Diagnostic performance of adrenal CT in the differentiation of adenoma and pheochromocytoma.

BACKGROUND: Differentiation of adenoma and pheochromocytoma on computed tomography (CT) may be problematic. PURPOSE: To investigate if adenoma and pheochromocytoma can be differentiated with adrenal CT. MATERIAL AND METHODS: A total of 147 pathologically proven adrenal masses (119 adenomas, 28 pheochromocytomas) that had undergone adrenal CT were retrospectively evaluated. Lesion attenuation on unenhanced phase (UEP), portal phase (PP), 15-min delayed phase (DP), absolute/relative percentage enhancement wash-out (APEW/RPEW), and qualitative features were recorded. Student's t-test for parametric data, Mann-Whitney U test for non-parametric data, and Fisher's exact test for categorical data were used. Diagnostic performance of CT attenuation was assessed by area under the curve (AUC) of the receiver operating characteristics. RESULTS: APEW of adenomas was not significantly different from pheochromocytomas; 68.4% and 59% (P = 0.284). Adenomas had significantly higher RPEW; 57.3% vs. 37.4% (P = 0.004). Of pheochromocytomas, 50% met APEW >60% or RPEW >40% criteria, and therefore were misclassified as adenoma on wash-out CT. Of those, 80% (4/5) were < 3 cm. UEP, PP, and DP attenuations of pheochromocytomas were significantly higher than adenomas; however, they were overlapping. AUC for UEP, PP, and DP was 0.906, 0.784, and 0.926, respectively. Larger pheochromocytomas were more likely to contain necrosis compared to smaller pheochromocytomas and adenomas; 41.6% vs. 12.5% vs. 3%. Homogeneous enhancement was seen in 25% of pheochromocytomas and 49% of adenomas (P = 0.018). No significant difference was found in terms of lesion borders and presence of fat/calcification (P > 0.05). CONCLUSIONS: A considerable percentage of pheochromocytomas, especially smaller ones, demonstrate adenoma-like wash-out on CT. Heterogeneous enhancement, higher attenuation, and necrosis are more suggestive of pheochromocytoma.

Conditional survival of patients with small renal masses undergoing active surveillance.

OBJECTIVES: To determine conditional survival for patients with small renal masses (SRMs) undergoing active surveillance (AS). MATERIALS AND METHODS: Patients were enrolled in a prospective AS protocol at our institution between May 2005 and January 2016. Patients with SRMs ≤4 cm with serial cross-sectional imaging available in-house for review were included. Overall survival (OS) was estimated using the Kaplan-Meier method and modelled via Cox proportional hazards models. The primary endpoints analysed were the conditional probability of survival and tumour growth over time. Landmark analysis was used to evaluate survival outcomes beyond the 2-year mark after the initial scan. The relative conditional survival of patients on AS was compared to those undergoing partial nephrectomy (PN) using inverse probability of treatment weighting. RESULTS: A total of 272 patients were included in this analysis. The mean initial SRM size was 1.74 ± 0.77 cm, and the mean mass size closest to the 2-year mark was 1.97 ± 0.83 cm. The likelihood of continued survival to 5 years improved after the 2-year landmark. Patients with masses <3 cm who survived the first 2 years on AS had a 0.84-0.85 chance of surviving to 5 years, and if they survived 3 years, the probability of surviving to 5 years improved to 0.91. A slow tumour growth (ß: 0.12; P < 0.001) with parallel growth rates was found for tumours <3 cm. Patients on AS and those who underwent PN had similar OS for ~7 years, beyond which PN demonstrated a trend of lower risk of death compared with AS (hazard ratio 0.57; P = 0.07). CONCLUSIONS: The conditional survival probability of patients with SRMs <3 cm on AS increased after 2 years. This information may prove useful to urologists and patients who are considering continuing AS vs intervention after the first 2 years on AS.

Comparison of enhancement quantification from virtual unenhanced images to true unenhanced images in multiphase renal Dual-Energy computed tomography: A phantom study.

