Small Melanoma Research Articles

On the Prognostic Implication of Delays in the Definitive Treatment of Uveal Melanoma

Background: Recent studies suggest that delays in the definitive treatment of uveal melanoma may increase the risk of metastatic disease. This topic has been the subject of considerable debate. Methods: In this study, we combine and contrast medical evidence from several recent publications seeking to clarify the association between treatment delays and prognosis. Results: Emerging evidence indicates that metastatic seeding may continue until the primary tumor is effectively treated. Metastases that arise later in the disease course may carry additional genetic aberrations, enhancing their capacity to establish fatal macrometastases. Importantly, previous reports of shared mutations between primary tumors and metastases should not be interpreted as evidence that all metastases are seeded early. On the contrary, some tumors acquire additional driver mutations in the later stages, which are subsequently shared between the primary tumors and metastases. The increased risk of metastasis in patients with local tumor recurrence further highlights the importance of timely treatment. Additionally, new data on circulating tumor cells and treatment timing challenge the traditional practice of observing small melanomas. Conclusions: Observation is still warranted for indeterminate lesions to confirm malignancy. However, once a melanoma diagnosis has been established, further observation is harmful, and treatment should be administered as soon as reasonably possible.

The Great Impostor: A challenging case of small-cell melanoma with isolated adrenal metastasis.

Small-cell melanoma masquerading as an adrenal non-Hodgkin lymphoma. The index report illustrates the deceptive cytomorphologic features of a small cell type malignant melanoma metastatic to the adrenal gland. The diagnosis was confirmed by performing immunocytochemistry on the cell block sections. The key cytomorphologic mimics and their distinctive features have also been highlighted.

Development and Validation of a Deep Learning Algorithm for Differentiation of Choroidal Nevi from Small Melanoma in Fundus Photographs

To develop and validate a deep learning algorithm capable of differentiating small choroidal melanomas from nevi. Retrospective multicenter cohort study. A total of 802 images from 688 patients diagnosed with choroidal nevi or melanoma. Wide field and standard field fundus photographs were collected from patients diagnosed with choroidal nevi or melanoma by ocular oncologists during clinical examinations. A lesion was classified as a nevus if it was followed for at least 5 years without being rediagnosed as melanoma. A neural network optimized for image classification was trained and validated on cohorts of 495 and 168 images and subsequently tested on independent sets of 86 and 53 images. Area under the curve (AUC) in receiver operating characteristic analysis for differentiating small choroidal melanomas from nevi. The algorithm achieved an AUC of 0.88 in both test cohorts, outperforming ophthalmologists using the Mushroom shape, Orange pigment, Large size, Enlargement, and Subretinal fluid (AUC 0.77) and To Find Small Ocular Melanoma Using Helpful Hints Daily (AUC 0.67) risk factors (DeLong's test, P<0.001). The algorithm performed equally well for wide field and standard field photos (AUC 0.89 for both when analyzed separately). Using an optimal operating point of 0.63 (on a scale from 0.00 to 1.00) determined from the training and validation datasets, the algorithm achieved 100% sensitivity and 74% specificity in the first test cohort (F-score 0.72), and 80% sensitivity and 81% specificity in the second (F-score 0.71), which consisted of images from external clinics nationwide. It outperformed 12 ophthalmologists in sensitivity (Mann-Whitney U, P=0.006) but not specificity (P=0.54). The algorithm showed higher sensitivity than both resident and consultant ophthalmologists (Dunn's test, P=0.04 and P=0.006, respectively) but not ocular oncologists (P>0.99, all P values Bonferroni corrected). This study develops and validates a deep learning algorithm for differentiating small choroidal melanomas from nevi, matching or surpassing the discriminatory performance of experienced human ophthalmologists. Further research will aim to validate its utility in clinical settings. Financial DisclosuresProprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Intralesional Vessel Diameter Measured by Optical Coherence Tomography Angiography Could Improve the Differential Diagnosis of Small Melanocytic Choroidal Lesions.

