bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic value of autoantibodies (auto-AB) in melanoma patients (pts) in the EORTC 18952 trial of adjuvant interferon (IFN) compared to observation (obs)
Authors: Bouwhuis M. , Suciu S. , Kruit W. , Salès F. , Patel P. , Punt C. , Stoitchkov K. , Delaunay M. , ten Hagen T. , Eggermont A. M. 
Published: March 2020

8507 Background: Appearance of auto-AB during IFN-adjuvant therapy is a prognostic factor in melanoma pts. We evaluated this in the EORTC 18952 trial including pts without IFN. Methods: Anti-cardiolipin (C) anti-thyreoglobulin (T) and anti- nuclear (N) AB levels of serial samples between 0 and 48 months (mt) were assessed centrally. Prognostic impact of CTN on relapse-free survival (RFS) was assessed by 3 methods: 1) usual Cox model (lead-time bias); 2) Cox Time dependent model using the latest positive CTN value; 3) Cox Time dependent model using the latest any CTN value. Results: In 278 pts the presence of auto-AB at any time was determined. Among them, 187 pts (43 stage IIb, 144 stage III), Obs (32) or 13-mt-IFN (80) or 25-mt-IFN (75), had their initial auto- AB status assessed: 60 (32%) were CTN-positive (pos) (similar % in 3 arms) and 127 (68%) were CTN-negative (neg). Of these 127 pts, during the study, at least once, the following became CTN-pos: Obs (7/24=29%), 13-mt-IFN (19/55=36%), 25-mt-IFN (20/48=42%); 1-yr conversion rate was 23%, 34% and 38% in the 3 arms respectively; 2-yr rate was 23%, 46% and 61%. Median follow-up = 4.2 yrs. Relapse occurred in 122/187 pts. Median RFS = 2.1 years. In the 187 pts with a known initial CTN-status, using the classical Cox model the hazard ratio (HR) of those who were/became CTN-pos vs the others, was 0.50. In order to overcome the Lead Time Bias, the Cox time dependent model was used: the HR for pts with at least one pos CTN-status vs always CTN-neg was 0.63 and for those with the latest CTN-status pos vs those with latest CTN-status neg was 0.87. All analyses were adjusted for # of pos nodes. Results were similar when only IFN pts or Obs only pts were considered (test for interaction: P>0.50), or when all pts (278) or only pts CTN-neg at randomization (127) were assessed. Initial CTN status known. Conclusions: We could not confirm presence or appearance of auto-AB as a strong prognostic factor in melanoma pts and did not find a strong interaction with IFN therapy. [Table: see text] [Table: see text]
A single-institution validation of the AJCC staging system for stage IV melanoma
Authors: Neuman H. , Patel A. , Hanlon C. , Brady M. S. , Halpern A. C. , Houghton A. N. , Coit D. G. 
Published: March 2020

8517 Background: We sought to validate the AJCC staging system for stage IV melanoma in a contemporary, prospective, single- institution cohort and explore additional clinical factors that may influence prognosis. Methods: A prospective institutional database identified 1319 patients with stage IV melanoma. To minimize tertiary center referral bias, only patients seen prior to a stage IV diagnosis were included (n=687). Variables were dichotomized: lactate dehydrogenase (LDH) (=200, >200), number of metastases (1, >1), and number of involved organs (1, >1). Kaplan-Meier curves were generated and Cox regression was used to identify factors independently predictive of survival. Results: Demographics are provided in the table . The median age at diagnosis of stage IV was 55 years (range 16–94) and the median disease free interval (DFI) was 12 months (0–181). The overall median survival was 10 months (5–21) with a median follow-up for survivors of 31 months (9–68); 569 deaths were observed. Cox regression analysis ( table ) identified younger age at stage IV diagnosis, a longer DFI, and a normal LDH to be predictive of improved survival. Patients with either distant skin/subcutaneous/nodal or pulmonary disease experienced prolonged survival when compared to patients with metastases to other visceral sites. Survival was improved in patients with a single metastatic site at diagnosis of stage IV. Gender, antecedent stage, and number of involved organs were not associated with outcome. Conclusions: In this single institution cohort of patients with stage IV melanoma, poorer survival in patients with non-pulmonary visceral metastases and/or abnormal LDH levels as described by the AJCC staging system was confirmed. Additionally, the number of metastases at the time of diagnosis of stage IV was the most powerful predictor of poorer survival and may be a variable to consider in future staging systems. No significant financial relationships to disclose. [Table: see text]
Serum S-100B protein is a strong independent prognostic marker for distant-metastasis free survival (DMFS) in stage III melanoma patients: An evaluation of the EORTC randomized trial 18952 comparing IFNα versus observation
Authors: Suciu S. , Ghanem G. , Kruit W. , Stoitchkov K. , Patel P. , Delaunay M. , ten Hagen T. , Musat E. , Salès F. , Eggermont A. M. 