Multiphase computed tomography (CT) exams are a commonly used imaging technique for the diagnosis of renal lesions and involve the acquisition of a true unenhanced (TUE) series followed by one or more postcontrast series. The difference in CT number of the mass in pre- and postcontrast images is used to quantify enhancement, which is an important criterion used for diagnosis. This study sought to assess the feasibility of replacing TUE images with virtual unenhanced (VUE) images derived from Dual-Energy CT datasets in renal CT exams. Eliminating TUE image acquisition could reduce patient dose and improve clinical efficiency. A rapid kVp-switching CT scanner was used to assess enhancement accuracy when using VUE compared to TUE images as the baseline for enhancement calculations across a wide range of clinical scenarios simulated in a phantom study. Three phantoms were constructed to simulate small, medium, and large patients, each with varying lesion size and location. Nonenhancing cystic lesions were simulated using distilled water. Intermediate (10-20 HU [Hounsfield units]) and positively enhancing masses (≥20 HU) were simulated by filling the spherical inserts in each phantom with varied levels of iodinated contrast mixed with a blood surrogate. The results were analyzed using Bayesian hierarchical models. Posterior probabilities were used to classify enhancement measured using VUE compared to TUE images as significantly less, not significantly different, or significantly higher. Enhancement measured using TUE images was considered the ground truth in this study. For simulation of nonenhancing renal lesions, enhancement values were not significantly different when using VUE versus TUE images, with posterior probabilities ranging from 0.23-0.56 across all phantom sizes and an associated specificity of 100%. However, for simulation of intermediate and positively enhancing lesions significant differences were observed, with posterior probabilities < 0.05, indicating significantly lower measured enhancement when using VUE versus TUE images. Positively enhancing masses were categorized accurately, with a sensitivity of 91.2%, when using VUE images as the baseline. For all scenarios where iodine was present, VUE-based enhancement measurements classified lesions with a sensitivity of 43.2%, a specificity of 100%, and an accuracy of 78.1%. Enhancement calculated using VUE images proved to be feasible for classifying nonenhancing and highly enhancing lesions. However, differences in measured enhancement for simulation of intermediately enhancing lesions demonstrated that replacement of TUE with VUE images may not be advisable for renal CT exams.

Utility of Intermediate-Delay Washout CT Images for Differentiation of Malignant and Benign Adrenal Lesions: A Multivariate Analysis.

OBJECTIVE: The objective of this study was to identify features that impact the diagnostic performance of intermediate-delay washout CT for distinguishing malignant from benign adrenal lesions. MATERIALS AND METHODS: This retrospective study evaluated 127 pathologically proven adrenal lesions (82 malignant, 45 benign) in 126 patients who had undergone portal venous phase and intermediate-delay washout CT (1-3 minutes after portal venous phase) with or without unenhanced images. Unenhanced images were available for 103 lesions. Quantitatively, lesion CT attenuation on unenhanced (UA) and delayed (DL) images, absolute and relative percentage of enhancement washout (APEW and RPEW, respectively), descriptive CT features (lesion size, margin characteristics, heterogeneity or homogeneity, fat, calcification), patient demographics, and medical history were evaluated for association with lesion status using multiple logistic regression with stepwise model selection. Area under the ROC curve (Az) was calculated from both univariate and multivariate analyses. The predictive diagnostic performance of multivariate evaluations was ascertained through cross-validation. RESULTS: Az for DL, APEW, RPEW, and UA was 0.751, 0.795, 0.829, and 0.839, respectively. Multivariate analyses yielded the following significant CT quantitative features and associated Az when combined: RPEW and DL (Az = 0.861) when unenhanced images were not available and APEW and UA (Az = 0.889) when unenhanced images were available. Patient demographics and presence of a prior malignancy were additional significant factors, increasing Az to 0.903 and 0.927, respectively. The combined predictive classifier, without and with UA available, yielded 85.7% and 87.3% accuracies with cross-validation, respectively. CONCLUSION: When appropriately combined with other CT features, washout derived from intermediate-delay CT with or without additional clinical data has potential utility in differentiating malignant from benign adrenal lesions.

Differentiation of Malignant and Benign Adrenal Lesions With Delayed CT: Multivariate Analysis and Predictive Models.

