bluuebunny/crossref_metadata_2025 huggingface dataset:
Cytogenetic analysis using multiple myeloma targets in POEMS syndrome
Authors: Bryce A. H. , Ketterling R. P. , Gertz M. A. , Kyle R. A. , Lust J. A. , Fonseca R. , Lacy M. , Greipp P. R. , Witzig T. A. , Rajkumar S. , Dispenzieri A.
Published: March 2020

8116

Background: POEMS syndrome, or osteosclerotic myeloma, is an uncommon plasma cell disorder associated with Peripheral neuropathy, Organomegaly, Endocrinopathy, M protein, and Skin changes, as well as bone lesions, Castlemans disease, and edema. The pathogenesis of POEMS is poorly understood, and its clinical course is distinct from Multiple Myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS). While various cytogenetic abnormalities have been well described in MM and MGUS, we provide the first report of testing for these abnormalities in POEMS syndrome. Methods: Using a prospectively held dysproteinemia database, we reviewed all cases of POEMS seen at our institution, identifying 36 with metaphase cytogenetic testing results, and 9 with fluorescence in situ hybridization (FISH) testing results. Combined cytoplasmic immunoglobulin/FISH testing (cIg- FISH) was performed with fluorescent-tagged antibodies to kappa/lambda immunoglobulin and FISH probes corresponding to the following anomalies: trisomies 3, 7, 9, 11, 15 and 17; del13/del13q; 14q32 split/del14; and t(11;14). Results: Five patients had insufficient plasma cells for cIg-FISH, and 9 were adequate for testing. Monosomy 13 was seen in 5 of the 9 cIg-FISH samples of which 2 of these cases also had apparent monosomy 14. cIg-FISH in one patient revealed trisomy 3 and 7. No abnormalities were seen at 11q13 (CCND1), 17p13 (p53) or translocations involving 14q32 (IGH). Thrity-eight total karyotypes analyses were attempted, though two showed an insufficient number of suitable metaphases. Of the 36 karyotype analyses, 31 were normal, 2 displayed characteristic plasma cell anomalies (hyperdiploid with structural anomalies), 2 treated patients displayed del20q anomalies and 1 patient had a constitutional 13;14 translocation. Conclusion: We are the first to report del13 as a possibly common abnormality in POEMS syndrome, detected by cIg-FISH in 5 of 9 (55%) samples with sufficient plasma cells, similar to the rate observed in MM and MGUS. The lack of abnormalities at 14q32 (IgH locus) is in contrast to MM and MGUS. Abnormal karyotypes, consistent with dividing plasma cells, are rare in POEMS, observed in only 2 of 36 (5.5%) cases. These observations could possibly lend insight into all three disorders.

No significant financial relationships to disclose.
Impact of intensive stem cell mobilization therapy on outcomes following autologous stem cell transplantation (ASCT) for non- Hodgkin lymphoma (NHL)
Authors: Damon L. E. , Damon L. , Kaplan L. , Martin T. , Linker C. A.
Published: March 2020

