bluuebunny/crossref_metadata_2025 huggingface dataset:
H pylori-positive gastric diffuse large B-cell lymphomas are potentially curable by H pylori eradication therapy
Authors: Kuo S. H. , Chen L. T. , Wu M. S. , Lin C. W. , Kuo K. T. , Wang H. P. , Hsu P. N. , Lin J. T. , Cheng A. L.
Published: March 2020

8093

Background: We have recently demonstrated that early-stage gastric diffuse large B-cell lymphomas (DLBCLs) with MALToma, as well as their MALToma counterparts, may respond to H pylori eradication therapy (HPET). The present study was conducted to evaluate the effect of HPET in stage IE gastric DLBCLs without MALToma. Methods: Seven patients (4 men and 3 women; age range, 35 to 83 years) with H pylori infection and stage IE gastric DLBCL without MALToma received HPET as first-line treatment from June 2002 through May 2006. Additional immunohistochemical reaction with anticytokeratin was performed to exclude lymphoepithelial lesions (minimal MALToma components) in DLBCL. All patients received intensive endoscopic follow-up examinations with biopsy to evaluate tumor response. Patients with significant improvement of gross lesions that accompanied regression of tumor cells were followed up without additional treatment. Patients without significant improvement were immediately referred to systemic chemotherapy. Tumors that resolved to Wotherspoon grade 2 or less after successful HPET were considered as complete histologic remission. Results: Successful HPET was achieved in all patients. There were 5 patients with complete histologic remission. The complete remission rate was 71.4% (95% confidence interval, 45.1% to 97.7%). The median duration between HPET and complete histologic remission was 2.6 months (range, 1.1 to 5.7 months). At a median follow-up of 24.2 months (range, 5.7 to 56.8 months), all patients with complete histologic remission after HPET were alive and free of lymphoma. Conclusions: A substantial portion of early-stage gastric DLBCLs without MALToma remain H pylori-dependent and can potentially be cured by HPET.

No significant financial relationships to disclose.
Alemtuzumab in clinical practice: A British Columbia experience
Authors: Hui D. , Lam W. , Toze C. , Delorme M. , Noble M. , Klimo P. , Sutherland J. , Gill K. , Connors J. , Sehn L.
Published: March 2020

8098

Background: Limited information is available on alemtuzumab in the non-clinical trial setting. We evaluated its efficacy and safety in 42 consecutive unselected patients who received alemtuzumab monotherapy in British Columbia between October 2002 and August 2006. Methods: Information on patient demographics, baseline clinical and pathologic characteristics, dose and schedule of treatment, clinical response, survival, and toxicities associated with alemtuzumab were collected retrospectively. Results: Thirty-nine of 42 patients had chronic lymphocytic leukemia, 2 had mycosis fungoides, and 1 had T-cell post-transplant lymphoproliferative disorder. In contrast to previous reports, 42% were treated by community practitioners and 83% received alemtuzumab subcutaneously. The median time from diagnosis to alemtuzumab was 58 months, with a median age of 63 years at alemtuzumab treatment. Patients received a median of 4 treatments prior to starting alemtuzumab. One of 42 patients (2%) achieved a complete response, 20 (48%) achieved a partial response, 13 (31%) had stable disease, and 4 (10%) had progressive disease. The median post-alemtuzumab overall survival was 15.1 months and the median progression-free survival was 5.4 months. Response to alemtuzumab correlated with an increased progression- free survival (11 months versus 3.6 months, p=0.001) and time to next treatment (15.7 months versus 5.4 months, p=0.004). Significant adverse events included grade 3 or 4 neutropenia (75%) or thrombocytopenia (42%), infections (54%) including CMV reactivation (6%), and death (12%). Patients who received alemtuzumab in the community setting had a higher incidence of febrile neutropenia (p=0.05) and infection (p=0.03) compared to academic centres, although no difference in overall survival was noted. Conclusion: Alemtuzumab can be safely administered in a wide variety of clinical settings, including community practice, and is associated with a high level of activity.

No significant financial relationships to disclose.
Prevention of active multiple myeloma (MM) using IL-1 receptor antagonist (IL-1ra) and low-dose dexamethasone (Dex) and monitoring the high sensitivity C-reactive protein (hsCRP)
Authors: Lust J. A. , Lacy M. Q. , Zeldenrust S. R. , Dispenzieri A. , Gertz M. A. , Greipp P. R. , Witzig T. E. , Kumar S. , Geyer S. M. , Donovan K. A.
Published: March 2020

8105

Background: IL-6 is the central myeloma growth factor and we have shown that abnormal production of IL-1beta in the myeloma microenvironment stimulates the generation of paracrine IL-6. A Phase II trial was completed using IL-1ra, which inhibits paracrine IL-6 production, and low dose Dexamethasone (Dex), which decreases IL-1 levels through myeloma cell apoptosis, in patients with smoldering/indolent MM (SMM/IMM). These patients are at the greatest risk for progression to active MM and most likely to benefit from anti- cytokine therapy. Methods: Patients that had ≥ 10% bone marrow plasma cells and/or an IgG or IgA M-spike ≥ 3 g/dL and did not require immediate chemotherapy were eligible. A total of 47 patients received 100 mg of IL-1ra SQ qd for 6 months unless clinical progression occurred. Responding patients were allowed to continue on therapy with IL-1ra alone. Low dose Dex (20 mg qweek) was added after 6 months of IL-1ra in non-responding patients. The primary endpoint was progression-free survival (PFS). Results: The 47 patients were at high risk for progression to active MM with 98% having ≥ 10% plasma cells, 89% generating IL-1 levels consistent with myeloma (≥ 1.0), and 32% having bone lesions. All 47 patients received IL-1ra initially and 25/47 subsequently received IL-1Ra/Dex. For the group of 47 patients, the median overall progression-free survival was 37.5 months. Three patients achieved a minor response (MR) to Anakinra alone; 5 pts achieved a PR and 4 patients an MR after addition of Dex. Seven patients had a decrease in the plasma cell labeling index (PCLI; a marker of myeloma cell growth) on Anakinra alone which paralleled a decrease in the high sensitivity CRP (a marker of serum IL-6 levels). The median PFS for patients without (n=12) and with (n=35) a ≥ 15% decrease in their baseline hsCRP was 6 months and > 3 yrs, respectively (p=0.002). Conclusions: In SMM/IMM patients at high risk for progression to active myeloma, treatment with IL-1 inhibitors (IL-1ra ± Dex) results in an increased PFS in patients that demonstrate a ≥15% reduction in the baseline CRP compared to those that do not respond.

