Irfan Kayani

Functional imaging of neuroendocrine tumors with combined PET/CT using 68Ga-DOTATATE (DOTA-DPhe1,Tyr3-octreotate) and 18F-FDG.

The aim was to assess the relevant distribution of the novel PET tracer 68Ga‐DOTATATE in neuroendocrine tumors (NETs) with combined positron emission tomography / computed tomography (PET/CT) and compare its performance with that of 18F‐FDG PET/CT.

The Role of 68Ga-DOTATATE PET in Patients with Neuroendocrine Tumors and Negative or Equivocal Findings on 111In-DTPA-Octreotide Scintigraphy

111In-diethylenetriaminepentaacetic acid (DTPA)-octreotide scintigraphy is currently the nuclear medicine imaging modality of choice for identifying neuroendocrine tumors. However, there are cohorts of patients in whom scintigraphy findings are negative or equivocal. We evaluated the role of 68Ga-DOTATATE PET in a selected group of patients with negative or weakly positive findings on 111In-DTPA-octreotide scintigraphy to determine whether 68Ga-DOTATATE PET is able to detect additional disease and, if so, whether patient management is altered. Methods: Fifty-one patients with a histologically confirmed diagnosis of neuroendocrine tumors were included. Of the 51 patients, 35 who were negative and 16 equivocal for uptake on 111In-DTPA-octreotide scintigraphy underwent 68Ga-DOTATATE PET. Findings were compared using a region-by-region analysis. All findings were verified with CT or MRI. After 68Ga-DOTATATE PET, all cases were reviewed to determine whether the 68Ga-DOTATATE PET findings resulted in any alteration in management, in terms of suitability for peptide receptor therapy, somatostatin analogs, and surgery. Results: Of the 51 patients, 47 had evidence of disease on cross-sectional imaging or biochemically. 68Ga-DOTATATE PET was positive in 41 of these 47 patients (87.2%). No false-positive lesions were identified. 68Ga-DOTATATE PET detected 168 of the 226 lesions (74.3%) that were identified with cross-sectional imaging. 68Ga-DOTATATE PET identified significantly more lesions than 111In-DTPA-octreotide scintigraphy (P < 0.001). There was no correlation between 68Ga-DOTATATE uptake and histologic grade of neuroendocrine tumors. 68Ga-DOTATATE imaging changed management in 36 patients (70.6%), who were subsequently deemed suitable for peptide receptor–targeted therapy. Conclusion: In patients with negative or equivocal 111In-DTPA-octreotide findings, 68Ga-DOTATATE PET identifies additional lesions and may alter management in most cases.

A Comparison of 68Ga-DOTATATE and 18F-FDG PET/CT in Pulmonary Neuroendocrine Tumors

Our purpose was to compare the performance of 68Ga-1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid-d-Phe1,Tyr3-octreotate (DOTATATE), a novel selective somatostatin receptor 2 PET ligand, and 18F-FDG in the detection of pulmonary neuroendocrine tumors using PET/CT, with correlation of uptake and tumor grade on histology. Methods: The imaging findings of the first 18 consecutive patients (8 men and 10 women) with pulmonary neuroendocrine tumors (11 typical carcinoids, 2 atypical carcinoids, 1 large cell neuroendocrine tumor, 1 small cell neuroendocrine carcinoma, 1 non–small cell lung cancer with neuroendocrine differentiation, and 2 cases of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia) who underwent 68Ga-DOTATATE and 18F-FDG PET/CT were reviewed. In all cases, the diagnosis was established on histology. Results: Of 18 patients, 15 had primary tumors (median size, 2.7 cm; range, 0.5–8 cm) and 3 had recurrent tumors. All typical carcinoids showed high uptake of 68Ga-DOTATATE (maximum standardized uptake value [SUVmax] ≥ 8.2), but 4 of 11 showed negative or minimal 18F-FDG uptake (SUVmax = 1.7–2.9). All tumors of higher grade showed high uptake of 18F-FDG (SUVmax ≥ 11.7), but 3 of 5 showed only minimal accumulation of 68Ga-DOTATATE (SUVmax = 2.2–2.8). Neither case of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia showed uptake of 68Ga-DOTATATE or 18F-FDG. Typical carcinoids showed significantly higher uptake of 68Ga-DOTATATE and significantly less uptake of 18F-FDG than did tumors of higher grade (P = 0.002 and 0.005). There was no instance of false-positive uptake of 68Ga-DOTATATE, but there were 3 sites of 18F-FDG uptake secondary to inflammation. 68Ga-DOTATATE was superior to 18F-FDG in discriminating endobronchial tumor from distal collapsed lung (P = 0.02). Conclusion: Typical bronchial carcinoids showed higher and more selective uptake of 68Ga-DOTATATE than of 18F-FDG. Atypical carcinoids and higher grades had less 68Ga-DOTATATE avidity but were 18F-FDG–avid.

