Risk Stratification in Cardiac Sarcoidosis With Cardiac Positron Emission Tomography: A Systematic Review and Meta-Analysis.

BACKGROUND: Although positron emission tomography (PET) imaging is well established for its diagnostic role in cardiac sarcoidosis, less is known about the prognostic value of PET and its use in risk stratification for major adverse cardiac events (MACE). OBJECTIVES: The goal of this study was to perform a systematic review and meta-analysis looking at the prognostic value of PET imaging in patients with cardiac sarcoidosis. METHODS: Study investigators systematically searched EMBASE (Excerpta Medica dataBASE), MEDLINE, PubMed, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, CINAHL (Cumulative Index to Nursing and Allied Health Literature), ClinicalTrials.gov, and the European Union Clinical Trial Registry for cardiac sarcoidosis and PET imaging. The primary outcome of interest was MACE. RESULTS: The search revealed 3,010 records, of which 55 studies were included. This represented 5,250 patients. Factors associated with MACE included the following: the combination of abnormal fluorodeoxyglucose (FDG) uptake and perfusion defect, which had an OR of 2.86 (95% CI: 1.74-4.71; P < 0.0001); abnormal perfusion or FDG uptake, which had an OR of 2.69 (95% CI: 1.67-4.33); abnormal FDG uptake, which had an OR of 2.61 (95% CI: 1.51-4.50); focal abnormal right ventricular uptake, which had an OR of 6.27 (95% CI: 3.19-12.32; P < 0.00001); and a lack of response to immunosuppression on serial PET, which had an OR of 8.43 (95% CI: 3.25-21.85; P < 0.0001). A QUIPS (Quality in Prognostic Studies) tool analysis found a low to moderate risk of bias, particularly given the small sample sizes in the individual studies. CONCLUSIONS: Multiple cardiac PET parameters provide risk stratification value in cardiac sarcoidosis. Focal right ventricular uptake and a lack of response to immunosuppressive therapy on serial PET imaging were particularly predictive of MACE.

Utility of 64Cu-Sarcophagine-Bombesin PET/CT in Men with Biochemically Recurrent Prostate Cancer and Negative or Equivocal Findings on 68Ga-PSMA-11 PET/CT.

Despite a high detection rate of 68Ga-prostate-specific membrane antigen (PSMA) PET/CT in biochemical recurrence (BCR) of prostate cancer, a significant proportion of men have negative 68Ga-PSMA-11 PET/CT results. Gastrin-releasing peptide receptor, targeted by the copper-chelated bombesin analog 64Cu-sarcophagine-bombesin (SAR-BBN) PET/CT, is also overexpressed in prostate cancer. In this prospective imaging study, we investigate the detection rate of 64Cu-SAR-BBN PET/CT in patients with BCR and negative or equivocal 68Ga-PSMA-11 PET/CT results. Methods: Men with confirmed adenocarcinoma of the prostate, prior definitive therapy, and BCR (defined as a prostate-specific antigen [PSA] level > 0.2 ng/mL) with negative or equivocal 68Ga-PSMA-11 PET/CT results within 3 mo were eligible for enrollment. 64Cu-SAR-BBN PET/CT scans were acquired at 1 and 3 h after administration of 200 MBq of 64Cu-SAR-BBN, with further delayed imaging undertaken optionally at 24 h. PSA (ng/mL) was determined at baseline. All PET (PSMA and bombesin) scans were assessed visually. Images were read with masking of the clinical results by 2 experienced nuclear medicine specialists, with a third reader in cases of discordance. Accuracy was defined using a standard of truth that included biopsy confirmation, confirmatory imaging, or response to targeted treatment. Results: Twenty-five patients were enrolled. Prior definitive therapy was radical prostatectomy (n = 24, 96%) or radiotherapy (n = 1, 4%). The median time since definitive therapy was 7 y (interquartile range [IQR], 4-11 y), and the Gleason score was 7 or less (n = 15, 60%), 8 (n = 3, 12%), or 9 (n = 7, 28%). The median PSA was 0.69 ng/mL (IQR, 0.28-2.45 ng/mL). Baseline PSMA PET scans were negative in 19 patients (76%) and equivocal in 6 (24%). 64Cu-SAR-BBN PET-avid disease was identified in 44% (11/25): 12% (3/25) with local recurrence, 20% (5/25) with pelvic node metastases, and 12% (3/25) with distant metastases. The κ-score between readers was 0.49 (95% CI, 0.16-0.82). Patients were followed up for a median of 10 mo (IQR, 9-12 mo). Bombesin PET/CT results were true-positive in 5 of 25 patients (20%), false-positive in 2 of 25 (8%), false-negative in 7 of 25 (28%), and unverified in 11 of 25 (44%). Conclusion: 64Cu-SAR-BBN PET/CT demonstrated sites of disease recurrence in 44% of BCR cases with negative or equivocal 68Ga-PSMA-11 PET/CT results. Further evaluation to confirm diagnostic benefit is warranted.