8119

Background: We retrospectively evaluated the impact of intense [I] stem cell mobilization therapy on event-free survival [EFS] and overall survival [OS] following ASCT for NHL. Methods: 80 patients (pt) were studied (2 Burkitt, 3 primary CNS, 3 follicular, 2 intravascular, 43 large cell, 12 mantle cell, 9 transformed, and 6 peripheral T-cell). Patients with very-high risk features (LDH > 500 IU/L, first remissions < 1 year, 2 or more extra-nodal sites, and/or primary CNS/intravascular/mantle cell/peripheral T-cell histology) were prospectively allocated to I stem cell mobilization (requiring hospitalization) with either cyclophosphamide [C] (6 g/m2) + etoposide [E] (2g/m2) + filgrastim [G-CSF] (±rituximab [R]) (n=5) or with cytarabine [A] (2 g/m2 bid for 8 doses) + E (40 mg/kg) + G- CSF (±R) (n=45). 30 pt were mobilized (outpatient) with C 4g/m2 + G-CSF ±R (non-intense [NI] mobilization). 76 pt received ASCT conditioning with carmustine [B] + E and C (CBV) and 2 with B + E + A and melphalan (BEAM); 2 pt did not undergo ASCT. Results: The median age was 54 (21–69 years [yr]) and 57% had an elevated LDH at presentation. 39 pt (49%) were primary induction failures (PIF). At NHL presentation, 38% were IPI high-intermediate or high risk. There were 3 non-relapse mortalities (4%): (2) B pneumonitis and (1) multi-organ failure (all following ASCT). With a median follow-up of 1.8 yr (0.1–6.4), the overall median EFS is 3 yr (48% [34–62] at 4 yr) and the median OS is 4.7 yr (59% [43–72] at 4 yr). Patients receiving I mobilization were similar to those receiving NI mobilization in terms of the # of prior therapies (median 2, each), the presenting IPI risk score, and the percent PIF (57% vs 41%; p=0.17). There were trends favoring I mobilization for both 4 yr EFS (58% [41–75] vs 35% [13–57]) and OS (66% [48–84] vs 52% [32–72]), neither statistically significant. In the sub-group of large B-cell NHL, 4 yr EFS was the same in pt receiving I mobilization (81% [63–98] vs 73% [50–96]; p=0.33) but OS was better (91% [79–100] vs 58% [35–82]; p=0.02). Conclusions: I stem cell mobilization therapy, compared to NI mobilization therapy, may improve outcomes for NHL pt with very-high risk features and may overcome the anticipated poor prognosis of these pt.

No significant financial relationships to disclose.
Phase I trial of escalating doses of total marrow irradiation (TMI) with helical tomotherapy and peripheral blood progenitor cell rescue (PBPC) following high-dose melphalan and PBPC as part of tandem high-dose therapy (THDT) for patients with multiple myeloma (MM)
Authors: Wong J. Y. , Somlo G. , Spielberger R. , Forman S. , Poppelwell L. , Schultheiss T. , Frankel P. , Krishnan A. , Sahebi F. , Parker P.
Published: March 2020

8121

Background: Attempts to combine total body irradiation (TBI) with high-dose melphalan (Mel) resulted in substantial organ toxicities and precluded optimal dosing of Mel. Helical tomotherapy may allow delivery of total marrow irradiation (TMI), while avoiding collateral toxicities. Methods: We designed a phase I/II study for patients (pts) with responding or stable stage I-III MM. Following PBPC mobilization, pts receive THDT first with Mel 200 mg/m2 and PBPC, and, ≥ 6 weeks later, escalating doses of TMI (starting dose: 200 cGy daily × 5 [1,000 cGy], up to 200 cGy twice daily × 5 days [2,000 cGy]) and PBPC. Maintenance consists of dexamethasone 40 mg/day × 4 days every 28 days and thalidomide 50–200 mg/day. Results: The median number of prior chemotherapy regimens is 2 (1- 4). The median duration from diagnosis to the HDT is 8 mos (4–13). Median age of pts is 53 (35–66). Sixteen pts with stages II (6) and III (10) MM have received Mel; 15 of 16 pts (8F/8M) have received treatment at dose levels 1–5 of TMI (1,000 cGy through 1,800 cGy); 1 pt is about to start TMI at 1,800 cGy. The median time between the first and second THCT cycles is 74 days (47–125). Hematopoietic toxicities were independent of TMI dose levels: granulocyte recovery to >1,000/microliter following Mel required 12 days (11–38) versus a median of 10 days after TMI (range; 9–12). Platelet (excluding 6 pts not needing plt transfusion) independence was seen by day 10 (8–13) versus 8 (6–11) following TMI. In the first 15 pts the estimated median radiation dose to normal organs was 15–60% of the targeted bone marrow dose. Reversible grade 3 non-hematologic toxicities by TMI dose levels included fatigue and febrile neutropenia (FN) (level 1: 1 pt each), FN (level 2: 1 pt); none (level 3); fatigue (level 4: 2 pts); anorexia and stomatitis (level 5: 1pt; anorexia: 1 pt). The median follow-up is 8 mos (3–21); 1 pt progressed at 8 mos. Final data on toxicities including patients already in screening for treatment at TMI 2,000 cGy, tolerability of maintenance, and response rate will be presented. Conclusion: TMI is feasible and could potentially be useful as part of THDT for patients with MM.

