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Aim: The development of biomarkers that can reliably and early predict response to immune checkpoint inhibitors (ICIs) is crucial in melanoma. In recent years, the gut microbiome has emerged as an important regulator of immunotherapy response, which may, moreover, serve as a surrogate marker and prognosticator in oncological patients under immunotherapy. Aim of the present study is to investigate if physiologic colonic [18F]FDG uptake in PET/CT before start of ICIs correlates with clinical outcome of metastatic melanoma patients. The relation between [18F]FDG uptake in lymphoid cell-rich organs and long-term patient outcome is also assessed. Methodology: One hundred nineteen stage IV melanoma patients scheduled for immunotherapy with ipilimumab, applied either as monotherapy or in combination with nivolumab, underwent baseline [18F]FDG PET/CT. PET/CT data analysis consisted of standardized uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) calculations in the colon as well as measurements of the colon-to-liver SUV ratios (CLRmean, CLRmax). Visual grading of colon uptake based on a four-point scale was also performed. Moreover, the spleen-to-liver SUV ratios (SLRmean, SLRmax) and the bone marrow-to-liver SUV ratios (BLRmean, BLRmax) were calculated. We also measured serum lipopolysaccharide (LPS) levels as a marker for bacterial translocation and surrogate for mucosal defense homeostasis. The results were correlated with patients' best clinical response, progression-free survival (PFS), and overall survival (OS) as well as clinical signs of colitis. Results: Median follow-up [95%CI] from the beginning of immunotherapy was 64.6 months [61.0–68.6 months]. Best response to treatment was progressive disease (PD) for 60 patients, stable disease (SD) for 37 patients, partial response (PR) for 18 patients, and complete response (CR) for 4 patients. Kaplan–Meier curves demonstrated a trend for longer PFS and OS in patients with lower colonic SUV and CLR values; however, no statistical significance for these parameters as prognostic factors was demonstrated. On the other hand, patients showing disease control as best response to treatment (SD, PR, CR) had significantly lower colonic MTV and TLG than those showing PD. With regard to lymphoid cell-rich organs, significantly lower baseline SLRmax and BLRmax were observed in patients responding with disease control than progression to treatment. Furthermore, patients with lower SLRmax and BLRmax values had a significantly longer OS when dichotomized at their median. In multivariate analysis, PET parameters that were found to significantly adversely correlate with patient survival were colonic MTV for PFS, colonic TLG for PFS, and BLRmax for PFS and OS. Conclusions: Physiologic colonic [18F]FDG uptake in PET/CT, as assessed by means of SUV, before start of ipilimumab-based treatment does not seem to independently predict patient survival of metastatic melanoma. On the other hand, volumetric PET parameters, such as MTV and TLG, derived from the normal gut may identify patients showing disease control to immunotherapy and significantly correlate with PFS. Moreover, the investigation of glucose metabolism in the spleen and the bone marrow may offer prognostic information. [ABSTRACT FROM AUTHOR]

Purpose : To investigate the prognostic value of [18F]FDG PET/CT as part of response monitoring in metastatic melanoma patients treated with immune checkpoint inhibitors (ICIs). Methods: Sixty-seven patients underwent [18F]FDG PET/CT before start of treatment (baseline PET/CT), after two cycles (interim PET/CT) and after four cycles of ICIs administration (late PET/CT). Metabolic response evaluation was based on the conventional EORTC and PERCIST criteria, as well as the newly introduced, immunotherapy-modified PERCIMT, imPERCIST5 and iPERCIST criteria. Metabolic response to immunotherapy was classified according to four response groups (complete metabolic response [CMR], partial metabolic response [PMR], stable metabolic disease [SMD], progressive metabolic disease [PMD]), and further dichotomized by response rate (responders = [CMR] + [PMR] vs. non-responders = [PMD] + [SMD]), and disease control rate (disease control = [CMR] + [PMR] + [SMD] vs. [PMD]). The spleen-to-liver SUV ratios (SLRmean, SLRmax) and bone marrow-to-liver SUV ratios (BLRmean, BLRmax) were also calculated. The results of PET/CT were correlated with patients' overall survival (OS). Results: Median patient follow up [95% CI] was 61.5 months [45.3 – 66.7 months]. On interim PET/CT, the application of the novel PERCIMT demonstrated significantly longer survival for metabolic responders, while the rest criteria revealed no significant survival differences between the