Tumor heterogeneity and permeability as measured on the CT component of PET/CT predict survival in patients with non-small cell lung cancer.

Purpose: We prospectively examined the role of tumor textural heterogeneity on positron emission tomography/computed tomography (PET/CT) in predicting survival compared with other clinical and imaging parameters in patients with non–small cell lung cancer (NSCLC). Experimental Design: The feasibility study consisted of 56 assessed consecutive patients with NSCLC (32 males, 24 females; mean age 67 ± 9.7 years) who underwent combined fluorodeoxyglucose (FDG) PET/CT. The validation study population consisted of 66 prospectively recruited consecutive consenting patients with NSCLC (37 males, 29 females; mean age, 67.5 ± 7.8 years) who successfully underwent combined FDG PET/CT-dynamic contrast-enhanced (DCE) CT. Images were used to derive tumoral PET/CT textural heterogeneity, DCE CT permeability, and FDG uptake (SUVmax). The mean follow-up periods were 22.6 ± 13.3 months and 28.5± 13.2 months for the feasibility and validation studies, respectively. Optimum threshold was determined for clinical stage and each of the above biomarkers (where available) from the feasibility study population. Kaplan–Meier analysis was used to assess the ability of the biomarkers to predict survival in the validation study. Cox regression determined survival factor independence. Results: Univariate analysis revealed that tumor CT-derived heterogeneity (P < 0.001), PET-derived heterogeneity (P = 0.003), CT-derived permeability (P = 0.002), and stage (P < 0·001) were all significant survival predictors. The thresholds used in this study were derived from a previously conducted feasibility study. Tumor SUVmax did not predict survival. Using multivariable analysis, tumor CT textural heterogeneity (P = 0.021), stage (P = 0.001), and permeability (P < 0.001) were independent survival predictors. These predictors were independent of patient treatment. Conclusions: Tumor stage and CT-derived textural heterogeneity were the best predictors of survival in NSCLC. The use of CT-derived textural heterogeneity should assist the management of many patients with NSCLC. Clin Cancer Res; 19(13); 3591–9. ©2013 AACR.

Donor Lymphocyte Infusions Modulate Relapse Risk in Mixed Chimeras and Induce Durable Salvage in Relapsed Patients After T-Cell–Depleted Allogeneic Transplantation for Hodgkin's Lymphoma

PURPOSE Reduced-intensity conditioning has minimized nonrelapse-related mortality rates after allogeneic transplantation in patients with Hodgkins lymphoma, and relapse has now become the major cause for treatment failure. We aimed to assess the impact of donor lymphocyte infusions (DLIs) on relapse incidence when administered for mixed chimerism and their utility as salvage therapy when given for relapse. PATIENTS AND METHODS This study reports the outcomes of 76 consecutive patients with multiply relapsed or refractory Hodgkins lymphoma who underwent allogeneic transplantation that incorporated in vivo T-cell depletion. Forty-two patients had related donors and 34 had unrelated donors. DLIs were administered in a dose-escalating fashion to 22 patients for mixed chimerism (median time of first dose, 9 months post-transplantation) and to 24 patients for relapse. RESULTS Three-year donor lymphocyte-related mortality was 7%, relating mainly to the induction of graft-versus-host disease. Nineteen (86%) of 22 patients receiving donor lymphocytes for mixed chimerism converted to full donor status. Four-year relapse incidence was 5% in these 22 patients compared with 43% in patients who remained relapse free but full donor chimeras at 9 months post-transplantation (P = .0071). Nineteen (79%) of 24 patients receiving donor lymphocytes for relapse responded (14 complete responses, five partial responses). Four-year overall survival from relapse was 59% in recipients of donor lymphocytes, contributing to a 4-year overall survival from transplantation of 64% and a 4-year current progression-free survival of 59% in all 76 patients. CONCLUSION These data demonstrate the potential for allogeneic immunotherapy with donor lymphocytes both to reduce relapse risk and to induce durable antitumor responses in patients with Hodgkins lymphoma after hematopoietic stem-cell transplantation that incorporates in vivo T-cell depletion.

