Brandon A. Howard

Stable RNA Interference–Mediated Suppression of Cyclophilin A Diminishes Non–Small-Cell Lung Tumor Growth In vivo

Cyclophilin A (CypA) was recently reported to be overexpressed in non-small-cell lung cancer, and represents a potentially novel therapeutic target. To determine the role of CypA in oncogenesis, stable RNA interference (RNAi)-mediated knockdown of CypA was established in two non-small-cell lung cancer cell lines (ADLC-5M2 and LC-103H), and these cells were grown as xenografts in severe combined immunodeficient mice. Tumor cell proliferation, apoptosis, and angiogenesis were measured by Ki67, terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling, and CD31 immunohistochemistry, respectively. Tumor glucose metabolism was assessed by fluorodeoxyglucose positron emission tomography imaging. Knockdown of CypA correlated in vivo with slower growth, less fluorodeoxyglucose uptake, decreased proliferation, and a greater degree of apoptosis in the tumors. These results establish the relevance of CypA to tumor growth in vivo, specifically to proliferation and apoptosis. Elucidation of the precise role of CypA in these pathways may lead to new targeted therapies for lung cancer.

FDG Uptake on Positron Emission Tomography Correlates with Survival and Time to Recurrence in Patients with Stage I Non–Small-Cell Lung Cancer

Introduction: Patients with stage I non–small-cell lung cancer (NSCLC) have a wide variation in outcomes, most likely because there are undetected metastases at presentation. We retrospectively reviewed patients with early stage lung cancer to determine if FDG uptake of the primary tumor as measured on positron emission tomography (PET) at the time of diagnosis was associated with overall survival (OS) or time to recurrence (TTR). Methods: We reviewed the Tumor Registry at our institution and identified 336 consecutive patients diagnosed with stage I NSCLC over a 5-year period who underwent an FDG-PET/computed tomography within 90 days before surgery. Kaplan–Meier curves were used to describe the survival and TTR experience within subgroups defined by PET maximum standardized uptake value (SUVmax). Cox proportional hazards model was used to assess the impact of PET SUVmax as a continuous variable on OS and TTR. Logistic regression was used to analyze the effect of SUVmax on dichotomized outcomes. Results: Three hundred thirty-six consecutive patients (176 women and 160 men) with stage I NSCLC were retrospectively reviewed. Mean SUVmax was 9.2 ± 6.9 (range 0.6–30.3). The hazard or risk of dying and recurrence increased significantly as SUVmax increased (p = 0.0008 and 0.024, respectively). Conclusions: Preoperative FDG uptake in the primary tumor in patients with stage I disease is associated with OS and TTR. This may be useful in identifying early stage patients who may benefit from more aggressive therapy after surgical resection.

Isolated recto-sigmoid colitis: a new imaging pattern of ipilimumab-associated colitis.

AbstractPurposeThe purpose of this study is to describe typical CT findings and distinct imaging patterns of ipilimumab-associated colitis in immunotherapeutic treatment of melanoma.Materials and methodsThis HIPAA-compliant retrospective study included 86 patients with melanoma imaged with CT or PET/CT of the abdomen and pelvis during or shortly after administration of ipilimumab. Twelve of 86 patients (14%) developed symptoms of colitis and underwent CT imaging of the abdomen and pelvis while symptomatic. Two radiologists reviewed CT images to evaluate for the presence of CT findings of colitis including mesenteric vessel engorgement, pericolonic inflammatory change, hyperenhancement of colonic mucosa, colonic wall thickening, fluid-filled colonic distension, pneumoperitoneum, pneumatosis, and diverticulosis in the inflamed segment of colon. One nuclear medicine radiologist reviewed PET images for abnormally increased FDG uptake in the colon. The diagnosis of ipilimumab-associated colitis was made based on clinical presentation, imaging findings, and laboratory data.ResultsCommon CT findings of ipilimumab-associated colitis included colonic mucosal hyperenhancement (10/12 [83%]), mesenteric vessel engorgement (9/12 [75.0%]), colonic wall thickening (9/12 [75%]), and pericolonic fat stranding (2/12 [16%]). No patient developed pneumatosis or pneumoperitoneum. Diffuse colitis was present in 4/12 (33%) patients. Segmental colitis with associated diverticulosis (was present in 2/12 (17%) patients). A third pattern, isolated recto-sigmoid colitis without diverticulosis, was observed in 6/12 (50%) patients. All patients with colitis demonstrated recto-sigmoid involvement.ConclusionsA third radiologic pattern of ipilimumab-associated colitis was observed in this study: isolated recto-sigmoid colitis without diverticulosis. All patterns of ipilimumab-associated colitis include recto-sigmoid involvement.