OBJECTIVE: The purpose of this study is to identify imaging and patient parameters that affect the diagnostic performance of delayed contrast-enhanced CT for distinguishing malignant from benign adrenal lesions larger than 1 cm in adult patients and to derive predictive models. MATERIALS AND METHODS: This retrospective study assessed 97 pathologically proven adrenal lesions that had undergone unenhanced, portal venous, and 15-minute delayed CT. Quantitatively, single-parameter evaluations of lesion attenuation (in Hounsfield units) and absolute percentage enhancement washout (APEW) and relative percentage enhancement washout (RPEW) were performed. In addition, descriptive CT features (lesion size, margin definition, heterogeneity vs homogeneity, fat, and calcification) and patients' demographic characteristics and medical history of malignancy were evaluated for association with lesion status using multiple logistic regression with stepwise model selection. Areas under the ROC curve (Az) were determined for univariate and multivariate analyses. Leave-one-lesion-out cross-validation was applied to ascertain the predictive performance of single-parameter and multivariate evaluations. RESULTS: The Az values for unenhanced attenuation, portal venous attenuation, delayed attenuation, APEW, and RPEW were 0.835, 0.534, 0.847, 0.792, and 0.871, respectively. Multivariate analyses revealed that portal venous attenuation, delayed attenuation, and APEW were significant features, with an Az of 0.923 when combined. The addition of the descriptive CT features increased the Az to 0.938; patient age and a history of malignancy were additional significant factors, increasing the Az to 0.956 and 0.972, respectively. The combined predictive classifier yielded 89% accuracy under cross-validation, compared with the best commonly applied single-parameter evaluation (77% for RPEW < 40%). CONCLUSION: Multivariate imaging evaluation applied to delayed contrast-enhanced CT alone, with or without patient characteristics, improves diagnostic performance for characterizing adrenal lesions beyond those of single-parameter evaluations. Predictive formulas assessing the probabilities of lesion benignity or malignancy are provided.

Quantification of the Effect of Shuttling on Computed Tomography Perfusion Parameters by Investigation of Aortic Inputs on Different Table Positions From Shuttle-Mode Scans of Lung and Liver Tumors.

OBJECTIVES: The aim of this study was to quantify the effect of shuttling on computed tomography perfusion (CTp) parameters derived from shuttle-mode body CT images using aortic inputs from different table positions. METHODS: Axial shuttle-mode CT scans were acquired from 6 patients (10 phases, 2 nonoverlapping table positions 1.4 seconds apart) after contrast agent administration. Artifacts resulting from the shuttling motion were corrected with nonrigid registration before computing CTp maps from 4 aortic levels chosen from the most superior and inferior slices of each table position scan. The effect of shuttling on CTp parameters was estimated by mean differences in mappings obtained from aortic inputs in different table positions. Shuttling effect was also quantified using 95% limits of agreement of CTp parameter differences within-table and between-table aortic positions from the interaortic mean CTp values. RESULTS: Blood flow, permeability surface, and hepatic arterial fraction differences were insignificant (P > 0.05) for both within-table and between-table comparisons. The 95% limits of agreement for within-table blood volume (BV) value deviations obtained from lung tumor regions were less than 4.7% (P = 0.18) compared with less than 12.2% (P = 0.003) for between-table BV value deviations. The 95% limits of agreement of within-table deviations for liver tumor regions were less than 1.9% (P = 0.55) for BV and less than 3.2% (P = 0.23) for mean transit time, whereas between-table BV and mean transit time deviations were less than 11.7% (P < 0.01) and less than 14.6% (P < 0.01), respectively. Values for normal liver tissue regions were concordant. CONCLUSIONS: Computed tomography perfusion parameters acquired from aortic levels within-table positions generally yielded higher agreement than mappings obtained from aortic levels between-table positions indicating differences due to shuttling effect.

Correction of Motion Artifacts From Shuttle Mode Computed Tomography Acquisitions for Body Perfusion Imaging Applications.

OBJECTIVE: The aim of this study was to investigate the feasibility of shuttle-mode computed tomography (CT) technology for body perfusion applications by quantitatively assessing and correcting motion artifacts. METHODS: Noncontrast shuttle-mode CT scans (10 phases, 2 nonoverlapping bed locations) were acquired from 4 patients on a GE 750HD CT scanner. Shuttling effects were quantified using Euclidean distances (between-phase and between-bed locations) of corresponding fiducial points on the shuttle and reference phase scans (prior to shuttle mode). Motion correction with nonrigid registration was evaluated using sum-of-squares differences and distances between centers of segmented volumes of interest on shuttle and references images. RESULTS: Fiducial point analysis showed an average shuttling motion of 0.85 ± 1.05 mm (between-bed) and 1.18 ± 1.46 mm (between-phase), respectively. The volume-of-interest analysis of the nonrigid registration results showed improved sum-of-squares differences from 2950 to 597, between-bed distance from 1.64 to 1.20 mm, and between-phase distance from 2.64 to 1.33 mm, respectively, averaged over all cases. CONCLUSIONS: Shuttling effects introduced during shuttle-mode CT acquisitions can be computationally corrected for body perfusion applications.

