bluuebunny/crossref_metadata_2025 huggingface dataset:
Developing genetic markers for melanoma risk assessment
Authors: Manga P. , Goldberg J. D. , Belitskaya-Levy I. , Lobach I. , Polsky D. , Pavlick A. , Shapiro R. , Berman R. , Osman I. , Ostrer H.
Published: August 2020

9046

Background: Risk assessment for melanoma is currently based on phenotype, family and exposure history. This approach is subject to recall bias and excludes at-risk groups such as those with darker skin pigmentation. Poorly stratified risk pools also result in unnecessary dermatologist visits and biopsies for those at lower risk. Use of genetic markers may improve risk assessment; however few susceptibility markers have been developed to date. There have been a number of reports of association between melanoma and genetic markers though few have been replicated or validated. In addition, these studies frequently utilized specific coding region variants as markers and failed to test the entire gene. We have therefore assembled a case-control cohort in which to search for potential biomarkers for melanoma risk by interrogating genes using recently developed tools for genetic analysis. A pilot study was performed to test the utility of our cohort. Methods: A cohort of 326 individuals diagnosed with melanoma and treated at the New York University Langone Medical Center and 400 controls obtained from the New York Cancer project was assembled. Candidate genes were selected based on involvement in determining melanoma predisposition factors (skin pigmentation and DNA repair capability) and previous studies showing association. Three genes, ERCC1, ERCC4 (DNA repair) and MATP (skin pigmentation) were selected. Tag Single Nucleotide Polymorphisms (tSNPs) were selected using Haploview (Hapmap.org) and DNA genotyped (Sequenom Inc, San Diego, CA). Odds ratios and confidence intervals were computed for each SNP. Results: An association was found between SNP rs11615 at the ERCC1 locus and melanoma (Odds ratio = 1.718, 95% Confidence interval: 1.259 - 2.343 for TT vs TC/CC). Conclusions: A tSNP approach is thus useful in identifying associations in our melanoma case-control cohort. Sequence variation at the ERCC1 locus contributes to melanoma risk and the gene will now be screened for clinically useful susceptibility biomarkers. Additional DNA repair and pigmentation genes will also be interrogated using this approach. Genes found to be associated with melanoma will be screened by high- density SNP analysis to identify the most appropriate biomarker/s for use in risk assessment.

No significant financial relationships to disclose.
Role of circulating angiogenin TGF-β1, VEGF-R1, and VEGF-R2 in metastatic malignant melanoma patients
Authors: Spano J. , Mouawad R. , Vignot S. , Magné N. , Khayat D.
Published: August 2020

9048

Background: Malignant melanoma is a disease capable of rapid progression and is associated with high angiogenesis. Thus, investigation of mechanisms involved in metastasis is essential to control this tumor. However, the angiogenesis regulators that are biologically relevant for melanoma are still unknown. We have previously reported that high levels of soluble VEGF in metastatic malignant melanoma (MMM) patients may represent a useful biomarker to predict the effect of biochemotherapy in terms of clinical response. In this study, we evaluate whether soluble levels of angiogenin, transforming growth factor-β1 and VEGFR-1 and -2 play a role in metastatic malignant melanoma patients and to determine if they have any relationship with clinicopathological parameters. Methods: Using a sensitive enzyme-linked immunosorbent assays, angiogenin TGF-β1, VEGF-R1 and VEGF-R2 were measured in sera of 70 patients with a fully documented history of metastatic malignant melanoma in comparison with 30 healthy controls. Results: Pretreatment circulating angiogenin, TGF- β1 VEGF-R1 and VEGF-R2 were detectable, variable in all samples from either melanoma patients or healthy donors Only serum transforming growth factor- β1 levels was significantly higher (p=0.005) in patients compared to healthy controls. No relationship was observed between sex, age or LDH level and all studied parameters. When tumor burden has been taken into consideration, a significant relationship was established between high circulating serum TGF-β1 (p= 0.001) levels and tumor burden were found, Similarly, higher serum VEGFR1 levels were correlated with tumor burden (P = 0.02). Conclusions: The presence of high circulating TGF-β1 and VEGF-R1 in metastatic malignant melanoma patients may prospectively identify high-risk patients with a worse prognosis. In addition, these two parameters may be promising targets for new therapeutic strategies in this pathology.

No significant financial relationships to disclose.
Evaluation of IL-10 polymorphisms in high-risk melanoma patients receiving adjuvant interferon
Authors: Gogas H. , Metaxas Y. , Polyzos A. , Mantzourani M. , Antoniadis A. , Floudas C. , Fountzilas G. , Pectasides D. , Tsoutsos D. , Spyropoulou-Vlachou M.
Published: August 2020

9049

Background: Attempts to identify patients who benefit from adjuvant treatment of interferon alfa-2b (IFN) have been disappointing. Interleukin-10 polymorphisms have been implicated with the prognosis of patients with advanced melanoma and associated with response to biochemotherapy. Several polymorphisms have been found within the IL-10 gene. We evaluated three IL-10 Single Nucleotide Polymorphisms (SNPs) in high-risk melanoma patients enrolled in a study of two regimens of high-dose IFN and compared the distribution of SNPs found in healthy controls. Methods: We genotyped DNA from peripheral blood of 280 stage IIb, IIc and III melanoma patients and 288 healthy controls for 592 C/A, 819 C/T and 1082 G/A with PCR and pyrosequencing technology (Biotage, Uppsala, Sweden). Results: At a median follow up of 56.3 months (95% CI 47.4–63.7), 147 patients have recurred and 94 have died. The median DFS was 53 months and the median OS 86 months. There were no statistically significant differences in the incidence of IL-10 polymorphisms between the melanoma patients and healthy controls. The incidence of these polymorphisms is presented in table . RFS and OS did not differ significantly between the alleles of these polymorphisms (p=0.88 and p=0.55 for 592 C/A, p=0.84 and p=0.68 for 819 C/T and p=0.26 and p=0.30 for 1082 G/A respectively). Conclusions: No SNP studied was correlated with improved RFS and OS in this high-risk group of melanoma patients.