Patient and tumor characteristics predictive of an elevated hepatopulmonary shunt fraction before radioembolization of hepatic tumors.

ObjectiveTo determine whether any patient or hepatic tumor characteristics are predictive of hepatopulmonary shunt fraction when performed before radioembolization. Materials and methodsA retrospective review was performed on 190 patients who underwent preradioembolization hepatic arteriography with calculation of hepatopulmonary shunt fraction using technetium-99m-labeled macroaggregated albumin perfusion scintigraphy. Patient and tumor characteristics including imaging features were reviewed for correlation with absolute shunt fraction, shunt fraction greater than 10%, and shunt fraction greater than 20%. ResultsMost tumor types showed some cases of elevated shunt fraction greater than 10%. Six patients had a shunt fraction greater than 20%: four were hepatocellular carcinoma and two were neuroendocrine tumor metastases. Univariate analysis showed that dominant tumor diameter, hepatic tumor burden, vascular invasion, hepatic venous invasion, and hypervascularity on angiography were associated with a shunt fraction greater than 10%. Only dominant tumor diameter and vascular invasion were associated with a shunt fraction greater than 20%. On multivariate analysis, only tumor diameter (odds ratio 1.2) and hepatic venous invasion (odds ratio 23.0) were associated independently with an increased shunt fraction greater than 10%. ConclusionMultiple patient and tumor-related characteristics were significantly correlated with the hepatopulmonary shunt fraction on univariate analysis. However, on multivariate analysis, only the dominant tumor diameter and presence of hepatic venous invasion were associated independently with a greater than 10% shunt fraction.

PET-CT: Current applications and new developments in the thorax

Positron emission tomography computed tomography(PET-CT) imaging has emerged as an essential clinical diagnostic tool in the evaluation of thoracic abnormalities. Currently, its primary role is for tumor imaging; it helps to differentiate benign from malignant nodules, stage tumors, determine response, and follow patients after therapy is complete. It has also been used for nononcologic diseases, but the indications are less well defined. PET is a fundamental component of the molecular imaging initiative, and as new more specific imaging probes and better instrumentation are developed, PET-CT is certain to improve diagnostic accuracy and become even more integrated into the imaging armamentarium.

Predictors of survival in 211 patients with stage IV pulmonary and gastroenteropancreatic mIBG positive neuroendocrine tumors treated with I-131 mIBG

This retrospective analysis identifies predictors of survival in a cohort of patients with meta-iodobenzylguanidine (MIBG)–positive stage IV pulmonary and gastroenteropancreatic neuroendocrine tumor (P/GEP-NET) treated with 131I-MIBG therapy, to inform treatment selection and posttreatment monitoring. Methods: Survival, symptoms, imaging, and biochemical response were extracted via chart review from 211 P/GEP-NET patients treated with 131I-MIBG between 1991 and 2014. For patients with CT follow-up (n = 125), imaging response was assessed by RECIST 1.1 if images were available (n = 76) or by chart review of the radiology report if images could not be reviewed (n = 49). Kaplan–Meier analysis and Cox multivariate regression estimated survival and progression-free survival benefits predicted by initial imaging, biochemical response, and symptomatic response. Results: All patients had stage IV disease at the time of treatment. Median survival was 29 mo from the time of treatment. Symptomatic response was seen in 71% of patients, with the median duration of symptomatic relief being 12 mo. Symptomatic response at the first follow-up predicted a survival benefit of 30 mo (P < 0.001). Biochemical response at the first clinical follow-up was seen in 34% of patients, with stability of laboratory values in 48%; response/stability versus progression extended survival by 40 mo (P < 0.03). Imaging response (20% of patients) or stability (60%) at the initial 3-mo follow-up imaging extended survival by 32 mo (P < 0.001). Additionally, multiple 131I-MIBG treatments were associated with 24 mo of additional survival (P < 0.05). Conclusion: Therapeutic 131I-MIBG for metastatic P/GEP-NETs appears to be an effective means of symptom palliation. Imaging, biochemical, and symptomatic follow-up help prognosticate expected survival after 131I-MIBG therapy. Multiple rounds of 131I-MIBG are associated with prolonged survival.