Published: March 2020

8518 Background: S100B serum levels have been reported to correlate with tumor stage and outcome, especially in metastatic melanoma. In the EORTC 18952 randomized trial assessing the value of intermediate doses (10 MU or 5 MU) of IFNa vs Observation, a side study on S100B has been set-up in order to assess 1) the prognostic importance of initial measurement of S100B; 2) the risk of developing distant metastases in patients with a S100B≥0.2 μg/l; 3) the prognostic importance of the latest measurement of S100B level on the subsequent outcome. Methods: The serial measurements of S100B, made by immunoluminometric assay LIA-mat (Sangtec Medical, Sweden) have been performed at randomization in 18952 study, at end of 4-week IFNa induction/observation, and thereafter, at month 1, 3, 6, 9, 12, 16, 20, 24, 30 and 36. The prognostic impact regarding DMFS of the latest value of S100B was assessed via the Cox time-dependent model. Results: A total of 211 patients, stage IIb (N=51) or stage III (N=160), were randomized in the 18952 study between 1996 and 2000, had their initial serum S100B protein level assessed: in 178 patients (84%) S100B was <0.2 μg/l and in 33 (16%) it was ≥0.2 μg/l. The 6-month DMFS rate was 90% (SE=2%) vs 70% (SE=8%) and the 1-year rate was 76% (SE=3%) vs 49% (SE=9%). The cumulative rate of developing metastases after the first assessment of S100B ≥0.2 μg/l (N=88) was 15% at 2 months, 45% at 6 months and 55% at 1 year. Using the Cox Time dependent model for DMFS, the estimated hazard ratio (HR) for those with the latest measurement S100B(t)≥0.2 μg/l vs S100B(t)<0.2 μg/l was 3.7 (95% CI 2.6–5.3), P<0.0001, in univariate analysis, and HR=4.4 (P<0.0001) when adjusted for the number of positive lymph nodes (HR=1.82, P<0.0001). The HR was 6.8 in stage III patients and 1.3 in stage IIb. In stage III, no treatment differences (IFNa vs Observation) were observed regarding DMFS and time to S100B≥0.2 μg/l. Conclusions: In stage III melanoma patients S100B protein is a strong prognostic marker regarding DMFS and probably S100B might be used as a surrogate endpoint for DMFS, but this requires further investigations (e.g. in EORTC 18991). In stage IIb, its prognostic importance was far lower. [Table: see text]
Protective effect of a brisk tumor infiltrating lymphocyte infiltrate in melanoma: An EORTC melanoma group study
Authors: Spatz A. , Gimotty P. A. , Cook M. G. , van den Oord J. J. , Desai N. , Eggermont A. M. , Keilholz U. , Ruiter D. J. , Mihm M. C. 
