bluuebunny/crossref_metadata_2025 huggingface dataset:
The characteristics and clinical course of MALT lymphoma: A 10-year single center analysis
Authors: Raderer M. , Troch M. , Woehrer S. , Streubel B. , Puespoek A. , Formanek M. , Turetschek K. , Jaeger U. , Drach J. , Chott A.
Published: March 2020

8099

Background: An evaluation of clinical characteristics and potential risk factors affecting outcome in patients with MALT lymphoma was performed at our institution. Patients and Methods: As of 1997, a total of 170 consecutive patients with histologically verified MALT lymphoma (99 female/71 male) underwent uniform staging and assessment of clinical characteristics including assessment of genetic changes, presence of autoimmune disease (AD), Helicobacter pylori (HP)-status, monoclonal immunoglobulins (MG) and plasmacytic differentiation (PD). All patients with follow-up at our institution were analysed, and influence of various parameters on dissemination and outcome were evaluated. Sixty-four patients (38%) had gastric MALT-lymphoma (GML) and 106 (62%) extragastric MALT-lymphoma (EGML). Results: 66/170 patients (39%) had multiorgan-involvement upon presentation, while only 3 patients had bone marrow involvement. Patients with EGML (49/106, 46%) were at significantly higher risk for multiorgan-disease than patients with GML (17/64, 27%, p = 0.013). 58 patients had genetic aberrations, with t(11;18) being more common in GML (p = 0.002) and trisomy 3 (p = 0.03) and trisomy 18 (p = 0.02) in EGML. Among GML, translocation t(11;18) was significantly associated with multiorgan-disease, as was trisomy18 in EGML (p = 0.038). After a median follow-up time of 40 months, 139 patients (86%) are alive. 58 patients (39%) have relapsed, with the median to relapse being 60 months. Overall, multifocality and extragastric origin (p < 0.001) were significantly associcated with relapse, while patients with t(11;18) had a significantly longer time to relapse (131 vs 49 months). Survival and relapse were not affected by the form of therapy applied (i.e. local vs systemic). An underlying AD was found in 65 patients (38%), and was significantly associated with EGML (p = 0.007) and multifocality (p = 0.04), but did not influence relapse and survival. HP-positivity was significantly associated with GML (p = 0.001), and patients with EGML did not respond to HP-eradication. Conslusion: Our data suggest dissemination and (late) relapse to be relatively common in MALT-lymphoma. Based on our findings, however, an individualized staging approach and risk-assessment is possible.

No significant financial relationships to disclose.
Novel therapy with 2-methoxyestradiol (2ME2) for the treatment of relapsed and plateau phase multiple myeloma
Authors: Lacy M. , Richardson P. , Gertz M. , Dispenzieri A. , Greipp P. , Witzig T. , Schlossman R. , Sidor C. , Anderson K. , Rajkumar S.
Published: March 2020

8108

Background: 2-methoxyestradiol (2ME2) is a natural endogenous product of estradiol metabolism with anti-angiogenic and anti-neoplastic properties that has demonstrated activity against multiple myeloma cell lines and xenografts in immunocompromised mice. We report results of the first phase II clinical trial of 2ME2 in pts with relapsed and plateau phase myeloma. Methods: This trial was designed with a one-stage design to accrue 60 pts in the setting of relapsed and plateau phase myeloma. 2ME2 was administered orally at a dose of 1000 mg daily. After the first 39 pts were accrued, based on the results of ongoing phase I trials, the dose of 2ME2 was increased to 800 mg twice daily for the remaining patients. Pts who were already on study at that point were also allowed to escalate their dose to 800 mg twice daily. The primary endpoint was overall response rate. Responses were assessed using Eastern Cooperative Oncology Group criteria. Results: Sixty patients were treated at Mayo Clinic and Dana Farber Cancer Institute. Median age was 60 years (range, 28–99). Thirty-one patients had relapsed/refractory myeloma and 29 patients had plateau phase myeloma. Median number of prior therapies was 4 including stem cell transplant (48%), thalidomide (62%), bortezomib (6%) and lenalidomide (3%). Therapy was well tolerated. Adverse events were anemia (35%), fatigue (35%), nausea (25%), diarrhea (20%), hot flashes (20%), headache (17%), muscle cramps (15%), and upper respiratory tract infection (15%). Most toxicities were mild (grade 1–2). Estimated progression-free survival rates for all pts at one, two, and three years are 24%, 16%, and 9% respectively. Three pts with plateau phase disease, have been on study for over 4 years without progression at 50, 60, and 63 months. Response assessment is ongoing; so far, whilst no partial responses have been seen, prolonged stable disease has been observed in 3 pts (5%). Conclusions: 2ME2 is a novel agent that appears to be safe and well tolerated. Although no responses have been seen, prolonged stable disease in some pts is promising. Preliminary pharmacokinetic data indicate that the dose of 2ME2 used in this study may be inadequate, and a new formulation with significantly better bioavailability will be tested soon in this patient population.

No significant financial relationships to disclose.
Inhibition of cell proliferation by lenalidomide is associated with stimulation of Egr1 transcriptional activity in a chromosome 5 deleted Burkitt’s lymphoma and multiple myeloma cell line
Authors: Gandhi A. K. , Kang J. , Verhelle D. , Stirling D. I. , Schafer P. H.
Published: March 2020