Treatment Response Imaging in Prostate Cancer.

Objective criteria for measuring treatment response in prostate cancer are critical to clinical research and practice. The Prostate Cancer Working Group 3 criteria are widely accepted relying only on conventional imaging for radiographic treatment response. Prostate-specific membrane antigen PET/computed tomography was proven to be superior to conventional imaging in initial diagnosis and biochemical recurrence of prostate cancer. Moreover, there is growing evidence of its role in treatment response assessment in prostate cancer. This study will review the different criteria for imaging treatment response on conventional and advanced molecular imaging for different therapies, and the future perspective in posttherapy imaging.

Development of a Visually Calculated SUVmean (HIT Score) on Screening PSMA PET/CT to Predict Treatment Response to 177Lu-PSMA Therapy: Comparison with Quantitative SUVmean and Patient Outcomes.

177Lu-PSMA therapy is an effective treatment in patients with metastatic castration-resistant prostate cancer. SUVmean is a valuable screening biomarker to assess the suitability for 177Lu-PSMA therapy but requires quantitative software. This study aims to develop a simple, clinically applicable prostate-specific membrane antigen PET/CT score that encompasses the elements of SUVmean without requiring additional quantification. Methods: Datasets from ethics-approved trials of patients with metastatic castration-resistant prostate cancer after androgen receptor signaling inhibition and taxane chemotherapy (or unfit for taxane), who were treated with 177Lu-PSMA-617 and 177Lu-PSMA I&T with a pretreatment screening with 68Ga-PSMA-11 PET/CT, and clinical outcome data, including a prostate-specific antigen (PSA) 50% response rate (PSA50), PSA progression-free survival (PSA-PFS), and overall survival (OS), were included. The screening 68Ga-PSMA-11 PET/CT of all participants was analyzed both semiquantitatively and visually. Semiquantitative analysis was used to derive the SUVmean Visual analysis of the 68Ga-PSMA-11 PET/CT images involved a binary visual heterogeneity assessment (homogeneous or heterogeneous), allocating a tumor SUVmax range (<15, 15-29, 30-49, 50-79, or ≥80). A 4-category score incorporating both heterogeneity and intensity of tumors (HIT) was then developed as a combination of heterogeneity and intensity (SUVmax range). The SUVmax was less than 15 for score 1, 15-79 with heterogeneous intensity for score 2, 15-79 with homogeneous intensity for score 3, and 80 or greater for score 4. This score was evaluated according to clinical outcomes (PSA50, PSA-PFS, and OS) and compared with SUVmean Results: Data from 139 participants were analyzed. In total, 75 (54%) patients achieved a PSA50 with a median PSA-PFS of 5.5 mo (95% CI, 4.1-6.0 mo) and an OS of 13.5 mo (95% CI, 11.1-17.9 mo). SUVmean was associated with PSA50 and survival outcomes when analyzed as a continuous variable or as quartiles. The PSA50 for HIT scores 1-4 was 0%, 39%, 65%, and 76%, respectively. The HIT score was strongly related to PSA-PFS and OS (log-rank test, P < 0.001 and P = 0.002). The median PSA-PFS for HIT scores 1-4 was 1.0, 4.1, 6.0, and 8.5, respectively, and the median OS was 7.6, 12.0, 18.5, and 16.9 mo, respectively. Cohen κ between readers for the HIT score was 0.71. Conclusion: A prostate-specific membrane antigen PET/CT score incorporating HIT derived from tools on a standard PET workstation is comparable with quantitative SUVmean as a prognostic tool following 177Lu-PSMA therapy.