No significant financial relationships to disclose.
Interferon alfa-induced autoimmunity and serum S100 levels as predictive and prognostic biomarkers in high-risk melanoma in the ECOG-intergroup phase II trial E2696
Authors: Stuckert J. J. , Tarhini A. A. , Lee S. , Sander C. , Kirkwood J. M.
Published: March 2020

8506

Background: Uncontrolled evidence demonstrates that adjuvant high-dose interferon alfa-2b (HDI) benefit in high-risk melanoma patients is predicted by autoimmunity induction, and the prognosis of melanoma has been correlated with levels of S-100 protein. We have evaluated these two serological markers in the context of a completed phase II study E2696. Methods: Patients with resectable AJCC stage IIB, III, and IV melanoma were randomly assigned to receive GM2-KLH/QS-1 (GMK vaccine) plus concurrent HDI (Arm A) or GMK plus sequential HDI (Arm B), or GMK without HDI (Arm C). Sera from 103 patients were banked at baseline and 3 additional time points, and have been tested for serum protein S100, and anti-nuclear, anti-thyroid peroxidase, anti-thyroglobulin, anti-mitochondrial, and total anti-cardiolipin autoantibodies (AA) using ELISA. Results: At a median follow-up of 96.5 mo (range: 17–109), the median relapse-free survival (RFS) was 28.3 mo, 95% CI (18.4, 43.6) (64 /103 patients relapsed). Median survival has not been reached (54/103 alive). AA were induced in 17 subjects (25%; n=69) receiving HDI and GMK versus 2 (6%; n=34) receiving GMK alone (2p-value=0.031). In HDI arms induced AA were detected = 12 weeks after therapy initiation. RFS was improved among HDI recipients with AA, but with the limited numbers in this phase II trial this trend does not achieve significance. In the multivariate (Cox regression model) analysis, adjusting for treatment (HDI vs. no HDI) and baseline S-100 value for later time points, S-100 level ≥0.08 microg/l was an independent prognostic factor for RFS at baseline (HR=1.96; p=0.0273), week 4–6 (HR=1.72; p=0.073), wk 12–14 (HR=1.81; p=0.048) and wk 52 (HR=4.3; p<0.001). The hazard ratio (HR) for OS was 1.86 at wk 12–14 (p=0.061), and 5.7 at wk 52 (p<.001). In the model using wk 52 S-100 value (at completion of HDI), the HR adjusted for treatment was 7.1 p=0.009. Conclusions: Autoimmunity is a predictive biomarker of RFS with HDI in the E2696 trial compared to GMK. Serum protein S-100 level ≥0.08 microg/l is an independent prognostic marker for RFS and OS most significant at baseline and 1 year of followup. Current studies will evaluate these markers in the larger phase III trial E1694 with 880 subjects.

[Table: see text]
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.
Incidence of pediatric melanoma in Texas: A report from the Texas Cancer Registry, 1995–2003
Authors: Spelman A. R. , Okcu M. F. , Bondy M. , Pappo A.
Published: March 2020

