PET/CT variants and pitfalls in malignant melanoma

Abstract18F-FDG PET/CT plays an increasingly pivotal role in the staging and post-treatment monitoring of high-risk melanoma patients, augmented by the introduction of therapies, including tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICIs), that have novel modes of action that challenge conventional response assessment. Simultaneously, technological advances have been regularly released, including advanced reconstruction algorithms, digital PET and motion correction, which have allowed the PET community to detect ever-smaller cancer lesions, improving diagnostic performance in the context of indications previously viewed as limitations, such as detection of in-transit disease and confirmation of the nature of small pulmonary metastases apparent on CT.This review will provide advice regarding melanoma-related PET protocols and will focus on variants encountered during the imaging of melanoma patients. Emphasis will be made on pitfalls related to non-malignant diseases and treatment-related findings that may confound accurate interpretation unless recognized. The latter include signs of immune activation and immune-related adverse events (irAEs). Technology-related pitfalls are also discussed, since while new PET technologies improve detection of small lesions, these may also induce false-positive cases and require a learning curve to be observed. In these times of the COVID 19 pandemic, cases illustrating lessons learned from COVID 19 or vaccination-related pitfalls will also be described.

Autoimmune colitis and neutropenia in adjuvant anti-PD-1 therapy for malignant melanoma: efficacy of Vedolizumab, a case report

Immune checkpoint inhibitors (ICIs) represent an important advance in the adjuvant treatment of patients with high-risk melanoma. Although the safety profile of anti-programmed cell death protein-1 (PD-1) is fairly acceptable, different immune-related adverse events (irAEs) are described. Herein we report for the first time a notably multidisciplinary combined approach on a malignant melanoma (MM) patient treated with anti-PD-1 antibody in adjuvant setting. In this novel approach, corticosteroid-refractory immune-mediated colitis (IMC) was effectively treated with Vedolizumab, a selective blockade of the α4β7 integrin and corticosteroids were successfully administered for autoimmune neutropenia. Notably, our patient also express HLA-B*35, a potential biomarker for predicting a genetic basis of autoimmune susceptibility. Our experience offers a possible future perspective about the use of Vedolizumab together with immunotherapy in a strategic early approach for high-risk patients genotyped for HLA.

88 Evidence of enhanced immune activation within the tumor microenvironment and the circulation of female patients with high-risk melanoma compared to males

BackgroundSex differences in tumor immunity and response to immunotherapy were shown in murine models and descriptive analyses from recent clinical trials. We recently reported that female gender is a favorable prognostic marker for survival benefit following ipilimumab and high dose interferon-alfa (HDI) adjuvant therapy of high-risk melanoma in the ECOG-ACRIN E1609 trial (N=1670). Therefore, we investigated differences in candidate immune biomarkers in the circulation and tumor microenvironment (TME) of female and male patients.MethodsGene expression profiling (GEP) was performed on the tumor biopsies of 718 (454 male, 264 female) patients. The primary endpoint was mRNA expression profiling using U133A 2.0 Affymetrix gene chips. Raw microarray data sets were normalized by using the Robust Multi-array Average (RMA) method using Affymetrix Power Tools (APT) as previously published. Multiple probe sets representing the same genes were collapsed by using the probe with maximum gene expression. Gene set enrichment analysis (GSEA) was performed by comparing the female and male tumor samples, and gene sets with FDR q-value <0.1 were deemed as significant. Similarly, peripheral blood (serum and PBMC) samples were tested for soluble (Luminex) and cellular (multicolor flow cytometry) prognostic biomarkers in a subset of patients (N=321; 109 female and 212 male). All patients provided an IRB-approved written informed consent.ResultsAmong the subset of patients tested for circulating biomarkers, females were significantly younger than males (P=0.03). Testing PBMCs, the percentages of CD3+ T cells (P=0.04) and CD3+CD4+ helper T cells (P=0.0005) were significantly higher in female patients compared to males. Also, there were trends toward higher levels of proinflammatory cytokines IL1beta (P=0.07) and IL6 (P=0.06) in females. On the other hand, males had significantly higher percentages of monocytes (P=0.03). Further, there were trends toward higher percentages of CD3+/CD4+/CD25hi+/Foxp3+ (P=0.1) and CD3+/CD4+/CD25+/CD127low+ (P=0.1) T-reg in male patients compared to females. Among the cohort of patients (N=718) with tumor GEP data, females were significantly younger than males (P=0.0009). GEP identified pathways and genes related to immune cell infiltration and activation that were significantly enriched in the tumors of females compared to males (table 1).Abstract 88 Table 1Immune pathways significantly enriched in tumors of femalesConclusionsFemale gender was associated with adjuvant immunotherapeutic benefits and female patients were more likely to have evidence of immune activation within the TME and the circulation, supporting a potentially important role for female related factors in the immune response against melanoma, and these require further investigation.AcknowledgementsWe are grateful to the patients and family members who participated in the E1609 trial and the E1609 trial investigators. This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O’Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180794, U10CA180820, U10CA180888, UG1CA233180, UG1CA233184. Biomarkers studies were supported under the following award number: P50CA12197310 (Tarhini and Kirkwood). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Trial RegistrationNCT01274338Ethics ApprovalThe E1609 study protocol was approved by the institutional review board of each participating institution and conducted in accordance with Good Clinical Practice guidelines as defined by the International Conference on Harmonization. All patients provided an IRB-approved written informed consent.ConsentNot applicable.