Pazopanib and depot octreotide in advanced, well-differentiated neuroendocrine tumours: a multicentre, single-group, phase 2 study.

BACKGROUND: Treatment options for advanced, well-differentiated neuroendocrine tumours (NETs) remain scarce. Pazopanib is an orally bioavailable, small molecule, multitargeted kinase inhibitor that inhibits VEGF receptors 1, 2, and 3. We did a study of the efficacy of pazopanib with depot octreotide in patients with advanced NETs. METHODS: We did a parallel cohort study of patients with metastatic or locally advanced grade 1-2 carcinoid tumours or pancreatic NETs, by use of a single-group, two-stage design. Patients received pazopanib 800 mg orally once per day and octreotide at their preprotocol dosage. The primary endpoint was the proportion of patients achieving an objective response, as assessed by investigators, by intention-to-treat analysis. This study is registered with ClinicalTrials.gov, identifier NCT00454363, and was completed in March, 2014. FINDINGS: Between April 12, 2007, and July 2, 2009, we enrolled 52 patients, including 32 individuals with pancreatic NETs and 20 individuals with carcinoid tumours. Seven (21·9%, 95% CI 11·0-38·8) of 32 patients with pancreatic NETs achieved an objective response. We detected no responses in the first stage of the cohort with carcinoid tumours, and we terminated accrual at 20 patients. Toxic effects included one patient with grade 4 hypertriglyceridaemia and one with grade 4 thrombosis, with the most common grade three events being aminotransferase increases and neutropenia, each of which happened in 3 patients. In all 52 patients, the most frequently observed toxic effects were fatigue (39 [75%]), nausea (33 [63%]), diarrhoea (33 [63%]), and hypertension (28 [54%]). INTERPRETATION: Treatment with pazopanib is associated with tumour response for patients with pancreatic NETs, but not for carcinoid tumours; a randomised controlled phase 3 study to assess pazopanib in advanced pancreatic NETs is warranted. FUNDING: US National Cancer Institute of the National Institutes of Health.

Predictive classification of correlated targets with application to detection of metastatic cancer using functional CT imaging.

Perfusion computed tomography (CTp) is an emerging functional imaging modality that uses physiological models to quantify characteristics pertaining to the passage of fluid through blood vessels. Perfusion characteristics provide physiological correlates for neovascularization induced by tumor angiogenesis. Thus CTp offers promise as a non-invasive quantitative functional imaging tool for cancer detection, prognostication, and treatment monitoring. In this article, we develop a Bayesian probabilistic framework for simultaneous supervised classification of multivariate correlated objects using separable covariance. The classification approach is applied to discriminate between regions of liver that contain pathologically verified metastases from normal liver tissue using five perfusion characteristics. The hepatic regions tend to be highly correlated due to common vasculature. We demonstrate that simultaneous Bayesian classification yields dramatic improvements in performance in the presence of strong correlation among intra-subject units, yet remains competitive with classical methods in the presence of weak or no correlation.

Effect on perfusion values of sampling interval of computed tomographic perfusion acquisitions in neuroendocrine liver metastases and normal liver.

OBJECTIVE: This study aimed to assess the effects of sampling interval (SI) of computed tomographic (CT) perfusion acquisitions on CT perfusion values in normal liver and liver metastases from neuroendocrine tumors. METHODS: Computed tomographic perfusion in 16 patients with neuroendocrine liver metastases was analyzed using distributed-parameter modeling to yield tissue blood flow, blood volume, mean transit time, permeability, and hepatic arterial fraction for tumor and normal liver. Computed tomographic perfusion values for the reference SI of 0.5 s (SI0.5) were compared with those of SI data sets of 1 second, 2 seconds, 3 seconds, and 4 seconds using mixed-effects model analyses. RESULTS: Increases in SI beyond 1 second were associated with significant and increasing departures of CT perfusion parameters from the reference values at SI0.5 (P ≤ 0.0009). Computed tomographic perfusion values deviated from the reference with increasing uncertainty with increasing SIs. Findings for normal liver were concordant. CONCLUSIONS: Increasing SIs beyond 1 second yield significantly different CT perfusion parameter values compared with the reference values at SI0.5.

Epidermal growth factor receptor-targeted therapy in locally advanced or metastatic squamous cell carcinoma of the penis.