Sequential FDG-PET/CT as a Biomarker of Response to Sunitinib in Metastatic Clear Cell Renal Cancer

Purpose: To test the hypothesis that sequential 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is a correlative marker in metastatic clear cell renal cancer (mRCC), patients were treated with sunitinib. Three sequential scans were conducted to determine whether the timing of the investigation was relevant. Experimental Design: Forty-four untreated mRCC patients were enrolled into this prospective phase II study. 18F-FDG-PET/CT scans were conducted before (n = 44) and after 4 weeks (n = 43) and 16 weeks (n = 40) of sunitinib given at standard doses. The primary endpoint was to correlate FDG-PET/CT response (20% reduction in SUVmax) at 4 and 16 weeks with overall survival (OS). Results: Forty-three (98%) patients had FDG-PET/CT avid lesions at diagnosis (median SUVmax = 6.8, range: <2.5–18.4). In multivariate analysis, a high SUVmax and an increased number of PET-positive lesions correlated with shorter OS [HR: 3.30 (95% CI: 1.36–8.45) and 3.67 (95% CI: 1.43–9.39), respectively]. After 4 weeks of sunitinib, a metabolic response occurred in 24 (57%) patients, but this did not correlate with progression-free survival (HR for responders = 0.87; 95% CI: 0.40–1.99) or OS (HR for responders = 0.80; 95% CI: 0.34–1.85). After 16 weeks of treatment, disease progression on FDG-PET/CT occurred in 28% (n = 12) patients which correlated with a decreased OS and PFS [HR = 5.96 (95% CI: 2.43–19.02) and HR = 12.13 (95% CI: 3.72–46.45), respectively]. Conclusions: Baseline FDG-PET/CT yields prognostic significant data. FDG-PET/CT responses occur in the majority of patients after 4 weeks of therapy; however, it is not until 16 weeks when the results become prognostically significant. Clin Cancer Res; 17(18); 6021–8. ©2011 AACR.

The safety and efficacy of sunitinib before planned nephrectomy in metastatic clear cell renal cancer

Background: The safety and efficacy of upfront sunitinib, before nephrectomy in metastatic clear cell renal cancer (mCRC), has not been prospectively evaluated. Methods: Two prospective single-arm phase II studies investigated either two cycles (study A: n = 19) or three cycles (study B: n = 33) of sunitinib before nephrectomy in mCRC. Results: Overall, 38 of 52 (73%) of patients obtained clinical benefit (by RECIST) before surgery. The partial response rate of the primary tumour was 6% [median reduction in longest diameter of 12% (range 8%−35%)]. No patients became ineligible due to local progression of disease. A nephrectomy was carried out in 37 (71%) of patients. Necrosis (>50%) was a prominent feature at nephrectomy in 49%. Surgical complications (Clavien–Dindo classification) occurred in 10 (27%) patients, including one death (3%). The median blood loss and surgical time were 725 (90–4200) ml and 189 (70–420) min, respectively. The median progression-free survival was 8 months (95% confidence interval 6–15 months). A comparison of two versus three pre-surgery cycles showed no significant difference in terms of surgical complications or efficacy. Conclusions: Nephrectomy after upfront sunitinib can be carried out safely. It obtains control of disease. Randomised studies are required to address if this approach is beneficial.

Idiopathic Pulmonary Fibrosis and Diffuse Parenchymal Lung Disease: Implications from Initial Experience with 18F-FDG PET/CT

The purpose of this study was to evaluate integrated 18F-FDG PET/CT in patients with idiopathic pulmonary fibrosis (IPF) and diffuse parenchymal lung disease (DPLD). Methods: Thirty-six consecutive patients (31 men and 5 women; mean age ± SD, 68.7 ± 9.4 y) with IPF (n = 18) or other forms of DPLD (n = 18) were recruited for PET/CT and high-resolution CT (HRCT), acquired on the same instrument. The maximal pulmonary 18F-FDG metabolism was measured as a standardized uptake value (SUVmax). At this site, the predominant lung parenchyma HRCT pattern was defined for each patient: ground-glass or reticulation/honeycombing. Patients underwent a global health assessment and pulmonary function tests. Results: Raised pulmonary 18F-FDG metabolism in 36 of 36 patients was observed. The parenchymal pattern on HRCT at the site of maximal 18F-FDG metabolism was predominantly ground-glass (7/36), reticulation/honeycombing (26/36), and mixed (3/36). The mean SUVmax in patients with ground-glass and mixed patterns was 2.0 ± 0.4, and in reticulation/honeycombing it was 3.0 ± 1.0 (Mann–Whitney U test, P = 0.007). The mean SUVmax in patients with IPF was 2.9 ± 1.1, and in other DPLD it was 2.7 ± 0.9 (Mann–Whitney U test, P = 0.862). The mean mediastinal lymph node SUVmax (2.7 ± 1.3) correlated with pulmonary SUVmax (r = 0.63, P < 0.001). Pulmonary 18F-FDG uptake correlated with the global health score (r = 0.50, P = 0.004), forced vital capacity (r = 0.41, P = 0.014), and transfer factor (r = 0.37, P = 0.042). Conclusion: Increased pulmonary 18F-FDG metabolism in all patients with IPF and other forms of DPLD was observed. Pulmonary 18F-FDG uptake predicts measurements of health and lung physiology in these patients. 18F-FDG metabolism was higher when the site of maximal uptake corresponded to areas of reticulation/honeycomb on HRCT than to those with ground-glass patterns.