8110

Background: The mechanism by which lenalidomide exerts its anti-proliferative effects in deletion 5q MDS clones or MM cells is not yet fully elucidated. Early growth response (Egr1) gene is a tumor suppressor gene located on chromosome 5q31.1 that encodes a transcription factor involved in the regulation of cell proliferation and apoptosis. We hypothesized that lenalidomide may act by enhancing the expression or activity of Egr1 in sensitive hematopoietic tumor cells, especially those with only a single copy of the Egr1 gene. Methods: Transcriptional activity was measured using luciferase reporter plasmids. Gene knockdown and expression studies used siRNA technology and qRT-PCR, respectively. Cell proliferation was measured by 3H-thymidine incorporation. Results: Lenalidomide stimulated the transcriptional activity of Egr1 in the lenalidomide-sensitive chromosome 5 deleted Burkitt's lymphoma Namalwa CSN.70 and in the MM cell line LP-1. Egr1 siRNA Namalwa cells proliferated more than mock controls, indicating that Egr1 functions as a tumor suppressor in Namalwa cells. Lenalidomide had no effect on expression of Egr1, but augmented Egr1 nuclear transport in a dose-dependent manner. Lenalidomide did not affect expression of the Egr1 downstream effector genes ATF3, fibronectin, p53, PTEN, and TGF-β1, while p21 levels increased. However, lenalidomide-induced p21 expression was not affected in Egr1 siRNA Namalwa cells. Interestingly, lenalidomide’s anti-proliferative potency was greater in Egr1 siRNA Namalwa but not in Egr1 siRNA LP-1 cells. Conclusions: Lenalidomide induces nuclear transport and transcriptional activation of the tumor suppressor Egr1, which may contribute to lenalidomide’s anti-proliferative activity in a non-p21 dependent manner. This activity may be related to the levels of Egr1 expression, explaining why del 5q31 myelodysplastic clones are especially sensitive to the cytotoxic effects of lenalidomide.

No significant financial relationships to disclose.
Effect of the green tea polyphenol epigallocatechin gallate (EGCG) on growth and IL-6 signalling pathways in malignant plasma cells
Authors: Burger R. , Czekalla H. , Richter K. , Ahrens T. , Guenther A. , Gramatzki M.
Published: March 2020

8114

Background: Epigallocatechin gallate (EGCG) is the predominant polyphenolic constituent of green tea leaves that possesses antitumor, antiinflammatory, and antioxidant activity. EGCG exerts its effects through potentially multiple mechanisms including inhibition of growth factor receptor signalling. The compound is currently under investigation in a phase I/II clinical trial for treatment of patients with early stage chronic lymphocytic leukemia at Mayo Clinic. The goal of our study was to examine the in vitro effects of EGCG in multiple myeloma (MM). Methods: A panel of human myeloma cell lines (n=6) including the IL-6 dependent INA-6 cell line was used to evaluate the sensitivity to EGCG. Cells were cultured for three days in the absence or presence of EGCG at concentrations between 6.25 μM and 100 μM. Cell viability was determined in a colorimetric tetrazolium (MTS) based assay and by trypanblue exclusion. For signalling experiments, INA-6 cells were IL-6 and serum starved and then treated with EGCG for two hours before IL-6 was added. Whole cell lysates were prepared and subjected to SDS-PAGE and Western blot analysis. Results: EGCG inhibited the in vitro growth of human myeloma cell lines by inducing cell death in a time and dose-dependent manner. IC50 concentrations were between 12,5 μM and 50 μM. IL-6 mediated growth of INA-6 cells was inhibited at similar doses. The addition of excess amounts of IL-6 could not protect from EGCG induced cytotoxicity. Pretreatment of INA-6 cells with EGCG resulted in a dose-dependent inhibition of IL-6 induced STAT3 tyrosine phosphorylation. In these cells, stimulation with IL-6 leads to upregulation of Mcl-1 expression. In contrast, phosphorylation of p44/p42 MAPK, which is constitutively activated in INA-6 cells, was not affected. Conclusion: EGCG has growth inhibitory activity on myeloma cells. Specific inhibition of signalling pathways that regulate expression of anti-apoptotic proteins could be one mechanism how EGCG exerts its activity. Our work provides the rationale for further studies to evaluate the effect of EGCG not only in B-CLL, but also in plasma cell tumors.

No significant financial relationships to disclose.
Outcome after second stem cell transplantation for relapsed multiple myeloma
Authors: Simpson L. , Verma R. , Kumar S. , Lacy M. , Dispenzieri A. , Hayman S. , Rajkumar S. V. , Litzow M. R. , Gertz M.
Published: March 2020

8118

Background: Autologous stem cell transplantation (ASCT) improves survival and remains the standard of care for patients with newly diagnosed myeloma considered eligible for transplant. However, ASCT is not curative and patients relapse after a median interval of 24–30 months. While new therapeutic options have become available for relapsed MM, repeat ASCT remains an option especially when previously collected stem cells are available. The outcome of pts going to a second SCT in the relapsed setting has not been studied extensively. Methods: We identified pts with myeloma who received a second SCT from a prospectively maintained database. Planned tandem ASCTs were excluded. 56 pts received a second SCT for relapsed MM, including 11 allogeneic SCTs. Among the 45 second ASCTs, 5 were followed by reduced intensity allogeneic SCT and were analyzed with the allogeneic group. Results: The median age at second ASCT was 60.2 yrs (range, 41.3–74.4) and 27 (68%) were males. The median time to second ASCT from diagnosis, first ASCT and relapse were 47.4 mos (22.8–158.6), 36.3 mos (13.5–129.8) and 7.2 mos (1–32) respectively. Among patients receiving second APBSC, 14 (35%) patients were alive with a median follow up of 10.5 mos (1–45 mos). All patients received melphalan conditioning. The median time to neutrophil engraftment was 15 days and platelet engraftment was 16 days. The median hospitalization was 4 days (range 0–33) and there was one transplant related death in the group. The best response included 13 pts with CR (33%), 4 with VGPR (10%), and 19 with PR (48%). MM has relapsed in 22 (55%) pts with a median PFS of 12.5 mos from second ASCT. The median estimated OS from diagnosis, first ASCT and second ASCT were 100.5 mos, 65.9 mos, and 30.6 mos respectively. Among the 16 pts receiving allogeneic SCT, 8 pts (50%) were alive at analysis with a median PFS and OS from transplant of 17.9 mos and 33.5 mos respectively. Conclusions: Second ASCT as salvage therapy for relapsed MM is a viable approach and has a favorable outcome in this selected group of patients. The toxicity, engraftment kinetics, hospitalization and the response rates are comparable to patients undergoing initial ASCT. Allogeneic SCT with or with out a preceding ASCT results in comparable survival in selected patients with high risk disease.

