Silvana C. Faria

Correlation of Computed Tomography and Positron Emission Tomography in Patients With Metastatic Gastrointestinal Stromal Tumor Treated at a Single Institution With Imatinib Mesylate: Proposal of New Computed Tomography Response Criteria

PURPOSE Response Evaluation Criteria in Solid Tumors (RECIST) are insensitive in evaluating gastrointestinal stromal tumors (GISTs) treated with imatinib. This study evaluates whether computed tomography (CT) findings of GIST after imatinib treatment correlate with tumor responses by [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) and develops reliable, quantitative, CT response criteria. PATIENTS AND METHODS A total of 172 lesions selected by RECIST were evaluated in 40 patients with metastatic GISTs treated with imatinib. All patients had pretreatment and 2-month follow-up CTs and FDG-PETs. Multivariate analysis was performed using tumor size and density (Hounsfield unit [HU]) on CT and maximum standardized uptake value (SUVmax) on FDG-PET. Patients were observed up to 28 months. RESULTS Mean baseline tumor size and density on CT were 5.3 cm and 72.8 HU, respectively, and mean baseline SUVmax on FDG-PET was 5.8. Thirty-three patients had good response on FDG-PET. A decrease in tumor size of more than 10% or a decrease in tumor density of more than 15% on CT had a sensitivity of 97% and a specificity of 100% in identifying PET responders versus 52% and 100% by RECIST. Good responders on CT at 2 months had significantly longer time to progression than those who did not respond (P = .01). CONCLUSION Small changes in tumor size or density on CT are sensitive and specific methods of assessing the response of GISTs. If the prognostic value of our proposed CT response criteria can be confirmed prospectively, the criteria should be employed in future studies of patients with GIST.

Phase I Study of a Novel Oral Janus Kinase 2 Inhibitor, SB1518, in Patients With Relapsed Lymphoma: Evidence of Clinical and Biologic Activity in Multiple Lymphoma Subtypes

PURPOSE The Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) pathway plays an important role in the pathogenesis of hematologic malignancies. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of SB1518, a potent JAK2 inhibitor, in patients with relapsed lymphoma. PATIENTS AND METHODS Patients with relapsed or refractory Hodgkin or non-Hodgkin lymphoma of any type except Burkitts or CNS lymphoma were enrolled. Patient cohorts received escalating doses of SB1518 orally once daily for 28-day cycles. Response was evaluated after 8 weeks. RESULTS Thirty-four patients received doses of 100 to 600 mg/d. The maximum tolerated dose was not reached. Treatment was well tolerated, with mostly grade 1 and 2 toxicities. Gastrointestinal toxicities were the most common treatment-related events. Cytopenias were infrequent and modest. Pharmacologically active concentrations were achieved at all doses. Dose-related linear increases in area under the concentration-time curve were seen on day 1, with no significant accumulation on day 15. Mean terminal half-life was 1 to 4 days, and mean time to peak concentration ranged from 5 to 9 hours. SB1518 inhibited JAK2 signaling at 4 hours postdose at all levels. Increases in fms-like tyrosine kinase-3 (FLT-3) ligand, reflecting FLT-3 inhibition, were seen in most patients. There were three partial responses (≥300 mg/d) and 15 patients with stable disease (SD), with most responses lasting longer than 2 months. Seven of 13 SDs had tumor reductions of 4% to 46%. CONCLUSION SB1518 has encouraging activity in relapsed lymphoma, providing the first proof-of-principle of the potential therapeutic value of targeting the JAK/STAT pathway in lymphoma in the clinical setting.

A phase I surrogate endpoint study of SU6668 in patients with solid tumors

Purpose. To evaluate the biologic effects of SU6668 in patients with solid tumors using comprehensive measures of pharmacokinetics (PK), functional imaging, and tissue correlative studies. Experimental design. Eligible patients with tumors accessible for core needle biopsy were treated with SU6668 at doses of 200 or 400 mg/m2/day. Functional computed tomography (CT) scan and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed at baseline and repeated 4 weeks and 12 weeks after treatment for analysis of tumor angiogenesis. The PK was analyzed using a high-performance liquid chromatography assay. Tumor specimens obtained via core needle biopsy at baseline and 4 weeks later were analyzed for the biologic effects of SU6668. Results. Six of a total of seven patients received treatment for at least 3 months and underwent comprehensive correlative studies, including PK, imaging, and tissue biopsy. Functional CT showed that five of six patients had decreased blood flow in tumors in response to treatment, and DCE-MRI results indicated significant change of area under the signal intensity vs. time curve (AUC) and/or maximum slope (maximum rate of signal intensity change) in two of four patients evaluated with this technique. PK studies showed that the mean apparent oral clearance (Cloral) measured on day 1 was 6.3 ± 2.7 L/hr/m2, yielding a mean AUC of 16.6 ± 4.3 mg/L·hr. By day 22, the Cloral was 40% more than that observed on day 1. Conclusion. It is feasible to evaluate the biologic effects of antiangiogenic agents using comprehensive surrogate measures.

