bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overall survival after the introduction of adjuvant treatment in stage III melanoma: A nationwide registry based study.
Authors: Helgadottir Hildur , Ny Lars , Ullenhag Gustav J. , Falkenius Johan , Mikiver Rasmus , Olofsson Bagge Roger , Isaksson Karolin 
Published: June 2023

9570 Background: Adjuvant treatments with PD-1 and BRAF+MEK inhibitors significantly prolong recurrence-free survival in stage III cutaneous melanoma. However, the effect on overall survival is still unclear. After the approval of adjuvant treatments with PD-1 inhibitors and BRAF+MEK inhibitors, based on recurrence-free survival data, these treatments have been widely implemented. However, there are significant side effects and costs of the treatment, and the overall survival effect remains a highly anticipated outcome. Methods: Clinical and histopathological parameters were obtained from the Swedish Melanoma Registry that covers nearly all (99%) primary cutaneous melanomas diagnosed. Information on deaths was received from the Cause of Death Registry, a virtually complete register of all deaths in Sweden. Patients diagnosed with stage III melanoma between 2016 and 2020 were included and divided depending on if they were diagnosed before or from July 2018, the timepoint when adjuvant treatment was introduced in Sweden (designated as pre- and post-cohorts). In Sweden, approved treatments are freely available for all residents and there is a high-adherence to national treatment guidelines. Data was retrieved for the age and sex of the patients, the site, histopathological subtype, Breslow thickness and ulceration of the primary melanoma, type of locoregional spread and numbers of affected lymph nodes. Patients were followed until the end of 2021. Melanoma-specific and overall survival were calculated using the Kaplan-Meier method and Cox regression analyses. Results: There were 1371 patients diagnosed with stage III melanoma in Sweden in 2016-2020. The median time of follow-up in the pre-cohort was 57 months (range 42-72 months) and in the post-cohort 27 months (range 12-42 months). The 2-year overall survival rates, comparing the 634 patients in the pre-cohort and the 737 in the post-cohort, were 84.3% (95% CI 81.4-87.3) and 86.1% (95% CI 83.4-89.0), respectively, with an adjusted HR 0.91 (95% CI 0.70-1.19, P= 0.51). Further, no significant overall or melanoma-specific survival differences were seen when comparing the pre- and the post-cohort in different subgroups depending on the age, sex or tumor characteristics. Conclusions: To our knowledge, this study is the first to assess the impact on overall survival from a national introduction of adjuvant treatment in stage III melanoma. In this nationwide, population and registry-based study, no survival benefit was detected in the cohort receiving adjuvant therapy. Considering also the significant side effects and costs, these findings encourage a careful assessment of the current recommendations on adjuvant treatment. To offer close follow-up, and only treat if relapse occurs, should be an option discussed with patients with fully resected stage III melanoma.
Intralesional therapy, limb infusion/perfusion, and immune checkpoint inhibitors as first-line therapy in surgically unresectable melanoma in-transit metastases.
Authors: DePalo Danielle K , Naqvi Syeda Mahrukh Hussnain , Ollila David W. , Hieken Tina J. , Block Matthew Stephen , van Houdt Winan J. , Wouters Michel W.J.M. , Asher Nethanel , Broman Kristy Kummerow , Duncan Zoey , Anderson Matilda , Gyorki David E. , Vetto John T. , Hui Jane Yuet Ching , Saw Robyn P.M. , Lo Serigne N. , Kim Youngchul , Van Akkooi Alexander Christopher Jonathan , Olofsson Bagge Roger , Zager Jonathan S. 
