Fabio Ponzo

Local radiotherapy and granulocyte-macrophage colony-stimulating factor to generate abscopal responses in patients with metastatic solid tumours: a proof-of-principle trial

BACKGROUND An abscopal response describes radiotherapy-induced immune-mediated tumour regression at sites distant to the irradiated field. Granulocyte-macrophage colony-stimulating factor is a potent stimulator of dendritic cell maturation. We postulated that the exploitation of the pro-immunogenic effects of radiotherapy with granulocyte-macrophage colony-stimulating factor might result in abscopal responses among patients with metastatic cancer. METHODS Patients with stable or progressing metastatic solid tumours, on single-agent chemotherapy or hormonal therapy, with at least three distinct measurable sites of disease, were treated with concurrent radiotherapy (35 Gy in ten fractions, over 2 weeks) to one metastatic site and granulocyte-macrophage colony-stimulating factor (125 μg/m(2) subcutaneously injected daily for 2 weeks, starting during the second week of radiotherapy). This course was repeated, targeting a second metastatic site. A Simons optimal two-stage design was chosen for this trial: an additional 19 patients could be enrolled in stage 2 only if at least one patient among the first ten had an abscopal response. If no abscopal responses were seen among the first ten patients, the study would be deemed futile and terminated. The primary endpoint was the proportion of patients with an abscopal response (defined as at least a 30% decrease in the longest diameter of the best responding abscopal lesion). Secondary endpoints were safety and survival. Analyses were done based on intention to treat. The trial has concluded accrual, and is registered with ClinicalTrials.gov, number NCT02474186. FINDINGS From April 7, 2003, to April 3, 2012, 41 patients with metastatic cancer were enrolled. In stage 1 of the Simons two-stage design, ten patients were enrolled: four of the first ten patients had abscopal responses. Thus, the trial proceeded to stage 2, as planned, and an additional 19 patients were enrolled. Due to protocol amendments 12 further patients were enrolled. Abscopal responses occurred in eight (27·6%, 95% CI 12·7-47·2) of the first 29 patients, and 11 (26·8%, 95% CI 14·2-42·9) of 41 accrued patients (specifically in four patients with non-small-cell lung cancer, five with breast cancer, and two with thymic cancer). The most common grade 3-4 adverse events were fatigue (six patients) and haematological (ten patients). Additionally, a serious adverse event of grade 4 pulmonary embolism occurred in one patient. INTERPRETATION The combination of radiotherapy with granulocyte-macrophage colony-stimulating factor produced objective abscopal responses in some patients with metastatic solid tumours. This finding represents a promising approach to establish an in-situ anti-tumour vaccine. Further research is warranted in this area. FUNDING New York University School of Medicines Department of Radiation Oncology and Cancer Institute.

Improving Specificity of Breast MRI Using Prone PET and Fused MRI and PET 3D Volume Datasets

MRI is a sensitive method for detecting invasive breast cancer, but it lacks specificity. To examine the effect of combining PET with MRI on breast lesion characterization, a prototype positioning device was fabricated to allow PET scans to be acquired in the same position as MRI scans—that is, prone. Methods: To test the hypothesis that fusion of 18F-FDG PET and MRI scans improves detection of breast cancer, 23 patients with suspected recurrent or new breast cancer underwent a routine whole-body PET scan, a prone PET scan of the chest, and a routine breast MRI scan. The attenuation-corrected prone PET and MRI datasets were registered twice by different operators. The fusion results were judged for quality by visual inspection and statistical analysis. A joint reading of the MRI and PET scans side by side and integrated images was performed by a nuclear medicine physician and a radiologist. Sensitivity and specificity of MRI and combined MRI and PET scans were calculated on the basis of pathology reports or at least 1 y of clinical and radiologic follow-up. Results: All fusions were verified to be well matched using specific anatomic criteria. A total of 45 lesions was assessed. Lesion size range was 0.6 to 10.0 cm. Of the 44 breasts examined, 29 were suspicious for cancer, of which 15 were found to be positive on surgical excision. In lesion-by-lesion analysis, sensitivity and specificity of MRI alone were 92% and 52%, respectively; after MRI and PET fusion, they were 63% and 95%, respectively. The positive predictive value and the negative predictive value for MRI alone were 69% and 85%, respectively; after MRI and PET fusion, they were 94% and 69%, respectively. Conclusion: Acquisition of prone PET scans using the new positioning device permitted acquisition of prone scans suitable for fusion with breast MRI scans. Fused PET and MRI scans increased the specificity of MRI but decreased the sensitivity in this small group of patients. Additional data are needed to confirm the statistical significance of these preliminary findings.