OBJECTIVE: To evaluate the safety and efficacy of epidermal growth factor receptor (EGFR)-targeted therapy in patients with advanced penile or scrotal cancer. PATIENTS AND METHODS: We retrospectively reviewed the charts of patients with penile or scrotal squamous cell carcinoma who had visited our tertiary cancer centre between 2002 and 2009, including their subsequent treatment and follow-up. We collected details of EGFR-targeted therapy and clinical outcomes. Treatment-associated time-to-disease-progression (TTP), overall survival (OS), responses to therapy and toxicity were evaluated. RESULTS: A total of 24 patients had received EGFR-targeted therapies, including cetuximab, erlotinib and gefitinib. The most common treatment given (to 67% of patients) was cetuximab combined with one or more cytotoxic drugs. The most common adverse effect was skin rash (71%). The median (range) TTP and OS were 11.3 (1-40) and 29.6 (2-205) weeks, respectively. The OS time for patients with visceral or bone metastases was significantly shorter than it was for those without (24.7 vs 49.9 weeks, P = 0.013). Among 17 patients treated with cetuximab alone or in combination with cisplatin, there were four partial responses (23.5%) including two patients with apparently chemotherapy-resistant tumours. CONCLUSIONS: Our results suggest that cetuximab has antitumour activity in metastatic penile cancer, and may enhance the effect of cisplatin-based chemotherapy. Prospective studies of EGFR-targeted therapies in men with these tumours are warranted.

Borderline resectable adrenal cortical carcinoma: a potential role for preoperative chemotherapy.

BACKGROUND: Adrenal cortical carcinoma (ACC) may have tumor or patient characteristics at presentation that argue against immediate surgery because of an unacceptable risk of morbidity/mortality, incomplete resection, or recurrence. This clinical stage can be characterized as borderline resectable ACC (BRACC). At present, systemic therapies in ACC can reduce tumor burden in some patients, creating an opportunity in BRACC for a strategy of preoperative chemotherapy (ctx) followed by surgery. MATERIALS AND METHODS: A single-institution retrospective review was conducted of all patients considered for surgery for primary ACC. Patients with BRACC treated with preoperative ctx were categorized as follows: group A, imaging suggesting a need for multiorgan/vascular resection; group B, imaging suggesting potentially resectable oligometastases; and group C, patients having marginal performance status/comorbidities precluding immediate surgery. Both the disease-free survival (DFS) and the overall survival (OS) were compared in BRACC patients treated with preoperative ctx+surgery and those who had upfront surgery. RESULTS: Fifty-three patients with primary ACC were considered for surgery (median follow-up: 49.9 months). Thirty-eight patients (71.7 %) had initial surgery and 15 of them (28.3 %) were considered BRACC and received preoperative therapy. Of these 15 patients, 12 (80 %) received combination therapy with mitotane and etoposide/cisplatin-based ctx, 2 (13 %) received mitotane alone, and 1 (7 %) received ctx alone. Six patients were defined as group A, 5 as group B, and 4 as group C. Thirteen (87 %) BRACC patients underwent surgical resection. BRACC patients were younger but had more advanced disease than the patients having initial surgery (stage IV in 40 vs 2.6 % [p < 0.01]). By Response Evaluation Criteria In Solid Tumors criteria, 5 patients (38.5 %) had a partial response, 7 (53.8 %) had stable disease, and 1 (7.7 %) had disease that progressed. Postoperative mitotane use was similar between groups (p = .15). Median DFS for resected BRACC patients was 28.0 months [95 % confidence interval (CI), 2.9-not attained] vs 13 months (95 % CI, 5.8-46.9) (p = 0.40) for initial surgery patients. Five-year OS rates were also similar: 65 % for resected BRACC vs 50 % for initial surgery (p = 0.72). CONCLUSIONS: The favorable outcome of patients with BRACC, despite more advanced stage of disease compared to those treated with surgery first, together with uncommon disease progression, suggests a benefit of neoadjuvant treatment sequencing in patients with BRACC.

Effect of pre-enhancement set point on computed tomographic perfusion values in normal liver and metastases to the liver from neuroendocrine tumors.