Phase I Study of Panobinostat plus Everolimus in Patients with Relapsed or Refractory Lymphoma

Purpose: To evaluate the safety and efficacy of panobinostat plus everolimus in patients with relapsed Hodgkin and non-Hodgkin lymphoma. The concept was supported by the single-agent clinical activity of histone deacetylase inhibitors and mTOR inhibitors, and on the in vitro mechanism-based synergistic antiproliferative activity. Experimental Design: This was a phase I study in patients with relapsed or refractory Hodgkin and non-Hodgkin lymphoma using panobinostat orally on Monday/Wednesday/Friday and everolimus orally daily. Toxicity and responses were assessed in dose-escalation cohort followed by expansion cohort at maximum-tolerated dose. Exploratory analysis of serum cytokine levels was performed. Results: Thirty patients were enrolled onto four dose levels. The dose-limiting toxicity was thrombocytopenia. The maximal tolerated dose was panobinostat 20 mg and everolimus 10 mg. Grade 3/4 toxicity included thrombocytopenia (64%), neutropenia (47%), anemia (20%), infection (10%), fatigue (7%), and dyspnea (7%). A total of 10 patients (33%; indolent lymphoma, T-cell lymphoma, mantle cell lymphoma, and Hodgkin lymphoma) achieved objective responses. In patients with Hodgkin lymphoma (n = 14), the overall response rate was 43% with complete response rate of 15%. In patients with Hodgkin lymphoma, multiple serum cytokine levels decreased significantly after treatment with this combination therapy. Of note, clinical responses were associated with a decrease in serum interleukin-5 levels (day 8, P = 0.013, and day 15, P = 0.021). Conclusions: Our data suggest that the combination therapy is active but with significant thrombocytopenia. Future studies should explore alternate scheduling and different compounds that target the same pathways to improve the tolerability of this novel combination. Clin Cancer Res; 19(24); 6882–90. ©2013 AACR.

Staging of pancreatic cancer with multidetector CT in the setting of preoperative chemoradiation therapy

BackgroundPreoperative chemoradiation can potentially improve outcomes in patients with pancreatic cancer. This study addresses its effect on staging pancreatic cancer with multidetector computed tomography (MDCT).MethodsFifty-five patients underwent a dual-phase MDCT pancreas protocol for proved pancreatic cancer. Of these, 16 patients underwent preoperative chemoradiation. Three radiologists independently reviewed images to assess for locally advanced disease, liver and peritoneal metastases on baseline studies of all 55 patients, and on follow-up preoperative studies for the 16 patients receiving preoperative therapy. Overall score for resectability was graded on a scale from 1 to 5 (1, definitely resectable; 5. definitely unresectable). Receiver operating characteristic curves and weighted (κ statistics were determined.ResultsThe areas under the receiver operating characteristic curves for readers 1, 2, and 3 were 0.98, 0.96, and 0.90, respectively. Weighted κ values for reader 1 versus reader 2, reader 1 versus reader 3, and reader 2 versus reader 3 were 0.90, 0.57, and 0.54, respectively. Interpreting scores of 1 to 3 for resectability as resectable disease, the mean values for sensitivity, specificity, negative predictive value, positive predictive value, and accuracy were 0.92, 0.91, 0.74, 0.98, and 0.92 respectively.ConclusionThe negative predictive value for MDCT for identifying unresectable pancreatic cancer in the setting of preoperative therapy is comparable to that reported in the absence of neoadjuvant therapy.

Perfusion CT in Patients With Metastatic Renal Cell Carcinoma Treated With Interferon

OBJECTIVE The objective of our study was to assess the potential value of tumor perfusion parameters measured by perfusion CT as possible biomarkers of prognosis and early indicator of treatment efficacy in patients with metastatic conventional renal cell carcinoma (RCC) treated with interferon. MATERIALS AND METHODS This study comprised 37 patients with metastatic RCC who were enrolled in a larger (n=118) randomized clinical trial of intermediate- versus low-dose interferon. Tumor perfusion parameters-that is, tumor blood flow, blood volume, mean transit time (MTT), and permeability-surface area product-of index metastatic lesions were obtained at baseline and at 8-week follow-up. Baseline perfusion parameters and changes at follow-up were compared, and their associations with patient progression-free survival were estimated. Univariate and multivariate analyses were performed. RESULTS Twenty-eight patients were assessable. Median progression-free survival was 5.3 months (95% CI, 2.4-7.4 months), with one partial response. Tumor blood flow at baseline was inversely associated with patient progression-free survival in both univariate (hazard ratio [HR]=1.006, p=0.025) and multivariate (HR=1.007, p=0.012) analyses. There were significant increases in tumor blood flow and reductions in MTT on follow-up scans compared with baseline scans (both, p=0.04), but no association between changes in perfusion parameters and progression-free survival was detected. CONCLUSION Patients with highly vascularized metastatic RCC as shown by high baseline tumor blood flow appear to have a worse prognosis than those who do not. Tumor perfusion may be a useful biomarker of prognosis and additionally, in the future, may assist in treatment stratification. The potential utility of perfusion CT as an early response indicator was probably inadequately assessed in this study because of the limited antiangiogenic activity of interferon in metastatic RCC.