In this study, we aimed to identify the features of indeterminate choroidal melanocytic lesions visualized on optical coherence tomography angiography (OCTA) and to identify the predictors of growth. We retrospectively evaluated 86 patients with indeterminate lesions treated at our centre from 2016 to 2021. Clinical management involved active surveillance followed by brachytherapy if growth was detected. The lesions were classified into two groups according to whether they grew (small melanomas) or remained stable (choroidal nevi). Growth was detected in 19 (22.1%) lesions. All patients underwent OCTA at baseline. These images were compared to identify the possible predictors of growth. Significant between-group differences were observed in thickness (p = 0.00), greatest basal diameter (p = 0.00), number of risk factors (p = 0.00), symptoms (p = 0.001; relative risk [RR]: 4.3), orange pigment (p = 0.00; RR: 6.02), and ultrasonographic hollowness (Kappa sign); p = 0.000; RR: 5.3). The melanomas had significantly more vessels with a diameter ≥ 76.3 µm (p = 0.02; RR: 2.46). The time to growth in these lesions was significantly shorter (p = 0.05) than in lesions with smaller vessels. These findings show that vessel diameter quantified by OCTA can help differentiate between choroidal nevi and small melanomas, when considered together with clinical risk factors.

High-Dose-Rate Yttrium-90 (90Y) Episcleral Plaque Brachytherapy for Iris and Iridociliary Melanoma

PurposeTo describe a pilot study on the use of single-session, high-dose-rate, FDA-cleared, yttrium-90 (90Y) plaque brachytherapy for iris and iridociliary melanoma. DesignA single-center, clinical case series. ParticipantsSix consecutive patients were included in this study. Each was diagnosed with an iris or iridociliary melanoma based on clinical examination with or without biopsy. MethodsEach tumor was staged according to AJCC criteria and received 90Y eye plaque brachytherapy. The main variables were tumor size, patient age, sex, and method of diagnosis (clinical or biopsy). Surgical techniques, treatment durations, and ocular side effects were recorded. Local control was defined as a lack of tumor growth or regression determined by clinical examinations, including slit-lamp and gonio photography, as well as high-frequency ultrasound measurements. Toxicity parameters included acute and short-term corneal/scleral change, anterior segment inflammation, and cataract progression. ResultsHigh-dose-rate 90Y plaque brachytherapy was used to treat small (AJCC cT1) category melanomas. Single-surgery high-dose-rate irradiations were performed under anesthesia. Due to short treatment durations, high-dose-rate 90Y did not require the additional procedures used for low-dose-rate plaque (e.g., sutures, amniotic membrane epicorneal buffering, Gunderson flaps, and second surgeries for plaque removal). Only conjunctival recession was used to avoid normal tissue irradiation. high-dose-rate 90Y treatment durations averaged 8.8 minutes (median 7.9, range 5.8-12.9). High-dose-rate 90Y brachytherapy was associated with no periorbital, corneal (Descemet’s folds), and/or conjunctival edema. There was no acute or short-term anterior uveitis, secondary cataract, scleropathy, radiation retinopathy, maculopathy, or optic neuropathy. Follow-up was a mean of 16.0 (range 12 to 24) months. Evidence of local control included a lack of expansion of tumor borders (n=6, 100%), darkening and/or atrophy of the tumor surface (n=5/6, 83%), and a mean 24.5% reduction in ultrasonographically measured tumor thickness. There were no cases of metastatic disease. ConclusionHigh-dose-rate 90Y brachytherapy allowed for single-surgery, minimally invasive, outpatient irradiation of iris and iridociliary melanomas.

Abstract B102: Development of covalent inhibitors targeting Ras Q61 hotspot mutants

Abstract Mutations in the proto-oncogenes RAS are a key driver of various cancers, including pancreatic, colorectal, non–small cell lung cancer (NSCLC), melanoma, and thyroid cancer. Despite being considered undruggable for many years, recent efforts have led to the FDA approval of two drugs, Sotorasib and Adagrasib. They covalently target the K-Ras mutant isoform K-Ras(G12C), thereby inhibiting its oncogenic effect. However, the use of these drugs is inherently limited to cancers driven by the K-Ras(G12C) mutant, which is very common only in NSCLC. Although other covalent inhibitors targeting the K-Ras mutants K-Ras(G12S) and K-Ras(G12R) have been developed, it has so far not been possible to target the other frequently mutated amino acid Q61. Here we present our approach for the development of novel covalent inhibitors specifically targeting Q61 mutations in Ras proteins, which are prevalent in melanoma, multiple myeloma, and thyroid cancer. We demonstrate how covalent inhibitors specifically react with the mutant Q61C in both K and H-Ras proteins as proof-of-concept and show our efforts to extend this to the other Q61 mutant isoforms. We base our strategy on the modification of well-established switch-II pocket K-Ras inhibitors and explore multiple novel scaffolds specifically designed to target mutations of Q61. In addition to its occurrence in various cancers, Ras(Q61X) is also a common resistance mutation in patients treated with MAPK inhibitors. This work could further increase the number of patients potentially benefiting from Ras(Q61X) targeting drugs. Citation Format: Julius Pampel, Johannes Morstein, Qinheng Zheng, David M. Peacock, Kevan M. Shokat. Development of covalent inhibitors targeting Ras Q61 hotspot mutants [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B102.