[Table: see text]

[Table: see text]
Biological factors in human cutaneous melanoma correlated to disease stage
Authors: Elias E. G. , Sharma B. K. , Hasskamp J. H. , Avergas A. M. , Beam S. L. , Broussard J. N. , Zapas J. L. , McCarron E. C. , Culpepper W. J.
Published: August 2020

9053

Background: Cutaneous melanoma cells express a variety of cytokines and growth factors (C/GF) as the tumor progresses. This study was undertaken to identify various C/GF at different stages of the disease with the hope of identifying prognostic factors. Methods: Immunohistochemical (IHC) studies were performed on 62 specimens of parafinized human melanoma comprised of 12 primaries, 10 local recurrences, 6 intransit, 15 regional lymph node and 19 distant metastases. Staining for 17 C/GF was performed using commercially available antibodies on Bond-Max automated IHC system. Results: The overexpression of C/GF in primary lesions was compared to distant metastases with regard to intensity and extent of staining. Data was dichotomized as positive (dark staining) or negative (lesser or no staining). There was simultaneous intense staining of 4–15 C/GF in primaries and 3–14 C/GF in metastatic lesions. Comparing primaries to metastases by Chi-Square using Fisher's exact test, statistical differences were seen in intensities of transforming growth factor-β (p<0.001), β-catenin (p<0.01), Bcl-2 (p<0.01). Staining intensities of IL-8 approached significance (p<0.058). Statistical differences in extent of staining between primaries and metastases were found for insulin-like growth factor-1 (p<0.01), fibroblast growth factor-basic (p<0.05) and IL-15 (p<0.05). Conclusions: Potential dynamic changes in overexpression or loss of expression of C/GF in metastatic melanoma is not clearly understood and may reflect on mutations. Melanoma is an extremely heterogeneous tumor and no single targeted therapeutic agent can control this disease.

No significant financial relationships to disclose.
A phase II trial of carboplatin (C) and nab-paclitaxel (ABI-007-nab-P) in patients with unresectable stage IV melanoma: Final data from N057E
Authors: Markovic S. N. , Suman V. J. , Kottschade L. A. , Amatruda T. , McWilliams R. R. , Dakhil S. R. , Nikcevich D. A. , Morton R. F. , Fitch T. R. , Jaslowski A. J.
Published: August 2020

9055

Background: There is increasing evidence that paclitaxel and carboplatin are clinically active in the treatment of metastatic melanoma (MM). Nab-P is an albumin-bound paclitaxel with ability to bind SPARC (secreted protein acid rich in cysteine), that is overexpressed in MM and associated with poor prognosis. This study explores the clinical activity of the combination of nab-P and C in patients (pts) with stage IV melanoma and SPARC correlatives. Methods: A parallel phase II trial was conducted in pts with unresectable stage IV melanoma, who were either chemotherapy naïve (CN) or were previously treated (PT). A treatment regimen consisting of nab-P (100 mg/m2) and C (AUC 2) was administered on days 1, 8, and 15 of a 28 day cycle. The primary aim of this study was to assess whether tumor response rate (CR + PR by RECIST) was ≤15% vs ≥35% in the CN group and ≤5% vs ≥ 20% in the PT cohort. Major eligibility criteria: ≥18 years of age, ECOG PS ≤2, adequate organ function, platinum or taxane naive, peripheral neuropathy < grade 2, and no untreated brain metastasis; no pregnant and/or nursing women. Tumor tissue was tested for SPARC and level 3 immunohistochemical staining was considered positive. Results: 76 pts (41-CN and 35 PT) enrolled from 11/2006 - 7/2007, 3 pts (2-CN, 1-PT) cancelled prior to starting treatment. The median number of cycles administered was 4 (range 1–18-CN and 1–10-PT). There were 11 (28.2%) confirmed responses (1 CR and 10 PRs) in the CN cohort (90% CI: 16.7–42.3%) and 3 (8.8%) confirmed responses (3 PRs) in the PT cohort (90% CI: 2.5–21.3%). Median PFS was 4.5 months (CN) and 4.1 months (PT). Median OS was 11.1 months (CN) and 10.9 months (PT).The most common severe toxicities in both groups (CTCAE ≥ grade 3) included neutropenia, thrombocytopenia, neuro-sensory, fatigue, nausea, and vomiting. PFS was not affected by SPARC positivity; however, based on limited data there is some evidence that OS may be longer with tumoral SPARC positivity (10.0 vs 12.8 mo; SPARC negative vs SPARC positive). Conclusions: The weekly combination of nab-P and C appears to be well tolerated with promising clinical activity as front line or salvage therapy in pts with MM. SPARC positivity may be associated with improved OS.