CT quantification of effects of thalidomide in patients with metastatic renal cell carcinoma

OBJECTIVE Our objective was to use functional CT to evaluate the effects of thalidomide in patients with metastatic renal cell carcinoma. SUBJECTS AND METHODS Patients with proven metastatic renal cell carcinoma were examined prospectively with functional CT. Functional CT studies (cine mode, 4 x 5 mm) were performed through the tumor after i.v. administration of a bolus of contrast material before and every 12 weeks after treatment with thalidomide. Quantitative values for blood flow, blood volume, mean transit time, and permeability-surface area product were calculated with commercial software. The average difference in percentage change in functional CT parameters from pretreatment to 12 and 24 weeks after treatment and the median difference in percentage change in functional CT parameters between response groups were assessed. We also tested whether percentage changes in functional CT parameters 12 weeks after treatment correlated with time to progression of disease and size of the perfused lesion. RESULTS Sixteen patients with a total of 23 tumors underwent at least one follow-up functional CT examination. Blood flow, blood volume, and permeability-surface area product decreased significantly 12 weeks (-18%, p = 0.0039; -15%, p = 0.0350; -24%, p = 0.0010) and 24 weeks (-28%, p = 0.017; -19%, p = 0.0300; -25%, p = 0.0031) after treatment with thalidomide. Time to progression correlated significantly with percentage change in blood flow (r = -0.34; p = 0.040) and permeability-surface area product (r = -0.36, p = 0.023) at 12 weeks. Responders had a significantly larger decrease in blood flow 12 weeks after treatment than did nonresponders (-29% vs -6%; p = 0.032). We also found a significant correlation between decrease in size of the perfused lesion and percentage decrease in blood flow 12 weeks after treatment (r = 0.50; p = 0.019). CONCLUSION Changes in functional CT parameters 12 weeks after treatment may be useful for monitoring the effects of thalidomide and predicting treatment outcome among patients with metastatic renal cell carcinoma. Further study with a larger clinical trial is needed.

Arterial variants in pancreatic adenocarcinoma

Surgery remains the only curative option for the treatment of pancreatic adenocarcinoma. Local tumor resectability depends on a number of factors, but most importantly, the relationship of the tumor to adjacent arterial structures. For example, surgery is rarely performed when the tumor involves the celiac axis or the superior mesenteric artery. Unexpected variant arterial anatomy or tumor involvement of aberrant arteries may complicate pancreatic surgery. The classic visceral arterial anatomy occurs in only 55%–60% of the population, with one or more variant vessels occurring in the remaining population. Knowledge of both variant and normal anatomy is essential for accurate preoperative planning. We describe here the arterial variant anatomy of the pancreas and its identification by multidetector CT imaging, with and without the aid of post-processed volume-rendered images.

Spectrum of Imaging Findings in the Abdomen After Radiotherapy

OBJECTIVE The objective of this article is to describe the imaging appearances of radiation injury to normal tissues in the abdomen that may be seen during imaging surveillance of oncology patients. CONCLUSION Therapeutic radiation is used to treat various malignant conditions in the abdomen. Radiation damages normal surrounding tissues as well as the intended tumor. Radiation changes vary based on the target organ and the time from completion of therapy. Familiarity with the spectrum of changes that may be seen on follow-up imaging studies should help in the differentiation of radiation injury from other causes such as recurrent malignancy.

Imaging in endometrial carcinoma

Endometrial carcinoma (EC) is the most common gynecologic malignancy in the United States. Prognosis depends on patient age, histological grade, depth of myometrial invasion and/or cervical invasion, and the presence of lymph node metastases. Although EC is staged surgically according to the International Federation of Gynecology and Obstetrics (FIGO) system, preoperative imaging can assist in optimal treatment planning. Several imaging techniques such as transvaginal ultrasonography (TVUS), computed tomography (CT), and magnetic resonance imaging (MRI) have been used as diagnostic tools for preoperative staging of EC. Recently, positron emission tomography (PET), PET/CT, and PET/MRI have also been used in staging these patients. In this article, we review the value of imaging in diagnosis, staging, treatment planning, and detection of recurrent disease in patients with EC.