Small extracellular vesicle-based human melanocyte and melanoma signature.

Intercellular communication is a cell-type and stimulus-dependent event driven not only by soluble factors but also by extracellular vesicles (EVs). EVs include vesicles of different size and origin that contain a myriad of molecules. Among them, small EVs (sEV; <200 nm) have been shown to modulate not just regional cell responses but also distant organ behavior. In cancer, distant organ modulation by sEVs has been associated to disease dissemination, which is one of the main concerns in melanoma. Description of broadly conserved alterations in sEV-contained molecules represents a strategy to identify key modifications in cellular communication as well as new disease biomarkers. Here, we characterize proteomes of cutaneous melanocyte and melanoma-derived sEVs to deepen on the landscape of normal and disease-related cell communication. Results reveal the presence of unique protein signatures for melanocytes and melanoma cells that reflect cellular transformation-related profound modifications. Melanocyte-derived sEVs are enriched in oxidative metabolism (e.g., aconitase 2, ACO2) or pigmentation (e.g., tyrosinase, TYR) related proteins while melanoma-derived sEVs reflect a generalized decrease in mature melanocytic markers (e.g., melanoma antigen recognized by T-cells 1, MART-1, also known as MLANA) and an increase in epithelial to mesenchymal transition (EMT)-related adhesion molecules such as tenascin C (TNC).

Understanding choroidal nevus risk factors for transformation into melanoma

A choroidal nevus is a common intraocular tumor in the United States, found in approximately 5% of Caucasian adults. The three main risks of melanocytic choroidal nevus include vision loss from a subfoveal nevus, development of subretinal fluid, and transformation of nevus into melanoma, a malignant counterpart. We explore clinical risk factors that predict benign melanocytic choroidal nevus transformation into a malignant choroidal melanoma. Based on a large analysis of 2,355 cases that were monitored longitudinally using multimodal imaging, the most recent list of clinical features includes tumor Thickness greater than 2 mm on ultrasonography, subretinal Fluid on optical coherence tomography, Symptomatic vision loss 20/50 or worse, Orange pigment on fundus autofluorescence, Melanoma hollow on ultrasonography, and DIaMeter greater than 5 mm on fundus photography. These factors are remembered with a mnemonic of the capital letters TFSOM-DIM for “To Find Small Ocular Melanoma Doing Imaging.” Analysis of these factors demonstrated a Kaplan-Meier mean five-year risk of 1% with no risk factors, 11% with any one factor, 22% with any two factors, 34% with any three factors, 51% with any four factors, and 55% with any five factors. There was no patient with six risk factors. Of those with combinations of four risk factors, six of 15 combinations yielded a 70%-100% rate of transformation; of those with combinations of five risk factors, two of five combinations yielded a 70%-100% rate of transformation. Choroidal nevus carries a risk for evolving into melanoma, and understanding of clinical and imaging features predictive of this outcome is highly important.

The role of multifocal electroretinography in the preclinical diagnosis of tumor-associated distant maculopathy in small melanoma of the choroid of extramacular localization