Published: March 2020

8519 Background: Tumor-infiltrating lymphocytes (TILs) in melanoma are responsible for tumor killing and may induce spontaneous regression. Brisk TILs in the melanoma vertical growth phase (VGP) is a strong, albeit not independent, prognostic factor associated with superior survival. This study investigated whether more detailed classes of TIL patterns, based on topography and intensity, are independent prognostic factors and identify patients with good prognosis. Methods: The study included 1,171 patients with cutaneous VGP melanoma with at least 3 years of follow up for whom slides were available for review. TIL infiltrate was assessed for pattern (absent, non brisk, brisk), intensity (scanty, moderate, dense), and topography (peripheral, central, both). Pattern was assessed qualitatively: brisk TIL infiltrate was defined as a continuous band of lymphocytes at the base of the melanoma, or throughout the tumor. Other studied variables were: thickness, mitotic count (MC), ulceration, gender, age, anatomic site, melanoma-related death (MRD). Subsequently, Chi-square tests, Kaplan-Meier curves (KM), logrank tests, and Cox models were applied to examine the relation between MRD, TIL categories and interaction with other variables. Results: A brisk infiltrate was observed in 21.2% of the cases. Adjusted hazard ratio for MRD as compared to the absent category was 0.82 (95% CI=0.64–1.06) in the non-brisk category, and 0.43 (95% CI=0.28–0.68) in the brisk category. Based on the Cox model, brisk TIL was an independent prognostic factor for MRD (p<0.001) controlling for thickness, MC, ulceration, gender, age and site. Intensity was significantly associated with MRD for melanomas with peripheral and central brisk TILs (p=0.027) but not for other melanomas. Remarkably, no death was observed in the 5.5% of melanomas with dense, brisk TIL infiltrate at ten years. Conclusions: A brisk TIL pattern was shown to have prognostic value for MRD underscoring the importance of TILs in the outcome of VGP melanoma patients. Furthermore, we identified a small population of “super-responder” patients whose tumor was characterised by a continuous and dense TIL infiltrate and who did not display signs of tumor progression. No significant financial relationships to disclose.
N0377: Results of NCCTG phase II trial of the mTOR inhibitor RAD-001 in metastatic melanoma
Authors: Rao R. D. , Allred J. B. , Windschitl H. E. , Maples W. J. , McWilliams R. R. , Creagan E. T. , Kaur J. S. , Kottchade L. A. , Gornet M. K. , Pockaj B. A. , Markovic S. N. 
Published: March 2020

8530 Background: RAD-001 (Everolimus) is an oral inhibitor of mammalian target of rapamycin (mTOR). Interim analysis results from a phase II study of RAD-001 in patients with metastatic melanoma (MM) were presented at ASCO 2005. This study was re-opened using a higher dose based on an improvement in the 16 week progression free survival (PFS) rate and good tolerability. Methods: A two- stage, phase II multi-institutional trial was conducted in patients with MM to assess that 16 weeks PFS rate was at least 50%. Inclusion criteria: measurable disease, ECOG performance score of 0–2. Exclusion criteria: presence of intracranial metastases, concurrent use of inducers of cytochrome 3A4 and abnormal organ function. The dose of RAD-001 in the second cohort was increased to 10 mg daily (increased from 30 mg weekly) based on evidence of safety of the higher dose. Results: Twenty-nine patients were enrolled; baseline information is available on 27. Median age was 63 yrs; 15 (56%) had >2 sites of metastatic disease. Most (48%) had stage M1c disease. PS was 0, 1 and 2 in 58%, 38% and 4%. All but 4 (15%) had received prior therapy. Grade 3 adverse events included stomatitis and fatigue (2 each), leukopenia, neutropenia, diarrhea, anorexia, dehydration, dyspnea, hyperglycemia, and hypersensitivity (1 each). Planned interim analysis was done after 20 patients were enrolled. 14 (70%) had progressed 16 weeks, failing to meet the decision rule needed (PFS >30%) to restart accrual. The median PFS for all 29 patients was 56 days. The median overall survival (OS) has not been reached. For the entire cohort of 53 pts treated on this study (at both dose levels), the median PFS, median OS were 59 and 286 days respectively. Conclusion: Interim analysis after enrollment of 20 patients at a higher dose of RAD-001 demonstrated significantly more toxicity and no added clinical efficacy. The 16 week PFS rate target was not reached, and accrual was suspended. No significant financial relationships to disclose.