How to Report PSMA PET.

Prostate cancer (PCa) is the most common cancer diagnosed in men in most developed countries and a leading cause of cancer-related morbidity and mortality. Prostate-specific membrane antigen positron emission tomography (PSMA-PET) has become a valuable tool in the staging and assessment of disease recurrence in PCa, and more recently for assessment for treatment eligibility to PSMA radioligand therapy (RLT). Harmonization of PSMA-PET interpretation and synoptic reports are needed to communicate concisely and reproducibly PSMA-PET/CT to referring physicians and to support clinician therapeutic management decisions in various stages of the disease. Uniform image interpretation is also important to provide comparable data between clinical trials and to translate such data from research to daily practice. This review provides an overview of the value of PSMA-PET across the different clinical stages of PCa, discusses published reporting criteria for PSMA-PET, identifies pitfalls in reporting PSMA, and provides recommendations for synoptic reports.

The Tyr Phenomenon: A Hypocalcemic Response in High-Volume Treatment Responders to 177Lu-Prostate-Specific Membrane Antigen Therapy.

177Lu-prostate-specific membrane antigen (PSMA) is an effective treatment for metastatic castration-resistant prostate cancer. Rarer treatment-related adverse events have not yet been described. Methods: We present case reviews of 2 men with a marked hypocalcemic osteosclerotic response to 177Lu-PSMA-I&T therapy. A clinical dataset of 177Lu-PSMA-I&T therapy was evaluated to estimate the incidence and clinical association with hypocalcemia. Results: Forty-one of the 127 men (32%) had a serum calcium drop, and 6 (5%) developed clinical hypocalcemia during 177Lu-PSMA therapy. The baseline total tumor volume was significantly higher in those who developed hypocalcemia (median, 3,249 cm3 [interquartile range, 1,856-3,852] vs. 465 [interquartile range 135-1,172]; P = 0.002). The mean prostate-specific antigen response in those with hypocalcemia was 78% (SD, 24%). Conclusion: Hypocalcemia may occur in response to 177Lu-PSMA-I&T, particularly with both high-volume bone metastases and a significant prostate-specific antigen response, and may be severe, requiring corticosteroids. Further evaluation of 177Lu-PSMA-induced hypocalcemia is required to better understand mechanisms, optimal treatments, and repercussions from any subsequent osteosclerotic response.

Survival predictors of 177Lu-Dotatate peptide receptor radionuclide therapy (PRRT) in patients with progressive well-differentiated neuroendocrine tumors (NETS).

PURPOSE: 177Lu-Dotatate is an emerging treatment modality for patients with unresectable or metastatic well-differentiated NETs. This study examines survival predictors in patients who received 177Lu-Dotatate. METHODS: A retrospective single-center review was conducted, examining 47 individuals with progressive well-differentiated NETs treated with 177Lu-Dotatate (four induction cycles of 5.5 GBq at 10-week intervals followed by eight maintenance cycles of 3.7 GBq at 6-month intervals). RESULTS: Median follow-up was 63.1 months with a median progression-free survival (PFS) of 34.1 months. However, median overall survival (OS) was not reached at the time of analysis. The presence of ≥ 5 bone metastases (hazard ratio HR 4.33; p = 0.015), non-gastroenteropancreatic (non-GEP) NETs (HR 3.22; p = 0.025) and development of interim ascites (HR 3.15; p = 0.047) independently predicted a worse OS. Patients with chromogranin A of ≥ 4 × upper limit of normal (ULN) had shorter OS (p < 0.001) and PFS (p = 0.004). Similarly, those with pre-existing ascites demonstrated a worse OS (p = 0.009) and PFS (p = 0.026). Liver metastases involving greater than 50% liver volume and the existence of unusual metastatic locations had a negative impact on OS (p = 0.033) and PFS (p = 0.026), respectively. CONCLUSION: High burden of skeletal and hepatic metastases, non-GEP-NETs, chromogranin A of ≥ 4 × ULN, unusual metastatic sites, pre-existing and interim ascites are predictors of poor outcomes in patients treated with 177Lu-Dotatate. These common indicators can be used for the risk stratification and identification of patients most likely to benefit from PRRT. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02236910, Retrospectively registered on September, 2014.