To assess the role of multifocal electroretinography (mf-ERG) in preclinical diagnosis of tumor-associated distant maculopathy in small choroidal melanoma (CM) of extramacular localization.Material and methods. 35 patients (35 affected and 35 fellow eyes) with small CM of extramacular localization and 23 healthy volunteers (46 eyes) aged 59.67 ± 14.2 years were given general ophthalmological examinations and mf-ERG. Density (nV/deg2), culmination time of the P1 component and amplitude (μV) of the N1 component were measured for 5 response rings (R1–R5) at different distances from the fixation point: central hexagon R1: 2.3° (fovea zone); R2: 2.3–6.9° (parafovea); R3: 6.9–14.3° (perifovea); R4: 14.3–20.8° and R5: 20.8–29.9° (middle periphery areas of the retina).Results. Eyes affected by CM showed a decrease in the density of the P1 component in the R1 hexagon by 25.7% of the normal values (p = 0.03). The fellow eyes showed an increase in the density of the P1 component in the R2 ring (p &lt; 0.05). The peak latency of the P1 component in the R1–R5 rings in the affected and fellow eye was found to elongate by 30–45% (p &lt; 0.05). The amplitude of the N1 component in the central hexagon of CM-affected eyes increased by 12.96%, whilst in the R4–R5 rings it decreased by 36–45% as compared with healthy individuals (p &lt; 0.05). The fellow eye showed supernormal values of the N1 amplitude in R1 and its suppression in R4 and R5 rings (p &lt; 0.05).Conclusion. The mf-ERG method is useful for preclinical diagnosis of tumor-associated distant maculopathy in small CM of extramacular localization. Changes in mf-ERG of the fellow eye in patients with small CM have been documented.

TP53 mutations correlate with the non‐coding RNA content of small extracellular vesicles in melanoma

AbstractNon‐coding RNAs (ncRNAs) are important regulators of gene expression. They are expressed not only in cells, but also in cell‐derived extracellular vesicles (EVs). The mechanisms controlling their loading and sorting remain poorly understood. Here, we investigated the impact of TP53 mutations on the non‐coding RNA content of small melanoma EVs. After purification of small EVs from six different patient‐derived melanoma cell lines, we characterized them by small RNA sequencing and lncRNA microarray analysis. We found that TP53 mutations are associated with a specific micro and long non‐coding RNA content in small EVs. Then, we showed that long and small non‐coding RNAs enriched in TP53 mutant small EVs share a common sequence motif, highly similar to the RNA‐binding motif of Sam68, a protein interacting with hnRNP proteins. This protein thus may be an interesting partner of p53, involved in the expression and loading of the ncRNAs. To conclude, our data support the existence of cellular mechanisms associate with TP53 mutations which control the ncRNA content of small EVs in melanoma.

Phase 1 trial of GD2-SADA:177Lu-DOTA drug complex in patients with recurrent or refractory metastatic solid tumors known to express GD2 including small cell lung cancer (SCLC), sarcoma, and malignant melanoma.

TPS3162 Background: GD2 is a disialoganglioside with high expression in small cell lung cancers (SCLC), sarcomas and melanomas and limited expression in normal tissues. The SADA platform represents a 2-step pretargeted radioimmunotherapy approach developed to optimize tumor targeting and reduce normal tissue irradiation. The GD2-SADA molecule is composed of a non-radioactive, bispecific antibody (anti-GD2 x anti-DOTA) linked to a tetramerization sequence from the p53 protein. In the first step, the GD2-SADA molecule is administered in a tetrameric form with a high affinity to the GD2 tumor target. In preclinical research, any unbound GD2-SADA molecule will disassemble to monomers and has shown to clear via the kidneys. In the second step, the radioactive payload 177Lu-DOTA is administered, which binds to the anti-DOTA part of the GD2-SADA and leads to radiation-induced damage at the target and has shown limited exposure to non-target tissues in preclinical research. This pre-targeting approach supports the concept of highly focused irradiation of the tumor target with the potential of administering higher radioactivity doses. Methods: Trial 1001 (NCT05130255) is a first-in-human, dose-escalation, single-arm, open-label, non-randomized, multicenter phase 1 trial with the purpose of evaluating safety and tolerability of GD2-SADA:177Lu-DOTA. The trial is composed of 3 parts: Part A is dose escalation of the GD2-SADA dose and testing of different intervals between GD2-SADA and 177Lu-DOTA. Part B is dose escalation of the 177Lu-DOTA radioactivity dose to establish its maximum tolerated dose (MTD). Part C involves repeated dosing to assess the safety profile and determine the Recommended Phase 2 Dose (RP2D). Parts B and C may only begin upon completion of dose-limiting toxicity (DLT) observation period of Parts A and B, respectively. Escalation is based on classical 3+3 design. Parts A, B, and C will include 18, 12, and 32 patients, respectively. Patients can only be assigned to one part of the trial. The trial will include adult/adolescent patients with either SCLC, sarcoma, or melanoma with radiographical relapse/progression on standard therapies. The patients must be in ECOG performance status 0-1 and have adequate hematological, renal, and liver function. The patients must have measurable disease according to RECIST 1.1. Patients with active CNS metastases are ineligible. Safety endpoints (DLTs and adverse events) will be summarized by trial part and cohort. Objective response according to RECIST 1.1 and disease control rates at 6, 12 and 24 months will be presented with exact 95% CI. PFS, OS, and duration of response will be estimated using Kaplan-Meier methods. Additional objectives include dosimetry, PK, and immunogenicity data. The study is actively enrolling at US sites. Clinical trial information: NCT05130255 .