Published: June 2023

9574 Background: Surgery remains the gold standard for resectable melanoma in-transit metastases (ITM). Unresectable ITM is a heterogenous disease with multiple treatment (tx) options including systemic therapies such as immune checkpoint inhibitors (ICI), regional therapies such as isolated limb infusion or perfusion (ILI/P), and intratumoral therapies such as talimogene laherparepvec (IT). Until now, there has been no direct comparison of these first-line tx for unresectable ITM. Methods: A retrospective chart review of patients (pts) with ITM treated first-line with IT, ILI/P, or ICI was performed at 11 institutions. Pts with unresectable ITM, synchronous nodal or distant metastatic disease were excluded. Results: 560 pts (54% women) were identified, 86 received IT, 353 received ILI/P, and 121 received ICI from 1990-2022. ICI pts were youngest, IT pts were oldest (p<0.001). Limb was the most common site of ITM. There was no difference in largest ITM size, but number of lesions (burden of disease (BOD)) was highest in ILI/P pts and lowest in IT pts (p=0.003). Toxicity (tox) requiring <90 days (p<0.001) or > 90 days (p=0.034) of pharmacologic tx as well as tox requiring hospitalization (p<0.001) was greatest in ICI pts. Lymphedema was more likely in ILI/P pts (p=0.016). Median follow-up was much longer for ILI/P pts at 8.0 yrs compared to 2.5 yrs for IT pts and 3.1 yrs for ICI pts. Overall response rate (ORR) was 82.2% in ILI/P pts, significantly higher than IT (72.1%, p=0.047) or ICI pts (63.6%, p<0.001). Overall survival was similar between modalities (p=0.167); however, ILI/P pts had worse progression-free survival (PFS) (p<0.0001) and melanoma-specific survival (MSS) (p=0.003). On multivariable analysis of MSS by number of ITM present, MSS remained worst if ILI/P was used for low BOD, ≤3 ITM (p=0.005), but no difference was seen between tx modalities for higher BOD, >3 ITM (p=0.211). Conclusions: ICI was used more often in younger pts with less BOD, IT in older pts with less BOD, and ILI/P in older pts with high BOD. Short and long-term tox was greater in ICI. ILI/P had the best ORR, but ICI and IT resulted in greater overall MSS. Multidisciplinary consideration of risks and benefits of each modality should guide ITM tx selection. [Table: see text]
Nature and management of melanoma recurrences following adjuvant anti-PD-1 (PD1) therapy.
Authors: Woodford Rachel , McKeown Janet , Hoeijmakers Lotte , Mangana Joanna , Lebbe Celeste , Zaman Farzana Yasmin , Aya Francisco , Marsiglio John , Goodman Rachel S , Rayson Victoria , Placzke Joanna , Kessels Jolien Isabel , Ramelyte Egle , Haque Waqas , Wilson Isabella , Trojaniello Claudia , Roberts-Thomson Rachel , Robert Caroline , Long Georgina V. , Menzies Alexander M. 
Published: June 2023

9575 Background: Despite improved outcomes with the use of adjuvant PD1 therapy, approximately 50% of patients (pts) develop recurrent disease by 5 years. Data to define best management of recurrences is lacking, including whether retreatment with PD1 has benefit. Methods: This was a multicentre, international retrospective study of pts with resected stage II-IV melanoma who commenced adjuvant PD1 therapy before January 2022 and then recurred. Demographics, disease characteristics, treatment, toxicity, recurrence patterns, management and outcomes were collected. Results: 711 pts from 17 sites were included. Med age was 60 [range 16-92], 64% (N=451) were male. 641 (91%) pts were stage III (A 7%, B 24%, C 54%, D 3%), 18 (2%) stage II, 51 (7%) stage IV. 80% (N=536) underwent SLNB prior to PD1, of which 44% (N=236) went onto CLND. 635 pts (90%) received PD1, 74 (10%) PD1 + other. Med time to recurrence was 6.2 months (m) (0-68.5); 63% (N=444) recurred ON PD1, while 36% (N=257) recurred OFF. 338 pts (48%) recurred within 6m of starting adjuvant, 166 (23%) between 6-12m, 140 (20%) 12-24m and 59 (8%) after 24m. Initial recurrences were locoregional (LR) alone in 315 (44%), 307 (43%) distant alone, and 78 (11%) both. Patients with LR recurrences alone underwent definitive surgery, or surgery + radiation in 98 (31%) and 42 (13%) respectively. After initial LR management, 164 (52%) had a further local and 129 (41%) distant recurrence. Those with initial distant recurrences were managed with definitive surgery (21, 7%), surgery + radiation (8, 3%) and radiation alone (14, 5%). Further ‘second’ adjuvant therapy was given in 27% (N=86) of LR and 6% (N=25) of distant recurrences. Definitive systemic therapy at first recurrence was given in 77% (N=296) distant and 23% (N=73) LR recurrences (Table). Conclusions: Patients recurring after adjuvant PD1 therapy do so early, and often while on drug. Patients with resected recurrences often receive “second adjuvant” therapy, although whether adjuvant or definitive, outcomes are poor. Novel drug therapies and clinical trials are required for those who recur despite PD1 therapy. [Table: see text]
Association of circulating tumor DNA kinetics with disease recurrence in patients with stage IIIB/C/IV melanoma treated with adjuvant immunotherapy in Checkmate 238.