OBJECTIVE: The objective of this study was to assess the effects of pre-enhancement set point (T1) positioning on computed tomographic perfusion (CTp) parameter values. METHODS: The CTp data from 16 patients with neuroendocrine liver metastases were analyzed with distributed parameter modeling to yield tissue blood flow (BF), blood volume, mean transit time, permeability, and hepatic arterial fraction for tumor and normal liver, with displacements in T1 of ±0.5, ±1.0, ±2.0 seconds, relative to the reference standard. A linear mixed-effects model was used to assess the displacement effects. RESULTS: Effects on the CTp parameter values were variable: BF was not significantly affected, but T1 positions of ≥+1.0 second and -2.0 seconds or longer significantly affected the other CTp parameters (P ≤ 0.004). Mean differences in the CTp parameter values versus the reference standard for BF, blood volume, mean transit time, permeability, and hepatic arterial fraction ranged from -5.0% to 5.2%, -12.7% to 8.9%, -12.5% to 8.1%, -5.3% to 5.7%, and -12.9% to 26.0%, respectively. CONCLUSIONS: CTp parameter values can be significantly affected by T1 positioning.

Beyond the three P's: adrenal involvement in MEN1.

Adrenal lesions (ALs) are often detected in patients with multiple endocrine neoplasia type 1 (MEN1). However, they are not well described in MEN1, making their clinical management unclear. This study examined the prevalence and outcomes of ALs found in MEN1. We performed a retrospective chart review of patients diagnosed with MEN1 from 1990 to 2021. ALs were diagnosed using abdominal or thoracic imaging and classified as being unilateral or bilateral, having single or multiple nodules, and as having diffuse enlargement or not. Measurable nodular lesions were analyzed for their size and growth over time. Patients' clinical and radiographic characteristics were collected. We identified 382 patients with MEN1, 89 (23.3%) of whom had ALs. The mean age at detection was 47 ± 11.9 years. We documented 101 measurable nodular lesions (mean size, 17.5 mm; range, 3-123 mm). Twenty-seven nodules (26.7%) were smaller than 1 cm. Watchful waiting was indicated in 79 (78.2%) patients, of whom 28 (35.4%) had growing lesions. Functional lesions were diagnosed in 6 (15.8%) of 38 that had functional work-up (diagnoses: pheochromocytoma (n = 2), adrenocorticotropic hormone-dependent hypercortisolism (n = 2), hyperandrogenism (n = 1), hyperaldosteronism (n = 1)); surgery was indicated for 5 (83.3%; n = 12 nodules), 2 of whom had bilateral, diffuse adrenal enlargement. Two patients were diagnosed with adrenocortical carcinoma and two with neoplasms of uncertain malignant potential. Radiographic or clinical progression of ALs is uncommon. Malignancy should be suspected on the basis of a lesion's growth rate and size. A baseline hormonal work-up is recommended, and no further biochemical work-up is suggested when the initial assessment shows nonfunctioning lesions.

Metastases to the liver from neuroendocrine tumors: effect of duration of scan acquisition on CT perfusion values.

PURPOSE: To assess the effects of acquisition duration on computed tomographic (CT) perfusion parameter values in neuroendocrine liver metastases and normal liver tissue. MATERIALS AND METHODS: This retrospective study was institutional review board approved, with waiver of informed consent. CT perfusion studies in 16 patients (median age, 57.5 years; range, 42.0-69.7 years), including six men (median, 54.1 years; range, 42.0-69.7), and 10 women (median, 59.3 years; range 43.6-66.3), with neuroendocrine liver metastases were analyzed by means of distributed parametric modeling to determine tissue blood flow, blood volume, mean transit time, permeability, and hepatic arterial fraction for tumors and normal liver tissue. Analyses were undertaken with acquisition time of 12-590 seconds. Nonparameteric regression analyses were used to evaluate the functional relationships between CT perfusion parameters and acquisition duration. Evidence for time invariance was evaluated for each parameter at multiple time points by inferring the fitted derivative to assess its proximity to zero as a function of acquisition time by using equivalence tests with three levels of confidence (20%, 70%, and 90%). RESULTS: CT perfusion parameter values varied, approaching stable values with increasing acquisition duration. Acquisition duration greater than 160 seconds was required to obtain at least low confidence stability in any of the CT perfusion parameters. At 160 seconds of acquisition, all five CT perfusion parameters stabilized with low confidence in tumor and normal tissues, with the exception of hepatic arterial fraction in tumors. After 220 seconds of acquisition, there was stabilization with moderate confidence for blood flow, blood volume, and hepatic arterial fraction in tumors and normal tissue, and for mean transit time in tumors; however, permeability values did not satisfy the moderate stabilization criteria in both tumors and normal tissue until 360 seconds of acquisition. Blood flow, mean transit time, permeability, and hepatic arterial fraction were significantly different between tumor and normal tissue at 360 seconds (P < .001). CONCLUSION: CT perfusion parameter values are affected by acquisition duration and approach progressively stable values with increasing acquisition times. Online supplemental material is available for this article.