No significant financial relationships to disclose.
Fully human antibody MOR202 against CD38 for the treatment of multiple myeloma and other blood-borne malignancies
Authors: Tesar M.
Published: March 2020

8106

MOR202 is one of MorphoSys’ internal development programs targeting the cell surface antigen CD38 that is found to be expressed on various cell lines derived from B cell, T cell, and myeloid/monocytic tumors. Especially in the indication of multiple myeloma (MM), which remains an incurable malignancy with a median survival of 3–4 years, a strong expression has been reported in the majority of patients’ tumor samples. CD38-specific human antibodies were selected from MorphoSys’ proprietary HuCAL GOLD phage display library by cell panning strategies. A lead candidate (MOR202) was selected from several antibodies recognizing different epitopes on CD38 and subjected to further in vitro and in vivo characterization as follows: MOR202 exhibits an affinity in the low nanomolar range, recognizes CD38 on many cell lines of different cancer origin and most importantly on all primary MM-patient samples in FACS and IHC. The fully human IgG1 MOR202 is able to kill CD38-expressing cell lines and primary MM cells from patients efficiently by ADCC in a concentration-dependent manner, whereas early progenitor cells are not affected as demonstrated by a clonogenic assay. Finally, excellent efficacy could be shown in a SCID-mouse xenograft model, resulting in significantly reduced tumour growth (RPMI8226) and overall survival, which was even superior to bortezomib tested in the same model.

No significant financial relationships to disclose.
Outcome following multiple lines of salvage chemotherapy prior to autologous stem cell transplant for relapsed or refractory diffuse large B-cell lymphoma (DLBCL)
Authors: Stakiw J. , Kuruvilla J. , Al-Farsi K. , Zadeh S. , Nagy T. , Keating A. , Crump M.
Published: March 2020

8120

Background: The standard of care for chemosensitive relapsed or refractory DLBCL is autologous stem cell transplant (ASCT). There is no standard approach for patients (pts) whose disease fails to respond to platinum-based salvage chemotherapy (pSC) although pts who undergo further salvage chemotherapy to demonstrate chemosensitivity may benefit from ASCT (Chen, et al, BMT 2002). We analyzed the overall response rate (ORR) to each line of salvage therapy for pts with relapsed or refractory DLBCL and the impact of the number of salvage regimens necessary to demonstrate chemosensitivity on overall and progression-free survival (OS and PFS) post-ASCT. Methods: We retrospectively reviewed our computerized database and charts between Jan 1/99 - Dec 31/05 and identified 203 pts relapsed after or refractory to anthracycline-based chemo treated with pSC. Pts typically received 2–3 cycles of pSC to assess chemotherapy sensitivity. Responding patients received etoposide 60 mg/kg and melphalan 160 mg/m2 supported by autologous PBSCs. Pts with stable or progressive disease following first line salvage chemotherapy (SC1) were offered alternate non-cross resistant second-line salvage chemotherapy (SC2) and proceeded to ASCT if chemosensitive. Results: Pt characteristics: Median age at time of salvage chemotherapy: 52 years (range 21–65); primary refractory: 48%; advanced stage disease at salvage: 50%; prior rituximab: 17%; prior radiation 26%. 119/203 pts did not respond to SC1, 81 pts received SC2 and 10 pts received 3 salvage regimens (SC3). ORRs to salvage were: SC1: 40%, SC2: 14%, SC3: 10%. Pts able to proceed to ASCT were: SC1: 37%, SC2: 14%, SC3: 0. With a median follow-up of 1.8 years, the 2-year OS post ASCT for the SC1 and SC2 groups was 69% and 56% respectively. The 2-year PFS post ASCT for the SC1 and SC2 groups were 58% and 40%. Conclusions: The ORR to platinum-based SC is low in this cohort of primary refractory/relapsed patients (40%), and only 14% of pts who received SC2 after pSC responded. Although some have prolonged PFS following SC2 and ASCT, additional strategies should be investigated in these patients.

No significant financial relationships to disclose.
Effect of rituximab (R) on clinical outcomes after autologous stem cell transplantation (ASCT) in pts with relapsed or refractory diffuse large B-cell lymphoma (DLBCL)
Authors: Adegbola O. , Andreadis C. , Schuster S. J. , Chong E. A. , Nasta S. D. , Porter D. L. , Luger S. M. , Tsai D. E. , Cunningham K. , Stadtmauer E. A.
Published: March 2020