87 Enhanced immunogenicity within the tumor microenvironment and the circulation of high-risk melanoma patients with unknown primary compared to those whose primary melanoma is known

BackgroundWe recently reported data supporting the unknown primary status as a potentially distinct prognostic group among high-risk melanoma patients treated with ipilimumab and high dose interferon-alfa (HDI) in the ECOG-ACRIN E1609 trial (N=1670) with improved RFS and OS outcomes compared to known primary. Therefore, we investigated differences in candidate immune biomarkers in the circulation and tumor microenvironment (TME) of patients with unknown compared to those with known primary melanoma enrolled in this trial that tested adjuvant ipilimumab at 3 and 10 mg/kg versus HDI.MethodsGene expression profiling (GEP) was performed on the tumor biopsies of 718 (102 unknown, 616 known primary) melanoma patients. The primary endpoint was mRNA expression profiling using U133A 2.0 Affymetrix gene chips. Raw microarray data sets were normalized by using the Robust Multi-array Average (RMA) method using Affymetrix Power Tools (APT) as previously published. Multiple probe sets representing the same genes were collapsed by using the probe with maximum gene expression. Gene set enrichment analysis (GSEA) was performed by comparing the unknown and known primary tumor samples, and gene sets with FDR q-value <0.1 were deemed as significant. Similarly, peripheral blood (serum and PBMC) samples were tested for soluble (Luminex) and cellular (multicolor flow cytometry) immune biomarkers in a subset of patients (N=321; 66 unknown and 255 known primary). All patients provided an IRB-approved written informed consent.ResultsUnknown primary melanoma cases represented 12.8% of the total E1609 study population (N=1670) including 11.7% on the ipilimumab arms and 14.7% on the HDI arm. Stratifying by stage, relapse free survival (RFS) (P=0.001) and overall survival (OS) (P=0.009) were significantly better for patients with unknown primary tumor compared to known primary. Including only ipilimumab-treated patients, RFS (P=0.005) and OS (P=0.023) were significantly better in favor of the unknown primary status. Among the cohort of patients with tumor GEP data (N=718), GEP identified pathways and genes related to autoimmunity, inflammation, immune cell infiltration and immune activation that were significantly enriched in the unknown primary tumors compared to known primaries (table 1). Among the subset of patients tested for circulating biomarkers, patients with unknown primary melanoma had significantly higher circulating levels of IL-2R than those with known primary (P=0.04).Abstract 87 Table 1Immune pathways enriched in unknown primary melanomaConclusionsUnknown primary high-risk melanoma patients had significantly better prognosis and evidence of significantly enhanced immune activation within the TME and the circulation, supporting the designation of unknown primary melanoma as a distinct prognostic marker in patients with high-risk melanoma.AcknowledgementsWe are grateful to the patients and family members who participated in the E1609 trial and the E1609 trial investigators. This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O’Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180794, U10CA180820, U10CA180888, UG1CA233180, UG1CA233184. Biomarkers studies were supported under the following award number: P50CA12197310 (Tarhini and Kirkwood). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.Trial RegistrationNCT01274338Ethics ApprovalThe E1609 study protocol was approved by the institutional review board of each participating institution and conducted in accordance with Good Clinical Practice guidelines as defined by the International Conference on Harmonization. All patients provided an IRB-approved written informed consent.ConsentNot applicable.

Feasibility of assessing utilities with a single-item standard gamble questionnaire in patients with melanoma

Objectives To determine the feasibility of eliciting utilities with a standard gamble self-completion questionnaire that uses a single-item approach in melanoma patients. Methods 150 patients with low-risk melanoma completed a paper standard gamble questionnaire. Six scenarios described the adjuvant treatment of high-risk melanoma with interferon alfa-2b with varied side effects. Patients were asked to directly state the maximum death risk they would accept to prevent these health states. Methods were the same as in a study by Kilbridge et al. (J Clin Oncol 19(3):812–823, 2021. 10.1200/JCO.2001.19.3.812), except that they used computerised interviews and an iterative risk variation (Ping–Pong method) to elicit utilities. Results The rate of missing values in the standard gamble was 1.0%. The percentage of patients who misordered scenarios was very similar to the reference study (11.3% vs. 11.2%). Mean utilities were also similar with a maximum difference of 0.02 points, but median utilities were not (between 0.21 points below and 0.05 points above the reference study). Conclusions One-item utility elicitation with questionnaires might be a feasible alternative to computerised face-to-face interviews to conduct a standard gamble in melanoma patients.

Functional assessment of cancer therapy questionnaire for melanoma in the Serbian population: A factor analytic approach

The aim of this study was to examine the psychometric properties of the Functional Assessment Cancer Therapy—Melanoma (FACT-M) questionnaire in the Serbian language. The FACT-M was translated into Serbian using the standard methodology after obtaining the licence from the Functional Assessment of Chronic Illness Therapy (FACIT) translation project team. This version of FACT-M was distributed to a cohort of consecutive patients with histologically confirmed high-risk skin melanoma treated at the tertiary referral center. To examine construct validity of the FACT-M in Serbian, we performed exploratory factor analysis (EFA) and confirmatory factor analysis (CFA). The FACT-General (FACT-G) did not fit the original 4-domain structure. Instead, we accepted a 7-domain structure which, aside from physical, emotional, social and functional well-being, had domains of ‘friends’ support’, ‘illness acceptance’ and ‘fear of death’. Melanoma scale (MS) and Melanoma surgery scale (MSS) did not fit the original one-dimensional structure. The MS was observed to have 4 domains: ‘pain’, ‘skin problems’, ‘abdominal metastases’ and ‘other problems’. The MSS was observed to have 2 domains: ‘having symptoms’ and ‘no symptoms’. It is suggested that the FACT-M questionnaire is analyzed using the newly extracted domains to examine quality of life of people with high-risk melanoma in Serbia.