No significant financial relationships to disclose.
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Authors: Tarella C. , Zanni M. , Rambaldi A. , Benedetti F. , Passera R. , Gianni A. M.
Published: March 2020

8123

Background: The high-dose sequential (HDS) chemotherapy approach, including early dose-intensification and autograft with peripheral blood progenitor cells (PBPC), was introduced several years ago (Gianni & Bonadonna, 1989); subsequently, it has been broadly used in the management of both non-Hodgkin s (NHL) and Hodgkin s Lymphoma (HL). The outcome of a large series of lymphoma patients treated with the HDS approach at 10 GITIL Centers is reported. Methods: Data have been collected on 1,266 patients, who received either the original or slightly modified HDS regimens. There were 213 HL and 1,053 NHL (630 intermediate/high-grade, 423 low-grade); median age was 46 yrs. Overall, 671 (53%) patients had refractory/relapsed disease, 595 (47%) were at diagnosis. Most patients were autografted with PBPC; 158 (12%) patients did not undergo autografting due to toxicity, disease progression or poor harvests. Results: Overall, 1,013 (80%) patients reached Complete Remission (CR) following HDS. As to December 2006, 93 (7%) patients died for early/late toxicities, 328 (26%) died for lymphoma, 844 are known to be alive. At a lead follow-up of 18 years, and a median follow-up of 5 yrs, the 5-yr Overall Survival (OS) projection is 64% (S.E.: 2%). The long-term survival was quite favorable in patients achieving a Complete Remission (CR), with a 5-yr OS projection of 76%. The prolonged OS in patients achieving CR was consistent in all lymphoma subtypes, i.e. both low and high-grade NHL (5-yr OS: 77% in both), and HL (5-yr OS: 72%). Patients at diagnosis had a significantly better outcome compared to patients treated for relapsed/refractory disease, again CR achievement was associated with prolonged survival in both subgroups (82% and 69%, respectively, at 5 yrs.). On multivariate Cox survival analysis, CR achievement was the most powerful predictor of long-term survival (HR 0.13, c.i.: 0.10–0.17). Lastly, achieving substantial tumor reduction before autografting had a major influence on the clinical outcome. Conclusions: 1. the HDS program is feasible in a multicenter setting; 2. the long-term outcome is well influenced by the CR status after HDS; 3. the influence of CR achievement on the long-term survival holds true in all lymphoma subtypes, including indolent lymphomas; 4. an adequate pre-autograft tumor debulking may contribute to a favorable long-term outcome.

[Table: see text]
Chemokines expressed in melanoma metastases associated with T cell infiltration
Authors: Gajewski T. , Meng Y. , Harlin H.
Published: March 2020

8501

Background: Despite frequent induction of tumor antigen-specific T cells in melanoma patients following vaccination, tumor regressions remain rare. This observation prompted systematic analysis of the melanoma tumor microenvironment to identify factors that may influence the effector phase of the anti-tumor immune response. Methods: Gene expression profiling using the Affymetrix platform was performed on a series of melanoma metastases, melanoma cell lines, and primary melanocyte cell lines. Confirmatory assays were done by real-time RT-PCR, protein array, immunohistochemistry (IHC), and in vitro chemokine migration assays. Results: Non- supervised hierarchical clustering revealed 3 major subsets of tumors, with the main clustering based on differential expression of T cell-derived transcripts. The presence of CD8+ T cells was confirmed by IHC. Tumors that contained T cells uniquely expressed high levels of multiple chemokines. Protein array confirmed high expression of CCL2, CCL4, and CCL5; real-time RT-PCR additionally confirmed relatively high levels of CXCL9, CXCL10, and CCL3 transcripts. Transwell assays confirmed that each of these 6 chemokines recruited CD8+ effector cells in vitro. Conclusions: We have identified a set of 6 chemokines that likely regulates recruitment of activated T cells into melanoma metastases. Tumors that lack such chemokines might not be capable of supporting the effector phase of the anti-tumor immune response. We suggest that chemokine profiling of tumor sites should be performed in clinical trials of active immunotherapy.

No significant financial relationships to disclose.
An international, randomized, phase III trial of bacillus Calmette-Guerin (BCG) plus allogeneic melanoma vaccine (MCV) or placebo after complete resection of melanoma metastatic to regional or distant sites
Authors: Morton D. L. , Mozzillo N. , Thompson J. F. , Kelley M. C. , Faries M. , Wagner J. , Schneebaum S. , Schuchter L. , Gammon G. , Elashoff R.
Published: March 2020

8508

Background: Active specific immunotherapy with BCG and an allogeneic, melanoma cell vaccine can induce antibody and T-lymphocyte immune responses to numerous antigens expressed by melanoma cells. This study compared overall and disease-free survival in patients receiving BCG plus placebo versus BCG plus MCV. Methods: Between June 1998 and November 2005, 1,656 patients without evidence of residual disease after resection of stage III (n = 1,160) or stage IV (n = 496) melanoma were randomly assigned to the two treatment arms (1:1). BCG was given as an immunologic adjuvant for the first two injections of both MCV and placebo, which thereafter were administered by intradermal injection every two weeks for the next three injections, every month for the remainder of the first year, every two months for the second year and every three months for years three, four and five. Results: Based on the recommendation of the independent Data and Safety Monitoring Board (DSMB), both studies were terminated after the interim analysis. The recommendation was based on a low probability of demonstrating significant improvement in survival of the BCG plus MCV arm if the study had continued to completion of follow-up and final analysis. Conclusions: This is the largest multicenter clinical trial of postoperative adjuvant immunotherapy after resection of melanoma metastatic to regional lymph nodes or distant sites. It is a landmark study not only because it represents the first randomized multicenter trial to use surgical resection as initial therapy for stage IV melanoma patients with up to five metastatic sites, but also because its results demonstrate excellent survival for the entire study population with 42.3% of stage IV and 63.4% of stage III patients projected to be alive at five years. Updated data for survival and immunologic endpoints which show a significant correlation between immune responses and survival will be provided at the meeting.