Prognostic relevance of pretreatment soluble vascular endothelial growth factors (A,C,D) and their receptors (R1, R2, and R3) in advanced melanoma patients
Authors: Mouawad R. , Soubrane C. , Khayat D. 
Published: March 2020

8540 Background and aims: Circulating vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs) were described as prognostic factors in several cancers. The aim of this study is to evaluate the prognostic values of these parameters in metastatic malignant melanoma diseases. Methods and Patients: Using enzyme-linked immunosorbent assays, VEGFs (A, C, D) and their receptors (1, 2, and 3) were measured in sera of 75 patients with metastatic malignant melanoma in comparison to 30 healthy controls. Disease free survival (DFS) and overall survival (OS) were calculated from the beginning of the treatment until either the progression or the death and analyzed using the Kaplan-Meier method. Results: Pretreatment median sVEGF-A, sVEGF-C as well as VEGFR-3 levels were significantly higher in MMM patients as compared to healthy ones p=0.0017, p=0.005, p<0.00001 respectively). None of the studied markers correlated with gender, age or LDH levels. An inverse correlation between soluble VEGFR-2 and VEGF-D levels was observed (r=−0.33 p=0.040). High soluble VEGF-C and VEGFR-3 were correlated to high tumor burden (p=0.02, p=0.045). However, a relationship with lymph node metastasis was observed with sVEGF-A but not with sVEGFR-3. As shown by univariate analysis, only elevated levels of sVEGF-R1 concentration were found to exert a significantly unfavorable impact on both disease-free (χ2=6.64, p= 0.014) and overall survival (χ2=8.03, p= 0.0046). Conclusions: Our results suggest that, in metastatic malignant melanoma patients, soluble VEGF-A and VEGF-R3 pretreatment levels may prospectively identify high-risk patients with a worse prognosis; serum VEGFR-1 level may be a predictive factor of time to progression and overall survival. A multivariate analysis (Cox test) is ongoing in order to confirm if this parameter is an independent prognostic factor. No significant financial relationships to disclose.
Protein S-100β serum levels predicts clinical outcome of high-risk melanoma patients treated with high-dose adjuvant interferon alfa2b
Authors: Garcia-Albeniz X. , Domingo-Domenech J. , Auge J. , Molina R. , Puig S. , Malvehy J. , Mármol M. , Gascón P. , Mellado B. , Castel T. 
Published: March 2020

8543 Background: S-100β serum levels have been shown to be useful to monitor response to therapy in metastatic melanoma patients. We have recently reported that S-100β levels could also be useful in the adjuvant context. In this study we analyze the clinical relevance of S-100β serum levels in an homogeneuos stage IIB-III group of patients treated with high-dose interferon. Methods: Patients with melanoma diagnosis were prospectively tested for serum S-100β protein by luminoimmunometric assay (LIA) before starting interferon (baseline) and every 3 months thereafter (on.therapy), until treatment was completed. Median time to progression and overall survival were assessed. Multivariate analysis using the Cox proportional hazards model with covariable dependent on time was perfomed since S-100β under therapy changes during time. Results: Ninety-seven patients were included. Median follow-up was 62.9 months (range 32.7–87.4). Median baseline S-100β levels were 0.06μg/l (range 0.06–0.53). S-100 was considered high (=0.15 μg/l) in 20.6% of the patients. High baseline S-100β levels were associated with positive lymph-node status (p=0.02). High S-100β levels (while on therapy) showed relation with positive lymph-node status (p=0.014), number of positive lymph-nodes (p=0.01), macroscopic lymph-node involvement (p=0.002) and second melanoma diagnosis at study entry (p=0.001). By univariate analysis, high baseline S-100β levels were associated with disease free survival (DFS) (p=0.004) and overall survival (OS) (p=0.0007). Similarly, high on therapy S-100β levels were associated with DFS (p<0.0001) and OS (p<0.0001). In the multivariate analysis, high on therapy S-100β levels (HR 1.029, CI95% 1.015–1.042; p<0.0001) was an independent prognostic factor for DFS. High on therapy S-100β levels (HR 1.017, CI 95% 1.10–1.026; p<0.0001) and high baseline S-100β levels (HR 3.31, CI 95% 1.10–9.89; p=0.032) were independent prognostic factors for OS. Conclusions: These results provide novel evidence of the clinical usefulness of serum S-100β levels determination for monitoring the clinical outcome of high-risk melanoma patients treated with adjuvant therapy. No significant financial relationships to disclose.