8122

Background: First-line chemotherapy cures ∼50% of pts with DLBCL, while salvage therapy followed by ASCT can cure another ∼30%. R significantly improves response rates to 1st line therapy. This retrospective study was designed to test the hypotheses that: 1) ASCT is effective in pts relapsed after R-chemotherapy and 2) addition of R to salvage improves outcomes after ASCT. Methods: We identified 84 pts with relapsed/refractory DLBCL who underwent ASCT at our institution between 1990 and 2006. In all, 32% received a R-chemo 1st line regimen and 27% received R with salvage. The median age at ASCT was 49 yrs and the median time from diagnosis to ASCT was 16 mos. High-dose regimens included BCV (48%), BEAM (8%) and alkylator/TBI (20%). Results: Overall response rate (ORR) after ASCT was 52%, with 37% of pts in CR by day 100. Among those in CR, 16% had a CR pre-ASCT, 72% had a lesser response, and 9% were chemo-resistant. The addition of R to salvage (23/84 pts) was favorably associated with ORR after ASCT (OR: 5.2, 95% CI: 1.1 - 25, p=0.029), even in pts who had failed a prior R regimen (p=0.013). Other factors favorably associated with ORR were response to salvage (p=0.046) and time to ASCT >12 mos (p=0.017). At last f/u (med: 22 mos, iqr: 7 - 55 mos), event-free (EFS) and overall survival (OS) were both 35%. The only factor associated with EFS and OS in univariate and multivariate analyses was ORR after ASCT (HR: 0.16, 95% CI: 0.07 - 0.37, p<0.001 and HR: 0.12, 95% CI: 0.05 - 0.28, p<0.001 respectively). Age at ASCT, time to ASCT, year of ASCT, mobilization/conditioning regimen, and failure of a R-chemo regimen were not associated with EFS or OS. Conclusions: Pts with DLBCL who have failed a R-chemo first-line regimen derive an equal benefit from ASCT as pts who are R-naïve, with significant long-term EFS and OS. Additionally, inclusion of R in salvage therapy prior to ASCT provides superior response rates, even after a failed prior R-chemo regimen. These results confirm the benefit of ASCT for pts with DLBCL in the rituximab era and argue for the incorporation of R and related agents in studies of high-dose therapy and ASCT.

No significant financial relationships to disclose.
Predicting clinical outcome through gene expression profiling in stage III melanoma
Authors: John T. , Black M. A. , Toro T. , Gedye C. A. , Davis I. D. , Leader D. , Guilford P. , Cebon J. S.
Published: March 2020

8502

Background: Melanoma patients with clinically involved regional lymph nodes (Stage IIIB&C) represent a prognostically heterogeneous population. Current prognostic factors cannot distinguish the 30% of patients who will achieve long term survival from those who will relapse early. We hypothesized that gene expression profiling could identify these different prognostic groups and provide a greater understanding of the genetic mechanisms involved. Methods: Lymph node sections from 29 patients with Stage IIIB & IIIC melanoma and divergent clinical outcome as defined by time to tumor progression (TTP), including 16 poor (TTP<6 months) and 13 good (TTP>28 months) prognosis patients, were subjected to molecular profiling using spotted oligonucleotide arrays containing 30,888 probes as an initial test set. The differentially expressed genes were determined using a Wilcoxon-Mann-Whitney t-test with the false discovery rate controlling method of Benjamini-Hochberg and validated using quantitative real-time RT-PCR. Using logistic regression, a predictive score algorithm was developed based on the 15 genes for which the correlation between the two platforms was the strongest. The score was then applied to two independent validation sets of 10 and 14 patient samples. Results: Supervised analysis using differentially expressed genes was able to distinguish the two prognostic groups in the test set. The score correlated directly with clinical outcome, with higher scores associated with improved TTP. When the score was then applied to two independent sets of Stage III melanoma patient samples, it predicted clinical outcome accurately in 90% of samples. Conclusions: Stage IIIB and IIIC melanoma can be prognostically sub-classified according to the expression of 15 genes. To our knowledge this is the first study focused on Stage III disease using ex vivo patient samples. These results are encouraging and this genetic signature is currently being validated on a larger cohort. This method will allow appropriate stratification of stage III melanoma patients in adjuvant clinical trials, ameliorating the inherent biological heterogeneity that can confound these studies.

[Table: see text]
Long-term protective effect of mature DC-LAMP+ dendritic cell accumulation in sentinel lymph nodes containing micrometastatic melanoma. An EORTC Melanoma group study
Authors: Scolyer R. A. , Elliott B. , Suciu S. , Eggermont A. M. , Mackie R. , Robert C. , Thompson J. F. , Angevin E. , Cook M. G. , Spatz A.
Published: March 2020

8509

Background: In a previous immunohistochemical study of dendritic cells (DCs) in sentinel lymph nodes (SLNs) draining regressing melanomas we found that the accumulation of mature DC-LAMP+ DCs in SLNs was associated with local expansion of antigen- specific memory effector cytotoxic T lymphocytes and the absence of metastasis in downstream lymph nodes. The aim of this study was to investigate the prognostic importance of the maximal density of mature DCs in SLNs using the anti-DC LAMP antibody. Methods: 458 consecutive patients with micrometastatic melanoma within SLNs and 3 yrs follow-up after SLN procedure or death within 3 yrs were eligible for analysis. Semi-quantitative evaluation of mature DCDC-LAMP+ maximum density was made as follows: the slide was examined at intermediate magnification (x100) to select the area containing the maximum number of DC-LAMP+ DCs, the number of DC-LAMP+ cells per mm2 was then determined at high magnification (x400) in 3 mm2 in high density areas. Results were reported as number of cells /mm2. The maximal density of mature DC-LAMP+ DCs was evaluated by three independent observers and categorized into three classes (<100/mm2, 100- <200/mm2, ≥200/mm2) according to previously reported cutpoints. Results: There was excellent inter-observer reproducibility for maximum density of mature DC-LAMP+ DCs scores (kappa score = 0.82). There were differences in the maximal density scores and staining intensity according to the center (P<0.001). The higher the mature DC density in the SLN the longer the duration of survival [p=0.047; hazard ratio (95% CI) = 0.70 (0.50–1.00)]. Conclusions: This study is the first to report the prognostic value of DC-LAMP+ DC counts in SLNs containing metastatic melanoma. Patients with a high density of mature DCs (≥200/mm2) have the lowest risk of death. It also provides evidence that a lack of DC maturation in the SLNs is important in biological facilitation of melanoma progression.