[Table: see text]
A new paradigm in the management of anorectal melanoma: Trans-anal excision with sphincter preservation and sentinel node biopsy
Authors: Iddings D. M. , Chen S. L. , Faries M. B. , Long L. , Essner R. , Morton D. L.
Published: March 2020

8513

Background: Anorectal melanoma is rare and highly lethal. Historically this disease has often been treated with abdominoperineal (APR) resection and delayed groin dissection for nodal relapse. As an alternative we have investigated trans-anal excision (TAE) with sphincter preservation and lymphatic mapping with sentinel node biopsy (SNB). We compared the outcomes of this more conservative treatment plan between our institutional data (JWCI) and the Surveillance, Epidemiology and End Results (SEER) data. Methods: JWCI prospective melanoma database (1974–2006) and the SEER database (1973–2003) were searched for pts diagnosed with anorectal melanoma (n=60 vs. n=183, respectively). Treatment, types of recurrence, and survival were recorded. Survival was estimated by the Kaplan-Meier method. Results: Lymphoscintography revealed lymphatic drainage to superficial inguinal nodal basin(s) in all cases. Among JWCI pts, the proportion of pts requiring delayed lymphadenectomy was significantly lower when TAE was performed with SNB versus without SNB (10.0% vs. 58.8%; p=0.018). Among JWCI lymphadenectomy specimens, immediate lymphadenectomy for a positive SNB was associated with fewer metastatic lymph nodes than delayed lymphadenectomy for palpable nodal recurrences (1.6 vs. 2.9; p=0.029), suggesting disease progression during observation. Over the past decade, APR rates were 11.5% for JWCI pts and 43.2% for and SEER pts, (p=0.004). JWCI pts and the SEER pts had median survivals of 33 and 17 months, respectively (p=0.009). TAE versus APR did not adversely affect the survival of JWCI pts (39 vs. 23 months; p=0.010) or SEER pts (18 vs. 16 months; p=0.875). Conclusion: Lymphatic mapping with SNB accurately identified the inguinal nodal basin as the most frequently involved basin and reduced the rate of recurrence and extent of nodal involvement. In this study, the largest to analyze surgical treatment and outcomes for pts with anorectal melanoma in the United States, national TAE rates differed from those at a tertiary melanoma center. TAE did not adversely affect survival in either dataset. Therefore, TAE plus SNB is preferred when negative margins can be obtained; APR should be reserved for locally advanced tumors that cannot be removed by TAE.

No significant financial relationships to disclose.
Sequentially-accumulated genetic alterations at chromosome 9p21 play a role in melanoma progression
Authors: Palmieri G. , Rozzo C. , Manca A. , Cossu A. , Lissia A. , Budroni M. , Botti G. , D'Atri S. , Castiglia D. , Sini M. C.
Published: March 2020

8522

Background: Cytogenetic and molecular studies indicated the chromosome 9p21 and its CDKN locus, with the p16/CDKN2A tumor suppressor genes, as the genomic regions involved into the pathogenesis of malignant melanoma (MM). To further elucidate the role of such regions in melanoma, we evaluated the 9p21-linked molecular alterations during the different phases of melanocytic tumorigenesis. Methods: Paraffin-embedded tissue sections from common nevi, dysplastic nevi, and melanomas, including primary and metastatic MM lesion, as well as melanoma cell lines were evaluated by both fluorescence in situ hybridization (FISH) using probes spanning the entire 9p21 region and immunohistochemistry (IHC) for p16/CDKN2A expression. Results: Allelic deletion at the CDKN locus and p16/CDKN2A gene silencing were both observed at increased rates moving from nevi to early or advanced primary melanomas and to correspondent metastases. Dysplastic nevi, primary and secondary melanomas were instead found to be heterozygously deleted at one or more loci within the 9p21 chromosome in a quite similar fraction (55–62%) of cases. Inactivation of the p16/CDKN2A gene was found at rates higher in melanoma cell lines (67%) than in vivo melanomas (62% secondary and 12.5% primary melanomas), with a normal p16/CDKN2A IHC staining in all analyzed nevi. Conclusions: Our findings indicate a model of sequential accumulation of genetic alterations from normal melanocytes to metastatic melanoma, with a) 9p21 allelic loss playing a role in melanocytic transformation and tumor initiation; b) deletions at CDKN locus and p16/ CDKN2A gene inactivation participating to tumor dissemination. Presence of such alterations could be further evaluated as markers of the different phases of melanoma progression.