Authors: Syeda Mahrukh M. , Wiggins Jennifer M , Alegun Josephine , Ali Saim , Tang Hao , Wang Sheen , Tsai Kao-Tai , Desai Keyur , Dolfi Sonia , Tenney Daniel J. , Ascierto Paolo Antonio , Larkin James , Del Vecchio Michele , Weber Jeffrey S. , Polsky David 
Published: June 2023

9577 Background: In patients (pts) with resected, stage III/IV melanoma receiving adjuvant immunotherapy, pre-treatment (pre-Tx) and on-treatment (on-Tx) circulating tumor DNA (ctDNA) combined with tumor features were evaluated to predict recurrence risk. Methods: We used analytically validated, mutation-specific droplet digital PCR (ddPCR) assays to measure ctDNA in pre- and on-Tx plasma samples from pts with resected stage IIIB/C/IV melanoma enrolled in CheckMate 238 (NCT02388906) receiving either adjuvant Nivolumab (NIVO) or Ipilimumab (IPI). Assay choice was based on detection of one of the 7 melanoma hot-spot mutations in pt tumors: BRAF V600E/K, NRAS Q61R/L/K, or TERT C228T/C250T. We evaluated associations between ctDNA detection, recurrence free survival (RFS), distant metastasis free survival (DMFS), and known immunotherapy tumor biomarkers including PD-L1, IFNg gene signature, CD8, and tumor mutational burden. Associations between ctDNA kinetics and RFS/DMFS were analyzed using Kaplan-Meier and Cox regression models. Results: Mutations were identified in 87% of tumors. ctDNA was detected in pre-Tx samples from 94/753 (12.5%) pts. Pre-Tx ctDNA was significantly associated with higher stage of disease, LDH ≥ ULN, PD-L1 < 5%, and tumor IFNg-RNA signature expression below the median. Detection of pre-Tx ctDNA was associated with shorter RFS and DMFS in both NIVO and IPI arms compared to undetectable ctDNA (Table). ctDNA detection on-Tx (week (w) 3, 7, 13, 25, 37, 49) was also associated with shorter RFS. Refined subgroup predictions that potentially impact therapy were achieved by incorporating pre- and on-Tx time points. Of those with baseline and w7 ctDNA results, pts in the NIVO arm with undetectable pre-Tx ctDNA (n=308) that became positive at w7 (n=22) had shorter RFS (median RFS 20.68 mos [95% CI, 2.79, NR]) than pts in whom on-Tx ctDNA remained undetectable (n=286) (median RFS, NR [95% CI, 61.1, NR]). Pts with positive pre-Tx ctDNA (n=42) that remained positive at w7 (n=23) had markedly shorter RFS (median RFS, 3.35 mos [95% CI, 2.73, 20.44]) vs pts in whom on-Tx ctDNA became undetectable (n=19) (median RFS, NR [95% CI, 14, NR]). Similar results were observed in the IPI arm. Conclusions: Pre- and on-Tx ctDNA measurements are associated with melanoma recurrence risk during adjuvant checkpoint inhibitor therapy. Incorporation of ctDNA with other tumor molecular features may improve prediction of RFS and DMFS in this setting. Clinical trial information: NCT02388906 . [Table: see text]
[18F]FDG-PET to identify pathological responses upon neoadjuvant immune checkpoint blockade in cutaneous squamous cell carcinoma.