No significant financial relationships to disclose.
Outcome analysis for melanoma patients undergoing deep pelvic lymph node dissection
Authors: Badgwell B. , Xing Y. , Gershenwald J. , Lee J. , Mansfield P. , Ross M. , Cormier J.
Published: March 2020

8514

Background: The benefits of deep pelvic lymph node dissection (DLND) for node-positive melanoma patients continue to be debated. The objective of our analysis was to assess factors associated with metastatic disease to deep pelvic nodes and examine survival outcomes following DLND. Methods: We retrospectively reviewed the records of 804 patients undergoing lymph node dissection (1990-2001). 97 patients underwent a superficial inguinofemoral lymph node dissection along with a DLND for indications which included: suspicious radiologic imaging (n= 31), documented superficial disease and concern for deep involvement (n = 57), and in-transit disease undergoing limb perfusion (n=9). Logistic regression was performed to identify factors associated with the metastatic tumor spread to deep nodes. Associations between clinicopathologic factors and disease-specific survival (DSS) were estimated using the Cox proportional hazards model. Results: Fifty-four patients (56%) had metastatic disease (median 2 positive lymph nodes, range 1–12) within their deep pelvis. With a median follow-up of 7.5 years, the 5-year DSS was 42% for patients with positive deep pelvic nodes and 52% for those with negative deep pelvic nodes (p = 0.07). When the number of metastatic deep nodes was stratified, the 5-year DSS for patients with 1 positive node, 2–3 positive nodes, and >3 positive nodes was 49%, 48%, and 27%, respectively (p = 0.04). Age ≥ 50 years (odds ratio [OR] = 3.5, p = 0.03), increasing number of positive superficial nodes (OR = 2.1, p < 0.001), and suspicious findings on pelvic CT images (OR = 11.9, p < 0.001) were associated with metastatic deep nodes. In the multivariate analysis, the number of positive deep nodes (hazard ratio [HR] = 1.1, p = 0.03), male gender (HR = 1.9, p = 0.03), and extra-capsular nodal extension of tumor (HR = 2.7, p < 0.001) were identified as adverse prognostic factors for DSS. Conclusions: Survival outcomes in patients with melanoma metastatic to ≤ 3 deep pelvic lymph nodes are comparable to those in patients without deep nodal involvement. These favorable outcomes support an aggressive surgical approach (i.e., DLND) in patients ≥ 50 years, with multiple positive superficial nodes, and suspicious CT findings.

No significant financial relationships to disclose.
Assessment of PI3 kinase as a druggable target in melanoma
Authors: Aziz S. A. , Pick-Golan E. , McCarthy M. M. , Flaherty K. T. , Camp R. L. , Rimm D. L. , Kluger H. M.
Published: March 2020

8521

Background: PI3 (phosphatidylinositol-3) kinase is central to a major intracellular signal transduction pathway that influences numerous cellular functions, including growth, differentiation and survival. Drugs that target PI3 kinase have demonstrated preclinical activity, and are undergoing further development. The PI3 kinase inhibitor, SF1126 is expected to enter clinical trials in 2007. The hallmarks for a valuable drug target include differential expression between normal and malignant cells and an association with disease progression. PI3 kinase expression has not been thoroughly evaluated in melanoma. We sought to determine the expression and prognostic value of PI3 kinase in a large cohort of primary and metastatic melanomas and to compare the expression with that of benign nevi. Methods: Tissue microarrays containing 548 melanomas and 540 benign nevi were employed to assess PI3 kinase expression. We used a novel method of in situ automated quantitative analysis (AQUA) of protein levels. We applied S100 conjugated to Cy3 to identify a melanoma tumor mask within a histospot, and measured PI3 kinase expression levels using Cy5 conjugated antibodies within the mask. Continuous AQUA scores were correlated with clinical and pathological variables. Results: PI3 kinase expression was higher in melanomas than in nevi by unpaired t-tests (p < 0.0001), and was significantly higher in metastatic than in primary specimens (p < 0.0001). High PI3 kinase scores were associated with Clark levels of IV-V (p = 0.0126), Breslow thickness > 2mm (p = 0.044) and absence of tumor infiltrating lymphocytes (p = 0.014). High PI3 kinase expression strongly correlated with decreased survival by Cox univariate analysis (p = 0.0024), but was not independent of disease stage. Conclusions: PI3 kinase expression is remarkably higher in malignant melanocytes than in benign nevi. Moreover, high PI3 kinase expression is associated with disease aggression, making PI3 kinase an attractive drug target for melanoma. This is the first large study assessing PI3 kinase levels in melanoma in a quantitative fashion. Assessment of the association between PI3 kinase levels and response to therapy is warranted.