No significant financial relationships to disclose.
Kinetics of response to ipilimumab (MDX-010) in patients with stage III/IV melanoma
Authors: Hamid O. , Urba W. J. , Yellin M. , Nichol G. M. , Weber J. , Hersh E. M. , Tchekmedyian S. , Hodi F. S. , Weber R. , O'Day S.
Published: March 2020

8525

Background: Ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4), enhances immune responses to tumor-associated antigens resulting in durable objective responses (OR). This abstract describes the kinetics of response after ipilimumab treatment. Methods: 5 studies (2 complete; 3 ongoing) in 269 treated patients with stage III/IV melanoma were reviewed and analyzed to determine the kinetics and duration of response after ipilimumab. Patients received ipilimumab alone or with dacarbazine, IL-2 or gp100 peptide vaccine. Ipilimumab doses ranged from 0.3–10mg/kg/dose (single or multiple). Complete and partial response (CR, PR), stable and progressive disease (SD, PD) were evaluated. Results: 41 patients (15%) had a confirmed OR at analysis. CR and PR was of late onset in some patients and occurred from ∼10–106 and ∼5–62 weeks (w) post-treatment initiation, respectively. In 28 patients onset of CR or PR occurred after >∼12w of treatment. PD preceded OR (without additional therapy) in 4 patients. In 2 patients, PD measured at ∼6w post-treatment initiation was followed by a PR at ∼12w. In 1 patient the PR changed to a CR at ∼24w and lasted for ∼188w+; the other patient maintained a PR for ∼17w. In the other 2 patients, PD at ∼12w was followed by SD at ∼17–20w and a PR after ∼30 and 62w; PRs in both patients lasted for ∼17 and 40w+, respectively. Duration of OR ranged from ∼6–187w+; ORs are ongoing in 25 patients. Late onset occurred irrespective of dose, regimen and therapeutic partner. Conclusions: Preliminary results suggest that ORs with ipilimumab may be later in onset and more durable than with traditional chemotherapy and may occur after progression. This late onset of effect likely reflects the immune-related mechanism of action of ipilimumab, and suggests that continued treatment/observation may be beneficial despite initial PD or SD. Acknowledgement: Dr. S. Rosenberg

[Table: see text]
Subgroup analysis of efficacy and safety analysis of a randomized, double-blinded controlled phase II study of STA-4783 in combination with paclitaxel in patients with metastatic melanoma
Authors: O'Day S. , Gonzalez R. , Lawson D. , Weber R. , Hutchins L. , Anderson C. , McLeod M. , Hurwitz C. , Haddad J. , Jacobson E.
Published: March 2020

8528

Background: STA-4783 (S), an inducer of heat shock protein 70 (hsp70) is a bis-thiobenzoylhydrazide compound. S leads to up-regulation of hsp70 in tumor cell lines. Xenograft models of solid tumors showed synergistic anti-tumor activity in combination with paclitaxel (P). The combination P + S, in phase I and II studies, showed dose-related hsp70 induction (evidence of biological activity) and tolerability. Methods: Eligibility was based on a diagnosis of metastatic cutaneous melanoma, ECOG <=2, and prior treatment with 1 or no chemotherapy regimens. A total of 81 patients (pts) were randomized 2:1 (P 80 mg/m2 + S 213 mg/m2:P 80 mg/m2) 3 weeks out of 4 at 21 US clinical sites. The primary endpoint was progression free survival (PFS); secondary endpoints were response rate (RR), and adverse events (AEs). Results: Based on intent-to-treat analysis, the median PFS was 3.68 months (m) for P + S vs. 1.84 m in the P only arm (p=.035). RR was 15.1% in the P + S arm and 3.6% in the P arm. Subgroup analysis showed chemo- naive pts (n=23) with P + S showed a median PFS of 8.28 m vs. 2.40 in the P arm (n=9). For pts with 1 prior chemotherapy, (n=29), PFS on P + S was 3.12 m vs. 1.77 m on P (n=19). Of 19 pts who crossed over at progression, data are available for 14. PFS ranged from 0.72 to 5.5 m. Three of the 14 evaluable pts treated with P alone had rapid progression (0.95, 1.6, and 1.7 m) then significant inversion of the time to progression with the addition of S to P (2.3, 5.5, and 4.2 m) suggesting study drug effect. Scans were done at identical intervals (8 weeks). The proportion of pts with AEs of grade 3 or higher was 54% (n=52) in the P + S group and 57% in the P group (n=28); pts on P received a median of 2 cycles, while pts in the P + S group received a median of 4. Adverse events leading to discontinuation were low in both groups: 10% for the P + S, and 14% for P. Conclusions: The addition of S to P showed an increase in PFS vs. P alone particularly in chemo-naïve pts. A few pts failing single agent P appeared to benefit from P + S. Despite the additional treatment duration in the P + S group the drugs were well- tolerated, and showed mainly P related adverse events. A phase III study is planned to confirm a role for P + S in metastatic melanoma.

[Table: see text]
Preliminary results from a phase I/II study of the combination of lenalidomide and DTIC in patients with metastatic malignant melanoma previously untreated with systemic chemotherapy
Authors: Bedikian A. Y. , Kim K. , Papadopoulos N. , Hwu W. , Ervin-Haynes A. , Pietronigro D. , Zeldis J. , Hwu P.
Published: March 2020

8533

Background: In metastatic melanoma (MM) no single agent has shown objective response greater than 21%, and none have made an impact on overall survival. DTIC is approved for MM with response rates of 7% to 21%. Lenalidomide, an immunomodulatory drug of the IMiDs class, was reported to enhance immune responses in MM patients. This study was designed to assess the safety and activity of lenalidomide in combination with DTIC in patients with metastatic melanoma (MM). Methods: Twenty-eight chemotherapy naive patients with unresectable stage III and IV MM enrolled in the study. All patients received 25 mg lenalidomide orally once daily on days 1–14 every 21 days and continued therapy as tolerated or until disease progression. DTIC was given IV over 1 hour on day 1 every 21 days. There were three dose levels for DTIC: 600 mg/m2, 800 mg/m2 and 1,000 mg/m2. Each dose level had 3–6 patients enrolled. Thirteen additional patients were to be enrolled at the MTD. Response and progression were evaluated using the RECIST criteria every 6 weeks. Results: As of December 21, 2006 twenty-six patients were evaluable for response. Median age was 65 (46–83) and 13 were female. Median ECOG was 1. Two patients (8%) exhibited an objective response (2 partial responses (PR)), 10 had stable disease (SD) for a tumor control rate (TCR) of 46 % and 14 progressive disease (PD). Thirteen patients have been enrolled at the MTD of 25 mg lenalidomide + 800 mg/m2 DTIC and most are still receiving therapy. Grade 3 or 4 adverse events occurred in 12 (43%) of the 28 patients receiving drug. Grade 3 events included: transient elevation of transaminases, increased temperature, headache, dizziness, low hemoglobin, and leg edema. Four patients (14%) experienced a Grade 4 adverse reaction (pulmonary emboli, low hemoglobin, cerebral hemorrhage, and cerebral ischemia). The most common Grade 1/2 adverse events included: fatigue, nausea, pruritis, muscle cramps, taste alteration, skin rash, and constipation. Conclusions: The MTD has been established at 25 mg lenalidomide + 800 mg/m2 DTIC. Preliminary results indicate that lenalidomide in combination with DTIC has manageable side effects in patients with MM. Evaluation of efficacy is ongoing.