8564

Background: Although melanoma is rare in the pediatric population, a sizable increase in the incidence of this disease has been previously reported in the pediatric population (J Clin Oncol 23:4735, 2005). In this study, we describe the incidence of pediatric melanoma in Texas in an effort to determine whether there has been a similar increase in Texas. Methods: Between 1995 and 2003, we identified 197 cases of melanoma (ICD codes 8720–8780) in children < 20 years of age. Baseline characteristics were compared by chi-square analysis and age-adjusted incidence rates were calculated based on the US 2000 standard population. Results: Between 1995 and 2003, the incidence of pediatric melanoma in Texas increased by 57.2% (95% CI 42.4 to 72) per year of age. There was an 18.1% (95% CI 9.8 to 26.4) increased incidence per year for Texas in contrast to the 12% (95% CI 5.2 to 18.8) national increase (SEER). Fifty-three of 254 counties (20.9%) reported cases during this time period. Cases were diagnosed at a median age of 16 years (range 0–19). The majority of cases were non-Hispanic white (91.7%). Over half the cases (54.3%) were diagnosed at Stage I and the lesions were largely distributed between the extremities (39.1%), torso (28.9%) and head, face and neck (27.4%). Older individuals (10–19 years of age) were more likely to be female (p=0.024), non-Hispanic white (p<0.001) and diagnosed at an earlier stage (p=0.023) than younger individuals (<10 years of age). The incidence in older individuals was over 6 times that in the younger individuals (IRR=6.32, 95% CI 4.19–9.87) Conclusions: The incidence of pediatric melanoma in Texas has rapidly increased over that past 10 years. This increase emphasizes the need for public awareness, primary and secondary prevention campaigns and prospective studies to identify risk factors.

No significant financial relationships to disclose.
Survival and treatment morbidity with therapeutic lymphadenectomy for regional nodal metastases from melanoma
Authors: Agrawal S. , Kraybill W. G. , Albini P. , Tan W. , Wilding G. E. , Kane J.
Published: March 2020

8571

Background: Therapeutic lymphadenectomy (TL) is potentially curative therapy for clinically palpable nodal metastatic melanoma. However, TL is associated with significant morbidity and a dismal prognosis. Methods: Review of the melanoma database identified 275 patients who underwent TL. Patient, tumor, and treatment-related variables associated with recurrence and overall survival were analyzed. Results: The study group comprised of 63% males with a nodal basin distribution of 47% axilla, 35% groin and 18% neck. Median age, number of positive lymph nodes and size of the largest lymph node were 51 years 2 nodes and 2.5 cm respectively. Median survival was 27.4 months (77%, 55% and 34% at 1, 2 and 5-years respectively). Regional recurrence at the lymphadenectomy site occurred in 76 (28%) patients. Distant metastases developed in 67 (88%) patients with and 126 (63%) without regional recurrence. On multivariate analysis, the most powerful predictor of both survival and regional recurrence was lymph node ratio (LNR- number of positive nodes/total dissected nodes). Median survival for LNR <0.13 was 39 months versus 19 months for ≥0.13 (p = 0.005). Older age and male sex were also predictive of a decreased survival. Treatment-related morbidity was rare and included lymphedema (12%), wound complications (3%) and nerve injury (1%). Conclusion: The overall survival and acceptable morbidity justifies TL for clinically positive nodal metastatic melanoma. LNR is predictive of survival and regional recurrence following TL. Due to significant distant and regional failure rates, in addition to systemic adjuvant therapy these patients may benefit from radiation therapy.

No significant financial relationships to disclose.
Temozolomide (TMZ) and cisplatin (CDDP) combination in naïve patients with stage IV melanoma. Definitive results of a phase II multicenter trial
Authors: Tourani J. , Wiersbicka E. , Mourey L. , Guillot B. , Sassolas B. , Bedane C.
Published: March 2020