No significant financial relationships to disclose.
Survival of patients (pts) with metastatic melanoma treated with the anti-CTLA4 monoclonal antibody (mAb) CP-675,206 in a phase I/II study
Authors: Gomez-Navarro J. , Antonia S. , Sosman J. , Kirkwood J. M. , Redman B. , Gajewski T. F. , Pavlov D. , Bulanhagui C. , Ribas A. , Camacho L. H.
Published: March 2020

8524

Background: The fully human anti-CTLA4 mAb CP-675,206 has demonstrated clinical activity in pts with metastatic melanoma. Prolonged survival was observed in a prior single-dose phase I study, even in pts who did not achieve objective tumor responses. Methods: A multidose phase I/II trial was conducted in pts (N = 119) with histologically confirmed stage IIIc (unresectable) or stage IV recurrent metastatic melanoma and ECOG PS = 1. The study consisted of a phase I, open-label, multidose study (3, 6, and 10 mg/kg) and a phase I expansion cohort for HLA-A2.1+ pts (10 mg/kg monthly [Q1M]), followed by a phase II open-label study of 2 dosing regimens: 10 mg/kg Q1M and 15 mg/kg every 3 months (Q3M). The primary endpoint was safety in phase I, immune monitoring in the expansion cohort, and response in phase II. Survival was analyzed as a secondary endpoint. Results: In the phase I study, Kaplan-Meier estimates of median overall survival were 17.6 months for all dose groups combined (n = 28). In the phase II study, median survival was 10.3 months in the 10 mg/kg arm and 11.0 months in the 15 mg/kg arm. Survival outcomes were favorable, compared with historical median survival of 7 months, independent of whether pts achieved an objective response. Updated survival data will be presented. Conclusions: Patients participating in a multiple dose study of CP-675,206 showed a survival time that was greater than expected on historic controls. These observations support the endpoints of an ongoing randomized phase III study in melanoma to further evaluate survival in the frontline setting.

[Table: see text]

[Table: see text]
Interferon-α as adjuvant therapy for melanoma: An individual patient data meta-analysis of randomised trials
Authors: Wheatley K. , Ives N. , Eggermont A. , Kirkwood J. , Cascinelli N. , Markovic S. N. , Hancock B. , Lee S. , Suciu S.
Published: March 2020

8526

Background: Many randomised trials have evaluated the role of adjuvant interferon-a (IFN) in high-risk melanoma, some suggesting benefit and others not. To assess the totality of current evidence, an individual patient data (IPD) meta-analysis of all available trials was performed. Methods: Standard IPD meta-analysis methods were used to assess event-free (EFS) and overall survival (OS), with odds ratios (OR) and 95% confidence intervals (CI) calculated. Trials were divided by dose of IFN - high (20 MU/m2), intermediate (5–10 MU), low (3 MU) and very low (1 MU). Subgroup analyses by patient age, gender and disease characteristics were also performed. Results: IPD was provided for 10 of 13 reported trials of IFN vs. no IFN (for the other 3 trials published data were used). 6067 patients (IPD available for 85%) were included in the analysis, with over 3,700 and 3,000 events for EFS and OS. There was statistically significant benefit for IFN for both EFS (OR=0.87, CI=0.81–0.93, p=0.00006) and OS (0.9, 0.84–0.97, p=0.008). There was no evidence of differences according to dose (Table 1; trend p>0.1) or duration of IFN. This proportional survival advantage translates into an absolute benefit of about 3% (CI 1%-5%) at 5 years. The effect of IFN did not differ with age, gender, tumor site, Breslow thickness, clinical nodes or disease stage. Only for ulceration was there some evidence of an interaction (p=0.03); patients with ulcerated tumors had greater benefit from IFN (EFS: OR=0.76, OS: OR=0.77) than those with no ulceration (EFS: OR=0.94, OS: OR=0.98). Conclusions: This meta-analysis provides evidence that adjuvant IFN significantly reduces the risk of relapse and improves overall survival, although the absolute survival benefit is relatively small. This analysis does not however, clarify the optimal (high, intermediate or low) dose of IFN. Given the large number of subgroup analyses performed, the apparent increased benefit in patients with ulceration requires confirmation.

No significant financial relationships to disclose.
An open-label phase II study of sorafenib and dacarbazine as first-line therapy in patients with advanced melanoma
Authors: Eisen T. , Marais R. , Affolter A. , Lorigan P. , Ottensmeier C. , Robert C. , Corrie P. , Chevreau C. , Erlandsson F. , Gore M.
Published: March 2020

8529

Background: Sorafenib (SOR) exerts anti-tumor and anti-angiogenic effects via inhibition of VEGFR-1,-2,-3, PDGFR-a, -β and Raf. In a phase I, study SOR + dacarbazine (DTIC) as first-line therapy for advanced melanoma patients (pts) was well-tolerated and had activity. Methods: In this multicenter, phase II, open-label, uncontrolled, 2-stage study, eligibility criteria included: measurable disease by RECIST, ECOG performance status 0 or 1, no prior chemotherapy. Prior immunotherapy was allowed. Planned sample size was 82 pts based on a Simon 2-stage optimal design. Pts were treated with oral SOR 400 mg bid daily combined with repeated 21-day cycles of iv DTIC 1,000 mg/m2 given on day 1 of each cycle until occurrence of progressive disease or intolerable toxicity. The primary endpoint was overall tumor response rate using RECIST. Secondary endpoints included progression-free survival (PFS), overall survival (OS), safety and toxicity. Results: 30 and 53 pts were treated in Stages I and II, respectively. Baseline characteristics were as follows: median age 56 yrs; 60% male, 34% ECOG 1, 80% AJCC Stage IV M1c; 31% elevated LDH. Eight (10%) pts had partial responses, 34 (41%) had stable disease, 32 (39%) had progressive disease and 9 (11%) were not evaluable. The median PFS was 14 wks (95% CI 12, 19; 28% censored). PFS rates at 3 & 6 mos were 56% (45%, 67%; 13% censored) and 33% (22%, 45%; 24% censored), respectively. Median OS was 41 wks (28, 59, 63% censored). Grade 3/4 drug-related adverse events included: neutrophils 33%, platelets 22%, hand-foot skin reaction 8%, fatigue 7% and abdominal pain 6%. 1 patient had febrile neutropenia. To correlate treatment response with mutational status, melanoma samples from 20 pts were analyzed for mutations in B-RAF (exon 15) and PI3Kinase (exons 9 & 20). 3 of 20 samples had V600E mutations in B- RAF; no PI3Kinase alterations were detected. Conclusions: Addition of SOR to DTIC was well-tolerated and resulted in encouraging PFS and OS rates in this poor prognostic cohort of patients. The data are promising as compared with published results of DTIC alone in metastatic melanoma (RR 7.5%, PFS 6 wks; Bedikian et al. 2006). A recently completed randomized Phase II trial will provide additional information on the efficacy of this combination regimen.