Outcomes with bevacizumab for radiation induced-brain necrosis.

e14006 Background: Radiation necrosis (RN) is post-radiation complication that leads to increased permeability and disruption of the blood brain barrier (BBB). This in turn leads to a pro-inflammatory state and an increased production of vascular-endothelial growth factor (VEGF). Bevacizumab is a monoclonal antibody against VEGF and is a potential treatment for RN. The objective of the study is to assess effectiveness of bevacizumab (BEV) for the treatment of brain RN in adults. Methods: Retrospective chart review of 22 patients with various solid malignancies including non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), metastatic melanoma and breast cancer with clinical or radiographic diagnosis of RN seen at Memorial Cancer Institute (MCI) in a 3-year period, from January 1st, 2019 to January 1st, 2023. Radiation doses ranged from 18-24 Gy (single fraction) or 24-27 Gy (3-fraction) for radiosurgery and 30-37.5 Gy for whole brain radiotherapy. Patients were identified that developed RN and VEGF inhibitors were subsequently given to assess effectiveness in the treatment of the condition. We evaluated the dose, frequency, number of treatments received, adverse effects and therapeutic benefits of BEV. Therapeutic benefit was defined as patients that received bevacizumab had a radiological and clinical improvement of the RN (clinical benefit). Brain imaging with MRI or PET/CT scan was completed both pre and post treatment to evaluate efficacy of treatment. Patients were initially given 4 cycles with a subsequent 4 more cycles if it was beneficial and tolerated treatment. Results: 22 patients were included in the study, 9 were males (41%) and median age 66 (range 31-81). 91% (20/22) had a diagnosis of lung cancer. 1 patient had a diagnosis of SCLC, while 19 were diagnosed with NSCLC. The study had a good representation of different races including Non-Hispanic Whites 7 (32%), Hispanics 10 (45%), Blacks 13% (3) and Asians 10% (2). Over 95% (21/22) of patients achieved a clinical benefit, while one patient did not (5%). Patients experienced improvement in cognitive function, headaches, dizziness, weakness, and other symptoms with BEV. MRIs showed improvement in edema and a reduction/stabilization of brain lesions. The most frequent dosing regimen used was BEV 10 mg/kg every two weeks. The median number of cycles given was 4 cycles (1-12). The most common adverse events were hypertension, minor nose bleeding, an occasional protein found in urine. There were no severe AEs or discontinuation of therapy with bevacizumab. Conclusions: This study demonstrated treatment with BEV 10 mg/kg every two weeks for a total of 12 cycles is well tolerated and has potential clinical benefit in RN in lung cancer patients with CNS metastasis. The therapeutic effects of VEGF inhibitors were seen in our small population study but warrants further investigation in a larger population study.

Comparing the impact of steroid sparing immunosuppression vs. steroid monotherapy for immune-related adverse events in non–small cell lung cancer and melanoma.