different response groups. Respectively on late PET/CT, both a trend for longer OS and significantly longer OS were observed in patients responding to ICIs with metabolic response and disease control after application of various criteria, both conventional and immunotherapy-modified. Moreover, patients with lower SLRmean values demonstrated significantly longer OS. Conclusion: In patients with metastatic melanoma PET/CT-based response assessment after four ICIs cycles is significantly associated with OS after application of different metabolic criteria. The prognostic performance of the modality is also high after the first two ICIs cycles, especially with employment of novel criteria. In addition, investigation of spleen glucose metabolism may provide further prognostic information. [ABSTRACT FROM AUTHOR]

Background: The usage of immune checkpoint inhibitors (ICIs) is the standard practice for the treatment of metastatic melanoma. However, a significant amount of patients show no response to immunotherapy, while issues on its reliable response interpretation exist. Aim of this study was to investigate the phenomenon of early disease progression in 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in melanoma patients treated with ICIs. Methods: Thirty-one patients under ICIs serially monitored with 18F-FDG PET/CT were enrolled. All patients exhibited progressive metabolic disease (PMD) after two ICIs' cycles according to the European Organization for Research and Treatment of Cancer (EORTC) criteria, and were characterized as unconfirmed PMD (uPMD). They were further followed with at least one PET/CT for either confirmation of PMD (cPMD) or demonstration of pseudoprogression remission. Patients were also evaluated with the PET Response Evaluation Criteria for Immunotherapy (PERCIMT). Moreover, in an attempt to investigate immune activation, the spleen to liver ratios (SLRmean, SLRmax) of 18F-FDG uptake were measured. Results: Median follow up was 69.7 months [64.6–NA]. According to EORTC, 26/31 patients with uPMD eventually showed cPMD (83.9%) and 5/31 patients showed pseudoprogression (16.1%). Patients with cPMD (n = 26) had a median OS of 10.9 months [8.5–NA], while those with pseudoprogression (n = 5) did not reach a median OS [40.9–NA]. Respectively, after application of PERCIMT, 2/5 patients of the pseudoprogression group were correctly classified as non-PMD, reducing the uPMD cohort to 29 patients; eventually, 26/29 patients demonstrated cPMD (89.7%) and 3/29 pseudoprogression (10.3%). One further patient with pseudoprogression exhibited transient, sarcoid-like, mediastinal/hilar lymphadenopathy, a known immune-related adverse event (irAE). Finally, patients eventually showing cPMD exhibited a significantly higher SLRmean than those showing pseudoprogression after two ICIs' cycles (p = 0.038). Conclusion: PET/CT, performed already after administration of two ICIs' cycles, can identify the majority of non-responders in melanoma immunotherapy. In order to tackle however, the non-negligible phenomenon of pseudoprogression, another follow-up PET/CT, the usage of novel response criteria and vigilance over emergence of radiological irAEs are recommended. Moreover, the investigation of spleen glucose metabolism may offer further prognostic information in melanoma patients under ICIs. [ABSTRACT FROM AUTHOR]

Background: An association between immune-related adverse events (irAEs) caused by immunotherapeutic agents and the clinical benefit of immunotherapy has been suggested. We retrospectively evaluated by means of 18F-FDG PET/CT lymphoid tissue changes in the mediastinal/hilar lymph nodes and the spleen in response to ipilimumab administration in metastatic melanoma.Methods: A total of 41 patients with unresectable metastatic melanoma underwent 18F-FDG PET/CT before the start of ipilimumab (baseline PET/CT), after two cycles (interim PET/CT) and at the end of treatment (late PET/CT). Data analysis was focused on the mediastinal/hilar lymph nodes and the spleen. The patients' best clinical response (BCR) was used as reference.Results: According to the BCR reference, 31 patients showed disease control (DC) and 10 patients showed progressive disease (PD). Mediastinal/hilar lymph node evaluation revealed that in total 4 patients in the interim or late PET/CT (10%) demonstrated a 'sarcoid-like lymphadenopathy' as response to treatment (LN-positive). All LN-positive patients responded to ipilimumab with DC. On the other hand, no significant differences between the DC and PD groups regarding both semi-quantitative and quantitative 18F-FDG PET spleen-related parameters at baseline and as response to treatment were detected.Conclusion: Based on our findings, 10% patients in the interim or late PET/CT showed 'sarcoid-like lymphadenopathy' as response to treatment. All these patients showed disease control, implying a relation between the appearance of sarcoid-like lymphadenopathy and the clinical benefit of anti-CTLA-4 therapy. On the other hand, quantitative 18F-FDG PET analysis of the spleen showed a poor performance in predicting clinical benefit to ipilimumab. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy has raised the issue of appropriate treatment response evaluation, due to the unique mechanism of action of the immunotherapeutic agents. Aim of this analysis is to evaluate the potential role of quantitative analysis of 2-deoxy-2-(18F)fluoro-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) data in monitoring of patients with metastatic melanoma undergoing ipilimumab therapy.Methods: 25 patients with unresectable metastatic melanoma underwent dynamic PET/CT (dPET/CT) of the thorax and upper abdomen as well as static, whole body PET/CT with 18F-FDG before the start of ipilimumab treatment (baseline PET/CT), after two cycles of treatment (interim PET/CT) and at the end of treatment after four cycles (late PET/CT). The evaluation of dPET/CT studies was based on semi-quantitative (standardized uptake value, SUV) calculation as well as quantitative analysis, based on two-tissue compartment modeling and a fractal approach. Patients’ best clinical response, assessed at a mean of 59 weeks, was used as reference.Results: According to their best clinical response, patients were dichotomized in those demonstrating clinical benefit (CB, n = 16 patients) and those demonstrating no clinical benefit (no-CB, n = 9 patients). No statistically significant differences were observed between CB and no-CB regarding either semi-quantitative or quantitative parameters in all scans. On contrary, the application of the recently introduced PET response evaluation criteria for immunotherapy (PERCIMT) led to a correct classification rate of 84% (21/25 patients).Conclusion: Quantitative analysis of 18F-FDG PET data does not provide additional information in treatment response evaluation of metastatic melanoma patients receiving ipilimumab. PERCIMT criteria correlated better with clinical response. [ABSTRACT FROM AUTHOR]

Purpose: The aim of the present study was to assess the value of interim 18F-FDG PET/CT performed after the first two cycles of ipilimumab treatment in the prediction of the final clinical response to this type of immunotherapy.Methods: The study group comprised 41 patients with unresectable metastatic melanoma scheduled for ipilimumab therapy. Whole-body 18F-FDG PET/CT was performed before the start of ipilimumab treatment (baseline PET/CT) and after the initial two cycles of ipilimumab treatment (interim PET/CT). Evaluation of patient response to treatment was based on the European Organization for Research and Treatment of Cancer (EORTC) 1999 criteria for PET as well as the recently proposed PET Response Evaluation Criteria for Immunotherapy (PERCIMT). The patients’ best clinical response, assessed at a median of 21.4 months (range 6.3-41.9 months) was used as reference.Results: According to their best clinical response, the patients were divided into two groups: those showing clinical benefit (CB) including stable disease, partial response and complete response (31 patients), and those showing no clinical benefit (no-CB including progressive disease (10 patients). According to the EORTC criteria, interim PET/CT demonstrated progressive metabolic disease (PMD) in 20 patients, stable metabolic disease (SMD) in 11 patients, partial metabolic response (PMR) in 8 patients, and complete metabolic response (CMR) in 2 patients. According to the PERCIMT, interim PET/CT demonstrated PMD in 9 patients, SMD in 24 patients, PMR in 6 patients and CMR in 2 patients. On the basis of the interim PET, the patients were divided in a similar manner to the division according to clinical response into those showing metabolic benefit (MB) including SMD, PMR and CMR, and those showing no metabolic benefit (no-MB) including PMD. According to this dichotomization, the EORTC criteria showed a sensitivity (correctly predicting CB) of 64.5%, a specificity (correctly predicting no-CB) of 90.0%, a positive predictive value (PPV) of 95.2%, a negative predictive value (NPV) of 45.0% and an accuracy of 70.7% in predicting best clinical response. The PERCIMT showed a sensitivity of 93.6%, a specificity of 70.0%, a PPV of 90.6%, a NPV of 77.8% and an accuracy of 87.8%. The McNemar test showed that the PERCIMT had a significantly higher sensitivity than EORTC criteria (p = 0.004), while there was no significant difference in specificity (p = 0.5). The agreement between the two sets of criteria was poor (McNemar test p = 0.001, and accordingly kappa = 0.46).Conclusion: The application of the recently proposed PERCIMT to interim 18F-FDG PET/CT provides a more sensitive predictor of final clinical response to immunotherapy than the application of the EORTC criteria in patients with metastatic melanoma. [ABSTRACT FROM AUTHOR]