No significant financial relationships to disclose.
A large first-line, randomized, dose-finding, phase II study on thymosin-alpha 1 (T-alpha 1) plus dacarbazine (DTIC) with or without interferon-alpha (IFN-alpha) compared to DTIC plus IFN-alpha in stage IV melanoma. Tumor response and survival results
Authors: Camerini R. , Mackiewicz A. , Testori A. , Trefzer U. , Jassem J. , Ferraresi V. , Maio M. , Garbe C. , Lange A. , Carminati P.
Published: March 2020

8535

Background: Thymosin alpha 1 is an immunomodulatory compound that promotes T cell maturation and upregulates T cell response. Ta1 showed clinical potential benefit in a previous pilot study in melanoma patients. Methods: Phase II, randomized, stratified, open-study testing different doses of Ta1 in association with DTIC and IFNa, as first-line therapy in stage IV melanoma patients (AJCC 2001) without brain metastases. The primary endpoint is tumor response and secondary overall survival. Four arms were initially planned: DTIC + IFNa + 1.6 or 3.2 mg Ta1, DTIC + 3.2 mg Ta1, and DTIC + IFNa (control group). A dose-response effect in a preliminary analysis on 142 patients led to the addition of a fifth arm with DTIC + IFNa + 6.4 mg Ta1. Ninety-five patients were allocated to each arm to test the hypothesis that P0 = 0.05 vs the alternative hypothesis that P1 = 0.15 (alpha = 5%, within-group statistical analysis, power = 95%). The five groups were analyzed independently one from the other, nine responses representing the minimal threshold for rejecting the null hypothesis Patients received DTIC (800 mg/m2) iv on day 1, Ta1 (1.6, 3.2 or 6.4 mg) sc on days 8–11 and 15–18, and IFNa (3 MIU) sc on days 11 and 18 during 28d cycles. Tumor response was evaluated every two cycles according to RECIST criteria, utilizing a central review. Results: Data of 483 pts (62% M1c; 25% M1b; 13% M1a) from 64 European sites are given in the table . Thirteen and 10 confirmed responses were observed for the DTIC+ 3.2 mg Ta1 and DTIC+ IFNa + 3.2 mg Ta1 arms (vs 5 in the control group) thus rejecting the null hypothesis that P0 = 0.05. No additional toxicity with the addition of Ta1 was observed. Conclusions: These results suggest a potential survival advantage with the addition of Ta1 to ‘standard‘ treatment of stage IV melanoma patients. The role of Interferon alpha in this therapeutic association is debatable.

[Table: see text] [Table: see text]
Interferon alfa-2b treatment following therapeutic vaccination with mRNA electroporated dendritic cells results in skin depigmentation and tumor regression in patients with advanced melanoma
Authors: Neyns B. , Corthals J. , Thielemans K.
Published: March 2020

8537

Background: Therapeutic vaccination with autologous dendritic cells (DC) and Interferon alfa-2b (IFNa) both have low activity in patients with advanced melanoma. Combination therapy might be advantageous because of their complementary mechanism of action. Methods: We are investigating the safety and activity of an autologous DC-based melanoma vaccine in patients with advanced melanoma in a single institution phase IB clinical trial. Following leucapheresis and enrichment in a semi-closed culture system, adherent PBMC are cultured in IL-4 and GM-CSF supplemented medium for 6 days and cryo-preserved. Upon thawing, 15.106 DC are electroporated with synthetic mRNA that encodes a fusion protein between LAMP and one of 6 melanoma associated antigens (MAGE.A-1, MAGE.A-3, MAGE.C2, MELANA/MART1, Tyrosinase and gp100). DC vaccines are administered by 6 bi-weekly ID/SC injections and every 6–8w thereafter. Results: 15 pts (10M/5F; median age 52, range 27–72) with stage IIIC-IV melanoma have been recruited. Ten pts were able to receive ≥ 6 vaccinations. Toxicity was limited to grade 1 or 2 local skin reactions at the vaccine administration sites in all pts. Two pts had a regression of subcutaneous (sc) metastases during DC vaccination and one of these pts remains disease-free after 18 mths of follow-up (following the resection of a single residual metastasis). An additional pt remains disease-free following surgery of in transit metastases at 8 months of follow-up. Three out of four pts who were treated with IFNa-2b (5 106 U 3x/week sc) at progression developed skin depigmentation (leucoderma punctata) and in 2 of these pts an objective tumor response was documented (PR and CR, including complete regression of skin, lymph, liver and skeletal metastases). Both responses are ongoing at 9 and 11 months of follow-up. Conclusions: These preliminary observations indicate a potential for IFNa-2b to mediate auto-immune breakthrough and tumor regression in advanced melanoma patients vacinated with a mRNA electroporated DC-vaccine. Further investigation of this combination immunotherapy in advanced melanoma patients is ongoing.