Role of Fusion of Prone FDG‐PET and Magnetic Resonance Imaging of the Breasts in the Evaluation of Breast Cancer

Abstract:  The purpose of this study is to report further about the statistically significant results from a prospective study, which suggests that fusion of prone F‐18 Fluoro‐deoxy‐glucose (FDG) positron emission tomography (PET) and magnetic resonance (MR) breast scans increases the positive predictive value (PPV) and specificity for patients in whom the MR outcome alone would be nonspecific. Thirty‐six women (mean age, 43 years; range, 24–65 years) with 90 lesions detected on MR consented to undergo a FDG‐PET scan. Two blinded readers evaluated the MR and the computer tomography (CT) attenuation‐corrected prone FDG‐PET scans side‐by‐side, then after the volumes were superimposed (fused). A semiautomatic, landmark‐based program was used to perform nonrigid fusion. Pathology and radiologic follow‐up were used as the reference standard. The sensitivity, specificity, PPV, negative predictive value (NPV), and accuracy (with 95% confidence intervals) for MR alone, FDG‐PET alone, and fused MR and FDG‐PET were calculated. The median lesion size measured from the MR was 2.5 cm (range, 0.5–10 cm). Histologically, 56 lesions were malignant, and 15 were benign. Nineteen lesions were benign after 20–47 months of clinical and radiologic surveillance. The sensitivity of MR alone was 95%, FDG‐PET alone was 57%, and fusion was 83%. The increase in PPV from 77% in MR alone to 98% when fused and the increase in specificity from 53% to 97% were statistically significant (p < 0.05). The false‐negative rate on FDG‐PET alone was 26.7%, and after fusion this number was reduced to 9%. FDG‐PET and MR fusions were helpful in selecting which lesion to biopsy, especially in women with multiple suspicious MR breast lesions.

PET/MRI for the Evaluation of Patients With Lymphoma: Initial Observations

OBJECTIVE The objective of our study was to assess the role of recently introduced hybrid PET/MRI in the evaluation of lymphoma patients using PET/CT as a reference standard. SUBJECTS AND METHODS In this prospective study 28 consecutive lymphoma patients (18 men, 10 women; mean age, 53.6 years) undergoing clinically indicated PET/ CT were subsequently imaged with PET/MRI using residual FDG activity from the PET/ CT study. Blinded readers evaluated PET/CT (reference standard), PET/MRI, and diffusion-weighted imaging (DWI) studies separately; for each study, they assessed nodal and extranodal involvement. Each FDG-avid nodal station was marked and compared on DWI, PET/MRI, and PET/CT. Modified Ann Arbor staging was performed and compared between PET/MRI and PET/CT. The maximum standardized uptake value (SUVmax) on PET/MRI for FDG-avid nodal lesions was compared with the SUVmax on PET/CT. The apparent diffusion coefficient (ADC) for FDG-avid nodal lesions was compared to SUVmax on PET/MRI. RESULTS Fifty-one FDG-avid nodal groups were identified on PET/CT in 13 patients. PET/MRI identified 51 of these nodal groups with a sensitivity of 100%. DWI identified 32 nodal groups for a sensitivity of 62.7%. PET/MRI staging and PET/CT staging were concordant in 96.4% of patients. For the one patient with discordant staging results, disease was correctly upstaged to stage IV on the basis of the PET/MRI finding of bone marrow involvement, which was missed on PET/CT. DWI staging was concordant with PET/CT staging in 64.3% of the patients. The increased staging accuracy of PET/MRI relative to DWI was significant (p=0.004). SUVmax measured on PET/MRI and PET/CT showed excellent statistically significant correlation (r=0.98, p<0.001). There was a poor negative correlation between ADC and SUVmax (r=-0.036, p=0.847). CONCLUSION PET/MRI can be used to assess disease burden in lymphoma with sensitivity similar to PET/CT and can be a viable alternative for lymphoma staging and follow-up.

Tc-99m sulfur colloid and Tc-99m tagged red blood cell methods are comparable for detecting lower gastrointestinal bleeding in clinical practice.