SEVERE HYPERCALCEMIA SECONDARY TO PARAFFIN OIL INJECTIONS IN A BODYBUILDER WITH SIGNIFICANT FINDINGS ON SCINTIGRAPHY.

OBJECTIVE: Non-parathyroid hormone (PTH) mediated hypercalcemia in young patients is rare. It encompasses a broad differential including malignancy, granulomatous diseases, Addison disease, and toxicity of vitamin A and D. We present an unusual case of non-PTH mediated hyper-calcemia in a previously healthy bodybuilder, secondary to multifocal granulomatous disease from paraffin oil injections. METHODS: The patient was evaluated with laboratory tests including serum calcium, 25-hydroxyvitamin D, 1,25-hydroxyvitamin D, parathyroid hormone, and parathyroid hormone-related peptide. Imaging studies such as thorax computed tomography and bone scans were also performed. RESULTS: A 31-year-old male bodybuilder presented with severe hypercalcemia (corrected calcium 3.1 mmol/L) and renal failure (creatinine 840 µmol/L), with suppressed PTH 1.0 pmol/L (normal, 1.6 to 6.9 pmol/L), and 1,25-vitamin D 205 pmol/L (normal, 60 to 208 pmol/L). He had used anabolic steroids for bodybuilding purposes for 8 years, with the possibility that he may also have used paraffin oil injections. Computed tomography imaging along with patient history suggested multiple paraffinomas in the pectoralis muscles causing granulomatous foreign body reaction as a potential cause for his hypercalcemia. He was prescribed a trial of prednisone, but he discontinued it due to symptoms of acne. Unfortunately, due to poor adherence with medical direction, management of his hypercalcemia remains challenging with inconsistent use of steroids and pamidronate infusions. CONCLUSION: Granulomatous foreign-body reactions are a rare side effect of paraffin oil injections used for muscle augmentation. These can lead to serious long-term side effects of severe hypercalcemia and renal failure, as seen in our patient. Prognosis is generally poor, with long term steroids as the preferred treatment.

Effect of sorafenib starting dose and dose intensity on survival in patients with hepatocellular carcinoma: Results from a Canadian Multicenter Database.

BACKGROUND: Sorafenib has been shown to improve survival in patients with advanced hepatocellular carcinoma (HCC), however, full dose can be difficult to tolerate. The aim of this study was to determine whether sorafenib starting dose and mean dose intensity affect survival. METHODS: Patients treated with sorafenib for HCC from January 2008 to July 2016 in several Canadian provinces were included and retrospectively analyzed. The primary end point was overall survival (OS) of patients starting on sorafenib full dose compared to reduced dose. Secondary analysis compared OS with different mean dose-intensity groups. Survival outcomes were assessed with Kaplan-Meier curves and Cox proportional hazards models. A propensity score analysis was performed to account for treatment bias and confounding. RESULTS: Of 681 patients included, sorafenib was started at full dose in 289 patients (42%). Median survival for starting full and reduced dose was 9.4 months and 8.9 months (P = .15) respectively. After propensity score matching and adjusting for potential confounders there was still no difference in survival (HR 0.8, 95% CI, 0.61-1.06, P = .12). Almost half of the patients (45%) received a dose intensity < 50%. Median survival for mean dose intensity > 75%, 50%-75%, and < 50% were 9.5 months, 12.9 months, and 7.1 months (P = .005) respectively. In multivariable models, starting dose(HR 1.16, 95% CI 0.93-1.44, P = .180) and mean dose intensity were not associated with survival. CONCLUSIONS: Starting HCC patients on a reduced dose of sorafenib compared to full dose may not compromise survival. Mean dose-intensity of sorafenib may also not affect survival.