No significant financial relationships to disclose.
Primary invasive melanoma on the head and neck: Distribution, ultraviolet exposure and histological subtype in 1,298 Australian patients
Authors: Long G. V. , Armstrong B. K. , Colman M. H. , Shaw H. M. , Thompson J. F. , Crotty K. A.
Published: March 2020

8541

Background: The aim of this study was to determine the subsite distribution of invasive cutaneous melanoma of the head and neck and correlate this with the melanoma histologic type and ultraviolet exposure (UVE) at each particular subsite. Methods: This study comprised 1,298 patients seen at the Sydney Melanoma Unit (SMU) between 1990 and 2000. In each case, the histopathologic diagnosis of invasive melanoma was established by highly experienced SMU histopathologists. Histologic details, gender and patient age at diagnosis were available in all patients except in 5% in whom Breslow thickness could not be determined. Nine head and neck subsites were assigned: scalp, forehead, eyelids, nose, lips, chin, ears, face and neck. The relative tumour density (RTD) at each subsite was then examined in relation to gender and age of the patient and the relative UVE at this subsite. Relative UVE values as determined using polyusulphone UV dosimeters were used. Results: There was a direct correlation between high UVE and RTD at each subsite except the forehead (135 patients) and neck (335 patients), particularly in women, with the neck subsite prevailing in patients <50 years of age. Superficial spreading melanoma was the most common histologic type at all subsites except the lips (15 patients), nose (53 patients) and chin (15 patients), where desmoplastic melanoma predominated. Lentigo maligna melanoma was not more common on subsites having high UVE, nor was there an obvious association between melanoma thickness and UVE. Conclusions: The UVE was an important determinant of melanoma distribution on the head and neck. The lower RTDs at the forehead and neck subsites in women were possibly due to gender differences in hairstyles. Paradoxically, lentigo maligna melanoma, commonly considered to occur almost exclusively on sun-damaged skin, was not more common on areas of high UVE.

No significant financial relationships to disclose.
BAY 43–9006 (sorafenib-BAY) alters proliferation pathways and mutant specific-PCR (MS-PCR) improves detection of BRAF mutations in metastatic melanoma (MM)
Authors: Pavlick A. C. , Liebes L. , Brooks P. , Yoon J. , Hamilton A. , Yee H. , Polsky D. , Buckley M. , Wright J. , Osman I.
Published: March 2020

8542

Background: Approximately 60% of melanomas carry BRAF mutations (mut). BAY is a multi-kinase inhibitor that inhibits the BRAF pathway. A phase II trial of BAY in MM is being conducted to: 1) determine if treatment (tx) with BAY can alter proliferation as measured by cyclin D1, Ki-67 and ERK, 2) assess for differential anti-tumor responses and 3) to assess a newly developed fluorescent-based PCR assay to detect mutant BRAF. Methods: Eligibility criteria: Biopsy (bx)-accessible, untreated MM. Measurable disease (RECIST). Stratification of tumor BRAF status determined by routine PCR sequencing for codon 600 mut prior to tx and fluorescent MS-PCR sequencing for confirmation. MS-PCR specifically amplified the M-BRAF allele without amplifying the wild-type (WT)allele. Tx: BAY 400 mg po BID D1–28 q4w. Repeat bx on Day 28. Bx assessed for Ki-67, cyclin-D1 and ERK. Serum collagen cryptic epitopes were measured serially. Re-imaging was done every 2 cycles and pts treated until POD. Results: 29 pts (9-M1a, 8-M1b, 12-M1c) enrolled. 26 wild type (WT) and 3 mutant (M) BRAF by routine PCR. Due to the low yield of mut on routine PCR, MS-PCR was done. 6 mutants were detected in the first 16 pts with MS-PCR compared to 2 with routine sequencing. Median age: 68 (range 22–91). 8 pts with LDH ≥ 1.5 × nl. Tox: Gr I-diarrhea(7), alopecia(4), rash(6), mucositis(4), nausea(4), pain(4), hand-foot(2); Gr II- HTN(4), fatigue(2),mucositis(1), rash(3), pain(3), hand-foot(2); Gr III-hand-foot(1), rash(1), fatigue(1) and intestinal perforation(1). Responses: 12 NE (2 WD, 8 early POD, 1 tox, 1 too early); M BRAF- 1 PR (lymph nodes and large SQ arm masses) and 2 PD; WT BRAF- 1 PR, 7 POD after 2 cycles, 6 SD. Matched paired biopsies demonstrated down regulation of tumor ki-67, erk and cyclin-D1. Collagen cryptic epitopes correlated with tumor responses. Conclusions: MM patients with tumors that were molecularly characterized for BRAF mutational status were entered on this single agent BAY trial and responses were seen in both M and WT arms. Down-regulation of Ki-67, cyclin D1 and ERK was demonstrated and MS-PCR improved the sensitivity to detect BRAF mut. Supported by NCI N01-CM17103 and TRI.

No significant financial relationships to disclose.
Clinical prognostic factors for distant metastases and survival in patients with primary uveal melanoma: A 10-year follow-up of a single center cohort study
Authors: Schmittel A. H. , Bechrakis N. E. , Martus P. , Gudacker G. , Mutlu D. , Scheibenbogen C. , Bornfeld N. , Foerster M. H. , Thiel E. , Keilholz U.
Published: March 2020