Effect of sampling frequency on perfusion values in perfusion CT of lung tumors.

OBJECTIVE: The purpose of this study was to assess as a potential means of limiting radiation exposure the effect on perfusion CT values of increasing sampling intervals in lung perfusion CT acquisition. SUBJECTS AND METHODS: Lung perfusion CT datasets in patients with lung tumors (> 2.5 cm diameter) were analyzed by distributed parameter modeling to yield tumor blood flow, blood volume, mean transit time, and permeability values. Scans were obtained 2-7 days apart with a 16-MDCT scanner without intervening therapy. Linear mixed-model analyses were used to compare perfusion CT values for the reference standard sampling interval of 0.5 second with those of datasets obtained at sampling intervals of 1, 2, and 3 seconds, which included relative shifts to account for uncertainty in preenhancement set points. Scan-rescan reproducibility was assessed by between-visit coefficient of variation. RESULTS: Twenty-four lung perfusion CT datasets in 12 patients were analyzed. With increasing sampling interval, mean and 95% CI blood flow and blood volume values were increasingly overestimated by up to 14% (95% CI, 11-18%) and 8% (95% CI, 5-11%) at the 3-second sampling interval, and mean transit time and permeability values were underestimated by up to 11% (95% CI, 9-13%) and 3% (95% CI, 1-6%) compared with the results in the standard sampling interval of 0.5 second. The differences were significant for blood flow, blood volume, and mean transit time for sampling intervals of 2 and 3 seconds (p ≤ 0.0002) but not for the 1-second sampling interval. The between-visit coefficient of variation increased with subsampling for blood flow (32.9-34.2%), blood volume (27.1-33.5%), and permeability (39.0-42.4%) compared with the values in the 0.5-second sampling interval (21.3%, 23.6%, and 32.2%). CONCLUSION: Increasing sampling intervals beyond 1 second yields significantly different perfusion CT parameter values compared with the reference standard (up to 18% for 3 seconds of sampling). Scan-rescan reproducibility is also adversely affected.

Effect of scan duration on CT perfusion values in metastases from renal cell carcinoma.

Objective: CT perfusion (CTp) values are affected by CT scan acquisition duration (tacq); their reproducibility is adversely affected by uncertainty in their measurement. The objectives were to assess the effects of tacq on CTp parameter values in metastases from renal cell carcinoma (mRCC) in thoracic and abdominal locations. Materials and Methods: 131 CTp evaluations in 53 patients with mRCC were retrospectively analyzed by distributed parameter modeling to yield tissue blood flow (BF), blood volume (BV), mean transit time (MTT), permeability (PS), and also hepatic arterial perfusion (HAP) and hepatic arterial fraction (HAF) for liver metastases and normal liver, with tacq from 25 to 590 s. Penalized piecewise polynomial regression (SPLINE) characterized functional relationships between CTp parameters and acquisition duration, tacq. Evidence for time-invariance was evaluated for each parameter at multiple time points by conducting inference on the fitted derivative to assess its proximity to zero as a function of acquisition time. Equivalence testing was implemented with three levels of confidence (low (20%), moderate (70%), high (95%)). Results: Systematic and non-systematic variability was observed for CTp parameter values with limited tacq. All parameters in all locations approached increasing stability with increasing tacq. PS, HAP and HAF required longer acquisition times than BF, BV and MTT to attain comparable levels of stability. Stabilization tended to require longer acquisition in liver than other tissues. tacq=380 s was required to obtain at least moderate level of confidence for all parameters and organs. Conclusion: Increasing tacq yields increasingly more stable CT perfusion parameters, and thereby better reproducibility.

NRAS mutation status is an independent prognostic factor in metastatic melanoma.