8572

Background: TMZ, an imidazol derivative, is a second-generation alkylating agent. TMZ has shown some efficacy in metastatic melanoma and recently received extended approval to treat brain tumours. The purpose of this study was to test the efficacy and safety of combination therapy with TMZ plus CDDP in patients with metastatic melanoma. Methods: Patients with stage IV melanoma were required to have histologically proven measurable metastasis. Patients received as a first-line therapy a combined treatment with TMZ (200 mg/m2/day), days 1–5 and CDDP (75 mg/m2/day) on day 1.The treatment was given every 28 days, maximum 6 cycles. The primary end point was an overall response rate. Secondary end points were: tolerance, progression free survival (PFS) and OS. Results: Thirty patients (pts) were enrolled from 09–2003 to 11–2005: 17 males and 13 females. Median age was 59 years (min: 26; max: 83). Initial performances status was 0 (22 pts) and 1 (8 pts). A total of 126 cycles of chemotherapy were administered. Clinical toxicity was mild and no toxic death occurred. Dose modifications for TMZ were required in 40% of pts and for CDDP in 13.3% of pts. 21 cycles of chemotherapy (21/126) had to be delayed due to toxicity. Grade 3 and 4 toxicity was observed in 12 pts (40 %). 16 pts withdrew because of tumor progression, 4 were removed because of adverse events including neutropenia (3 pts) and medullar aplasia and sepsis (1 pt). No complete response was observed among the 28 evaluable pts. Five pts (17.8%) achieved a partial response. An additional 6 pts (21.4%) showed disease stabilization & 17 pts (60.7%) revealed progressive disease. So the overall response rate was 17.8%. Median PFS of 29 evaluable pts was 111 days (min: 28; max: 808). Median response duration was 216 days. Conclusions: This combination therapy with TMZ and CDDP according to this schedule had an acceptable tolerance but gave a poor response rate comparatively to those reported previously by Tas and al (30%). Definitive data will be produced in June 2007.

No significant financial relationships to disclose.
Routine PET and PET-CT scans in melanoma patients with positive sentinel node biopsy is of limited benefit
Authors: Constantinidou A. , Hofman M. , O'Doherty M. , Acland K. , Healy C. , Harries M.
Published: March 2020

8582

Background: Positron emission tomography (PET) scanning is increasingly used for the staging and management of malignant melanoma. The role of PET as a routine procedure in patients with positive sentinel node biopsy (SNB) is not yet established. We report in the series with longest follow up outcomes of PET scans performed in patients with subclinical lymph node disease. Methods: Case notes of 29 sequential patients with melanoma of Breslow thickness greater than 1mm who had PET scans within 130 days after a positive SNB were reviewed. Four patients had a PET after the lymph node dissection (LND). Results: 2 patients (6%) had a positive PET scan neither of which was melanoma related. The first patient had a thyroid tumour confirmed with fine needle aspiration biopsy and the second patient had increased uptake in the chest wall which on verification with bone scan proved to be old trauma. 28 patients (96%) had a LND and this was positive in 5 cases (17%). With a median follow up of 23 months 21 patients remained disease free. Out of the 8 patients (27%) who presented with recurrence 2 (25%) were successfully treated with further surgery and remained in remission, 4 (50%) died, 1 (12.5%) was lost from follow-up and 1 (12.5%) is followed up in another hospital. In none of the 29 cases did the early PET scan after a positive SNB alter subsequent melanoma management. Conclusions: The role of PET scanning soon after a positive sentinel node biopsy appears to be of uncertain benefit. It is questionable whether any imaging is beneficial at this stage. The results of this review suggest that PET scanning might not be indicated for this group of patients but larger prospective studies are required to confirm this. Patients Characteristics No % Male 15 (51) Female 14 (49) Melanoma Type: Nodular 8 (27) Superficial spreading 15 (51) Other 2 (6) Unknown 4 (13) Breslow thickness: 1.0–1.9 13 (44) 2.00–3.9 14 (49) ○= 4.0 2 (6) Ulceration: Yes 3 (10) No 25 (86) Unknown 1 (3) Age Median 56

No significant financial relationships to disclose.
A pilot, multi-dose, placebo-controlled evaluation of american ginseng (panax quinquefolius) to improve cancer-related fatigue: NCCTG trial N03CA
Authors: Barton D. L. , Soori G. S. , Bauer B. , Sloan J. , Johnson P. A. , Figueras C. , Duane S. , Dakhil S. , Liu H. , Loprinzi C. L.
Published: March 2020