2637 Background: The effect of steroid-sparing immunosuppressive agents (SSIAs) for immune-related adverse events (irAEs) on immune checkpoint inhibitor (ICI) antitumor activity is not well-known. We compared tumor outcomes of patients who received corticosteroid monotherapy versus those who received an addition of SSIA for irAE treatment. Methods: We conducted a retrospective case-control study of patients age ≥18 years with melanoma or non-small cell lung cancer (NSCLC) who were treated with ≥1 ICI at a quaternary care center between 1/1/2016-11/1/2021. Patients must have received systemic corticosteroids or an SSIA for irAE treatment at least 1 week prior to death. Patients were divided into two cohorts: only corticosteroids (CS cohort) or steroids+SSIA (SSIA cohort). We used propensity score nearest-neighbor matching to match on tumor type, stage, and prior lines of therapy. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Secondary outcomes included time from start of irAE treatment to irAE resolution. Hazard ratios (HR) for PFS and OS were calculated using the Cox proportional hazard regression method with time to steroid and SSIA as a time-varying covariate. Results: After matching, 48 patients were included, 24 in each cohort. Median age was 65. 41.7% of patients had NSCLC and 58.3% melanoma, 79.2% had stage 4 disease. 62.5% received ICIs as first line therapy, 33.3% as second-line, and 4.2% as third-line or higher. There was no significant demographic difference between the cohorts. Colitis was the most common irAE (39.6%). After adjusting for age, tumor type, tumor stage, and weeks from ICI start to steroid start, patients in the SSIA cohort had a shorter OS (HR 2.31, p = 0.037). We did not find a statistically significant difference for PFS (unadjusted HR 0.52, p = 0.20; adjusted HR 0.62, p = 0.34). Time from irAE treatment to resolution was longer in the SSIA cohort (8.1 weeks) compared to the CS cohort (4.9 weeks), but this did not reach statistical significance (p = 0.07). Conclusions: We found an association between decreased OS and use of SSIAs for irAE treatment compared to CS monotherapy, but no significant difference in PFS between the two cohorts. Large, prospective, randomized controlled trials are needed to separate the effects of SSIAs from high-dose CS in order to guide optimal treatment of irAEs.

Dermoscopic predictors of melanoma in small diameter melanocytic lesions (mini-melanoma): a retrospective multicentric study of 269 cases.

Incidence of cutaneous melanoma is steadily growing, and its early recognition is of paramount importance. Small, pigmented lesions often represent a challenge for the clinician, as predictors of melanoma have not yet been uniquely identified in this setting. To identify dermoscopic features that aid in distinguishing small diameter melanomas (≤5 mm) from equivocal melanocytic nevi measuring ≤5 mm. A retrospective multicenter study was conducted to collect demographics, clinical and dermoscopic pictures of (i) histology-proven flat melanomas, measuring ≤5 mm, (ii) histology-proven but clinically/dermoscopically equivocal melanocytic nevi measuring ≤5 mm, and (iii) histology-proven flat melanomas, measuring >5 mm. An independent dermoscopic evaluation was performed. Differences in predefined dermoscopic features were assessed across the three groups. A total of 103 melanomas measuring ≤5 mm were collected; 166 control lesions, comprising 85 large (>5 mm) melanomas and 81 dubious, clinically equivocal melanocytic nevi measuring ≤5 mm were included. Of the 103 mini-melanomas, only 44 were melanoma in situ. Five dermoscopic predictors of melanoma were identified for the assessment of flat, non-facial melanocytic lesions measuring ≤5 mm, namely: atypical pigment network, blue-white veil, pseudopods, peripheral radial streaks, and presence of more than one color. The latter were combined into a predictive model capable of identifying melanoma with 65% sensitivity and 86.4% specificity, at a cut-off score of 3. Among melanomas measuring ≤5 mm, presence of a blue-white veil (P = 0.0027) or negative pigment network (P = 0.0063) was associated with invasiveness. A set of five dermoscopic predictors of melanoma, atypical pigment network, blue-white veil, pseudopods, peripheral radial streaks, and presence of more than one color is proposed for the assessment of flat, non-facial melanocytic lesions measuring ≤5 mm.

NKX3.1 immunohistochemistry and methylome profiling in mesenchymal chondrosarcoma: additional diagnostic value for a well-defined disease?