[Table: see text]
VEGF serum levels during bevacizumab plus paclitaxel combination in metastatic melanoma
Authors: Viteri S. , Diaz-Lagares A. , González A. , Martin Algarra S. , Redondo P. , Espinos J. , González Cao M.
Published: March 2020

8534

Background: Angiogenesis has an important role in melanoma progression. A prognostic value has been suggested for serum VEGF in melanoma. The novel agent bevacizumab (Bev) has demonstrated in combination with chemotherapy high activity in other tumors. We studied the combination of weekly paclitaxel (TXL) and bevacizumab (Bev) in previously treated metastatic melanoma patients (pts) and analyzed serum VEGF levels before and during treatment. Methods: TXL 70 mg/m2 weekly and Bev 10 mg/kg biweekly during 5 consecutive weeks every six weeks. VEGF levels pre-treatment and at response evaluation were analyzed with enzyme-linked immunoassays. Results: 13 pts have been treated: male/female: 4/9, median age: 45 (29–71), median PS ECOG: 2 (0–3), stage distribution M1b/ M1c: 2/11, high LDH levels: 8 pts. Median number of previous lines: 3 (1–6). Hematological toxicity: G III lymphopenia in 6 pts, G III leucopenia in 2 pts, G III thrombocytopenia in 1 pt and G I anemia in 3 pts. Non-hematological toxicities: alopecia in 7 pts, diarrhea G I in 4 pts, epistaxis G I in 8 pts. Response (and time to progression, months [m]): 2/12 PR (6 m and 4 m), 1/12 MR (6 m), 7/12 SD (7+ m, 7 m, 4 m, 4+ m, 3 m, 3 m, 3+ m), 2/12 PD. Responses were seen in soft tissue, lung and brain metastases. Overall survival at 12 months was 43.3%. Pre-treatment serum levels were high in five patients and they became negative at response evaluation (1 pt achieved MR, 3 pts SD and 1 pt PD). Unexpectedly patients with high pre-treatment VEGF levels had long survival: 4/5 patients remain alive and 2 pts have survived over one year: 12+ m, 12+ m, 5 m, 3+ m, 3.5+ m.VEGF was undetectable pre-treatment and at response evaluation in 7 pts, only 2/7 pts remained alive: 15+ m, 8 m, 7.5 m, 7 m, 6.8+ m, 3 m, 2.6 m. Conclusions: The combination of Bev and weekly TXL is active in melanoma and it has a good tolerance profile. Serum VEGF could be a good marker in this setting. Further research is needed to confirm these results.

No significant financial relationships to disclose.
Shedding of distinct cryptic epitope (HU177) in sera of melanoma patients
Authors: Zakrzewski J. , Ng B. , Warycha M. , Christos P. , Shapiro R. , Berman R. , Pavlick A. , Liebes L. , Brooks P. , Osman I.
Published: March 2020

8550

Background: Our preclinical data suggest that a newly identified cryptic epitope HU177 within collagen regulates endothelial and tumor cell adhesion in-vitro and angiogenesis and tumor growth in-vivo. We investigated whether 1) HU177 shedding can be measured in melanoma patients’ sera, and 2) if HU177 concentration correlates with clinicopathological features, recurrence and survival. Methods: Sera from 291 melanoma patients (primary Stage I, n=140; II n=41; III n=29; recurrent/metastatic n=81) and 30 normal volunteers prospectively enrolled at the NYU School of Medicine were analyzed for HU177 epitope concentration (ng/ml) by ELISA. Microtiter plates were incubated overnight with monoclonal antibody (anti-HU177 epitope). Patients’ sera and standards (denatured type-IV collagen) were added in duplicate followed by dilutions of biotinylated anti-collagen type IV polyclonal and HRP-labeled anti-biotin antibodies with multiple washes after each incubation. Absorbance was monitored at 400 nm. Results: The mean concentration of anti-HU177 epitope was 5.8 ng/ml (range 0.1 to 139.8). Normal volunteers were 1.6±0.3 (mean ± SEM). A significant correlation was observed between HU177 concentration and tumor thickness in patients who presented with primary melanoma (=1.00 mm, n=113, 3.8±0.4; 1.01–3.99 mm, n=72, 8.9 ±2.1; =4.00 mm, n=22, 10.3±2.2; P=0.003 by ANOVA test) and nodular melanoma histological subtype (nodular, n=47, 10.5±3.1; superficial spreading, n=95, 4.4±0.5; others, n=68, 6.0±2.1; P=0.02, ANOVA). Multivariate analysis confirmed the independent correlation between higher HU177 concentration and nodular subtype after controlling for tumor thickness (P=0.04). Primary patients with ulcerated melanomas and those who developed recurrences both showed higher HU177 epitope levels, however, the difference was not significant (P>0.05). Conclusions: This is the first study on HU177 epitope shedding in melanoma patients. Data demonstrate the clinical feasibility of HU177 testing in melanoma patients’ sera and suggest that HU177 epitope shedding correlates with thicker primary melanomas. Longer follow-up is required to better define the prognostic value of HU177 epitope shedding in melanoma patients.