9001

Background: Fatigue is one of the most common symptoms in people diagnosed with cancer. Ginseng is a popular herb for treatment of this. It has been termed an “adaptogen”, felt to be able to restore balance to the body; its potential anti-fatigue efficacy is supported by animal data. The purpose of this pilot trial was to evaluate three doses of American Ginseng versus placebo for cancer-related fatigue. Methods: Patients with a life expectancy = 6 months and a history of cancer-related fatigue who had been experiencing fatigue = 1 month were eligible. Exclusion criteria included prior use of ginseng, chronic systemic steroids and brain malignancies. Other etiologies for fatigue, such as pain, were also excluded. Participants were randomized to receive, in a double blind manner, placebo, 750 mg/d, 1,000 mg/d or 2,000 mg/d of American Ginseng in BID dosing for 8 weeks. Endpoints included The Brief Fatigue Inventory (BFI), the Vitality Subscale of the SF-36 and several numeric analogue questions of perceived benefit; endpoints were measured at baseline, 4 weeks and 8 weeks. Area under the curve (AUC) and change from baseline were calculated. Results: Two hundred eighty two patients (69–72 per arm) were enrolled from 10/21/2005 to 07/05/2006. Available 8-week data are provided in the table below; higher numbers are better. There were no statistically significant differences in any grade of toxicity between active and placebo arms, and an equivalent number of patients discontinued the study due to adverse events in each arm. Conclusion: This randomized pilot trial provided data to suggest that American Ginseng doses of 1000–2000 mg/d may be effective for alleviating cancer related fatigue. Therefore, further study of American Ginseng in cancer survivors appears warranted.

No significant financial relationships to disclose.

[Table: see text]
A placebo-controlled trial of Sertraline's effects on symptoms, well-being and survival in advanced cancer: The ZEST Trial
Authors: Wilcken N. R. , Goldstein D. , Nowak A. K. , Beale P. J. , Jefford M. , Dhillon H. , O'Connell R. , Heritier S. , Simes R. J. , Stockler M.
Published: March 2020

9002

Background: Depression, anxiety, fatigue and impaired well-being are common, important and closely related in advanced cancer. We sought to determine the effects of sertraline (a well-tolerated, SSRI antidepressant) on these symptoms and survival in a broad cross-section of people with advanced cancer but without major depression. Methods: 189 participants (pts) were randomly allocated to sertraline 50 mg daily or placebo. Assessments were at baseline; months 1, 2, 4, 6, 9, 12; and, then 3-monthly. Outcome measures rated by pts included the: Centre for Epidemiologic Studies Depression scale (CES-D); Hospital Anxiety and Depression Scale (HADS-A, HADS-D); and the Functional Assessment of Cancer Therapy General and Fatigue scales (FACT-G and FACT-F). Clinicians completed Spitzer's Quality of Life Index (SQLI). Outcomes on all scales are expressed from 0 (worst) to 100 (best). The primary analyses of sertraline's effects on quality of life were based on scores at 4 and 8 weeks adjusted for baseline scores using generalised estimating equations. Efficacy analyses are by intention to treat; toxicity analyses by treatment received. P-values and 95% confidence intervals (CI) are 2-sided. Results: Recruitment was stopped after the first planned interim analysis of 150 pts showed a trend in overall survival favouring placebo (univariable logrank p=0.04; multivariable Cox model hazard ratio 1.61, CI 1.1 to 2.5, p=0.02). This trend was weaker at the final analysis including all 189 patients and longer follow-up (univariable logrank p=0.09); and, after accounting for baseline factors (multivariable Cox model hazard ratio 1.27, CI 0.87 to 1.8, p=0.2). Sertraline had no significant effects (scale: benefit over placebo, 95% CI) on depression (CES-D: 0.4, −2.6 to 3.4), anxiety (HADS-A: 2.0, −1.5 to 5.5), fatigue (FACT-F: 0.3, −4.3 to 4.9), overall quality of life (FACT-G: 1.7, −1.3 to 4.7) or clinicians’ ratings (SQLI: 2.0, −2.5 to 6.5). Subgroup and sensitivity analyses also excluded significant benefits. Sertraline was discontinued more often and earlier than placebo (logrank p = 0.03). The trial was closed for lack of benefit. Conclusions: Sertraline did not improve symptoms, well-being or survival and should be reserved for those with a proven indication.

No significant financial relationships to disclose.