BACKGROUND: There is a need for improved prognostic markers in melanoma. In this study, the authors tested the prognostic significance and clinicopathologic correlations of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) mutations in patients with metastatic melanoma. METHODS: Clinical and pathologic data were collected retrospectively on melanoma patients who were clinically tested for BRAF (exon 15) and NRAS (exons 1 and 2) mutations at The University of Texas M. D. Anderson Cancer Center. Analyses were performed to identify significant associations of mutations with tumor and patient characteristics and with survival from the diagnosis of stage IV disease. RESULTS: The genotypes of the full cohort (n = 677) were 47% BRAF mutation, 20% NRAS mutation, and 32% wild-type for BRAF and NRAS ("WT"). Tumor mutation status was associated (P = .008) with the risk of central nervous system involvement at the diagnosis of stage IV disease, with a higher prevalence observed in BRAF-mutant (24%) and NRAS-mutant (23%) patients than in WT patients (12%). Among patients with nonuveal melanoma who underwent mutation testing within 6 months of stage IV diagnosis (n = 313), patients with NRAS mutations had a median survival of 8.2 months from stage IV diagnosis, which was shorter than the median survival of WT patients (15.1 months; P = .004). Multivariate analysis of this population incorporating age, sex, metastases (M1) category, serum lactate dehydrogenase level, and mutation status confirmed that NRAS mutations are associated independently with decreased overall survival (vs WT; P = .005; hazard ratio, 2.05). CONCLUSIONS: Patients with BRAF or NRAS mutations were more likely than WT patients to have central nervous system involvement at the time they were diagnosed with distant metastatic disease. NRAS mutation status was identified as an independent predictor of shorter survival after a diagnosis of stage IV melanoma.

Perifosine plus docetaxel in patients with platinum and taxane resistant or refractory high-grade epithelial ovarian cancer.

OBJECTIVES: On the basis of reversal of taxane resistance with AKT inhibition, we initiated a phase I trial of the AKT inhibitor perifosine with docetaxel in taxane and platinum-resistant or refractory epithelial ovarian cancer. METHODS: Patients with pathologically confirmed high-grade epithelial ovarian cancer (taxane resistant, n=10; taxane refractory, n=11) were enrolled. Peripheral blood samples and tumor biopsies were obtained and (18)F-FDG-PET and DCE-MRI scans were performed for pharmacodynamic and imaging studies. RESULTS: Patients received a total of 42 treatment cycles. No dose-limiting toxicity was observed. The median progression-free survival and overall survival were 1.9 months and 4.5 months, respectively. One patient with a PTEN mutation achieved a partial remission (PR) for 7.5 months, and another patient with a PIK3CA mutation had stable disease (SD) for 4 months. Two other patients without apparent PI3K pathway aberrations achieved SD. Two patients with KRAS mutations demonstrated rapid progression. Decreased phosphorylated S6 correlated with (18)F-FDG-PET responses. CONCLUSIONS: Patients tolerated perifosine 150 mg PO daily plus docetaxel at 75 mg/m(2) every 4 weeks. Further clinical evaluation of effects of perifosine with docetaxel on biological markers and efficacy in patients with ovarian cancer with defined PI3K pathway mutational status is warranted.

PET/CT in the management of patients with stage IIIC and IV metastatic melanoma considered candidates for surgery: evaluation of the additive value after conventional imaging.

OBJECTIVE: The purpose of this article is to determine how often unexpected (18)F-FDG PET/CT findings result in a change in management for patients with stage IV and clinically evident stage III melanoma with resectable disease according to conventional imaging. SUBJECTS AND METHODS: Thirty-two patients with oligometastatic stage IV and clinically evident stage III melanoma were identified by surgical oncologists according to the results of conventional imaging, which included contrast-enhanced CT of the chest, abdomen, and pelvis and MRI of the brain. The surgical plan included resection of known metastases or isolated limb perfusion with chemotherapy. Thirty-three FDG PET/CT scans were performed within 36 days of their contrast-enhanced CT. The impact of PET/CT was defined as the percentage of cases in which a change in the surgical plan resulted from the unanticipated PET/CT findings. RESULTS: PET/CT revealed unexpected melanoma metastases in 12% of scans (4/33). As a result, the surgery was canceled for two patients, and the planned approach was altered for another two patients to address the unexpected sites. In 6% of scans (2/33), the unexpected metastases were detected in the extremities, which were not included in conventional imaging. Three scans (9%) showed false-positive FDG-avid findings that proved to be benign by subsequent stability or resolution with no therapy. CONCLUSION: In patients with surgically treatable metastatic melanoma, FDG PET/CT can detect unexpected metastases that are missed or not imaged with conventional imaging, and can be considered as part of preoperative workup.