[Table: see text]
Phase II trial of tanespimycin (KOS-953), a heat shock protein-90 (Hsp90) inhibitor in patients with metastatic melanoma
Authors: Kefford R. , Millward M. , Hersey P. , Brady B. , Graham M. , Johnson R. G. , Hannah A. L.
Published: March 2020

8558

Background: Tanespimycin binds to and inhibits the activity of Heat Shock Protein 90 (Hsp90). Hsp90 inhibition results in the degradation of a variety of RAF family proteins, including mutant BRAF. As the majority of melanomas have activation of the BRAF-MAPK pathway, we postulate that tanespimycin will interrupt the MAPK pathway and may lead to clinically significant anti-melanoma effects. Methods: This is a multi-center two-stage Simon design study; continuation to the second stage required at least 1 pt with progression free survival (PFS) of at least 24 weeks (the primary endpoint of this trial). Eligibility: pts with stage M1 melanoma, measurable/unresectable disease, up to 1 prior chemotherapy treatment for metastatic disease and ECOG PS 0 or 1. Tanespimycin (275 mg/m2 IV) was given D1,4,8,11 q 3/52 until disease progression or toxicity. Where available, assessment of BRAF mutation (V600E) was performed on historical tissue. Results: 14 pts have been enrolled, 3 were non-evaluable. Data are available for the first 11 pts (9 evaluable) completing accrual to the 1st stage of the Simon design. Demographics: 8 M/6 F; median age 55 years (range 30, 83). A total of 30 treatment cycles were administered (n=11); with relative dose intensity of 89%; 1 pt required a dose reduction. Grade 1–2 toxicity included nausea, vomiting, diarrhoea, anorexia, fatigue, headache, raised alkaline phosphatase/ALT/AST, and back pain. Four pts (29%) experienced Grade 3–4 toxicities: 1) reversible metabolic acidosis with LFT and electrolyte abnormalities; 2) anorexia, dehydration and fatigue; 3) raised gamma-GT; 4) abdominal pain. Two pts withdrew due to toxicity. Of the 4 pts with available tissue: 2 had V600E BRAF positive mutations. One pt achieved a ≥ 24 week PFS, meeting the conditions for accrual of Stage 2. This pt (with V600E mutation) was assessed as having a best response of stable disease as per RECIST, in addition to reduction in size and number of extensive subcutaneous nodules. Conclusions: There is evidence of clinical activity of single-agent tanespimycin in metastatic melanoma. Further accrual with determination of BRAF status to a total of 30 pts will better define the activity of tanespimycin in this population.

No significant financial relationships to disclose.
Aerosolized sargramostim for the treatment of metastatic melanoma to the lungs
Authors: Markovic S. N. , Suman V. J. , Schaefer P. , Morton R. , Rowland K. M.
Published: March 2020

8565

Background: Previous studies using low-dose (250 ug/dose) aerosolized sargramostim (granulocyte macrophage colony stimulating factor: aero-GM-CSF) for the treatment of metastatic melanoma, revealed anecdotal clinical responses that appeared to correlate with an increase in the number of tumor specific cytotoxic T lymphocytes (CTL) in blood. Herein, we address whether or not further dose escalation of aero-GM-CSF is safe, results in greater increase of melanoma specific CTLs, and affects clinical outcomes. Methods: A 5+5 dose escalation clinical trial was conducted to determine the dose of aero-GM-CSF that would increase in the frequency of peripheral blood melanoma specific CTLs in HLA-A2+ patients with metastatic melanoma to the lungs. Aero-GM-CSF was administered twice daily on days 1–7 and 15–21 of a 28 day cycle at doses of: 500, 750, 1,000, 1,250, 1,500, 1,750, and 2,000 ug per cohort. If at most 2 of 5 patients at a dose level reported a 5-fold increase in CTLs, dose escalation occurred. If not, 5 additional patients were treated at that dose. Dose escalation continued until =2 of 5 patients at a dose level developed severe toxicity, at least 7 of the 10 patients at a dose level reported a 5-fold increase in CTLs, or all dose levels were exhausted. Results: The study accrued 40 patients from August 2002 to July 2006. Four patients cancelled participation prior to treatment. One patient was replaced (500 ug) as he died within 13 days of registration. Among the 35 remaining patients, median age was 58 (23–84), 72% were male, and 72% had a PS=0. Dose escalation was not terminated due to toxicity. Toxicities = grade 3 (at least probably treatment related) included: grade 3 fatigue (1) at 1,000 ug; and grade 3 cough (1), and grade 4 dyspnea (1) at 1,750 ug. At the 2,000 ug dose, most patients (4 of 5) exhibited a greater than 2-fold increase in melanoma specific CTLs. Two of these patients remain on treatment: one with partial response at 14.0 months and the other with stable disease at 6.5 months. A 5-fold increase in tumor specific CTLs was not achieved in any patient. Conclusions: Aero-GM-CSF therapy administered at up to 2,000 ug/dose appears safe and seems to correlate with increased frequencies of tumor specific CTLs in a dose-dependent fashion. Further dose escalation followed by clinical efficacy testing is warranted.