No significant financial relationships to disclose.
A phase II trial of imatinib mesylate in Merkel cell carcinoma (neuroendocrine carcinoma of the skin): A Southwest Oncology Group Study (S0331)
Authors: Samlowski W. E. , Moon J. , Tuthill R. J. , Heinrich M. C. , Balzer-Haas N. S. , Merl S. A. , DeConti R. C. , Thompson J. A. , Flaherty L. E. , Sondak V. K.
Published: August 2020

9056

Background: Merkel cell carcinoma (MCC, neuroendocrine carcinoma of the skin) frequently stains strongly for c-KIT (CD-117) expression. We therefore evaluated imatinib mesylate as a treatment for MCC. Methods: Eligibility included patients with measurable metastatic or unresectable MCC with CD117 expression by immunostaining. A Zubrod performance status of 0–2, adequate hematologic, renal, and hepatic function was also required. Imatinib 400 mg daily was administered orally in 28-day cycles. Results: A total of 25 patients were accrued to this trial from 13 institutions, with 6 accrued through Intergroup participation by the Eastern Cooperative Oncology Group. Two patients were ineligible (one was found not to express CD117 on central pathology review, and one lacked measurable disease). These 23 patients were included in the analysis. Imatinib was well tolerated with Grade 1 or 2 nausea, diarrhea, and hematologic toxicity as the most frequent side effects. There were no complete responses (0%) and 1 confirmed partial response (4%) in the 23 evaluable patients (4% objective response rate, CI 0 -22%). In addition, stable disease was observed in 3 patients (9, 4 and 3 months). Median progression-free survival was 1 month (95% CI: 1–2 months). Estimated 6 month PFS was 4%. Median overall survival was 5 months (95% CI 2–8 months). The estimated one-year overall survival was 17% (95% CI: 0% - 33%). There were three on-study deaths. All were attributed to tumor progression. One patient achieved a partial response and another had prolonged disease stabilization while receiving treatment. DNA sequencing of c-KIT was performed on tumor tissue from on a non- responding patient and the one patient with long-term stable disease (9 months). Neither demonstrated an activating mutation in c-KIT. Unfortunately, the patient with partial response withdrew consent for the study and DNA sequencing could not be performed. Conclusions: The majority of patients progressed rapidly within 1–2 cycles of treatment. The observed progression-free survival and overall survival were not adequate to conclude that this agent was active in advanced MCC. The planned second stage of patient accrual was not opened.

No significant financial relationships to disclose.
In vivo molecular changes in patients (pts) with metastatic melanoma treated with EMD121974 (selective antagonist of avβ3 integrin)
Authors: Joseph R. W. , Prieto V. G. , Papadopolus N. , Papadopolus N. , Bedikian A. , Colevas A. D. , Kim K.
Published: August 2020

9058

Background: αvβ3 integrin promotes the proliferation of tumor-associated endothelial ells and potentiates the survival of melanoma cells through activation of downstream kinases. Here we report the molecular changes of downstream kinases in tumors of pts with metastatic melanoma treated with cilengitide, a selective antagonist of αvβ3, in a phase II study. Methods: In this study, 26 pts were treated, and all tissues were embedded in OCT and immediately frozen in liquid nitrogen at -80° C until further analysis. Immunohistochemical staining was performed for the expression of αvβ3, pFAK, pERK1/2 and pAKT. Results: There were 1 pt with a partial response (PR) and 3 pts with stable disease (SD) in the study. All 26 pts had pre-treatment biopsies, and 18 underwent second biopsy on day 8. Adequate paired tumor samples were available in 16 pts for αvβ3, 11 pts for pAKT, and 9 pts for pERK1/2 and pFAK. Six (23%) of 26 pts had intratumoral expression of αvβ3 (defined as ≥25% of tumor cells stained positive) pre-treatment. The sole responder and 2 of 3 pts with SD did not express avβ3 at baseline. Cilengitide decreased the expression of αvβ3 (p = 0.04), but not the expression of the downstream kinases. The decreased expression of αvβ3 with treatment was correlated with the decrease in pERK1/2 expression (p = 0.03) but not with pAKT or pFAK. Conclusions: Although cilengitide decreased melanoma expression of αvβ3, its clinical efficacy was minimal in this study. These data suggest that the benefit of cilengitide in pts with disease control (PR+SD) was secondary to anti-angiogenic activity rather than direct anti-tumoral effect. Supported in part by NCI grant N01 CM-17003 and CA16672.

[Table: see text]

No significant financial relationships to disclose.
Phase I/II study of the association of sorafenib and temozolomide (extended schedule) in patients with metastatic melanoma: A new clinical response profile with massive tumor necroses
Authors: Robert C. , Lazar V. , Lacroix L. , Farace F. , Lassau N. , Dromain C. , Poirier V. , Zitvogel L. , Soria J. , Mateus C.
Published: August 2020

9062

Background: Recent progress in melanoma research identified a wide variety of different melanomas in term of biology, clinical behavior and chemosensitivity profiles. This phase I/II study of association of sorafenib (SOR) and temozolomide (TMZ) evaluates the safety and efficacy of this association in patients with metastatic melanoma and tries to correlate clinical responses to early biological and imaging parameters. We report the ph I results and preliminary results of the ph II (still recruiting pts). Methods: Safety was the primary objective of the phase I and three escalating dose levels were tested. Primary objective of the phase II is PFS at 12 weeks and 32 patients were recruited at the recommended (45 planned). Secondary objectives evaluate tumour vascularization by dynamic contrast enhanced ultrasonography (DCE-US), PK profile of TMZ, number and function of circulating lymphocytes, melanoma RNA expression profiles and mutational status (BRAF, NRAS, c-KIT, PTEN, PI3K, βcat), circulating endothelial and progenitor cells. Results: 13 evaluable pts were included in the phase I. The recommended doses are SOR: 400 mg bid and TMZ: 150 mg/m2 /d every other week. Toxicity was manageable. SOR did not influence TMZ PK. RECIST evaluation showed 1 CR (+ 12 months), 1 PR (+ 13 months), 3 SD, 8 PD. Among the 23 evaluable pts included in the phase II, 1 PR, 11 SD and 11 PD were observed. Five pts presented rapid and massive metastases necrosis with obvious tumour cavitation on CT which is very unusual during the course of melanoma treatment. Devascularization seen on DCE-US after 1 month was predictive of tumour response. Integrated correlative biological parameters are being analyzed and will be presented. Conclusions: SOR+TMZ association is well tolerated and gives promising results in some patients with metastatic melanoma. Unexpected major tumour necrosis has been observed in 5 patients. Early tumour devascularization observed by DCE-US seems predictive for tumour response. Extensive biological studies are being performed and might give useful clues allowing the identification of melanoma subtypes that are sensitive to this treatment regimen.