Utility of Radionuclide Bone Scintigraphy in Complex Regional Pain Syndrome

Purpose of ReviewTo describe the current understanding of the role of three-phase bone scintigraphy (TPBS) in the diagnosis and management of complex regional pain syndrome (CRPS), discuss its advantages and limitations, and present three examples of TPBS patterns typically seen in CRPS patients.Recent FindingsCRPS is a debilitating disorder frequently presenting with pain to ordinarily non-painful stimuli, redness, swelling, following fractures, stroke, myocardial infarction, surgery, or even minor trauma, and its diagnosis, based on clinical criteria and supportive imaging findings, is difficult. Of the available adjunctive diagnostic imaging modalities, radionuclide bone scintigraphy using a TPBS protocol is the most sensitive and specific for detecting abnormalities commonly seen with this condition—classically, increased periarticular uptake on delayed phase of TPBS, with variable increased uptake on perfusion phases, depending on chronicity. Recent studies have (1) demonstrated a more heterogeneous correlation of TPBS findings with CRPS diagnosis using the current Budapest criteria than in studies using older criteria, (2) pointed to the utility of novel quantitative scintigraphic techniques, and (3) highlighted the value of the early perfusion phases of TPBS in predicting treatment response.SummaryTPBS remains a valuable imaging adjunct to clinical diagnosis of CRPS. In combination with a multi-modal analgesic approach, TPBS can be used to follow disease course and potentially treatment response, although prospective trials are needed to further delineate its role.

A practical method of I-131 thyroid cancer therapy dose optimization using estimated effective renal clearance.

In thyroid cancer patients with renal impairment or other complicating factors, it is important to maximize I-131 therapy efficacy while minimizing bone marrow and lung damage. We developed a web-based calculator based on a modified Benua and Leeper method to calculate the maximum I-131 dose to reduce the risk of these toxicities, based on the effective renal clearance of I-123 as measured from two whole-body I-123 scans, performed at 0 and 24 h post-administration.

Difference in appearance between prone and supine myocardial perfusion images obtained on a high-efficiency cadmium zinc telluride SPECT camera.

ObjectiveThe recent introduction of high-efficiency solid-state gamma cameras for myocardial perfusion single photon emission computed tomography has enabled lower patient radiation dose, faster imaging, and improved image quality. However, artifacts still complicate interpretation. Prone imaging is a common maneuver to reduce artifacts and increase accuracy for detection of coronary artery disease, but its effect on imaging relative to supine imaging has not been fully characterized in these new systems. MethodsIn this IRB-approved, HIPAA-compliant retrospective study, 30 patients were reviewed, who underwent prone and supine imaging on the GE 530c multipinhole cadmium zinc telluride camera under both rest and stress conditions. Informed consent was waived. Perfusion was scored visually by two readers on a five-point scale according to the 17-segment model. Differences were assessed for significance using a multivariate linear effects model and restricted maximum likelihood method. ResultsProne positioning resulted in increased activity in the basal inferior (P<0.001), basal inferolateral (P=0.009), basal inferoseptal (P<0.001), and mid-inferior (P<0.001) segments when taking into account factors such as stress versus rest, perfusion scores of other segments, and reader. ConclusionProne imaging on the GE 530c camera increases measured tracer activity in the basal inferior, basal inferolateral, basal inferoseptal, and mid-inferior segments. Caution is advised when diagnosing myocardial ischemia in these territories, particularly if clinical data are unavailable.

Definitive diagnosis of cerebrospinal fluid leak into the pleural space using 111In-DTPA cisternography.

A 58-year-old woman with a calcified disk extrusion causing severe spinal stenosis underwent T8 to T9 diskectomy and spinal fusion. A postoperative pseudomeningocele was treated with lumbar drain and fibrin glue. Performed for persistent right pleural effusion, CT myelogram failed to show communication between the cerebrospinal fluid (CSF) and pleural space--even on 2-hour delayed images. Subsequent 111In-DTPA cisternogram clearly demonstrated CSF leakage into the right pleural space at 2 hours, and surgical repair yielded good results. Radionuclide cisternography is a highly useful method to detect CSF leak, especially when it is occult on CT yet suspected clinically.