Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma:Response monitoring and resistance prediction with positron emission tomography and tumor characteristics (REPOSIT): study protocol of a phase II, open-label, multicenter study

BACKGROUND: In patients with BRAFV600 mutated unresectable stage IIIc or metastatic melanoma, molecular targeted therapy with combined BRAF/MEK-inhibitor vemurafenib plus cobimetinib has shown a significantly improved progression-free survival and overall survival compared to treatment with vemurafenib alone. Nevertheless, the majority of BRAFV600 mutation-positive melanoma patients will eventually develop resistance to treatment. Molecular imaging with F-18-Fluorodeoxyglucose (F-18-FDG) PET has been used to monitor response to vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of F-18-FDG uptake within 2 weeks following treatment. Furthermore, preliminary results suggest that metabolic alterations might predict the development of resistance to treatment. F-18-Fluoro-3'-deoxy-3' L-fluorothymidine (F-18-FLT), a PET-tracer visualizing proliferation, might be more suitable to predict response or resistance to therapy than F-18-FDG. METHODS: This phase II, open-label, multicenter study evaluates whether metabolic response to treatment with vemurafenib plus cobimetinib in the first 7 weeks as assessed by F-18-FDG/F-18-FLT PET can predict progression-free survival and whether early changes in F-18-FDG/F-18-FLT can be used for early detection of treatment response compared to standard response assessment with RECISTv1.1 ceCT at 7 weeks. Ninety patients with BRAFV600E/K mutated unresectable stage IIIc/IV melanoma will be included. Prior to and during treatment all patients will undergo F-18-FDG PET/CT and in 25 patients additional F-18-FLT PET/CT is performed. Histopathological tumor characterization is assessed in a subset of 40 patients to unravel mechanisms of resistance. Furthermore, in all patients, blood samples are taken for pharmacokinetic analysis of vemurafenib/cobimetinib. Outcomes are correlated with PET/CT-imaging and therapy response. DISCUSSION: The results of this study will help in linking PET measured metabolic alterations induced by targeted therapy of BRAFV600 mutated melanoma to molecular changes within the tumor. We will be able to correlate both F-18-FDG and F-18-FLT PET to outcome and decide on the best modality to predict long-term remissions to combined BRAF/MEK-inhibitors. Results coming from this study may help in identifying responders from non-responders early after the initiation of therapy and reveal early development of resistance to vemurafenib/cobimetinib. Furthermore, we believe that the results can be fundamental for further optimizing individual patient treatment

Left ventricular diastolic dyssynchrony assessed with phase analysis of gated myocardial perfusion SPECT: a comparison with tissue Doppler imaging

Cardiac Dysfunction and Arrhythmia

Optimal left ventricular lead position assessed with phase analysis on gated myocardial perfusion SPECT

The aim of the current study was to evaluate the relationship between the site of latest mechanical activation as assessed with gated myocardial perfusion SPECT (GMPS), left ventricular (LV) lead position and response to cardiac resynchronization therapy (CRT). The patient population consisted of consecutive patients with advanced heart failure in whom CRT was currently indicated. Before implantation, 2-D echocardiography and GMPS were performed. The echocardiography was performed to assess LV end-systolic volume (LVESV), LV end-diastolic volume (LVEDV) and LV ejection fraction (LVEF). The site of latest mechanical activation was assessed by phase analysis of GMPS studies and related to LV lead position on fluoroscopy. Echocardiography was repeated after 6 months of CRT. CRT response was defined as a decrease of a parts per thousand yen15% in LVESV. Enrolled in the study were 90 patients (72% men, 67 +/- 10 years) with advanced heart failure. In 52 patients (58%), the LV lead was positioned at the site of latest mechanical activation (concordant), and in 38 patients (42%) the LV lead was positioned outside the site of latest mechanical activation (discordant). CRT response was significantly more often documented in patients with a concordant LV lead position than in patients with a discordant LV lead position (79% vs. 26%, p < 0.01). After 6 months, patients with a concordant LV lead position showed significant improvement in LVEF, LVESV and LVEDV (p < 0.05), whereas patients with a discordant LV lead position showed no significant improvement in these variables. Patients with a concordant LV lead position showed significant improvement in LV volumes and LV systolic function, whereas patients with a discordant LV lead position showed no significant improvements.Cardiovascular Aspects of Radiolog

Metabolic biomarker–based BRAFV600 mutation association and prediction in melanoma

The aim of this study was to associate and predict B-rapidly accelerated fibrosarcoma valine 600 (BRAFV600) mutation status with both conventional and radiomics 18F-FDG PET/CT features, while exploring several methods of feature selection in melanoma radiomics. Methods: Seventy unresectable stage III–IV melanoma patients who underwent a baseline 18F-FDG PET/CT scan were identified. Patients were assigned to the BRAFV600 group or BRAF wild-type group according to mutational status. 18F-FDG uptake quantification was performed by semiautomatic lesion delineation. Four hundred eighty radiomics features and 4 conventional PET features (SUVmax, SUVmean, SUVpeak, and total lesion glycolysis) were extracted per lesion. Six different methods of feature selection were implemented, and 10-fold cross-validated predictive models were built for each. Model performances were evaluated with areas under the curve (AUCs) for the receiver operating characteristic curves. Results: Thirty-five BRAFV600 mutated patients (100 lesions) and 35 BRAF wild-type patients (79 lesions) were analyzed. AUCs predicting the BRAFV600 mutation varied from 0.54 to 0.62 and were susceptible to feature selection method. The best AUCs were achieved by feature selection based on literature, a penalized binary logistic regression model, and random forest model. No significant difference was found between the BRAFV600 and BRAF wild-type group in conventional PET features or predictive value. Conclusion: BRAFV600 mutation status is not associated with, nor can it be predicted with, conventional PET features, whereas radiomics features were of low predictive value (AUC 5 0.62). We showed feature selection methods to influence predictive model performance, describing and evaluating 6 unique methods. Detecting BRAFV600 status in melanoma based on 18F-FDG PET/CT alone does not yet provide clinically relevant knowledge