No significant financial relationships to disclose.
A phase I study of systemic sorafenib in combination with isolated limb infusion with melphalan (ILI-M) in patients (pts) with locally advanced in-transit melanoma
Authors: McMahon N. , Beasley G. M. , Sanders G. , Augustine C. , Padussis J. , Coleman A. , Selim M. A. , Peterson B. , Brady M. S. , Tyler D. S.
Published: August 2020

9065

Background: Sorafenib is a multi-kinase inhibitor that may also enhance the cytotoxicity of concurrently administered chemotherapy. In a preclinical model of regionally advanced melanoma, the combination of systemic Sorafenib and regional melphalan led to augmented tumor responses. Methods: A Phase I multicenter study was performed to evaluate the safety and pharmacokinetics (PK) of systemic Sorafenib in combination with ILI-M in patients with measurable in-transit melanoma of the extremity. Sorafenib dose escalation cohorts consisted of 200mg, 300mg, and 400mg administered systemically twice daily for one week prior and one week after a standard dose ILI-M corrected for ideal body weight. Tumor biopsies pre-therapy and pre-ILI were obtained to assess molecular changes associated with Sorafenib pretreatment. Response was defined at 3 months using RECIST. Results: Nine pts with high disease burden, including 7 previous ILI-M alone failures, have been treated; 3 in the first cohort and 6 in the second cohort. There were no grade 5 toxicities. Four patients had CTCAE Grade 4 toxicities including neutropenia (2), CPK elevation (1), and skin ulceration (1). In the remaining 5 patients, there were no >grade 3 toxicities. The maximally tolerated dose (MTD) has not yet been defined. Initial in field response determination in 6 of the 9 patients out at least 3 months includes 2 partial responses and 4 disease progressions. Conclusions: Systemic Sorafenib administered pre and post ILI-M is a well tolerated, novel targeted therapy approach to regionally advanced melanoma. An additional 10 patients will be enrolled to define the MTD. Correlation of response with drug PK, Sorafenib downregulation of pErk and Mcl1, and a melphalan resistance signature is in progress.

No significant financial relationships to disclose.
Utility of routine PET/CT and MRI staging in patients with sentinel lymph node positive melanoma
Authors: Meyers M. O. , Yeh J. J. , Amos K. D. , Long P. , Frank J. , Ollila D. W.
Published: August 2020

9071

Background: The utility of routine radiographic staging in sentinel lymph node (SLN) positive stage III melanoma is unclear. Although body computed tomography (CT) has proven unlikely to identify occult metastasis at the time of diagnosis, there is some suggestion that whole body positron emission tomography combined with computed tomography (PET/CT) may be more sensitive in the detection of clinically unsuspected metastatic melanoma. We evaluated the ability of routine PET/CT and brain MRI to detect occult metastatic disease at the time of diagnosis in patients with SLN positive stage III melanoma. Methods: All clinically node- negative patients with cutaneous melanoma and a positive SLN who completed staging with PET/CT from 2003 through 2008 were identified from a prospective, IRB-approved, single-institution database. Data were analyzed to determine the positive (PPV) and negative (NPV) predictive values of PET/CT in detecting occult metastatic disease. Results: 72 patients had a positive SLN and were staged with PET/CT and 61 with brain MRI. There were 41 men and 31 women. Median age was 55 years. Median Breslow depth was 2.50 mm. 5 patients were T1, 25 T2, 22 T3, and 20 T4. 46 % were ulcerated. MRI was negative in all 61 patients. PET/CT was interpreted as suspicious for metastasis in 8 patients (11%) and negative in 64 (92%). 6 (8%) of the suspicious PET/CT scans were subsequently proven to be negative for malignancy and 1 (1.4%) proven to be an incidental thyroid cancer. Only 1 patient (1.4%) was found to have metastatic melanoma, an in transit metastasis that was previously unrecognized. PPV was 13% and NPV 100% for PET/CT. No patients were found to have occult distant metastases by either brain MRI or PET/CT. Conclusions: Patients with SLN positive stage III melanoma are unlikely to have occult metastatic disease detected by PET/CT or brain MRI and should not have further therapy delayed to obtain imaging. These findings are consistent with prior reports of body CT alone and question the utility of routine staging with current imaging modalities in patients with SLN positive melanoma. Future research should be directed toward improved imaging techniques in order to detect early micrometastatic melanoma.