Imiquimod: A TLR-7 agonist as adjuvant for a recombinant protein cancer vaccine
Authors: Adams S. , O'Neill D. , Nonaka D. , Manches O. , Chiriboga L. , Siu K. , Shao Y. , Gnjatic S. , Pavlick A. , Bhardwaj N. 
Published: March 2020

8545 Purpose: This clinical trial evaluates the safety and adjuvant activity of imiquimod, a toll-like receptor (TLR)-7 agonist, when given with a NY-ESO-1 protein vaccine. Imiquimod, by locally activating and recruiting dendritic cells (DCs) into the skin, is expected to stimulate antigen uptake by DCs, induce maturation and migration to draining lymph nodes, and to induce antigen-specific T and B cell immunity. Methods: Pilot study; 9 patients with resected stage 2B-3C malignant melanoma. Four 21 day cycles consisted of topical imiquimod cream (250 mg) on days 1–5 and id. injected NY-ESO-1 protein (100 mcg) into the site on day 3. Blood was drawn at several time points for immune monitoring; skin punch biopsies were obtained from control, imiquimod and vaccination sites 48 hours after the last vaccination. Results: The regimen was tolerated well, all patients completed four vaccinations. AEs were mild and transient and included injection site reactions (8/9 patients), fatigue (4/9 patients) and fever (2/9 patients). Significant levels of antigen-specific CD4+ or CD8+ T cell responses were not detected in ex-vivo ELISPOT assays. However, intracellular cytokine staining assays after in vitro pre-stimulation indicated that 6 of 8 subjects developed NY-ESO-1 CD4+ T cell responses. Humoral immunity was manifest by the induction of anti-NY-ESO-1 antibodies in 7/9 patients post-vaccination. Histochemistry of skin sections showed significant dermal mononuclear cell infiltrates in Imiquimod treated skin, whereas none were seen in untreated skin (p<0.01). IHC revealed markedly increased numbers of CD3+ (T-cells), CD68+ (macrophages/monocytes), CD123+ (plasmacytoid DCs) and DC-LAMP+ (mature myeloid DCs) immune cells in Imiquimod treated skin when compared with control skin of the same patients (p<0.05). Conclusion: Imiquimod, a topical immune response modifier, generated clear inflammatory infiltrates in the dermis, with significant increases in antigen-presenting cells and T cells. Imiquimod was well tolerated when used as an adjuvant to an NY-ESO-1 protein vaccine. Systemic immunity of both humoral and cellular types was induced in the majority of patients; however, responses were weak and the vaccine combination needs to be optimized in future studies. No significant financial relationships to disclose.
Long-term survival in patients with metastatic melanoma vaccinated with melanoma-antigen loaded dendritic cells
Authors: Fay J. W. , Banchereau J. , Palucka K. 