The Effect of VEGF-Targeted Therapy on Biomarker Expression in Sequential Tissue from Patients with Metastatic Clear Cell Renal Cancer

Purpose: To investigate how biologically relevant markers change in response to antiangiogenic therapy in metastatic clear cell renal cancer (mRCC) and correlate these changes with outcome. Experimental Design: The study used sequential tumor tissue and functional imaging (taken at baseline and 12–16 weeks) obtained from three similar phase II studies. All three studies investigated the role of VEGF tyrosine kinase inhibitors (TKI) before planned nephrectomy in untreated mRCC (n = 85). The effect of targeted therapy on ten biomarkers was measured from sequential tissue. Comparative genomic hybridization (CGH) array and DNA methylation profiling (MethylCap-seq) was performed in matched frozen pairs. Biomarker expression was correlated with early progression (progression as best response) and delayed progression (between 12–16 weeks). Results: VEGF TKI treatment caused a significant reduction in vessel density (CD31), phospho-S6K expression, PDL-1 expression, and FOXP3 expression (P < 0.05 for each). It also caused a significant increase in cytoplasmic FGF-2, MET receptor expression in vessels, Fuhrman tumor grade, and Ki-67 (P < 0.05 for each). Higher levels of Ki-67 and CD31 were associated with delayed progression (P < 0.05). Multiple samples (n = 5) from the same tumor showed marked heterogeneity of tumor grade, which increased significantly with treatment. Array CGH showed extensive intrapatient variability, which did not occur in DNA methylation analysis. Conclusion: TKI treatment is associated with dynamic changes in relevant biomarkers, despite significant heterogeneity in chromosomal and protein, but not epigenetic expression. Changes to Ki-67 expression and tumor grade indicate that treatment is associated with an increase in the aggressive phenotype of the tumor. Clin Cancer Res; 19(24); 6924–34. ©2013 AACR.

An International Survey of Hospital Practice in the Imaging of Acute Scaphoid Trauma

OBJECTIVE Scaphoid fractures are relatively common. If not treated promptly there may be risk of long-term disability. However, unnecessary wrist immobilization is inconvenient and may hinder professional activities. Therefore, early accurate diagnosis is essential. Currently, the American College of Radiology deems MRI and radiographs as the most appropriate investigations in imaging acute scaphoid trauma. Our objective was to assess scaphoid imaging protocols. MATERIALS AND METHODS To assess scaphoid imaging protocols, an international survey of imaging practice was performed. Two hundred hospitals worldwide were sent a survey regarding their scaphoid trauma imaging protocols. Only replies from hospitals that had full CT, MRI, and scintigraphy facilities were accepted. RESULTS Data were obtained from 105 hospitals, of which 23 had fixed protocols. The number of scaphoid radiographic views varied from two to six. Before second-line investigations were initiated, repeat radiographs were usually performed in 76 of the 105 hospitals. In 29 hospitals, other imaging techniques were used without further radiography. The usual second-line investigation was MRI in 31/105, CT in 19/105, and scintigraphy in 14/105. Further protocols included CT or MRI in 10/105, CT or scintigraphy in 6/105, scintigraphy or MRI in 6/105, CT then MRI (if CT was negative) in 1/105, both CT and scintigraphy in 1/105, and scintigraphy then CT (if positive) in 1/105. There was equal preference among MRI, CT, and scintigraphy in 10/105 centers, and clinical examination and radiographs were used alone in 6/105. CONCLUSION The survey reveals marked inconsistency in the imaging of acute scaphoid injury. Although other factors may have played a role, limited scientific evidence regarding the ideal imaging in acute scaphoid trauma may be the root of this inconsistency.