Authors: Breukers Sabine , Crommelin Robert D. , Smit Laura , De Boer J.P. , Navran Arash , van Houdt Winan J. , de Bree Remco , Devriese Lot A. , Haanen John B. A. G. , Zuur Charlotte L. , Wondergem Maurits 
Published: June 2023

9584 Background: To improve clinical prospects of patients with locally advanced cutaneous SCC (CSCC), we tested the efficacy of neoadjuvant nivolumab with or without ipilimumab prior to standard of care curative surgery ± radiotherapy; the MATISSE trial (NCT04620200). Neoadjuvant immunotherapy-response prediction via FDG-PET imaging was demonstrated feasible in the IMCISION trial (PMID 34937871), where a decrease of ≥12.5% in total-lesion glycolysis (TLG) upon immunotherapy identified deep pathological responders to immunotherapy in head and neck SCC prior to surgery with 95% accuracy. The current research investigates the predictive power of FDG-PET to identify deep pathological responses to neoadjuvant immunotherapy in MATISSE patients. Methods: 26 patients with primary CSCC (stage I‒IVa) were treated with neoadjuvant nivolumab with (n = 14) or without (n = 12) ipilimumab (weeks 0 and 2). FDG-PET/CT scans were evaluable at baseline and shortly before surgery (week 4) in 20 patients. Images were analysed for SUVmax, metabolic tumor volume (MTV), and TLG. Responders to immunotherapy were defined as having a major or partial pathological response to immunotherapy (MPR and PPR, showing ≤ 10% and 11-50% remaining viable cancer cells at time of surgery, respectively). Results: Overall, median SUVmax, MTV, and TLG decreased upon immunotherapy at the primary tumor site in responders (n = 15),whereas median SUVmax, MTV and TLG increased in non-responders (Table). Three patients with stable or increased SUVmax, MTV and TLG, also showed a pathological response and were classified as pseudo-progressive. Another patient with a MPR had an increase in SUVmax, but a decrease in MTV and TLG. All patients with any decline in SUVmax, MTV or TLG at the primary tumor site showed a pathological response (PPV 100%) and none of them developed a relapse at median follow-up 9.0 months. Conclusions: Primary tumor response assessment using FDG-PET-based ΔSUVmax, ΔMTV and ΔTLG accurately identifies pathological responses early upon neoadjuvant immunotherapy in cutaneous SCC. FDG-PET could, upon validation, select CSCC patients for response-driven treatment adaptation in future trials. FDG-PET-CT upon neoadjuvant immunotherapy in CSCC, changes in PET-parameters and predictive values of any decline in SUVmax, MTV or TLG. Clinical trial information: NCT04620200 . [Table: see text]
FDG-PET/CT response and prediction of pathological response to neoadjuvant nivolumab and ipilimumab for clinical stage III melanoma.