No significant financial relationships to disclose.
Second primary melanoma: Risk factors, histopathologic features, and survival
Authors: Schoellhammer H. F. , Torisu-Itakura H. , Huynh Y. , Sim M. , Faries M. B. , Morton D. L.
Published: August 2020

9073

Background: Melanoma incidence in the United States is expected to be 4.3% of all cancers in 2008. Cutaneous melanoma patients are at risk for second primary melanoma development. Our goal was to characterize the histopathologic features, risk factors, and patient survival for second primary melanoma. Methods: A review of the melanoma database established in 1971 at John Wayne Cancer Institute was conducted identifying patients with American Joint Committee on Cancer (AJCC) stage I and II cutaneous melanoma who later developed a second primary melanoma. Patients were grouped by Breslow thickness, Clark level, and histopathologic subtype (superficial spreading [SSM], nodular, acral lentiginous, lentigo maligna, and in situ). Multivariate analysis involving age, gender, Breslow thickness, Clark level, and ulceration status was performed to determine an effect on development of second primary. Kaplan-Meier survival curves were plotted for single primary and second primary melanoma patients. Results: Second primary melanoma was identified in 411 (3.7%) of 10,968 patients with AJCC stage I-II melanoma. The most common first primary subtype was SSM, and 93% of these patients had in situ or SSM as the second primary. Sixty-five percent of first primaries had a Breslow thickness of ≤1 mm, and 75% of second primaries had a thickness ≤1 mm. Forty-nine percent of first primaries had Clark level I or II, but 68% of second primaries had Clark level I or II. In multivariate analysis, only increasing age was significantly associated with the likelihood of second primary melanoma (p<0.0001). With increasing follow-up time the hazard ratio of second primary melanoma was 1.31 for every decade. Overall survival for second primary melanoma patients was better than for single primary patients (p<0.0001). Conclusions: Most second primary melanoma patients will have SSM or in situ, with a decreased Clark level and Breslow thickness. Contrary to expectations, patients developing second primary melanoma did not exhibit decreased overall survival. Increased follow-up time after first primary melanoma is a significant risk factor for second primary development, thus illustrating the importance of lifelong patient follow-up.

No significant financial relationships to disclose.
Effect of the farnesyl transferase inhibitor lonafarnib on sensitivity of melanoma cells to the multikinase inhibitor sorafenib and on Rheb farnesylation and mTOR signaling
Authors: Meier F. E. , Niessner H. , Flaherty K. , Schadendorf D. , Sinnberg T. , Schittek B. , Garbe C.
Published: August 2020

9077

Background: Farnesyl transferase inhibitors (FTIs) inhibit the post-translational farnesylation of a number of target proteins, including Ras and Rheb, preventing their signaling function. Ras signals to the RAF-MEK-ERK (MAPK) and PI3K-AKT-mTOR (AKT) signaling pathways which are constitutively activated in melanoma and appear to play a major role in tumor progression and drug resistance. Rheb positively regulates mTOR signaling. Methods: Using a panel of melanoma cell lines we evaluated the effects of the FTI lonafarnib alone and in combination with chemotherapeutic agents (temozolomide, cisplatin) or pharmacological MAPK pathway inhibitors (sorafenib, U0126, PD98059) or AKT pathway inhibitors (LY294002, wortmannin, rapamycin) on proliferation, survival and invasive tumor growth of melanoma cells in monolayer and organotypic culture. Results: Lonafarnib did not significantly inhibit growth of metastatic melanoma cells. Also, lonafarnib did not sensitize melanoma cells to the chemotherapeutic agents tested. Most combinations of the FTI lonafarnib with MAPK or AKT pathway inhibitors lacked significant enhancement of growth inhibition compared to monotherapy. In contrast, lonafarnib significantly augmented the growth inhibitory effects of the multikinase inhibitor sorafenib in eight metastatic melanoma cell lines tested. These effects did not appear to depend on BRAF or NRAS mutation status. Moreover, lonafarnib combined with sorafenib induced marked apoptosis and abrogated invasive melanoma growth. Interestingly, the FTI lonafarnib did not inhibit phosphorylation of ERK or AKT but of p70S6K, a downstream target of Rheb and mTOR signaling. Conclusions: These data suggest that lonafarnib sensitizes melanoma cells to sorafenib by inhibiting mTOR signaling via inhibition of Rheb farnesylation.

No significant financial relationships to disclose.
Survival of advanced melanoma patients with normal LDH treated with oblimersen, temozolomide, and nab-paclitaxel
Authors: Pavlick A. C. , Ott P. , Escalon J. , Madden K. , Yepes E. , Staha J. , Mendoza S. , Gandhi A. , Yee H. , Liebes L.
Published: August 2020

9080

Background: Oblimersen (OBL), temozolomide (TMZ), and abraxane (ABX) act synergistically in preclinical studies with melanoma cell lines. Bcl-2 antisense therapy in combination with dacarbazine was encouraging in advanced melanoma patients(pts) with normal LDH. Methods: Chemotherapy-naïve advanced melanoma pts (ECOG PS ≤ 2, baseline LDH ≤1.1 × ULN, measurable disease per RECIST) were enrolled on a phase I/II protocol. The treatment regimen consisted of 56-day cycles of OBL (7 mg/kg/d continuous IV infusion, d 1–7 and 22–28), TMZ (75 mg/m2/d, d 1–42), and ABX (175 mg/m2 in Cohort 1, 260 mg/m2 in Cohort 2, d 7 and 28). Immunohistochemical (IHC) staining for Bcl-2, Bcl-XL, BAK and caspase 3 was performed in pre- and post-therapy tumor samples. Serum shed collagen cryptic epitope levels were monitored. Results: 18 pts were treated (Cohort 1 = 14 pts [1–6 cycles];Cohort 2 = 4 pts [2–3 cycles]). Median age was 58 years (range: 34–78). Disease sites included liver (6), other visceral sites (10), skin, subcutaneous tissue, and lymph nodes (2). The overall survival (OS) was 14.7 months and showed a trend towards superiority when compared to both arms of the prior oblimersen trial (DTIC, OS 9.7 months, p = 0.078 and DTIC-OBL, OS 11.4 months, p = 0.31) in pts with the same LDH cut-off (Bedikian et al. JCO. 2006). 50% of pts survived > 1 year. One CR lasted 25+ mo, five PR (>50% tumor reduction) lasted > 2 cycles, and 7 SD lasted > 3 cycles. Five PD after 1 cycle were seen. One ocular melanoma pt survived 15 mo despite PD. Shed cryptic epitopes correlated with clinical response versus disease progression. Alteration of the tumor biology based on phenotypic changes in Bcl-2, Bcl-xL, BAK and caspase 3 correlated with response to treatment. Conclusions: Our data suggest that the combination of OBL, TMZ, and ABX is synergistic in advanced melanoma pts with normal LDH, possibly translating into improved OS compared to prior regimens with dacarbazine ± OBL. Biomarker studies support the rationale that Bcl-2 antisense therapy specifically impacts apoptotic signaling pathways in melanoma cells from metastatic tumor. The survival data in the limited number of pts enrolled in cohort 1 and 2 of this trial are encouraging; further exploration with this combination is underway using 1-hour infusions of OBL.