Purpose: Evaluation of response to immunotherapy is a matter of debate. The aim of the present study was to evaluate the response of metastatic melanoma to treatment with ipilimumab by means of F-FDG PET/CT, using the patients' clinical response as reference. Methods: The final cohort included in the analyses consisted of 41 patients with metastatic melanoma who underwent F-FDG PET/CT before and after administration of ipilimumab. After determination of the best clinical response, the PET/CT scans were reviewed and a separate independent analysis was performed, based on the number and functional size of newly emerged F-FDG-avid lesions, as well as on the SUV changes after therapy. Results: The median observation time of the patients after therapy was 21.4 months (range 6.3-41.9 months). Based on their clinical response, patients were dichotomized into those with clinical benefit (CB) and those without CB (No-CB). The CB group (31 patients) included those with stable disease, partial remission and complete remission, and the No-CB group (10 patients) included those with progressive disease. The application of a threshold of four newly emerged F-FDG-avid lesions on the posttherapy PET/CT scan led to a sensitivity (correctly predicting CB) of 84% and a specificity (correctly predicting No-CB) of 100%. This cut-off was lower for lesions with larger functional diameters (three new lesions larger than 1.0 cm and two new lesions larger than 1.5 cm). SUV changes after therapy did not correlate with clinical response. Based on these findings, we developed criteria for predicting clinical response to immunotherapy by means of F-FDG PET/CT (PET Response Evaluation Criteria for Immunotherapy, PERCIMT). Conclusion: Our results show that a cut-off of four newly emerged F-FDG-avid lesions on posttherapy PET/CT gives a reliable indication of treatment failure in patients under ipilimumab treatment. Moreover, the functional size of the new lesions plays an important role in predicting the clinical response. Validation of these results in larger cohorts of patients is warranted. [ABSTRACT FROM AUTHOR]

Despite markedly improved treatment options for metastatic melanoma, resistance to targeted therapies such as BRAF inhibitors (BRAFi) or BRAFi plus MEK inhibitors (MEKi) remains a major problem. Our aim was to characterize progression on BRAFi therapy and outcome of subsequent treatment. One hundred and eighty patients with BRAF-mutant metastatic melanoma who had progressed on treatment with single- agent BRAFi from February 2010 to April 2015 were included in a retrospective data analysis focused on patterns of progression, treatment beyond progression (TBP) and subsequent treatments after BRAFi therapy. Analysis revealed that 51.1% of patients progressed with both new and existing metastases opposed to progression of only preexisting (28.3%) or only new (20.6%) metastases. Exclusive extracranial progression occurred in 50.6% of patients compared to both extra- and intracranial (29.4%) or sole cerebral progression (20%). Multivariable analyses demonstrated that single site progression and primary response to BRAFi were associated with improved progressionfree survival. Progression with exclusively new or only existing metastases and a baseline Eastern Cooperative Oncology Group (ECOG) of 0 were associated with prolonged overall survival (OS). TBP had no significant impact on OS. Other subsequent treatments showed low efficacy with the exception of anti- PD-1 antibodies. In conclusion we identified specific patterns of progression which significantly correlate with further prognosis after progression on BRAFi treatment. In contrast to previously published data, we could not demonstrate a significant survival benefit for BRAFi TBP. Subsequent therapies had strikingly low efficacy except for PD-1 inhibitors. [ABSTRACT FROM AUTHOR]