Authors: De Barros E Silva Milton Jose , Tavares Monique Celeste , Lima Joao Paulo S. N. , Buzaid Antonio C. , Garcia Daniel , Camargo Veridiana Pires De , Molina Andre , Bertolli Eduardo , Lobo Matheus , Van Akkooi Alexander Christopher Jonathan , Pinto Clovis , De Paula Rafaela Brito , Lima Eduardo , Rinck José Augusto , Duprat Joao 
Published: June 2023

9585 Background: Neoadjuvant immunotherapy with nivolumab 3mg/kg and ipilimumab 1 mg/kg (N3+I1) for two cycles for clinical stage III melanoma have shown rates of major pathological response (MPR) of approximately 60%.The prognosis of this group seems to be excellent so far. On the other hand, patients classified as pathological non-responders have a worse outcome and early identification of this group may allow us to tailor the treatment before surgery. Methods: We conducted a multicenter retrospective analysis of patients with clinical stage III melanoma treated with neoadjuvant N3+I1 for two cycles who did baseline and pre-operative 18F-FDG-PET/CT. The total number of FGD avid lesions and the percentual difference between the maximum SUV per lesion was calculated. The pathological results were correlated to FGD-PET/CT findings. Results: Between January 2019 and January 2023, 28 patients with clinical stage III melanoma treated with N3+I1 who had baseline and preoperative 18F-FDG PET were identified. Gender: 20 (71%) males, median age (range):55 (34-78), BRAFV600E/K mut: 15(53%), positive nodes on baseline PET/CT:1 = 26 (92%), 2 = 1(4%), and 3 = 1(4%). All known lesions identified by CT scan were also captured by FGD-PET/CT. Site of node(s): axilla = 12 (43%), cervical = 10 (36%), and inguinal = 6(21%). All but one patient received 2 cycles of N3+IP1(1 patient had grade 3 toxicity and received only one cycle). Pathological response: MPR = 19(68%), non-MPR: 8 (28%), and 1(4%) did not undergo surgery due to widespread progression. An increase in maximum SUV and/or appearance of new lesion(s), n = 8(28%), was correlated to non-MPR or metastatic disease in all cases, including a patient who developed sarcoidosis-like reaction with increase of SUV in the index lesion (+68%) and appearance of inflammatory mediastinal lymph-nodes. The median increase was (range): +73% (+11% to 483%). Reduction or stable maximum SUV with no appearance of new lesion, n = 20 (72%), was associated with MPR in 19 patients (95%). One patient,who had G3 colitis (with the need of infliximab), had 32% of reduction in maximum SUV but 100% of viable tumor cells on pathological report. The median decrease (range) was -76% (-1.2% to -100%). Conclusions: FGD-PET/CT may help to predict pathological response in patients with clinical stage III melanoma who undergo to neoadjuvant nivolumab and ipilimumab.
Survival outcomes associated with liver-directed therapies in patients with metastatic uveal melanoma.
Authors: Caplan Michael M , Chen Lanyi Nora , Krishnasamy Venkatesh , Sperling David , Weintraub Joshua , DeStephano David , Pan Samuel M , McDonnell Diana , Marr Brian P , Carvajal Richard D. , Khan Shaheer 
Published: June 2023

9590 Background: Metastatic uveal melanoma (mUM) is characterized by a hepatotropic pattern of spread and poor outcomes. Tebentafusp, the only FDA approved therapy, is restricted to patients (pts) with the HLA-A*02:01 genotype. As a result, a variety of liver-directed therapies (LDT) are commonly used for management of hepatic metastases. Methods: Pts with mUM with hepatic metastases who underwent LDT, including radiofrequency ablation, microwave ablation, hepatic metastatectomy, Yttrium-90 radioembolization (SIRT), transarterial chemoembolization (TACE), bland embolization, and immunoembolization (IE), were identified from an institutional database. Data collected included: age, gender, tumor location and size, baseline liver function tests (LFT) and lactate dehydrogenase (LDH), molecular tumor characteristics (where available), type(s) of LDT received, systemic therapies received, and vital status. Time from onset of hepatic metastasis until death (Liver-OS), as well as time from initial diagnosis of primary uveal melanoma until death (Ocular-OS) were calculated. Results: A total of 119 pts were identified. The median age at diagnosis was 53.8 years (range 26-83), 47% were female. At the time of LDT initiation, 33% had bilobar disease and 16% had extrahepatic metastasis. 18% pts had elevated LFTs and 55% had elevated LDH. 72% of pts had M1a disease, 24% had M1b and 4% had M1c disease. 45% of pts received more than one form of LDT. SIRT (31%) was the commonly administered initial LDT, followed closely by IE (26%) and TACE (9%). 86% of pts received systemic therapy including 42% who received immune checkpoint blockade overlapping with LDT. Molecular profiling in 26 pts revealed recurrent mutations in BAP1 (n = 18) and SF3B1 (n = 8). The median ocular-OS across all pts was 71.0 months (95% confidence intervals (CI), 62.8-99.4). The median liver-OS across all pts was 31.8 months (95% CI 25.2-35.3). In pts who received TACE, IE, or SIRT exclusively (n = 44), the median Liver-OS was 15.2 months (95% CI 12.8-NA) for TACE (n = 8), 23.3 months (95% CI 15.8-NA) for SIRT (n = 28), and 28.2 months (95% CI 22.6-NA) for IE (n = 8). Conclusions: Our results provide additional support for the utilization of LDT in pts with mUM, as demonstrated by improved OS compared to historical survival data.