No significant financial relationships to disclose.
Effects of riluzole (RZ) and ionizing radiation (IR) in metabotropic glutamate receptor-1 (GRM1) positive human melanoma
Authors: Green C. , Schiff D. , Khan A. , Goyal S. , Goydos J. , Chen S. , Haffty B.
Published: August 2020

9083

Background: Melanoma has long been known to be relatively radio-resistant. GRM1 is a metabotropic glutamate receptor that has been detected in human melanoma cell lines and biopsies. Riluzole (RZ), a glutamate release inhibitor, has been shown to arrest GRM1 positive human melanoma cells in G2/M and sub-G1 phases of the cell cycle. The purpose of this study was to determine if RZ enhances the lethal effects of IR in human melanoma. Methods: ATP luminescence assays were performed. Clonogenic assays were performed and cell survival curves generated. Cell cycle analysis was performed utilizing flow cytometry. Western blot analysis was performed utilizing cleaved PARP and caspase-3 antibodies as markers of apoptosis. Results: Luminescence assays revealed 25uM Riluzole to be the necessary concentration for clonogenic assays. At 2Gy, there was a 48% reduction (p≤0.05) in cell survival in RZ-treated cells. At 4 Gy, there was a 19% reduction (p≤0.05) in cell survival in RZ-treated cells. No differences were seen at 6 and 8 Gy. Cell cycle analysis showed that the combination of IR and RZ was superior to IR alone in increasing the number of cells in sub-G1, which represents apoptotic death. Western blot analysis showed that the combination of IR and RZ showed yielded increased cleaved PARP and caspase-3 activity when compared to IR alone. Conclusions: Riluzole is a FDA approved drug that has long been used in ALS. It is relatively non-toxic and crosses the blood brain barrier. Our data shows that Riluzole in combination with radiation eliminates the radio-resistant shoulder of the C8161 survival curve. RZ and IR, as combination therapy are more lethal than IR or RZ alone in human melanoma, as demonstrated by flow cytometry and WB analysis. This data has promising implications for melanoma patients with brain metastases.

No significant financial relationships to disclose.
Influence of geriatric consultation with Comprehensive Geriatric Assessment (CGA) on therapeutic decision in elderly cancer patients
Authors: Chaibi P. , Magne N. , Breton S. , Chebib A. , Duron J. , Tagzirt M. , Hannoun L. , Piette F. , Khayat D. , Spano J.
Published: August 2020

9505

Background: Elderly patients represent an heterogeneous population in which anticancer therapeutic decision is often difficult and may be helped by CGA. We report 2 years activity of the geriatric assessment consultation of our institution, and its impact on therapeutic decision Methods: Since January 2007, we propose a geriatric consultation for elderly cancer patients for whom therapeutic decision appears complex to oncologists. This consultation included a CGA, with focuses on items like comorbidity, dependance, cognitive impairment, depression and malnutrition using international well known scales. Results: 161 patients (57 men, 104 women) (median age 82,4 years, extremes 73 -97) were seen at the geriatric consultation. Most of the patients (134/161) were in fist line treatment for colorectal (54), other digestive (28), breast (30) and pulmonary (14) cancers. Cancer was metastatic in 86 patients (53 %). Geriatric assessment found: severe comorbidity (grade 3 or 4 in CIRS-G scale) in 75 patients, dependance for at least one activity of daily living (ADL) in 52 patients, cognitive impairment in 42 patients, including 13 patients with already diagnosed Alzheimer disease, malnutrition in 104 patients (65 %), depression in 39 patients. According to prior oncologist decision, there have been no change in therapeutic decision in 29 patients only. Geriatric interventional treatment was delivered to 122 patients (76 %). Anticancer treatment was changed in 79 patients (49 %), including delayed therapy in 5 patients, less intensive therapy in 29 patients and more intensive therapy in 45 patients. Patients for whom final decision was delayed or less intensive therapy had significantly more frequent severe comorbidity (23/34, p < 0.01) and dependance for at least one ADL (19/34, p < 0.01). Patients for whom final decision was more intensive therapy had significantly more frequent metastatic disease (33/45, p < 0.01) Conclusions: Geriatric evaluation did influence therapeutic decision in 82 % of the patients. Follow up data will be presented to evaluate quality of final therapeutic decision, especially data concerning dose intensity and toxicity for patients with a more intensive therapy final decision.