No significant financial relationships to disclose.
The usefulness of positron emission tomography (PET) scanning to identify early recurrent melanoma in high risk resected stage III and IV patients: A retrospective review
Authors: Kottschade L. A. , Lowe V. , Markovic S. N.
Published: March 2020

8566

Background: The incidence of malignant melanoma has risen dramatically over the past decades. Prognosis for patients with metastatic melanoma is poor and treatment options are limited. Complete surgical resection is frequently front line therapy for patients with resectable metastases. However this is only an option if relapse is diagnosed early. PET imaging using 2-flourine-18, 2-fluro-2-deoxy-D-glucose (FDG) has been used successfully for staging of metastatic melanoma. However it's usefulness in surveillance for patients at high-risk of relapse (resected stage III and IV disease) has not been well studied. We conducted a retrospective review of our institutional experience using PET scanning as part of regular follow up in patients with resected stage III or IV melanoma for the purpose of detection of early recurrence. Methods: Retrospective review of the medical records of 667 consecutive patients seen at Mayo Clinic from 12/13/1999–1/1/2007, with the diagnosis of malignant melanoma for whom PET imaging was performed or reviewed at our institution. Eligibility criteria included: resected stage III or IV melanoma with at least 2 PET scans (<1 year apart) as part of regular clinical follow-up (surveillance). Frequency of PET scanning was variable and at physician discretion. Results: Of the 667 patients, 110 patients were deemed eligible for review. There were 98 recurrences among 65 patients. Of these 37 recurrences (38%) were found by PET scanning alone (asymptomatic); 61 recurrences (62%) were found by other methods (physical exam, CT, MRI, etc). Of the 37 recurrences found by routine PET scanning 17 (46%) were completely resected; of the other 61 recurrences found by other methods 33 (54%) were completely resected. Conclusions: PET scanning as regular surveillance for patients with high risk melanoma, may be a useful tool in early identification of asymptomatic melanoma relapse amenable to complete surgical resection (additional 1/3 of cases). Considering the potential clinical benefit of completely resected melanoma relapse, and the retrospective nature of this review, these data are hypothesis-generating and warrant further investigation.

No significant financial relationships to disclose.
Preoperative lactate dehydrogenase (LDH) serum level has impact on survival of melanoma patients after therapeutic lymph node dissection (TLND) but not on patients after completion lymph node dissection (CLND)
Authors: Ruka W. , Nowecki Z. I. , Rutkowski P. , Dziewirski W. , Pienkowski A. , Salamacha M. , Zurawski Z. , Zdzienicki M.
Published: March 2020

8568

Background: The aim of the study was to evaluate the additional prognostic value of preoperative LDH serum level on overall survival (OS) of AJCC stage III cutaneous melanoma patients. Methods: The preoperative LDH serum level was available in 402 consecutive melanoma patients, who underwent radical LND (196 CLND after positive sentinel node biopsy and 206 TLND for clinically/cytologically detected regional lymph node metastases) between 1994 and 2004. Median follow-up time was 36 months (range: 6–110 months). Results: LDH serum level was increased before LND in 92 patients (22.9%) in the entire group of stage III melanoma patients [56 patients (27%) in TLND group and in 36 patients (18.4%) in CLND group (p=0.03)]. There were significant differences for OS (calculated from the date of LND) between patients with normal and high preoperative LDH level in the entire group of patients: median OS time was 51.2 months (95% CI: 34.8–91.9) and 27.9 months (95% CI: 18.2-); 5-year OS rate was 45.2% and 37.5%, respectively (p=0.0079 in univariate analysis and p=0.02 in multivariate analysis). However, to these differences mainly contributed the patients from TLND group: for patients with normal and high preoperative LDH level median OS time was 36.6 months (95% CI: 24.9–57.6) and 15.1 months (95% CI: 12.4- 27.9); 5-year OS rate was 40.0% and 20.3%, respectively (p=0.0013 in univariate analysis and p=0.01 in multivariate analysis). We did not observe any differences between patients with normal and high preoperative LDH level in CLND group: median OS time was 60.0 months (95% CI: 39.8-) and 65 months (95% CI: 45.6-); 5-year OS rate was 51% and 58%, respectively (p=0.703 in univariate analysis). Conclusions: Pre-LND increased LDH serum level has additional negative impact on OS of melanoma patients with palpable nodal metastases after TLND.

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A phase II study of arsenic trioxide (ATO) in patients with metastatic melanoma
Authors: Tarhini A. A. , Kirkwood J. M. , Gooding W. E. , Stuckert J. J. , Agarwala S. S.
Published: March 2020

8569

Background: Arsenic trioxide (ATO) is a promising new agent in the treatment of both solid and hematologic tumors. ATO cytotoxicity and apoptosis induction has been demonstrated in vitro with numerous human cancer cell lines including human melanoma. Methods: We conducted a safety and efficacy single arm study of ATO in patients (18 years or older) with inoperable AJCC stage IV melanoma. One cycle consisted of a loading dose of 0.32 mg/kg/day for 4 days in week 1, followed by 0.25 mg/kg/day twice per week for 6 weeks, followed by 1 week of rest for a total cycle length of 8 weeks when response assessment was performed. Results: A total of 21 patients (5 females and 16 males) were accrued with a median age of 63.8 years (range 32.9 - 81.6). All patients had metastatic melanoma including AJCC stage IV M1a (2), M1b (6) and M1c (13). ECOG performance included 0 (11) and 1 (10). One patient had metastatic choroidal melanoma and 20 had cutaneous melanoma. Twenty patients had received prior therapy including chemotherapy (17), immunotherapy (11) and radiation (3). Six patients completed 1 cycle, seven 2 cycles, one 3 cycles, one 4 cycles and two 5 cycles of ATO. Four patients did not complete the first cycle and are not evaluable for response. Possible treatment related Grade 3/4 toxicities included one case of idiopathic thrombocytopenic purpura and one case of elevated LDH. Among 17 evaluable patients, 1 (6%) had partial response lasting 7 months, 8 (47%) had disease stabilization after 1 cycle, but all eventually progressed. A total of 19 patients have died and 2 are alive at a median follow up of 17.5 weeks. Median time to progression is 14 weeks, 95% CI (9, 38) and median survival is 52.9 weeks, 95% CI (14.4, 66.1). Conclusions: ATO as a single agent is well tolerated with modest activity in metastatic melanoma that may be enhanced in combination with other agents that induce apoptosis.

No significant financial relationships to disclose.