Mesenchymal chondrosarcoma (MCS) is a rare and highly aggressive tumour of soft tissue and bone that is defined by an underlying and highly specific fusion transcript involving HEY1 and NCOA2. Histologically, the tumours show a biphasic appearance consisting of an undifferentiated blue and round cell component as well as islands of highly differentiated cartilage. Particularly in core needle biopsies, the chondromatous component can be missed and the non-specific morphology and immunophenotype of the round cell component can cause diagnostic challenges. We applied NKX3.1 immunohistochemistry which was recently reported as a highly specific marker as well as methylome and copy number profiling to a set of 45 well characterised MCS cases to evaluate their potential diagnostic value. Methylome profiling revealed a highly distinct cluster for MCS. Notably, the findings were reproducible also when analysing the round cell and cartilaginous component separately. Furthermore, four outliers were identified by methylome profiling for which the diagnosis had to be revised. NKX3.1 immunohistochemistry showed positivity in 36% of tumours, the majority of which was rather focal and weak. Taken together, NKX3.1 expression showed a low sensitivity but a high specificity in our analysis. Methylome profiling on the other hand represents a sensitive, specific and reliable tool to support the diagnosis of MCS, particularly if only the round cell component is obtained in a biopsy and the diagnosis is not suspected. Furthermore, it can aid in confirming the diagnosis in case RNA sequencing for the HEY1::NCOA2 fusion transcript is not available.

Interaction between Age and Primary Site on Survival Outcomes in Primary GI Melanoma over the Past Decade.

Primary malignant melanomas of the Gastrointestinal mucosa are uncommon. Most cases of gastrointestinal (GI) melanomas are secondary, arising from metastasis at distant sites. The purpose of this study is to assess to what extent the interaction between independent prognostic factors (age and tumor site) of primary GI melanoma influence survival. Furthermore, we also aimed to investigate the clinical characteristics, survival outcomes, and independent prognostic factors of patients with primary GI melanoma in the past decade. A total of 399 patients diagnosed with primary GI melanoma, between 2008 and 2017, were enrolled in our study by retrieving data from the Surveillance, Epidemiology, and End Results (SEER) database. We analyzed demographics, clinical characteristics, and overall mortality (OM) as well as cancer-specific mortality (CSM) of primary GI melanoma. Variables with a p value < 0.1 in the univariate Cox regression were incorporated into the multivariate Cox model (model 1) to determine the independent prognostic factors, with a hazard ratio (HR) of greater than 1 representing adverse prognostic factors. Furthermore, we analyzed the effect of the interaction between age and primary location on mortality (model 2). Multivariate cox proportional hazard regression analyses revealed higher OM in age group 80+ (HR = 5.653, 95% CI 2.212-14.445, p = 0), stomach location of the tumor (HR = 2.821, 95% CI 1.265-6.292, p = 0.011), regional lymph node involvement only (HR = 1.664, 95% CI 1.051-2.635, p < 0.05), regional involvement by both direct extension and lymph node involvement (HR = 1.755, 95% CI 1.047-2.943, p < 0.05) and distant metastases (HR = 4.491, 95% CI 3.115-6.476, p = 0), whereas the lowest OM was observed in patients with small intestine melanoma (HR = 0.383, 95% CI 0.173-0.846, p < 0.05). Multivariate cox proportional hazard regression analyses of CSM also revealed higher mortality of the same groups and lower CSM in small intestine and colon melanoma excluding the rectum. For model 2, considering the interaction between age and primary site on mortality, higher OM was found in age group 80+, followed by age group 40-59 then age group 60-79, regional lymph node involvement only, regional involvement by both direct extension and lymph node involvement and distant metastases. The small intestine had a lower OM. The rectum as primary location and the age range 40-59 interacted to lower the OM (HR = 0.14, 95% CI 0.02-0.89, p = 0.038). Age and primary gastric location did not interact to affect the OM. For the CSM, taking into account the interaction between age and the primary location, higher mortality was found in the same groups and the colon location. The primary colon location also interacted with the age group 40-59 to increase the CSM (HR = 1.38 × 109, 95% CI 7.80 × 107-2.45 × 1010, p = 0). In this United States population-based retrospective cohort study using the SEER database, we found that only the age range 40-59 interacted with the rectum and colon to lower and increase mortality respectively. Primary gastric location, which was the single most important location to affect mortality, did not interact with any age range to influence mortality. With those results, we hope to shed some light on this rare pathology with a very dismal prognosis.

A phase I/II study of MCS110 with BRAF/MEK inhibition in patients with melanoma after progression on BRAF/MEK inhibition.