No significant financial relationships to disclose.
The impact of cancer on geriatric syndromes in older Medicare beneficiaries
Authors: Fan L. , Reeve E. , Mohile S.
Published: August 2020

9506

Background: Geriatric syndromes are highly prevalent in the elderly population and are associated with increased morbidity and mortality. The impact of a history of cancer on the presence of geriatric syndromes has not been well described. Methods: Using the 2003 Medicare Current Beneficiary Survey (MCBS), we analyzed a national sample of 12,480 community-based elders. Differences in prevalence of geriatric syndromes between those with and without cancer were estimated. Multivariate logistic regressions were used to identify independent predictors of geriatric syndromes, including the specific type of cancer. Results: 2349 (18%) reported current or history of cancer. Among cancer subjects, 63% had a prevalence ≥ 1 geriatric syndrome as compared to 57% of the non-cancer subjects (p<0.0001). Cancer subjects overall had a significantly higher prevalence of hearing trouble, incontinence, falls, depression, and osteoporosis than those without cancer (all p values <0.001). Adjusting for possible confounders including age and comorbidity, subjects with any diagnosis of cancer were more likely to have hearing trouble (OR 1.31, 95% CI: 1.10–1.56), incontinence (OR 1.35, 95% CI: 1.16–1.57), falls (OR 1.18, 95% CI: 1.05–1.31), depression (OR 1.19, 95% CI: 1.03–1.39), and osteoporosis (OR 1.20, 95% CI: 1.06–1.35). A cancer history was not significantly associated with dementia and poor eyesight. Analysis of specific cancer subtypes showed the following: lung cancer predicted vision and hearing trouble and depression; prostate cancer predicted incontinence and falls; and cervical/uterine cancer predicted incontinence, falls, and osteoporosis. Conclusions: Elderly cancer patients have a higher prevalence of geriatric syndromes than those without cancer. We advocate the use of geriatric assessment tools to detect geriatric syndromes in older cancer survivors as these may greatly reduce quality of life. More research is needed to evaluate whether cancer and/or its treatment leads to higher prevalences of geriatric syndromes in older cancer survivors and whether in older cancer survivors, geriatric syndromes are linked to higher morbidity or mortality.

No significant financial relationships to disclose.
Neuroprotective effect of SSRI among 781 cancer patients receiving chemotherapy: A URCC CCOP Study
Authors: Jean-Pierre P. , Mohile S. , Morrow G. , Figueroa-Moseley C. , Berenberg J. , Atkins J. , Weiss M.
Published: August 2020

9512

Background: Cancer and its treatment impact important areas of cognitive function such as attention and memory, which are essential to patients effective psychosocial functioning and quality of life. Previous studies reported that 17% to 75% of cancer patients reported cognitive dysfunction during and after treatment. Few studies, however, have examined the effectiveness of pharmacological interventions to control cancer-related cognitive dysfunction (CRCD). The present study examines the effect of paroxetine hydrochloride (Paxil, P) on CRCD. Methods: The sample included 574 female and 207 male cancer patients between 22 and 87 years. Memory Problems was assessed using a Self-Reported Memory Problem (SRMP) measures derived from the Fatigue Symptom Checklist that relate to memory dysfunction. Cronbach coefficient alpha (α) and a principal components analysis (PCA) were conducted to determine reliability and appropriateness of the SRMP for this sample. A repeated measure ANOVA (r-ANOVA) and t-tests were used to assess changes in mean scores on the SRMP and the effect of P versus placebo. Depression was assessed using the CESD. Results: Scale reliability assessment showed α = .90, supporting the reliability of the SRMP. The PCA revealed a one-component structure that explained 72% of the variance. The r-ANOVA showed a significant difference between scores on the SRMP at baseline (after first chemotherapy cycle, and before P) and follow-up (after four cycles of chemotherapy, after P) (Wilks' Lambda = .99, F (1, 583) = 5.52, p = 0.02). The t-tests also showed a significant effect of P on CRMP (p < 0.05). P had a significant effect after controlling for depression (p < 0.001) Conclusions: CRCD is a serious problem for patients that can be alleviated by P. Future studies should examine the usefulness of other psychotropic agents and combined behavioral and pharmacologic interventions to control CRCD. Supported by NCI Grants U10CA37420, R25CA102618, and 3U01CA116924–04S1.

No significant financial relationships to disclose.
Randomized trial of short-course versus long-course radiotherapy for palliation of painful vertebral bone metastases: A retrospective analysis of RTOG 97–14
Authors: Howell D. D. , James J. L. , Hartsell W. F. , Suntharalingam M. , Machtay M. , Suh J. H. , Demas W. F. , Sandler H. M. , Kachnic L. A. , Berk L. B.
Published: August 2020

9521

Background: RTOG 97–14 [Hartsell et al, breast/prostate cancer patients (pts) with painful bone metastases randomized to 8 Gy/1 fraction or 30 Gy/10 fractions], revealed no difference in pain relief or narcotic use 3 months post randomization. The 8 Gy regimen resulted in fewer acute toxicities, but higher rates of retreatment for recurrent pain. Single 8 Gy fractions for painful vertebral bone mets have not been well accepted, possibly due to provider concerns about efficacy and toxicity. The present study evaluates treatment differences in the subset of pts treated specifically for painful vertebral bone mets (PVBM). Methods: PVBM were treated to the cervical, thoracic, and/or lumbar spine. Chi-square test was used to evaluate population differences between PVBM and non-PVBM. Amongst PVBM, differences in retreatment rates (cumulative incidence method, Gray's test) and in pain relief/BPI worst pain score, narcotic use, and toxicity 3 months post randomization (chi-square test) were evaluated. Results: Of 909 eligible pts, 235 (26%) were PVBM. PVBM and non-PVBM pts differed in % of males [55% vs. 47%,p=0.03] and pts with multiple painful sites [57% vs. 38%,p<0.01]. Amongst PVBM, more 30 Gy pts had multiple sites treated [65% vs. 49%, p=0.02]. T [10% vs. 20%, p=0.01] here was no statistically significant difference (8 vs. 30 Gy) in pain relief [70% vs. 62%, p=0.59] or narcotic use [27% vs. 24%, p=0.76] at 3 months. There were significant differences in acute grade 2–4 toxicityand acute grade 2–4 GI toxicity [6% vs. 14%, p=0.01] at 3 months, lower toxicity seen in 8 Gy. Late toxicity was rare, with 1 grade 3 CNS event (8 Gy) and 1 grade 4 lung event (30 Gy). 8 Gy showed significantly higher 3-year retreatment rates [15% vs. 5%, p=0.01]. Conclusions: Although a clinically different pt population, the results for PVBM are comparable to those of the entire study population. Both 8 Gy/1 fraction and 30 Gy/10 fractions resulted in comparable pain relief and narcotic use at 3 months. Both were well tolerated with few adverse effects. 8 Gy had less acute toxicity, and a higher need for retreatment than 30 Gy. This may have implications for future research comparing single fraction conventional radiation therapy with stereotactic spine radiosurgery.