Purpose The objective of this study was to determine whether the Tc-99m red blood cells (Tc-99m RBC) method has a true advantage over the Tc-99m sulfur colloid (Tc-99m SC) technique in a busy clinical practice for detecting and localizing lower gastrointestinal bleeding sites. Methods Three hundred fifty-nine consecutive gastrointestinal bleeding studies performed during the past 4 years were reviewed retrospectively. One hundred ninety-three scans were obtained with Tc-99m SC (scan duration, 30 minutes) and 138 studies were performed after the administration of Tc-99m RBC (scan duration, 1 hour). In addition, 28 examinations with Tc-99m SC were followed immediately by Tc-99m RBC scans for a duration of several hours. The results of the two methods were analyzed and the performance of the two techniques was compared. Results Among 193 scans performed using the Tc-99m SC method, 47 (24.4%) successfully identified the location of the bleeding site, whereas in 138 scans performed using Tc-99m RBC, 38 (27.5%) were successful for this purpose. In the remaining 28 scans in which the Tc-99m SC scan was followed by the Tc-99m RBC study, only 4 (14.3%) positive bleeding sites were identified after a prolonged imaging period. Discussion The theoretical advantages of the Tc-99m RBC technique compared with the Tc-99m SC method cannot be substantiated by this study. Our findings suggest that the efficacy of these two methods is nearly equal at a practical level. Conclusion The simpler and cost-effective Tc-99m SC method is as efficient as the Tc-99m RBC method when the scanning time is limited to 1 hour and optimal imaging and interpretation schemes are used.

Comparison of Whole-Body 18F FDG PET/MR Imaging and Whole-Body 18F FDG PET/CT in Terms of Lesion Detection and Radiation Dose in Patients with Breast Cancer

Purpose To compare fluorine 18 ((18)F) fluorodeoxyglucose (FDG) combined positron emission tomography (PET) and magnetic resonance (MR) imaging with (18)F FDG combined PET and computed tomography (CT) in terms of organ-specific metastatic lesion detection and radiation dose in patients with breast cancer. Materials and Methods From July 2012 to October 2013, this institutional review board-approved HIPAA-compliant prospective study included 51 patients with breast cancer (50 women; mean age, 56 years; range, 32-76 years; one man; aged 70 years) who completed PET/MR imaging with diffusion-weighted and contrast material-enhanced sequences after unenhanced PET/CT. Written informed consent for study participation was obtained. Two independent readers for each modality recorded site and number of lesions. Imaging and clinical follow-up, with consensus in two cases, served as the reference standard. Results There were 242 distant metastatic lesions in 30 patients, 18 breast cancers in 17 patients, and 19 positive axillary nodes in eight patients. On a per-patient basis, PET/MR imaging with diffusion-weighted and contrast-enhanced sequences depicted distant (30 of 30 [100%] for readers 1 and 2) and axillary (eight of eight [100%] for reader 1, seven of eight [88%] for reader 2) metastatic disease at rates similar to those of unenhanced PET/CT (distant metastatic disease: 28 of 29 [96%] for readers 3 and 4, P = .50; axillary metastatic disease: seven of eight [88%] for readers 3 and 4, P > .99) and outperformed PET/CT in the detection of breast cancer (17 of 17 [100%] for readers 1 and 2 vs 11 of 17 [65%] for reader 3 and 10 of 17 [59%] for reader 4; P < .001). PET/MR imaging showed increased sensitivity for liver (40 of 40 [100%] for reader 1 and 32 of 40 [80%] for reader 2 vs 30 of 40 [75%] for reader 3 and 28 of 40 [70%] for reader 4; P < .001) and bone (105 of 107 [98%] for reader 1 and 102 of 107 [95%] for reader 2 vs 106 of 107 [99%] for reader 3 and 93 of 107 [87%] for reader 4; P = .012) metastases and revealed brain metastases in five of 51 (10%) patients. PET/CT trended toward increased sensitivity for lung metastases (20 of 23 [87%] for reader 1 and 17 of 23 [74%] for reader 2 vs 23 of 23 [100%] for reader 3 and 22 of 23 [96%] for reader 4; P = .065). Dose reduction averaged 50% (P < .001). Conclusion In patients with breast cancer, PET/MR imaging may yield better sensitivity for liver and possibly bone metastases but not for pulmonary metastases, as compared with that attained with PET/CT, at about half the radiation dose. (©) RSNA, 2016 Online supplemental material is available for this article.