Prognosis for patients with metastatic melanoma has been improved dramatically with the development of BRAF/MEK directed therapy and immune checkpoint inhibition. However, resistance to therapy remains a challenge, particularly with BRAF/MEK targeted therapy which often has a limited duration of efficacy. Pre-clinical data suggest that adding CSF1 inhibition to BRAF/MEK targeted therapy may reduce resistance and increase efficacy. We performed a phase I/II study to determine the safety and efficacy of CSF1 inhibition with MCS110 in combination with BRAF/MEK inhibition with dabrafenib/trametinib in patients with BRAF V600E/K mutant metastatic melanoma. The trial was terminated early due to a decision by the study sponsor to cease further development of MCS110. Between September 2018 to July 2019 six patients were enrolled on the study. Patients were evenly split between female (50%) and male (50%) with a median age of 59.5 yrs. (26-71). Five patients experienced grade 3 toxicities that were possibly related to one of the therapies, there were no grade 4 or grade 5 events. One patient had a partial response (PR) by RECIST 1.1, one patient had stable disease (SD), 3 patients had disease progression (PD). Median progression free survival was 2.3 months (90% CI: 1.3 mos to not reached). MCS110 in combination with dabrafenib and trametinib was reasonably well tolerated in a small melanoma population. One response was observed in this small sample of patients suggesting this combination might be worthy of further exploration.

Abstract 5653: LCB97, an antibody drug conjugate (ADC) targeting a novel tumor antigen for the treatment of multiple solid tumors

Abstract LCB97 is an antibody-drug conjugate (ADC) directed against a novel tumor antigen, composed of monomethyl auristatin E (MMAE) as payload (DAR 4) and the humanized IgG1 antibody AFF4 generated by Elthera. AFF4 targets a novel antigen preferentially expressed in various solid tumors including pancreatic cancer, ovarian cancer, colon cancer, breast cancer and melanoma. LCB97 generated by using LCB’s ConjuAllTM technology with AFF4 showed potent cytotoxicity in various cancer cell lines including breast cancer (BC), ovarian cancer (OC), pancreatic cancer (PaC), small cell lung cancer (SCLC), colorectal cancer (CRC) and melanoma. LCB97 also showed excellent anticancer efficacy in several cell line-derived xenograft (CDX) models, including BC, CRC, OC and melanoma. Preliminary toxicity assessment in cynomolgus monkeys (an AFF4 cross reactive species) demonstrated that LCB97 was well tolerated within the estimated therapeutic index of ~20 for repeat dosing. In conclusion, LCB97, generated by combining theAFF4 monoclonal antibody of Elthera and the highly innovative ConjuAllTM platform technology of LegoChem Biosciences is a promising next-generation ADC for the treatment of various solid cancers, including BC, CRC, melanoma, OC and PaC. Citation Format: Yeojin Jeong, Gunther Spohn, Flavio Mehli, Chul-Woong Chung, Changsik Park. LCB97, an antibody drug conjugate (ADC) targeting a novel tumor antigen for the treatment of multiple solid tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5653.

Atezolizumab (Tecentriq) for Alveolar Soft Part Sarcoma

Atezolizumab (Tecentriq – Genentech), an immune checkpoint inhibitor, has been approved by the FDA for treatment of unresectable or metastatic alveolar soft part sarcoma (ASPS) in patients 2&gt;=years old. It was previously approved for treatment of non-small cell lung cancer, small cell lung cancer, hepatocellular cancer, and melanoma (see Table 1). Atezolizumab is the first drug to be approved in the US for treatment of ASPS. ASPS is a rare disorder that affects mostly adolescents and young adults; &lt;1% of soft tissue sarcomas are ASPS.

Primary Small Bowel Amelanotic Melanoma and Intestinal Intussusception: A Case Report

Primary gastrointestinal melanomas (PGM) are usually asymptomatic in the early stages, leading to misdiagnosis. We reported the case of a 75-year-old male patient admitted to our service due to hematochezia, and fatigue. Primary investigation showed small bowel intussusception and surgical treatment was performed. Histopathology and immunohistochemistry analysis identified primary small bowel amelanotic melanoma at an advanced tumor stage. Whereas the patient had a sudden impairment of performance status during hospitalization, no curative oncological approach could be performed. This report highlights the clinical and imaging findings that led to the primary gastrointestinal amelanotic melanoma diagnosis in an elderly patient with intestinal intussusception. The early recognition of prior intussusception signs in adults and elder patients may lead to an earlier oncological diagnosis and a better prognosis.