Long-term outcomes of chronic immune-related adverse events from adjuvant anti-PD-1 therapy for high-risk resected melanoma.
Authors: Goodman Rachel S , Lawless Aleigha , Woodford Rachel , Fa'ak Faisal , Tipirneni Asha , Patrinely James Randall , Yeoh Hui-Ling , Rapisuwon Suthee , Haydon Andrew , Osman Iman , Mehnert Janice M. , Long Georgina V. , Sullivan Ryan J. , Carlino Matteo S. , Menzies Alexander M. , Johnson Douglas Buckner 
Published: June 2023

9591 Background: Adjuvant anti-PD1 improves relapse-free survival in high-risk, resected melanoma, but can lead to irAEs, which become chronic in up to 41% of patients (Patrinely et al, JAMA Onc 2021). Given the expanding use of anti-PD-1 in earlier settings in many tumors, it is imperative to assess their long-term effects. We aimed to determine the incidence, characteristics, and long-term outcomes, including resolution vs persistence, of chronic irAEs from adjuvant anti-PD1. Methods: We retrospectively analyzed patients (pts) treated with adjuvant anti-PD1 for resected stage III-IV melanoma from 2015-2022 from 6 institutions; all pts had at least 18 month follow up post-anti-PD1 discontinuation. Demographics, disease characteristics, treatment and recurrence details, and outcomes were collected. Type, grade, duration, treatment, and resolution of acute (onset during treatment) and chronic irAEs (defined as those extending 6+ months after treatment cessation) were characterized. Results: Among 318 pts, 226 (64%) developed acute irAEs arising during treatment, including 44 (20%) with grade 3-5 irAEs. Chronic irAEs developed in 147 (46%) pts, of which 74 (50%) were grade 2+, 6 (4%) were grade 3-5, and 100 (68%) were symptomatic. With long-term follow-up (median 35 months), 52 (35%) pts experienced resolution of chronic irAEs while 95 (30% of the full cohort) had persistent chronic irAEs at last follow-up. Among these 95 pts with persistent chronic irAEs, 43 (45%) were grade 2+, 42 (44%) were symptomatic, 24 (16%) were on steroids, and 42 (29%) were on other management. The most common persistent chronic irAEs were hypothyroid (n = 38), arthritis (n = 18), dermatitis (n = 9), and adrenal insufficiency (n = 8). Of 37 pts with chronic irAEs who received additional immunotherapy, 12 (32%) had a flare, 10 (27%) had no effect, and 20 (54%) had a distinct irAE. Conclusions: In this large cohort of anti-PD1 treated pts, chronic irAEs were common (46%) and frequently were persistent with long-term follow up (30%, most often hypothyroid and arthritis). Prolonged monitoring and management are needed for these long-term survivors. [Table: see text]