8546

Background: Metastases from uveal melanoma have an extremely poor prognosis. Factors predicting development of metastases and survival are of critical importance for future adjuvant trials investigating innovative immunotherapeutic approaches in patients with uveal melanoma. Methods: We reanalyzed all patients with uveal melanoma, who received primary treatment in 1994 and 1995 in our hospital, from whom we previously had reported 5-year follow-up data. Data on primary tumor, local therapy and follow-up were collected. Results: Of 271 patients 78.2% of patients were available for 10 years follow up. Median follow-up was 123 months. A total of 68 patients (25.1%) developed metastases. Kaplan-Meier analysis revealed a 10-year progression free survival (PFS) of 65% for the whole patient cohort. 10-year PFS was 25% in patients with extraocular tumor growth (EOG). Patients with ciliary body involvement (CBI) or a largest tumor diameter (LTD) > 14 mm had a 10-year PFS of 56.3% and 52%, respectively, which was significantly lower than in patients without ciliary body involvement or LTD < 14 mm. 10-year overall survival was 57.5% for the whole patient cohort. 10-year survival was 20% in patients with EOG and 42.3% in patients with CBI and 43.2% in patients with LTD > 14 mm. Univariate analysis revealed EOG, CBI and LTD > 14 mm to be predictive for overall survival (p < 0.02, log-rank test for all variables). Conclusions: This study confirmed our previous 5-year follow-up data and determined determined ciliary body involvement and a largest tumor diameter > 14 mm to be the most important clinical risk factor for metastases and survival. Therefore patients with ciliary body involvement and LTD > 14 mm are candidates for adjuvant therapeutic interventions within future trials.

No significant financial relationships to disclose.
Differential expression of insulin like growth factor binding protein-4 (IGFBP4) in melanoma progression
Authors: Yu J. Z. , Yee H. , Warycha M. , Christos P. , Shapiro R. , Berman R. , Pavlick A. , Liebes L. , Brooks P. , Osman I.
Published: March 2020

8557

Background: Members of the IGFBP family are thought to regulate tumor progression through both IGF-dependent and independent mechanisms. Moreover, IGFBPs may exhibit distinct functions depending on whether they are present locally in tissue or systemically. Our preclinical data suggest that IGFBP4 serves as an endogenous inhibitor of angiogenesis and melanoma tumor growth. To examine the clinical validity of our observations, we compared IGFBP4 expression in tissue and sera in primary melanoma patients with a low risk of metastases versus patients with established metastatic disease. Methods: Eighty-nine melanoma patients (primary stage IA, n=57; metastatic, n=32; 44 M, 45 F; Median Age=56) prospectively enrolled in the Interdisciplinary Melanoma Cooperative Group at the NYU School of Medicine were studied. IGFBP4 protein expression in tumors was assessed in 83 patients using goat anti-human IGFBP4 antibody (R&D Systems) in an immunohistochemical assay. For each case, the percentage of tumor cells that stained positively was estimated. IGFBP4 concentration in the serum was measured in 64 patients by an ELISA assay (Diagnostic Systems Laboratories, Inc.). Fifty-eight patients had both sera and tumor specimens available for correlation. Results: The median IGFBP4 expression in tumor specimens from primary patients was 70% compared to 5% in metastatic patients (P=0.002, Wilcoxon rank-sum test). The median concentration of IGFBP4 in sera was 43.8 ng/ul in primary patients versus 41.0 ng/ul in metastatic patients (P=0.83). A weak association between IGFBP4 expression in tissue and IGFBP4 shedding in sera was observed (Spearman correlation coefficient=0.16, P=0.24) in the 58 cases with both sera and tissue available. Conclusions: Our data demonstrate that IGFBP4 expression in melanoma clinical specimens decreases in the progression from primary to metastatic melanoma, consistent with its potential role as an inhibitor of angiogenesis. Data also suggest that IGFBP4 tissue expression may be more clinically relevant than its sera shedding. Future studies using a larger sample size and extended follow up are needed to further define the role of IGFBP4 in melanoma progression.

No significant financial relationships to disclose.
Phase II trial of carboplatin, weekly paclitaxel, and biweekly bevacizumab in patients with unresectable stage IV melanoma
Authors: Perez D. G. , Suman V. , Amatruda T. , Gornet M. , Morton R. , Jilani S. , Constantinou C. , Egner J. , Markovic S.
Published: March 2020

8560

Background: In patients with metastatic melanoma, the combination of chemotherapy with an agent that specifically targets vascular endothelial growth factor (VEGF) might be able to control tumor growth and progression much more effectively than chemotherapy alone. Methods: A two-stage phase II clinical trial was conducted in patients with unresectable stage IV melanoma to assess the anti-tumor activity and toxicity profile of the combination of paclitaxel (80 mg/m2 IV on days 1, 8 and 15 of a 28-day cycle), carboplatin (AUC = 6 IV on day 1) and bevacizumab (10 mg/kg IV on days 1 and 15). The primary end point of the study was the 8-week progression-free survival rate (PFS). Enrollment to the second stage of the study was opened if 8 or more of the first 20 patients enrolled remained progression-free at 8 weeks. Eligible patients had measurable disease by RECIST criteria, a performance status (PS) of 0–2 and acceptable pre-registration organ function. Exclusion criteria included: brain metastases, significant recent bleeding, uncontrolled hypertension and ongoing anticoagulation. The study opened in February 2006 and completed full study accrual in August 2006. Data from the 20 patients enrolled in the first stage are presented here. Results: Patients (60% male) had a median age of 63 and had a good performance status (85% had PS of 0). M1c disease was present in 45% of patients and 35% had undergone previous chemotherapy for stage IV melanoma (50% prior immunotherapy). Only 6 patients did not complete more than 2 cycles of chemotherapy due to refusal (3), desire for alternative treatment (1) or progression (2). Median follow-up among the 15 patients still alive was 5.5 months (range: 6 weeks - 9 months). The 8-week PFS rate was 70% (14/20). The median time to progression was 163 days. One partial response was observed. There were 3 disease-related deaths at 65, 120 and 190 days post-registration. The most common toxicities were neutropenia (95%; 45% = grade 3), anemia (95%; 15% = grade 3), fatigue (90%; 5% = grade 3), leukopenia (85%; 25% = grade 3), and thrombocytopenia (75%; 5% = grade 3). Conclusions: The combination of paclitaxel, carboplatin and bevacizumab appears to be well tolerated and clinically active in patients with stage IV melanoma.

No significant financial relationships to disclose.