The role of 18F-FDG PET/CT in retroperitoneal sarcomas—A multicenter retrospective study

Background: The role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in the evaluation of retroperitoneal sarcomas is poorly defined. We evaluated the correlation of maximum standardized uptake value (SUVmax) with pathologic tumor grade in the surgical specimen of primary retroperitoneal dedifferentiated liposarcoma (DDLPS) and leiomyosarcoma (LMS). Methods: Patients with the above histological subtypes in three participating institutions with preoperative 18F-FDG PET/CT scan and histopathological specimen available for review were included. The association between SUVmax and pathological grade was assessed. Correlation between SUVmax and relapse-free survival (RFS) and overall survival (OS) were also studied. Results: Of the total 58 patients, final pathological subtype was DDLPS in 44 (75.9%) patients and LMS in 14 (24.1%) patients. The mean SUVmax was 8.7 with a median 7.1 (range, 2.2–33.9). The tumors were graded I, II, III in 6 (10.3%), 35 (60.3%), and 17 (29.3%) patients, respectively. There was an association of higher histological grade with higher SUVmax (rs = 0.40, p =.002). Increasing SUVmax was associated with worse RFS (p =.003) and OS (p =.003). Conclusion: There is a correlation between SUVmax and pathologic tumor grade; increasing SUVmax was associated with worse OS and RFS, providing a preoperative noninvasive surrogate marker of tumor grade and biological behavior

Single agent Talimogene Laherparepvec for stage IIIB-IVM1c melanoma patients: A systematic review and meta-analysis

Single-agent Talimogene Laherparepvec (T-VEC) was developed for treatment of unresectable and injectable stage III-IV melanoma. Since its approval and reimbursement, studies have reported varying response rates. The purpose of this systematic review and meta-analysis was to investigate the efficacy and safety of T-VEC. Of 341 publications that were identified, eight studies with a total of 642 patients were included. In patients with stage IIIB-IVM1a, the pooled complete- and overall response rate (CRR and ORR) were 41% and 64%, respectively. In patients with stage IIIB-IVM1c, the pooled CRR and ORR were 30% and 44%, respectively. In patients with stage IVM1b and IVM1c, the pooled CRR and ORR were 4% and 9%, respectively. Adverse events (AEs) were seen in 41–100% of all patients and 0–11% of AEs were severe. In conclusion, single agent T-VEC achieves the highest response rates in patients with early metastatic melanoma and is well-tolerated with generally only mild toxicities

Prediction of Cardiac Resynchronization Therapy Response - Value of Cardiac 123-Iodine Meta-Iodobenzylguanidine Imaging

Cardiovascular Aspects of Radiolog

The Predictive Value of FDG PET/CT for Determining Progression-Free Survival in Advanced Stage III-IV BRAF -Mutated Melanoma Patients Treated With Targeted Therapy-What Can Be Learned From Progression?

PURPOSE: The aims of this study were to investigate whether (early) PERCIST response monitoring with 18 F-FDG PET/CT is predictive for progression-free survival (PFS) in unresectable stage III or IV melanoma patients treated with BRAF/MEK inhibitor (MEKi) and to define dissemination patterns at progression with a lesion-based evaluation in direct comparison to baseline to improve our understanding of 18 F-FDG PET/CT during BRAF/MEKi. PATIENTS AND METHODS: This prospective multicenter single-arm study included 70 patients with unresectable stage III/IV BRAF -mutated melanoma who underwent contrast-enhanced CT and 18 F-FDG PET/CT at baseline and 2 and 7 weeks during treatment with vemurafenib plus cobimetinib and at progression if possible. Tumor response assessment was done with RECIST1.1 and PERCIST. Follow-up PET/CT scans were visually compared with baseline to assess dissemination patterns. RESULTS: Using RECIST1.1, PFS was not significantly different between the response groups ( P = 0.26). At 2 weeks, PERCIST median PFS was 15.7 months for patients with complete metabolic response (CMR) versus 8.3 months for non-CMR ( P = 0.035). The hazards ratio (HR) for progression/death in non-CMR versus CMR was 1.99 (95% confidence interval [CI], 1.03-3.84; P = 0.040) and 1.77 (95% CI, 0.91-3.43; P = 0.0935) when adjusting for lactate dehydrogenase (LDH). At 7 weeks, median PFS for PERCIST CMR was 16.7 months versus 8.5 months for non-CMR ( P = 0.0003). The HR for progression/death in the non-CMR group was significantly increased (HR, 2.94; 95% CI, 1.60-5.40; P = 0.0005), even when adjusting for LDH (HR, 2.65; 95% CI, 1.43-4.91; P = 0.0020). At week 7, 18 F-FDG PET/CT was false-positive in all 4 (6%) patients with new FDG-avid lesions but CMR of known metastases. When 18 F-FDG PET/CT was performed at progressive disease, 18/22 (82%) patients had progression of known metastases with or without new 18 F-FDG-avid lesions. CONCLUSIONS: This study shows that PERCIST response assessment at week 7 is predictive for PFS, regardless of LDH. At 2 weeks, patients with CMR have longer PFS than patients with non-CMR, but different PET parameters should be investigated to further evaluate the added value of early 18 F-FDG PET/CT. Disease progression on PET/CT is predominated by progression of known metastases, and new 18 F-FDG-avid lesions during BRAF/MEKi are not automatically a sign of recurrent disease.</p