No significant financial relationships to disclose.
A pilot study of vascular endothelial growth factor inhibition with bevacizumab in patients with lymphedema following breast cancer treatment
Authors: Miller K. , Christmon D. , Perkins S. , Sun J. , Schneider B. , Storniolo A. , Clare S. , Ozerdem U. , Sledge G.
Published: August 2020

9523

Background: Lymphedema is a significant long-term complication of primary therapy for breast cancer. Anecdotally, several patients (pts) with metastatic disease treated with bevacizumab monotherapy noted improvement in long-standing lymphedema. This pilot study was conducted to explore these observations prospectively. Methods: We used an existing biospecimen bank to conduct a case-control study to compare VEGF-A, -C, -D and VEGFR-3 serum concentrations in breast cancer pts with and without lymphedema (matched for age and LN status). In a separate pilot trial, pts with significant unilateral lymphedema receive bevacizumab, 15 mg/kg every 3 weeks. Baseline assessments include arm volume, interstitial fluid pressure (IFP), extracellular fluid volume by lymphometer (ECF), quality of life (QOL) and plasma VEGF-C, -D, and R3. IFP is measured serially for 24 hours after the first treatment; arm volume, ECF, QOL, and plasma VEGF-C/D/R3 are assessed at 3 and 6 weeks. Results: Samples were available for 16 pts with chronic lymphedema and 31 matched controls. Median VEGF-C levels were significantly increased in pts with lymphedema (6895 pg/ml vs. 5349 pg/ml, p=0.001). Twelve pts have been enrolled in the pilot trial. Median duration of lymphedema was 6.3 years (0.5–16.6) Median time since surgery was 5.5 years (1.9–17.6); median time since radiation (n=10) was 5.1 years (1.3–8.3). Complete IFP data is available in 9 pts. Baseline IFP was significantly higher in the affected compared to unaffected arm (7.63 vs. -0.87 mmHg; p=0.0023). Mean IFP in the affected arm decreased an average of 41.9% 24 hours after bevacizumab infusion (7.63 vs. 4.88 mmHg; p=0.07). ECF, VEGF-1, and VEGF-R3 levels all significantly decreased three weeks after initial treatment. Two patients met the definition of response with a ≥ 25% reduction in excess arm volume though the mean difference in excess arm volume did not significantly change (p=0.19). Conclusions: Preliminary data supports the hypothesis that VEGF plays a central role in the development and persistence of lymphedema after local therapy for breast cancer. Bevacizumab acutely decreases IFP, leading to a decrease in ECF and modest improvement in arm volume.

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Gender and quality of life for colorectal cancer survivors with an ostomy
Authors: Krouse R. S. , Herrinton L. J. , Grant M. , Wendel C. S. , Green S. B. , Baldwin C. M. , McMullen C. K. , Matayoshi E. , Coons S. J. , Hornbrook M. C.
Published: August 2020

9525

Background: Intestinal stomas can pose significant challenges for colorectal cancer (CRC) survivors. Specifying common challenges and sub-group differences will further the development of tailored interventions to improve health-related quality of life (HRQOL) for survivors with an ostomy. Methods: This matched cross-sectional study collected survey and medical records data from CRC survivors in three regions of Kaiser Permanente (Northern California, Northwest, and Hawaii). The survey instrument included the modified City of Hope Quality of Life-Ostomy (mCOH-QOL-Ostomy) and SF-36v2 questionnaires. Eligible colorectal cancer patients were at least five years beyond diagnosis. Two groups of CRC survivors were surveyed: those with a permanent ostomy (cases) and those that did not require an ostomy (controls). Survivors were matched on tumor site (rectum vs. colon), gender, age, and time since diagnosis. To identify differences in HRQOL associated with having an ostomy, outcomes were compared between the two groups using regression analysis with adjustment for tumor site (rectum vs. colon), age, comorbidity score, income, and work status. Results: Our response rate was 52 percent (675/1304). Cases and controls had similar demographic characteristics. Men and women showed significant differences in the relationship between ostomy and HRQOL and are reported separately. Based on the mCOH-QOL-Ostomy, both male and female cases had significantly worse social well-being compared to controls, while only female cases showed significantly worse overall HRQOL and psychological well-being. Based on the SF-36v2, statistically significant and clinically meaningful differences between female cases and controls were observed for scores on seven of the eight scales and on the standardized summary scores. For men, mental health was statistically significantly lower for cases than for controls, but the difference did not reach a meaningful level. Conclusions: CRC survivors with an ostomy experience multiple HRQOL challenges compared to persons who never had an ostomy, even five years beyond the diagnosis. Men and women report a different profile of challenges, suggesting the need for targeted or gender-specific interventions to improve HRQOL in this population.

[Table: see text]