Published: March 2020

8547 Background: Previous clinical trials have demonstrated safety and tolerability of cancer antigen-loaded dendritic cells (DCs) in the treatment of metastatic melanoma. Further, DCs administered to patients with metastatic melanoma are immunogenic and induce durable clinical responses even in patients who failed previous cytotoxic therapy. This report is an analysis of long term clinical outcomes of DC vaccinated patients from our institution. Methods: Between March 1999 and February 2005 seventy patients with metastatic melanoma were treated with DC vaccines in four sequential phase I-IIa clinical trials. Most patients had M1b or M1c metastatic disease. DCs were generated either from CD34+ hematopoietic progenitors or from monocytes. Forty nine HLA-A*0201+ patients received vaccines pulsed with melanoma antigen derived peptides (MART-1, MAGE-3, TYR and gp100). Twenty one patients received DCs loaded with killed allogeneic melanoma cells. KLH was used as helper antigen and, in HLA-A*0201+ patients, Flu-Matrix peptide was used as control antigen. Patients received up to eight DC vaccinations over a maximum of 7 months. Results: DC vaccinations were safe and tolerable. Fifteen out of 70 (21%) patients are alive as of November 2006. The median survival in this group of surviving patients is 46 months (range 22–92 months). Three patients had no evidence of disease upon completion of DC vaccinations by clinical and positron emission tomography scanning. Four patients had experienced objective clinical responses by RECIST criteria (2 CRs and 2 PRs) based on clinical examination and computerized tomography or magnetic resonance imaging. These included two patients that had failed previous cytotoxic and cytokine therapy. Eight patients are alive with disease. Five of 15 long term survivors had no additional therapy other than DC vaccinations including a patient with CR of liver lesions who remains free of disease 80 months post DC vaccination. Conclusions: DC vaccines bring clinical benefit and elicit durable responses in a fraction of patients with metastatic melanoma. These vaccines may provide a survival advantage. Future studies are underway to improve DC vaccine efficacy for treatment of metastatic melanoma. No significant financial relationships to disclose.
Temozolomide combined with the PI3K inhibitor LY294002 or the mTOR inhibitor rapamycin inhibits melanoma cell growth, survival and invasion
Authors: Meier F. E. , Lasithiotakis K. , Schittek B. , Sinnberg T. , Garbe C. 
Published: March 2020

8559 Background: Potential therapeutic targets in the treatment of metastatic melanoma have emerged, to which pharmacological inhibitors have been designed, which may enhance tumor chemosensitivity. In melanoma, dacarbazine is considered to be the most effective agent although total responses do not exceed 20% The clinical activity of temozolomide is similar to that of dacarbazine, but temozolomide has the advantages of being absorbed orally and of crossing the blood-brain barrier. Many clinical trials of targeted therapy and chemotherapy combinations lack rigorous preclinical evaluation and may neglect relevant mechanistic interactions. The PI3K-AKT-mTOR (AKT) and RAS-RAF- MEK-ERK (MAPK) signaling pathways are constitutively activated in melanoma, and appear to play a role in chemoresistance. Methods: In this study, a panel of pharmacological inhibitors was utilized in order to block the AKT and MAPK signaling pathways at different levels (AKT: PI3K, mTOR; MAPK: RAF, MEK) in 5 human metastatic melanoma cell lines. The effects on chemosensitivity to temozolomide and cisplatin was then investigated. Results: The effects of most inhibitors on chemosensitivity varied significantly between the different cell lines. However, LY294002, a PI3K inhibitor and rapamycin, an mTOR inhibitor, consistently enhanced chemosensitivity. Treatment of melanoma cells with temozolomide or cisplatin combined with LY294002 or rapamycin had a strong effect on melanoma cell growth and survival. Invasive melanoma growth in organotypic cultures of human skin was suppressed completely. The most pronounced potentiation of efficacy was seen with temozolomide in combination with rapamycin. Conclusions: These data suggest that LY294002 and rapamycin can render melanoma cells susceptible to apoptosis, induced by chemotherapeutic agents such as temozolomide and cisplatin. Since both temozolomide and rapamycin are used clinically, the combination of temozolomide with rapamycin might potentially be utilized as an approach in melanoma treatment. This combination merits clinical investigation. No significant financial relationships to disclose.