Simple Summary: The fractal dimension (FD) and the multifractal spectrum (MFS) are nonlinear quantitative measures which express the heterogeneity in the distribution of the tracer, F-18-fluorodeoxyglucose, (18F-FDG), in the body of patients suffering from metastatic melanoma. Given the well-documented, high accumulation of the tracer in tumor/metastatic sites, the measures expressing the tracer distribution also express the extent of metastases in the body. As such, FD and MFS can be employed to detect the presence of melanoma and to monitor the therapeutic outcome using the PET-CT follow-up digitized scans of the patients. In the present study, the FD and MFS measures of patients are evaluated before and during treatment with PD-1 inhibitors and are compared with the corresponding values of healthy controls. The MFS predictions agree with the PET Response Evaluation Criteria for Immunotherapy (PERCIMT) in 81% of the cases, while the FD agrees in 77% of all cases. Therefore, the quantitative MFS is proposed as an additional, alternative biomarker for monitoring the immunotherapy outcome in melanoma patients, after treatment with PD-1 inhibitors. Longitudinal whole-body PET-CT scans with F-18-fluorodeoxyglucose (18F-FDG) in patients suffering from metastatic melanoma were analyzed and the tracer distribution in patients was compared with that of healthy controls. Nineteen patients with metastatic melanoma were scanned before, after two and after four cycles of treatment with PD-1 inhibitors (pembrolizumab, nivolumab) applied as monotherapy or as combination treatment with ipilimumab. For comparison eight healthy controls were analyzed. As quantitative measures for the comparison between controls and patients, the nonlinear fractal dimension (FD) and multifractal spectrum (MFS) were calculated from the digitized PET-CT scans. The FD and MFS measures, which capture the dispersion of the tracer in the body, decreased with disease progression, since the tracer particles tended to accumulate around metastatic sites in patients, while the measures increased when the patients' clinical condition ameliorate. The MFS measure gave better predictions and were consistent with the PET Response Evaluation Criteria for Immunotherapy (PERCIMT) in 81% of the cases, while FD agreed in 77% of all cases. These results agree, qualitatively, with a previous study of our group when treatment with ipilimumab monotherapy was considered. [ABSTRACT FROM AUTHOR]

Simple Summary: The reliable and early during-the-course-of-treatment assessment of tumor response to the novel immunotherapeutic agents is a matter of debate, posing relevant challenges to conventional imaging modalities. In this prospective study, including 25 metastatic melanoma patients, we explored the prognostic significance of quantitative, dynamic 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) performed early during programmed cell death protein 1 (PD-1) blockade. At a median follow-up of 24.2 months, several semiquantitative and quantitative PET/CT parameters derived from tumor lesions and reference tissues had an impact on progression-free survival (PFS). In particular, 18F-FDG standardized uptake value (SUVmean, SUVmax) and fractal dimension (FD) of melanoma lesions adversely affected PFS, while FD of the thyroid, as well as SUVmax and k3 of the bone marrow, positively affected PFS. These findings underline the potential predictive role of quantitative, dynamic, interim PET/CT—performed in combination with conventional, static, whole-body PET/CT—in metastatic melanoma patients under PD-1 blockade. The advent of novel immune checkpoint inhibitors has led to unprecedented survival rates in advanced melanoma. At the same time, it has raised relevant challenges in the interpretation of treatment response by conventional imaging approaches. In the present prospective study, we explored the predictive role of quantitative, dynamic 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) performed early during immunotherapy in metastatic melanoma patients receiving treatment with programmed cell death protein 1 (PD-1) inhibitors. Twenty-five patients under PD-1 blockade underwent dynamic and static 18F-FDG PET/CT before the start of treatment (baseline PET/CT) and after the initial two cycles of therapy (interim PET/CT). The impact of semiquantitatively (standardized uptake value, SUV) and quantitatively (based on compartment modeling and fractal analysis) derived PET/CT parameters, both from melanoma lesions and different reference tissues, on progression-free survival (PFS) was analyzed. At a median follow-up of 24.2 months, survival analysis revealed that the interim PET/CT parameters SUVmean, SUVmax and fractal dimension (FD) of the hottest melanoma lesions adversely affected PFS, while the parameters FD of the thyroid, as well as SUVmax and k3 of the bone marrow positively affected PFS. The herein presented findings highlight the potential predictive role of quantitative, dynamic, interim PET/CT in metastatic melanoma under PD-1 blockade. Therefore, dynamic PET/CT could be performed in selected oncological cases in combination with static, whole-body PET/CT in order to enhance the diagnostic certainty offered by conventional imaging and yield additional information regarding specific molecular and pathophysiological mechanisms involved in tumor biology and response to treatment. [ABSTRACT FROM AUTHOR]