, gastroenterologist and interventional radiologist enhance the likelihood of successful patient care.

Percutaneous CT–guided Radiofrequency Ablation of Symptomatic Bilateral Adrenal Metastases in a Single Session

Percutaneous computed tomography (CT)-guided radiofrequency (RF) ablation has been used in the palliative treatment of symptomatic bilateral adrenal tumors, often with each tumor addressed separately over the course of multiple treatment sessions. In the present case, a 71-year-old man with a diagnosis of lung cancer and painful bilateral metastases to the adrenal glands underwent percutaneous CT-guided RF thermal ablation of both adrenal masses in a single session (left adrenal mass, 4.7 cm; right adrenal mass, 4.3 cm), without occurrence of blood pressure instability or other acute complications. Measurement of plasma levels of cortisol, adrenocorticotropic hormone (ACTH), and glucose before and after RF ablation revealed transient changes that suggested preservation of endocrine feedback mechanisms. The patient experienced marked relief in pain bilaterally. By 5 days after the procedure, cortisol, ACTH, and glucose levels returned to preprocedural levels. On further follow-up at 6 months, the patient noted a lack of endocrine sequelae and continued pain relief.

Image-guided Percutaneous Splenic Interventions

In the spleen, image-guided interventional procedures such as biopsy and catheter drainage have not been widely performed because of the perceived increased risk of complications. The ability of image-guided biopsy to allow tissue diagnosis of a focal splenic mass without the need for splenectomy is the driving force behind use of this procedure in oncology patients. The literature on image-guided splenic biopsy suggests that the highest biopsy yield is achieved with core biopsy and the lowest complication rate is achieved with fine-needle aspiration. Image-guided catheter drainage is an effective alternative to splenectomy for management of infected splenic collections. In clinical practice, image-guided splenic biopsy, fluid aspiration, and catheter drainage have high success rates. Image-guided alcohol ablation is effective in treatment of splenic cysts. The literature on splenic radiofrequency ablation (RFA) is sparse; therefore, further studies are needed to determine the role of RFA in management of splenic neoplasms and hypersplenism. Image-guided percutaneous thrombin injection can be used to treat splenic artery pseudoaneurysms. Awareness of the correct interventional techniques and their limitations is important for safe performance of image-guided percutaneous splenic interventions.

Focal nodular hyperplasia: Central scar enhancement pattern using gadoxetate disodium

To illustrate the unusual enhancement pattern of the focal nodular hyperplasia central scar using Gadoxetate Disodium.

Imaging of Brown Fat Associated with Adrenal Pheochromocytoma

The association of adrenal pheochromocytoma and brown fat has been described in the pathology literature and scantily in the radiology literature. We present a case of diffuse collection of brown fat in both perinephric spaces associated with left adrenal pheochromocytoma, and describe the computed tomography and magnetic resonance imaging findings.