Prone mammoPET acquisition improves the ability to fuse MRI and PET breast scans.

Purpose: This study compared prone acquisition of PET scans with traditional supine acquisition to improve fusion of PET scans with MRI scans and improve evaluation of enhancing breast lesions detected on MRI. Materials and Methods: MRI breast scans are acquired in the prone position using a breast coil to allow the breasts to hang pendant. An apparatus was fabricated to allow prone acquisition of PET scans. Fused scans from 2 patients acquired both prone and supine were contrasted with those from 3 patients acquired supine only. All 5 MRI scans were acquired on standard scanners. The PET scans were acquired with a PET/CT unit using a low-dose CT scan for attenuation correction. The PET and MRI volumes were matched twice (using a semiautomated registration method) by different operators. The additional value of fusion was judged using reports from the original (nonfused) MRI and PET, joint rereading of the volumes side by side, and examination of fused images. Results: Of 12 enhancing lesions on breast MRI, 7 demonstrated uptake on PET/CT. In the 3 supine-only cases, the fused images were not interpretable because of the marked distortion of the breasts. In the 2 prone cases, the fused images increased our confidence in characterizing a lesion as benign or malignant. Interpretations were confirmed by clinical follow up in 2 or histologic results in 3 patients. Conclusions: PET MRI fusion is feasible and may assist in localizing lesions detected on either study. A more extensive study is underway to confirm the value of this fusion technique.

Fluorodeoxyglucose (FDG) uptake in pulmonary rheumatoid nodules

A 60-year-old female patient with a 5-year history of rheumatoid arthritis (RA) presented with pulmonary nodules on chest radiograph and computed tomography (CT) scan. The positron emission tomography (PET) demonstrated mild fluorodeoxyglucose (FDG) uptake in these nodules, which is characteristic of benign lesions. Histopathological correlation confirmed this. Although rheumatoid pulmonary nodules are benign, confirmation to exclude coincidental malignancy is very important. FDG-PET is a noninvasive imaging technique, which acts as a metabolic biopsy and can help in avoiding morbidity and cost of invasive tissue sampling.

Outcome of small lung nodules missed on hybrid PET/MRI in patients with primary malignancy.

To assess outcomes of lung nodules missed on simultaneous positron emission tomography and magnetic resonance imaging (PET/MRI) compared to the reference standard PET and computed tomography (PET/CT) in patients with primary malignancy.

Standardized Uptake Values from PET/MRI in Metastatic Breast Cancer: An Organ-based Comparison With PET/CT

Quantitative standardized uptake values (SUVs) from fluorine‐18 (18F) fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) are commonly used to evaluate the extent of disease and response to treatment in breast cancer patients. Recently, PET/magnetic resonance imaging (MRI) has been shown to qualitatively detect metastases from various primary cancers with similar sensitivity to PET/CT. However, quantitative validation of PET/MRI requires assessing the reliability of SUVs from MR attenuation correction (MRAC) relative to CT attenuation correction (CTAC). The purpose of this retrospective study was to assess the utility of PET/MRI‐derived SUVs in breast cancer patients by testing the hypothesis that SUVs derived from MRAC correlate well with those from CTAC. Between August 2012 and May 2013, 35 breast cancer patients (age 37–78 years, 1 man) underwent clinical 18F‐FDG PET/CT followed by PET/MRI. One hundred seventy metastases were seen in 21 of 35 patients; metastases to bone in 16 patients, to liver in seven patients, and to nonaxillary lymph nodes in eight patients were sufficient for statistical analysis on an organ‐specific per patient basis. SUVs in the most FDG‐avid metastasis per organ per patient from PET/CT and PET/MRI were measured and compared using Pearsons correlations. Correlations between CTAC‐ and MRAC‐derived SUVmax and SUVmean in 31 metastases to bone, liver, and nonaxillary lymph nodes were strong overall (ρ = 0.80, 0.81). SUVmax and SUVmean correlations were also strong on an organ‐specific basis in 16 bone metastases (ρ = 0.76, 0.74), seven liver metastases (ρ = 0.85, 0.83), and eight nonaxillary lymph node metastases (ρ = 0.95, 0.91). These strong organ‐specific correlations between SUVs from PET/CT and PET/MRI in breast cancer metastases support the use of SUVs from PET/MRI for quantitation of 18F‐FDG activity.